3M Corporate Toxicology and 3M Center, Building 0220-02-E-02
St. Paul, MN 55144-1000

Regulatory Services 3 
651 733 177 ax
0503.. 534;:
2: i}

:62Certi?ed Mail
May 22, 2003

Document Processing Center Cont,? I,
EPA East Room 6428 Attn: Section 8(e) by
Of?ce of Pollution Prevention and Toxics



Washington DC 20460?0001

RE: TSCA SUBSTANTIAL RISK NOTICE ON: l-Butanesulfonamide,
1,1,2,2,3 ,3 ~N?methyl, (CAS 34454?97-2)

Dear Sirs:

3M has received data for a subchronic oral toxicity study in rats conducted with a
chemical intermediate 1-butanesulfonamide, 
hydroxyethyl)-N-methyl, (CAS 34454?97-2) (?uorochemical alcohol) indicating

developmental effects.

The study was conducted by Argus Research; a copy of the final report is enclosed.
Male rats were administered the ?uorochemical alcohol at doses of 0, 10, 50 or 250
mg/kg/day beginning fourteen days before cohabitation and continuing until after
cohabitation, for a minimum of 28 days of dosage. Female rats were administered the
substance at the same dosage levels beginning fourteen days before cohabitation and

continuing until day 5 of lactation.

In the 250 mg/kg/day dosage group, several significant effects were observed. The
number of liveborn pups was signi?cantly decreased and the number of stillborn pups
was signi?cantly increased. The number of pups found dead or presumed
cannibalized on days 1 and 2 to day 5 postpartum was signi?cantly increased. The
viability index and number of pups surviving per litter on postpartum day 5 were
signi?cantly reduced. These effects at the highest dosage level (250 mg/kg/day) were

not observed in the lower dosage groups.

6-nreanz

Additionally, some rats in the 50 and 250 mg/kg/day dosage groups were observed to
have signi?cantly increased liver weights and microscopic changes in the liver,

thymus and/or stomach.

3M uses the ?uorochemical alcohol as a chemical intermediate to manufacture
polymeric materials. In the manufacturing setting and as administered during toxicity
testing, it contains approximately 93?94% of CAS 34454?97-2 and 4-5% functionally



313w id


related branched isomers and monohydrides. The ?uorochemical alcohol is present in
?nal products at trace amounts.

Please contact James Zappia (651-733-5180) if you have any questions or if we can
provide additional information.

Once a docket number has been assigned for this submittal, please send the docket
number postal card to Cheri Kedrowski, 3M Center Bldg. St. Paul, MN
55 144.

Sincerely,

arry obel, MPH
Staff Vice President and Medical Director

  

Enclosure

FINAL REPORT

PROTOCOL 418-027

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST

STUDY NUMBER: 

FINAL REPORT DATE: 25 MARCH 2003

PROTOCOL 418?027 ORAL (GAVAGE) COMBINED REPEATED DOSE

SUBJECT

1.

1.1.

1.2.

1.3.

1.4.

2.

2.1.

2.2.

2.3.

2.4.

2.5.

2.6.

2.7.

3.

3.1.

TOXICITY STUDY OF 7599.7 WITH THE
TOXICITY
SCREENING TEST

STUDY NUMBER: T-7599

 

TABLE OF CONTENTS
we
SUMMARY AND CONCLUSION 1-1
Methods 1-1
Results - Males 1?3
Results - Females 1?3
Conclusion 1-5
DESCRIPTION OF TEST PROCEDURES 2-1
Conduct of Study 2?1
Test Substance Information 2?3
Vehicle Information 2-4
Test Substance Preparation and Storage Conditions 2-5
Test System 2?6
Husbandry 2-8
Methods 2-10
RESULTS Male Rats 3-1
Mortality, Clinical and Necropsy Observations 3?1

ii



SUBJECT 
3.2. Terminal Body Weights and Organ Weights and Ratios of Organ

Weight to Terminal Body Weight and Brain Weight 3?2
3.3. Hematology and Clinical Chemistry 3?2
3.4. Body Weights and Body Weight Changes 3-2
3.5. Absolute (g/day) and Relative (g/kg/day) Feed Consumption Values 3?3
3.6. Mating and Fertility 3?3
3.7. Functional Observational Battery 3-3
3.8. Motor Activity 3?3
4. RESULTS - Female Rats 4?1
4.1. Mortality, Clinical and Necropsy Observations 4?1
4.2. Terminal Body Weights and Organ Weights and Ratios of Organ Weight

to Terminal Body Weight and Brain Weight 4?2
4.3. Hematology and Clinical Chemistry 4?2
4.4. Body Weights and Body Weight Changes 4?2
4.5. Absolute (g/day) and Relative (g/kg/day) Feed Consumption Values 4-3
4.6. Estrous Cycling, Mating and Fertility 4-3
4.7. Functional Observational Battery 4?4
4.8. Motor Activity 4?4
4.9. Natural Delivery and Litter Observations 4?4
4.10. Pup Clinical and Necropsy Observations 4-5
REFERENCES 4?6
APPENDIX A - REPORT FIGURES
Figure 1. Body Weights - Male Rats A?l

SUBJECT
Figure 2.
Figure 3.
Figure 4.
Figure 5.

Figure 6.

APPENDIX 

Table 1.

Table B2.

Table B3.

Table B4.

Table B5.

Table B6.

Table B7.

Table B8.

Table B9.

Table 10.

Table B11.

Table 12.

Table B13.

Table 14.

Body Weights - Female Rats

Motor Activity Number of Movements Male Rats
Motor Activity - Time Spent in Movement Male Rats
Motor Activity - Number of Movements Female Rats
Motor Activity - Time Spent in Movement Female Rats
REPORT TABLES - Fo GENERATION MALE RATS

Clinical Observations - Summary - Fo Generation Male Rats

Necropsy Observations Summary - Fo Generation Male Rats

Terminal Body Weights and Organ Weights Summary 
Fo Generation Male Rats

Ratios of Organ Weight to Terminal Body Weight - Summary -
Fo Generation Male Rats

Ratios of Organ Weight to Brain Weight Summary -
Fo Generation Male Rats

Hematology - Summary - Fo Generation Male Rats

Clinical Chemistry - Summary - Fo Generation Male Rats
Body Weights Summary - Fo Generation Male Rats

Body Weight Changes Summary Fo Generation Male Rats

Absolute Feed Consumption Values (g/day) Summary 
Fo Generation Male Rats

Relative Feed Consumption Values (g/kg/day) - Summary 
Fo Generation Male Rats

Mating and Fertility - Summary - Fo Generation Male Rats
Functional Observational Battery - Summary - Male Rats

Motor Activity - Summary Fo Generation Male Rats

iv

PAGE

A-2



A-5

B-6

B-9



B-13

B-14





B-17

B-23

SUBJECT

Table B15.

Table 16.

Table 17.

Table 18.

Table 19.

Table B20.

Table B21.

Table B22.

Table B23.

Clinical Observations - Individual Data Fo Generation Male Rats
Necropsy Observations - Individual Data - Fo Generation Male Rats
Terminal Body Weights, Organ Weights and Ratios of

Organ Weight to Terminal Body Weight Individual Data 

Fo Generation Male Rats

Brain Weights, Organ Weights and Ratios of Organ Weight to
Brain Weight - Individual Data Fo Generation Male Rats

Body Weights - Individual Data Fo Generation Male Rats

Feed Consumption Values Individual Data - Fo Generation
Male Rats

Mating and Fertility - Individual Data - Fo Generation Male Rats
Functional Observational Battery - Individual Data - Male Rats

Motor Activity Individual Data - Fo Generation Male Rats

APPENDIX - REPORT TABLES F0 GENERATION FEMALE RATS

Table 1.

Table C2.

Table C3.

Table C4.

Table C5.

Table C6.

Table C7.

Table C8.

Clinical Observations Summary - Fo Generation Female Rats

Necropsy Observations Summary Fo Generation Female Rats

PAGE
B-25



B-34





B-66
B-70
B-74



01


Terminal Body Weights and Organ Weights - Summary F0 Generation

Female Rats

Ratios of Organ Weight to Terminal Body Weight - Summary 
Fo Generation Female Rats

Ratios of Organ Weight to Brain Weight - Summary 
Fo Generation Female Rats

Hematology Summary Fo Generation Female Rats
Clinical Chemistry Summary - Fo Generation Female Rats

Body Weights - Precohabitation Summary Fo Generation
Female Rats



C-8

C-11

C-14

SUBJECT

Table C9.

Table C10.

Table C11.

Table C12.

Table C13.

Table 14.?

Table C15.

Table C16.

Table C17.

Table C18.

Table C19.

Table C20.

Table C21.
Table C22.

Table C23.

PAGE

Body Weight Changes Precohabitation Summary Fo Generation
Female Rats

Maternal Body Weights Gestation - Summary - Fo Generation
Female Rats

Maternal Body Weight Changes Gestation Summary 
Fo Generation Female Rats

Maternal Body Weights - Lactation - Summary - Fo Generation
Female Rats

Maternal Body Weight Changes Lactation Summary -
Fo Generation Female Rats

Absolute Feed Consumption Values (g/day) Precohabitation 
Summary Fo Generation Female Rats

Relative Feed Consumption Values (g/kg/day) Precohabitation -
Summary - Fo Generation Female Rats

Maternal Absolute Feed Consumption Values (g/day) Gestation 
Summary - Fo Generation Female Rats

Maternal Relative Feed Consumption Values (g/kg/day) - Gestation 
Summary Fo Generation Female Rats

Maternal Absolute Feed Consumption Values (g/day) - Lactation -
Summary Fo Generation Female Rats

Maternal Relative Feed Consumption Values (g/kg/day) Lactation 
Summary Fo Generation Female Rats

Mating and Fertility, Estrous Cycling and Days in Cohabitation 
Summary Fo Generation Female Rats

Functional Observational Battery Summary - Female Rats
Motor Activity - Summary Fo Generation Female Rats

Natural Delivery Observations - Summary Fo Generation
Female Rats

Vi





C-18





C-21

C-22



C-24



C-26

C-27

C-29

C-35



SUBJECT

Table C24.

Table C25.

Table C26.

Table C27.

Table C28.

Table C29.

Table C30.

Table C31.

Table C32.

Table C33.

Table C34.

Table C35.

Table C36.

Table C37.

Table C38.

PAGE
Litter Observations (Naturally Delivered Pups) Summary -
F1 Generation Litters 
Clinical Observations from Birth to Day 5 Postpartum Summary 
F1 Generation Pups C-41
Necropsy Observations - Summary F1 Generation Pups 
Clinical Observations - Individual Data - Fo Generation
Female Rats 
Necropsy Observations - Individual Data Fo Generation
Female Rats C-48

Terminal Body Weights and Organ Weights and Ratios of Organ
Weight to Terminal Body Weight - Fo Generation Female Rats

Organ Weights and Ratios of Organ Weight to Brain Weight -
Individual Data - Fo Generation Female Rats

Body Weights - Precohabitation Individual Data - Fo Generation
Female Rats

Maternal Body Weights - Presumed Gestation - Individual Data 
Fo Generation Female Rats

Maternal Body Weights Lactation - Individual Data - Fo Generation
Female Rats

Feed Consumption Values - Precohabitation - Individual Data 
Fo Generation Female Rats

Maternal Feed Consumption Values - Presumed Gestation -
Individual Data - Fo Generation Female Rats

Maternal Feed Consumption Values - Lactation - Individual Data -
Fo Generation Female Rats

Mating and Fertility, Estrous Cycling and Days in Cohabitation -
Individual Data Fo Generation Female Rats

Functional Observational Battery - Individual Data Female Rats

Vii

C-51

C-59





C-71



C-79

C-83

C-87

C-89

SUBJECT PAGE
Table C39. Motor Activity Individual Data Fo Generation Female Rats 
Table C40. Natural Delivery, Implantation Sites, and Pup Viability and Sex 

Individual Data Fo Generation Female Rats/F 1 Generation Litters C-101
Table C41. Pup Body Weight Litter Averages from Birth to Day 5 Postpartum -

Individual Data - F1 Generation Litters C-103
Table C42. Pup Body Weights from Birth to Day 5 Postpartum Individual

Data 1 Generation Pups C-105
Table C43. Pup Vital Status and Sex from Birth to Day 5 Postpartum Individual

Data F1 Generation Pups C-113
Table C44. Clinical Observations from Birth to Day 5 Postpartum -

Individual Data - Fl Generation Pups C-1l7
Table C45. Necropsy Observations - Individual Data - F1 Generation Pups 18
APPENDIX - PROTOCOL AND AMENDMENTS D?l to 

APPENDIX - DEVIATIONS FROM THE PROTOCOL AND THE

STANDARD OPERATING PROCEDURES OF

THE TESTING FACILITY E-l to 
APPENDIX - CERTIFICATE OF ANALYSIS F-1
APPENDIX - ANALYTICAL REPORT G?l
APPENDIX - TEMPERATURE AND RELATIVE HUMIDITY REPORT H?l
APPENDIX I POSITIVE CONTROL DATA 1?1 to 1-4
APPENDIX - HISTOPATHOLOGY REPORT ?l to 10
APPENDIX HEMTOLOGY AND CLINICAL CHEMISTRY

REPORTS K?l to 
APPENDIX STATEMENT OF THE STUDY DIRECTOR L?l

APPENDIX QUALITY ASSURANCE STATEMENT M-l to M-2



 l-l

TITLE: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY
OF 7599.7 WITH THE 
TOXICITY SCREENING TEST

ARGUS RESEARCH PROTOCOL NUMBER: 418?027
STUDY NUMBER: T-7599

1. SUMMARY AND CONCLUSION
1.1. Methodsa

Sixty male and sixty female rats were assigned to four
dosage groups (Groups I through IV), 15 rats per sex per group. The test substance was
7599.7 and the vehicle was aqueous 0.5% or 1.0% (CMC).
The 0.5 CMC was used for the first four days of the study and the 1.0% CMC was used
for the remainder of the study. The test substance or vehicle was administered to the
male rats beginning 14 days before cohabitation and continuing until sacrifice, after
completion of the cohabitation period, after a minimum of 28 days of dosage and to the
female rats beginning 14 days before cohabitation and continuing until day 5 of lactation
(DL 5). Dosages were 0 (Vehicle), 10, 50 and 250 mg/kg/day. The dosage volume was
adjusted daily.

Within each dosage group, consecutive order was be used to assign the first five male and
the first five female rats to a functional observational battery (FOB) and motor activity
assessment. The next five rats per sex in each group were assigned to hematology and
clinical biochemistry evaluations. The last five rats per sex in each group were assigned
to metabolite analysis. Histological evaluations were performed on the last ten rats per
sex in each group. Rats were observed for Viability at least twice each day of the study.
Observations for clinical signs of effects of the test substance, abortions, premature
deliveries and deaths were made daily before dosage. Postdosage observations were
recorded approximately 60 i 10 minutes after dosage administration and on the day of
sacrifice. Once before the first dosage and at least once weekly thereafter, detailed
clinical observations were conducted for all male and female rats. Body weights for male
and female rats were recorded daily during the dosage period and at sacrifice. Feed
consumption values for male rats were recorded weekly during the dosage period. Feed
consumption values for female rats were recorded weekly to cohabitation and on
gestation days (DGs(if necessary) and on lactation days
(DLs) and 5.

 

a. Detailed descriptions of all procedures used in the conduct of this study are
provided in the appropriate sections of this report and in APPENDIX 
(PROTOCOL AND AMENDMENTS).

 1-2

Estrous cycling was evaluated by examination of vaginal cytology beginning with the day
after the first administration and then until spermatozoa were observed in a smear of the
vaginal contents and/or a copulatory plug was observed in situ during the cohabitation
period. Female rats were evaluated for adverse clinical signs observed during parturition,
duration of gestation, litter sizes and pup viability at birth. Maternal behavior was
evaluated on DLs 1 and 5.

Motor activity was evaluated on five male and five female rats per group once during the
course of the study, before scheduled sacrifice. Day 1 of lactation was defined as the day
of birth and was also the first day on which all pups in a litter were individually weighed.
Each litter was evaluated for viability at least twice daily. The pups in each litter were
counted twice daily. Clinical observations were recorded once daily. Pup body weights
were recorded on?DLs 1 and 5. After 36 days of dosage, all male rats were sacrificed and
on DL 6, all surviving female rats were sacrificed. A gross necropsy was performed.
The testes and epididymides of all male rats were weighed, and the testes, epididymides,
seminal vesicles with coagulating gland and prostate were retained. The ovaries and the
uterus with cervix of each female rat were weighed, and ovaries, uterus, vagina and a
mammary gland were retained.

The following organs were individually weighed: liver, kidneys, adrenals, thymus, testes,
epididymides, spleen, brain, heart, ovaries and uterus. The following tissues or
representative samples were retained: brain, small and large intestines, lungs, 
nodes, peripheral nerve, stomach, kidneys, spleen, thymus, trachea, urinary bladder,
testes, epididymides, seminal vesicles, prostate, spinal cord, liver, adrenals, heart,
thyroid/parathyroid, uterus, bone marrow, ovaries, uterus, vagina, mammary gland
(female rats only) and gross lesions. Histological examination was conducted for the
assigned ten rats per sex from the control and high dosage groups. Histological
evaluations were performed on the livers of ten male and ten female rats, the thymuses of
ten female rats and the stomachs of ten male rats in the 10 and 50 mg/kg/day dosage
groups.

At scheduled sacrifice, blood was collected from the five male and five female rats per
group assigned to hematology and clinical chemistry sample collection. One aliquot was
analyzed for hematologic parameters. Two blood smear slides were prepared for each
sample for measurements of differential leukocyte count. Plasma from another aliquot
was measured for prothrombin time and activated partial thromboplastin time. Serum
from a third aliquot was analyzed for clinical chemistry parameters. Blood samples were
collected from the five rats per sex per group assigned to metabolite analysis. The liver
was excised and the organ weight recorded.

On DL 5, pups were sacrificed and examined for gross lesions. Pups found dead on
DLs 2 to 4 were examined for gross lesions and for possible cause of death.

 1-3

1.2. Results - Males

All male rats survived to scheduled sacrifice. Significant increases in excess salivation,
perioral substance and urine?stained abdominal fur occurred in the 250 mg/kg/day dosage
group. All other clinical observations and all necropsy observations were considered
unrelated to the test substance.

Body weight gains were significantly reduced in the 250 mg/kg/day dosage group 36. Body weight gains were also significantly decreased in
the 50 mg/kg/day dosage group on DSs 1 to 36. Body weights were significantly reduced
on DS 29 and 36 in the 250 mg/kg/day dosage group. Absolute feed consumption values
were significantly reduced in the 50 and 250 mg/kg/day dosage groups on D83 1 to 8 and
significantly reduced in the 250 mg/kg/day dosage groups 36.
Relative feed consumption values were significantly reduced and
250 mg/kg/day dosage groups.

Terminal body weights of the male rats were significantly reduced in the 250 mg/kg/day
dosage group. Absolute weights of the left and right kidneys were significantly increased
in the 50 and 250 mg/kg/day dosage groups and the absolute weight of the liver was
significantly increased in the 250 mg/kg/day dosage group. The ratios of the weights of
these organs to terminal body weights were significantly increased in the 50 and

250 mg/kg/day dosage groups. Relative to the brain weight, only the liver weight in the
250 mg/kg/day dosage group was significantly increased. Treatment-related microscopic
changes were observed in the liver of male rats in the 50 and 250 mg/kg/day dosage
groups and in the stomach of male rats in the 250 mg/kg/day dosage group.

Dosages of the test substance as high as 250 mg/kg/day did not affect any hematology or
clinical chemistry values evaluated. All mating and fertility parameters were unaffected
by dosages of the test substance as high as 250 mg/kg/day.

There were no statistically significant or biologically important differences among the
four dosage groups in the measures of the functional observational battery (FOB). Body
weights recorded during the functional operational battery for the treated groups were not
significantly different than the control group for the male rats. There were no statistically
significant or biologically important differences among the four dosage groups in the
measures of motor activity on DS 86.

1.3. Results - Females

All female rats survived to scheduled sacrifice. All clinical and necropsy observations
were considered unrelated to the test substance. Body weight gains were significantly
reduced during the precohabitation period in the 250 mg/kg/day dosage group 15. Body weights and body weight gains were not significantly affected by
dosages of the test substance during gestation or lactation.

Terminal body weights of the female rats were reduced in the 250 mg/kg/day dosage
group. Absolute liver weight was significantly increased in the 250 mg/kg/day dosage
group. The ratios of the weight of this organ and the weight of the right kidney to

418-0272PAGE 1-4

terminal body weights were significantly increased in the 250 mg/kg/day dosage group.
Only the ratio of the liver weight to brain weight in the 250 mg/kg/day dosage group was
significantly increased. Treatment-related microscopic changes were observed in the
liver and thymus of female rats in the 250 mg/kg/day dosage group.

Dosages as high as 250 mg/kg/day did not affect any hematology or clinical chemistry
values evaluated. Absolute and relative feed consumption values were not significantly
affected by dosages of the test substance during the precohabitation, gestation or lactation
periods. All estrous, mating and fertility parameters were unaffected by dosages of the
test substance as high as 250 mg/kg/day. There were no statistically significant or
biologically important differences among the four dosage groups in the measures of the
FOB. Body weights recorded during the functional operational battery for the treated
groups were not significantly different than the control group for the female rats. There
were no statistically significant or biologically important differences among the four
dosage groups in the measures of motor activity on DS 86.

The number of livebom pups was significantly reduced and number of stillborn pups was
significantly increased in the 250 mg/kg/day dosage group. The number of pups found
dead or presumed cannibalized on day 1 and days 2 to 5 postpartum was significantly
increased in the 250 mg/kg/day dosage groups. The Viability index and number of pups
surviving per litter on postpartum day 5 were significantly reduced in the 250 mg/kg/day
dosage group. Pup body weights per litter were also reduced in the 250 mg/kg/day
dosage group on postpartum days 1 and 5.

Values for the numbers of dams delivering litters, duration of gestation, averages for
implantation sites per delivered litter, gestation index, numbers of dams with stillborn
pups, dams with all pups dying, stillborn pups, surviving pups per litter on postpartum
day 1 and pup sex ratios were comparable among the four dosage groups. No clinical or
necropsy observations in the F1 generation pups were attributable to dosages of the test
substance as high as 250 mg/kg/day.

 1?5

1.4. Conclusion

On the basis of these data, the paternal (NOAEL) for 
7599.7 is 10 mg/kg/day (the 50 mg/kg/day dosage caused reduced weight gain during
precohabitation, reduced absolute and relative feed consumption values, increased
absolute and relative liver and kidney weight, and liver histopathology). The maternal
NOAEL is 50 mg/kg/day (the 250 mg/kg/day dosage caused reduced weight gain during
precohabitation, reduced terminal body weights, increased absolute and relative liver
weight, and histopathology of the liver and thymus). The reproductive NOAEL is greater
than 250 mg/kg/day (all estrous, mating and fertility parameters were unaffected by
dosages of the test substance as high as 250 mg/kg/day). The NOAEL for viability and
growth in the is 50 mg/kg/day (dosages of 250 mg/kg/day caused postnatal
mortality and decreased pup body weights).

?4 rAr/erwmw

Alan M. Hoberman, DABT Date
Director of Research

     


it. 0nd G. 7 Date
Associate Director ..

Study Director

     

 

  
 

 2-1

2. DESCRIPTION OF TEST PROCEDURES
2.1. Conduct of Study
2.1.1. Sponsor

3M Corporate Toxicology, 3M Center, Building St. Paul, Minnesota
55 144? 1000

2.1.2. Testing Facility

Argus Research, 905 Sheehy Drive, Building A, Horsham, 19044-1297

2.1.3. Study Number

418-027

2.1.4. Sponsor?s Study Number



2.1.5. Purpose of the Study

The purpose of this study was to provide information on the possible health hazards that
may result from repeated exposure of BR male and female
rats to a test substance beginning before cohabitation, through mating and continuing for
at least 28 days (male rats) or through parturition until day 5 of lactation (female rats).
This repeated dose study incorporated a reproduction/developmental toxicity screening
test to provide initial information on possible effects on male and female reproductive
performance gonadal function, mating behavior, conception, development of the
conceptus and parturition). The study also placed emphasis on neurological effects as a
specific endpoint and was designed to identify the neurotoxic potential of a test
substance, which may warrant further in-depth investigation.

2.1.6. Study Design

The requirements of the Organisation for Economic Co?operation and Development
were used as the basis for study design.

2.1.7. Regulatory Compliance

This study was conducted in compliance with Good Laboratory Practice (GLP)
regulations of the Organisation for Economic Co-operation and Development 
US. Food and Drug Administration and the Japanese Ministry of Health and
Welfare There were no deviations from the GLP regulations that affected the
quality or integrity of the study. Quality Assurance Unit findings derived from the
inspections during the conduct of this study are documented and have been provided to
the Study Director and the Testing Facility Management.

 2?2

2.1.8. Ownership of the Study

The Sponsor owns the study. All raw data, analyses, reports and preserved tissues are the
property of the Sponsor.

2.1.9. Study Monitor

Paul H. Lieder, DABT

2.1.10. Study Director

Raymond G. York, DABT, Associate Director of Research
Address as cited above for Testing Facility

2.1.11. Technical Performance

John F. Barnett, B.S. (Director of Laboratory Operations)
Christine A. O?Brien (Research Associate)

Lorna A. Sinotte, B.S. (Laboratory Technician)

Stephanie M. Dorizio, B.A. (Necropsy Laboratory Technician)
Christopher K. Ruppert, B.S. (Formulation Laboratory Technician)

2.1.12. Report Preparation

Raymond G. York, DABT

0 Ann Frazee, M.S. (Study Coordinator)

oAnne M. Conklin, B.S. (Data Management Specialist)
Jennifer M. Hughes (Report Administrator)

2.1.13. Report Review

Mildred S. Christian, Fellow, ATS (Executive Director of Research)
Alan M. Hoberman, DABT (Director of Research)

2.1.14. Date Protocol Signed

15 February 2002

2.1.15. Dates of Technical Performance
2.1.15.1. Male Rats

Rat Arrival 12 FEB 02
Dosage Period (14 days before cohabitation and

through a 14?day cohabitation period until

sacrifice after at least 28 days of dosageFOB and Motor Activity Evaluation Scheduled Sacrifice 26 MAR 02

 2-3

2.1.15.2. Female Rats

Rat Arrival 12 FEB 02
Dosage Period (14 days before cohabitation
through DL3 Dosage Period Estrous Cycle Evaluation Cohabitation Period

Male Male Delivery PeriodC (Sacrifice (Rats that did not deliver a litterFOB Evaluation and Motor Activity Evaluation 31 MAR 02 12 APR 02
Pup Sacrifice (Scheduled Sacrifice (2.1.16. Records Maintained

The original report, raw data and reserve samples of each lot of bulk test substance and
bulk vehicle components are retained in the archives of Argus Research. Any preserved
tissues are retained in the archives of the Testing Facility for one year after the mailing of
the draft final report, after which time the Sponsor will decide their final disposition. All
unused prepared formulations were discarded at the Testing Facility. Unused bulk test
substance will be returned to the Sponsor.

2.2. Test Substance Information
2.2.1. Description

7599.7 amber waxy solid

 

DL is an abbreviation for day of lactation.

DG is an abbreviation used for day of (presumed) gestation.

c. The day of birth is designated lactation day 0 (postpartum day 0) in the Health
Effects Test Guidelines - Reproduction and Fertility Effects (Office of Prevention,
Pesticides and Toxic Substances 870.3800, August, 1998) and in the OECD
Guideline for the Testing of Chemicals Combined Repeated Dose Toxicity
Study with the Reproduction/Developmental Toxicity Screening Test (Section 4,
No. 422, 22 March 1966). This same day is designated day 1 postpartum (day 1
of lactation) in the Standard Operating Procedures of the Testing Facility.
Throughout this study, the day of birth was designated day 1 postpartum (day 1 of
lactation) and all subsequent ages of the F1 generation rats and days of the
lactation period were determined and cited accordingly.



 2?4

2.2.2. Lot Number
6
2.2.3. Date Received and Storage Conditions

The test substance was received on 18 February 2002 and stored at room temperature,
protected from light.

2.2.4. Special Handling Instructions

Standard safety precautions (use of protective clothing, gloves, dust-mist/HEPA-filtered
mask, safety goggles or safety glasses and a face?shield) were worn during formulation
preparation and dosage. A half?face respirator was worn when the bulk test substance
was not being used in a chemical fume hood.

2.2.5. Analysis of Purity

Information to document or certify the identity, composition, method of 
strength and purity of the test substance was provided by the Sponsor to the Testing
Facility. A Certificate of Analysis is available in APPENDIX F.

2.3. Vehicle Information
2.3.1. Description

Aqueous 0.5% or 1.0% (CMC) (medium viscosity) prepared
an off?white powder, and reverse osmosis membrane processed
water.

The 0.5 CMC was used for the first four days of the study. Beginning
22 February 2002, the 1.0% CMC was used for the remainder of the study.

2.3.2. Lot Number

120K0252

2.3.3. Date Received and Storage Conditions

The was received on 11 September 2001 from Sigma Chemical
Co., St. Louis, Missouri, and stored at room temperature. R.O. deionized water is
available from a continuous source at the Testing Facility and is maintained at room
temperature.

 2?5

2.3.4. Special Handling Instructions

Standard safety precautions (use of protective clothing, gloves, 
mask, safety goggles or safety glasses and a face?shield) were taken when handling the
vehicle components and prepared vehicle.

2.3.5. Analysis of Purity

Neither the Sponsor nor the Study Director was aware of any potential contaminants
likely to have been present in the vehicle that would have interfered with the results of
this study. The expiration date of the is September 2005.

2.4. Test Substance Preparation and Storage Conditions

Formulations were prepared weekly at the Testing Facility. Prepared test substance and
vehicle formulations were stored refrigerated, protected from light.

 2-6

 

 

 

 

 

 

 

 

 

 

 

 

 

 

2.4.1. Sample Information
Date Storage/Shipping Date
Sample Type Size Retained Conditions Shipped To Shipped
Bulk Test Substance 5 26 FEB 02a Room temperature, SRIC 26 FEB 02
1 12 APR 02b protected from light 15 APR 02
Concentrationd 2 mL 03 APR 026 Refrigerated, 03 APR 02
(all levels) 2 mL 04 APR 02,f protected from light 04 APR 02
Homogeneityg 2 mL 18 FEB 02 Refrigerated, 18 FEB 02
(all levels) 2 mL 28 FEB 02 protected from light 28 FEB 02
Stabilityh 2 mL 18 FEB 02% RefrigeratedFEB 02J protected from light 28 FEB 02
Bulk Test Substance 1 22 APR 02 Room temperature, Testing Facility 23 APR 02
Reserve protected from light Archives
Vehicle Components Room temperature Testing Facility
Reserve Archives
RD. Deionized Water sample of the bulk test substance was retained for use in the preparation of analytical standards
and for possible spectrophotometric analysis.
b. A sample of the bulk test article was retained on the last day of dosage administration and shipped
for analysis.
0. Southern Research Institute, Birmingham, Alabama.
d. Quadruplicate samples were taken from each concentration on the last day of preparation. Two

 

i.
j.

2.4.2.

samples from each quadruplicate set were shipped for analysis. The remaining samples were
retained at the Testing Facility as backup samples.

Sample for 1 mg/mL.

Samples for 0, 5 and 25 mg/mL

Quadruplicate samples were taken from the top, middle and bottom of each concentration on the first
day of preparation. Two samples of each quadruplicate set were shipped for analysis. The
remaining samples were retained at the Testing Facility as backup samples.

Two sets of duplicate samples from each concentration were taken on the ?rst day of preparation.
One sample of each duplicate set was shipped for analysis. These samples were analyzed as soon
after preparation as possible and ten days after the first analysis. The remaining samples were
retained at the Testing Facility as backup samples.

Prepared using 0.5% 

Prepared using 1.0% 

Analytical Results

Results of the analytical analyses are available in APPENDIX G.

2.5. Test System
2.5.1. Species

Rat

2.5.2. Strain

BR 

 2-7

2.5.3. Supplier (Source)

Charles River Laboratories, Inc., Raleigh, North Carolina

2.5.4. Sex

Male and Female

2.5.5. Rationale for Test System

The BR rat was selected as the Test System because: 1) it
is one mammalian species accepted for use in toxicity studies and it has been widely used
throughout industry; 2) this strain of rat has been demonstrated to be sensitive to
reproductive and developmental toxins; and 3) historical data and experience exist at the
Testing 

2.5.6. Test System Data

2.5.6.1. Male Rats

Number of Rats 70
Approximate Date of Birth 04 DEC 01
Approximate Age at Arrival 71 days
Weight the Day after Arrival 282 - 333
Weight at Study Assignment 303 - 354

2.5.6.2. Female Rats

Number of Rats 7O
Approximate Date of Birth 10 DEC 01
Approximate Age at Arrival 65 days
Weight the Day after Arrival 185 226
Weight at Study Assignment 210 230

2.5.7. Method of Randomization

Upon arrival, the male and female rats were assigned to individual housing on the basis
of computer- generated random units. After an acclimation period of at least five days,
male and female rats were selected for study on the basis of physical appearance and
body weights recorded during acclimation. The rats were assigned to four dosage groups
(Groups I through IV), 15 rats per sex per group, using a computer?generated (weight-
ordered) randomization procedure.

Within each dosage group, consecutive order was used to assign the first five male and
the first five female rats to a functional observational battery (FOB) and motor activity
assessment. The next five rats per sex in each group were assigned to hematology and
clinical biochemistry evaluations. The last five rats per sex in each group were assigned

 2-8

to metabolite analysis. Histological evaluations were performed on the last ten rats per
sex in each group.

2.5.8. System of Identi?cation

Male and female rats assigned temporary numbers at receipt and given unique permanent
identification numbers when assigned to the study. Rats were permanently identified
using Monel? self piercing ear tags (Gey Band and Tag Co., Inc., No. MSPT 20101).
Cage tags were marked with the study number, permanent rat number, sex, test substance
identification, generation and dosage level.

Pups were not individually identified during lactation; all parameters were evaluated in
terms of the litter.

2.6. Husbandry
2.6.1. Research Facility Registration

USDA Registration o. under the Animal Welfare Act, 7 U.S.C. 2131 et seq.

2.6.2. Study Room

The study room was maintained under conditions of positive air?ow relative to a hallway
and independently supplied with a minimum of ten changes per hour of 100% fresh air
that had been passed through 99.97% HEPA filters. Room temperature and humidity
were monitored constantly throughout the study. Room temperature was targeted at 
to to relative humidity was targeted at 30% to 70%3.

2.6.3. Housing

F0 generation rats were individually housed in stainless steel wire?bottomed cages except
during cohabitation period and postpartum periods. During cohabitation, each pair of
male and female rats was housed in the male rat?s cage. Beginning no later than DG 20,
F0 generation female rats were individually housed in nesting boxes. Each dam and
delivered litter was housed in a common nesting box during the postpartum period. All
cage sizes and housing conditions were in compliance with the Guide for the Care and
Use of Laboratory Animals(8).

2.6.4. Lighting

An automatically-controlled ?uorescent light cycle was maintained at 12?hours light:
12?hours dark, with each dark period beginning at 1900 hours EST.

 

a. See APPENDIX (TEMPERATURE AND RELATIVE HUMIDITY REPORT).

41 2?9

2.6.5. Sanitization

Cage pan liners were changed at least three times weekly. Cages were changed
approximately every other week. Bedding was changed as often as necessary to keep the
rats dry and clean.

2.6.6. Feed

Rats were given ad libitum access to Certified Rodent Diet?#5002 (PMI Nutrition
International, Inc., St. Louis, Missouri) in individual feeders. Rats were fasted overnight
before sacrifice.

2.6.7. Feed Analysis

Analyses were routinely performed by the feed supplier. contaminants at levels
exceeding the maximum concentration for certified feed or deviations from expected
nutritional requirements were detected by these analyses. Copies of the results of the
feed analyses are available in the raw data.

Neither the Sponsor nor the Study Director was aware of any potential contaminants
likely to have been present in the feed that would have interfered with the results of this
study.

2.6.8. Water

Local water that had been processed by passage through a reverse osmosis membrane
(R.O. water) was available to the rats ad libitum from an automatic watering access
system and/or individual water bottles attached to the cages. Chlorine was added to the
processed water as a bacteriostat.

2.6.9. Water Analysis

The processed water is analyzed twice annually for possible chemical contamination
(Lancaster Laboratories, Lancaster, and for possible bacterial
contamination (Analytical Laboratories, Inc., Chalfont, Copies of the
results of the water analyses are available in the raw data.

Neither the Sponsor nor the Study Director was aware of any potential contaminants
likely to have been present in the water that would have interfered with the results of this
study.

2.6.10. Bedding Material

Bed-o?cobs? bedding (The Andersons Industrial Products Group, Maumee, Ohio) was
used as the nesting material.

2.6.11.

Bedding Analysis

2?10

Analyses for possible contamination are conducted semi-annually. Copies of the results

of the bedding analyses are available in the raw data.

Neither the Sponsor nor the Study Director was aware of any potential contaminants
likely to have been present in the bedding that would have interfered with the results of

 

 

 

 

 

 

 

 

 

 

 

 

 

 

this study.
2.7. Methods
2.7.1. Dosage Administration
Dosage Number of 
Dosage Dosagea Concentration Volume Rats per Ass1gned Numbers
Group (mg/kg/ day) (mg/mL) (mL/kg) SCX Male Rats Female Rats
17601, 17602, 17603, 17604, 17662, 17672, 17673, 17674,
. 17607, 17608, 17618, 17630, 17680, 17681, 17690, 17694,
I 0 (?3111016) 0 10 15 17631,17639, 17648, 17652, 17695,17703, 17713, 17715,
17656, 17658, 17660 17716, 17717, 17719
17615, 17616, 17624, 17626, 17663, 17665, 17666, 17668,
11 10 1 10 15 17632, 17634, 17635, 17638, 17671, 17675, 17679, 17684,
17642, 17643, 17645, 17649, 17688, 17698, 17702, 17704,
17651, 17653, 17655 17707, 17708, 17710
17605, 17610, 17611, 17613, 17661, 17667, 17669, 17670,
111 50 5 10 15 17619, 17620, 17623, 17627, 17676, 17687, 17693, 17697,
17628, 17633, 17640, 17646, 17700, 17701, 17705, 17706,
17650, 17657, 17659 17709, 17718, 17720
17606, 17609, 17612, 17614, 17664, 17677, 17678, 17682,
IV 250 25 10 15 17617, 17621, 17622, 17625, 17683, 17685, 17686, 17689,
17629, 17636, 17637, 17641, 17691, 17692, 17696, 17699,
17644, 17647, 17654 17711, 17712, 17714
a. The test substance was considered 100% pure for the pupose of dosage calculatons.
2.7.2. Rationale for Dosage Selection

Dosages were selected by the Sponsor based on previous studies conducted with the test
substance, taking into account possible differences in sensitivity between pregnant and
nonpregnant rats. The highest dosage was expected to cause toxic effects but not
mortality or obvious suffering. The descending sequence of the lower dosage levels were
selected for the purpose of demonstrating any dosage?related response, with no adverse

effects expected at the lowest level.

2.7.3.

Route and Rationale for Route of Administration

The oral (gavage) route was selected for use because: 1) in comparison with the dietary
route, the exact dosage can be accurately administered; and 2) it is one possible route of
human exposure.

 

 2?11

2.7.4. Method and Frequency of Administration
2.7.4.1. Fo Generation Rats

Male rats were administered the test substance and/or the vehicle once daily beginning
14 days before cohabitation (maximum 14 days) and continuing until sacrifice, after
completion of the cohabitation period, after a minimum of 28 days of dosage. Female
rats were administered the test substance and/or the vehicle once daily beginning 14 days
before cohabitation (maximum 14 days) and continuing until DL 5. The dosage volume
was adjusted daily on the basis of the individual body weights recorded before
intubationa. The rats were intubated once daily at approximately the same time each day.

2.7.4.2. F1 Generation Pups

F1 generation pups were not directly administered the test substance and/or vehicle, but
may have been possibly exposed to test substance and/or vehicle during maternal
gestation (in utero exposure) or via maternal milk during the lactation period.

2.7.5. Method of Study Performance
2.7.5.1. 0 Generation Rats

Within each dosage group, consecutive order was used to assign rats to cohabitation, one
male rat per female rat. The cohabitation period consisted of a maximum of 14 days.
Female rats with spermatozoa observed in a smear of the vaginal contents and/or a,
copulatory plug in situ were considered to be DG 0 and assigned to individual housing.
Female rats that were not mated with a male rat within the first seven days of
cohabitation were assigned an alternate male rat that had mated (same dosage group) and
remained in cohabitation for a maximum of seven additional days.

Rats were observed for viability at least twice each day of the study. Rats were examined
for clinical observations and general appearance weekly during the acclimation period.
Observations for clinical signs of effects of the test substance, abortions, premature
deliveries and deaths were made daily before dosage. On the first day of dosage,
postdosage observations were recorded at approximately hourly intervals for the first four
hours after administration. The observation at four hours after administration was at the
end of the normal working day. Postdosage observations for subsequent days of dosage
were recorded approximately 60 i 10 minutes after dosage administration and on the day
of sacrificeb.

Once before the first dosage and at least once weekly thereafter, detailed clinical
observations were conducted for all male and female rats. These observations were made

 

a. See APPENDIX (DEVIATIONS FROM THE PROTOCOL AND THE
STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY),

item 1.
b. See APPENDIX E, items 2 and 3.

 2-12

outside the cage in a standard arena at the same time each day of conduct. Effort was
made to ensure that variations in the test conditions were minimal and that observations
were conducted by observers unaware of treatment groups. Signs noted included, but
were not limited to: changes in skin, fur, eyes, mucous membranes, occurrence of
secretions and excretions and autonomic activity lacrimation, piloerection, pupil
size, unusual respiratory pattern). Changes in gait, posture and response to handling as
well as the presence of clonic or tonic movements, stereotypic behavior excessive
grooming, repetitive circling), difficult or prolonged parturition or bizarre behavior

self?mutilation, walking backwards) were also recorded.

Body weights for male and female rats were recorded weekly during the acclimation
period, daily during the dosage period and at sacrifice. Feed consumption values for
male rats were recorded weekly during the dosage period. Feed left was recorded on the
day before sacrifice. Feed consumption values for female rats were recorded weekly to
cohabitation and (if necessaryFeed left was recorded on the day before sacrifice. During cohabitation, when two
rats occupied the same cage with one feed jar, replenishment of feed jars was
documented but individual values were not recorded or tabulated. Male and female rats
were fasted overnight before sacrifice.

Estrous cycling was evaluated by examination of vaginal cytology beginning with the day
after the first administration and then until spermatozoa were observed in a smear of the
vaginal contents and/or a copulatory plug was observed in situ during the cohabitation
period.

Female rats were evaluated for adverse clinical signs observed during parturition,
duration of gestation (DG 0 to the day the first pup was observed), litter sizes (all pups
delivered) and pup Viability at birth. Maternal behavior was evaluated on DLs and 5.
Variations from expected maternal behavior were recorded, if and when present, on all
other days of the postpartum period.

On one occasion during the course of the study, shortly before scheduled sacrifice, a
functional observational battery was conducted on five male and five female
rats per group. For male rats, this assessment was conducted approximately one week
before scheduled sacrifice. Female rats were tested during the lactation period, the day
before scheduled sacrifice. To avoid hyperthermia of pups, dams were separated from
their litters for no longer than 30 to 40 minutes.

The FOB evaluation was conducted by an observer unaware of the group assignment of
the rat. The following parameters were assessed:

1. Lacrimation, salivation, palpebral closure, prominence of the eye,
pupillary reaction to light, piloerection, respiration, and urination and
defecation (autonomic functions).

 2-13

2. Sensorimotor responses to Visual, auditory, tactile and painful stimuli
(reactivity and sensitivity).

3. Reactions to handling and behavior in the open field (excitability).

4. Gait pattern in the open field, severity of gait abnormalities, air righting
reaction, Visual placing response and landing foot splay (gait and
sensorimotor coordination).

5. Forelimb and hindlimb grip strength.

6. Abnormal clinical signs including but not limited to convulsions, tremors
and other unusual behavior, hypotonia or hypertonia, emaciation,
dehydration, unkempt appearance and deposits around the eyes, nose or
mouth.

The ability of this battery to detect the effects of positive control substances has been
established (Testing Facility Positive Control Data) and is available in APPENDIX 1.

Motor activity was evaluated on five male and five female rats per group once during the
course of the study. For male rats, this assessment was conducted approximately one
week before scheduled sacrifice. Female rats were tested during the lactation period, the
day before scheduled sacrifice.

The movements of each rat were monitored by a passive infrared sensor mounted outside
a stainless steel, wire-bottomed cage (40.6 25.4 17.8 cm). Each test session was

1.5 hours in duration with the number of movements and time spent in movement
tabulated at each five?minute interval. The apparatus monitored a rack of up to 32 cages
and sensors during each session, with each rat tested in the same location on the rack
across test sessions. Groups were counterbalanced across testing sessions and cages.
Data demonstrating that the test system is capable of detecting increases in activity
produced by positive control substances (Testing Facility Positive Control Data) is
available in APPENDIX 1.

2.7.5.2. F1 Generation Pups

Day 1 of lactation (p0stpartum) was defined as the day of birth and was also the first day
on which all pups in a litter were individually weighed (pup body weights were recorded
after all pups in a litter were delivered and groomed by the dam).

Each litter was evaluated for viability at least twice daily. The pups in each litter were
counted once daily. Clinical observations were recorded once daily. Pup body weights
were recorded on DLs 1 and 5 (terminal weight).

 2?14

2.7.6. Gross Necropsy
2.7.6.1. F0 Generation Rats

After 36 days of dosage, all male rats were sacrificed on the day following the last
dosage, day 37 of study (DS 37) and on DL 6, all surviving female rats were sacrificed.
Rats were sacrificed by carbon dioxide and a gross necropsy of the
thoracic, abdominal and pelvic viscera was performed. Gross necropsy of all male and
female rats included an initial physical examination of external surfaces and all orifices,
as well as the cranial, thoracic and abdominal cavities and their contents. Special
attention was paid to the organs of the reproductive system. The number of implantation
sites and corpora lutea were recorded. Tissue trimming and histopathology was
performed under the supervision of or by a Board?Certified Veterinary Pathologist.
Gross lesions were retained in neutral buffered 10% formalin and examined
histologically. Representative photographs of gross lesions are available in the raw data.

The testes and epididymides of all male rats were weighed, and the testes, epididymides,
seminal vesicles with coagulating gland and prostate were retained in neutral buffered
10% formalin. The testes were fixed in Bouin's solution for 48 to 96 hours before being
retained in neutral buffered 10% formalin. The ovaries and the uterus with cervix of each
female rat were weighed, and ovaries, uterus, vagina and a mammary gland were retained
in neutral buffered 10% formalin. Uteri of apparently nonpregnant rats were examined
after being pressed between glass plates to confirm the absence of implantation sites, and
retained in neutral buffered 10% formalin.

Ten rats per sex per group not assigned to functional observational battery and motor
activity tests were assigned to histological evaluations. The following organs were
excised, trimmed and individually weighed as soon as possible after excision to avoid
drying: liver, kidneys, adrenals, thymus, testes, epididymides, spleen, brain, heart, ovaries
and uterus (with cervix)a. The following tissues or representative samples were retained
in neutral buffered 10% formalin: brain (representative regions including cerebrum,
cerebellum, pons), small and large intestines (including Peyer's patches), lungs (perfused
with neutral buffered 10% formalin), nodes (submandibular and mediastinal),
peripheral nerve (sciatic), stomach, kidneys, spleen, thymus, trachea, urinary bladder,
testes (fixed in Bouin's solution for 48 to 96 hours before being retained in neutral
buffered 10% formalin), epididymides, seminal vesicles (with coagulating gland),
prostate, spinal cord (cervical, thoracic and lumbar), liver, adrenals, heart,
thyroid/parathyroid, uterus, bone marrow, ovaries, uterus, vagina, mammary gland
(female rats only) and gross lesions. Histological examination of retained tissues,
including reproductive organs, was conducted for the assigned ten rats per sex from the
control and high dosage groups. Histological evaluations were performed on the livers of
ten male and ten female rats, the thymuses of ten female rats and the stomachs of ten
male rats in the 10 and 50 mg/kg/day dosage groups. Tissues to be examined

 

a. See APPENDIX E, item 4.

 2-15

histologically were shipped to Research Pathology Services, Inc., New Britain,

for evaluation. Results of the histological evaluation are available in
APPENDIX J.

At scheduled sacrifice, the five male and five female rats per group assigned to
hematology and clinical chemistry sample collection were exsanguinated from the
inferior vena cava following sacrifice. Rats were fasted overnight before sacrifice.
Approximately 5 mL of blood was collected. The tubes containing the samples were
labeled with the protocol number, Sponsor study number, animal number, group number,
dosage level, day of study, collection interval, date of collection, species, generation and
storage conditions.

Approximately 1 mL of blood was collected into EDTA-coated tubes and maintained on
wet ice or refrigerated until shipment for analysis of the following hematologic
parameters: count (RBC), hematocrit (HCT), hemoglobin (HGB), mean
corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC),
mean corpuscular volume (MCV), total leukocyte count (WBC), differential leukocyte
count, platelet count (PLAT), mean platelet volume (MPV) and cell morphology. Two
blood smear slides were prepared at the Testing Facility for each sample for
measurements of differential leukocyte count.

Approximately 1.8 mL of blood was added to a tube containing 0.2 mL of sodium citrate
(0.129 M). The contents were mixed and maintained on wet ice until the tubes were
centrifuged (within 30 minutes of the collection time). The resulting plasma was
transferred to a transport tube and immediately frozena. Plasma samples were maintained
on dry ice or in a freezer (S until shipped for measurement of prothrombin time
(PT) and activated partial thromboplastin time (APTT).

Approximately 2 mL of blood was collected into serum separator tubes and centrifuged.
The resulting sera samples were immediately frozen on dry ice and maintained frozen
until shipment for analysis of the following parameters: total protein (TP),
triglycerides (TRI), albumin (A), globulin (G), albumin/globulin Ratio glucose
(GLU), cholesterol (CHOL), total bilirubin (TBILI), urea nitrogen (BUN), creatinine
(CREAT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline
phosphatase (ALK), calcium (CA), phosphorus (PHOS), sodium (NA), potassium (K)
and chloride 

Samples for hematology and clinical chemistry analyses were shipped to Redfield
Laboratories, A Division of Redfield, Arkansas. Results of these analyses are
available in APPENDIX K.

Blood samples (approximately 3 mL) were collected from the five rats per sex per group
assigned to metabolite analysis. Blood was collected from the vena cava. Each sample
was divided into two aliquots. One aliquot of 2 mL was transferred into an EDTA?coated
(purple top) tube and refrigerated. The second aliquot (approximately 1 mL) was

 

a. See APPENDIX E, item 5.

 2-16

transferred into a serum tube, allowed to clot and spun in a centrifuge. The resulting
serum was transferred into polypropylene tubes labeled with the protocol number,
Sponsor study number, animal number, group number, dosage level, day of study,
collection interval, date of collection, species, generation and storage conditions. All
samples were immediately frozen on dry ice and maintained frozen until
shipment for analysis.

The liver was excised and the organ weight recorded. One lobe (right lateral) was placed
in a conical tube and ?ash frozen in an ice/alcohol bath. Liver samples were maintained
frozen until shipment for analysis.

Liver and serum samples were shipped on dry ice and whole blood will be shipped on ice
packs. Samples to be analyzed were shipped to Southern Research Institute,
Birmingham, Alabama, for analysis. Results of these analyses are available in
APPENDIX K.

Female rats that did not deliver a litter were sacrificed on DG 25. Gross necropsy,
examination and tissue retention were conducted as described above for rats at scheduled
sacrifice.

Dams with no surviving pups were sacrificed after the last pup was found dead, missing
or presumed cannibalized. Gross necropsy, examination and tissue retention was
conducted as described above for rats at scheduled sacrifice. Gross lesions were
preserved in neutral buffered 10% formalin for possible future evaluation.
Representative photographs of gross lesions are available in the raw data.

2.7.6.2. F1 Generation Pups

On DL 5, pups were sacrificed by carbon dioxide and examined for gross
lesions. Necropsy included a single cross-section of the head at the level Of the frontal?
parietal suture and examination of the cross-sectioned brain for apparent hydrocephaly.
Gross lesions were preserved in neutral buffered 10% formalin for possible future
evaluation. Representative photographs of gross lesions are available in the raw data.

Pups that died before initial examination of the litter for pup viability were evaluated for
vital status at birth. The lungs were removed and immersed in water. Pups with lungs
that sank were identified as stillborn; pups with lungs that ?oated were identified as
liveborn, and to have died shortly after birth. Pups found dead on DLs 2 to 4 were
examined for gross lesions and for the cause of death.

 2?17

2.7.7. Data Collection and Statistical Analyses

Data generated during the course of this study were recorded either by hand or using the
Argus Automated Data Collection and Management System, the Vivarium Temperature
and Relative Humidity Monitoring System, the Coulbourn Instruments Passive Infrared
Motor Activity System, the Coulbourn Instruments Auditory Startle System, the
Coulbourn Instruments Spatial Delayed Alternation System, and/or the passive avoidance
software. All data were tabulated, summarized and/or statistically analyzed using the
Argus Automated Data Collection and Management System, the Vivarium Temperature
and Relative Humidity Monitoring System, Microsoft Excel [part of Microsoft Office 97
(version and/or The SAS System (version 6.12).

 2-18

Averages and percentages were calculated. Litter values were used where appropriate.
The following schematic represents the statistical analyses of the data:

Type of Testa

I. Parametric Il. Nonparametricb
A. Bartlett's Test? A. Kruskal-Wallis Test

(575% ties at any concentration)

 

 

 

Significant at p50.001 Not Significant Significant at ng.O5 Not Significant

Nonparametric Analysis of Variance Dunn's Test

Significant at p30.05 Not Significant

Dunnett's Test

B. Fisher's Exact Test on

Proportion of Ties
ties at any concentration)

B. Analysis of Variance with Repeated Measures

Significant at ng.05 Not Significant

(Dosage) (Dosage Block Interaction)
Dunnett's Test One-way ANOVA for each block

 

Significant at p50.05 Not Significant

Dunnett's Test

Test for Proportion Data
Variance Test for Homogeneity
of the Binomial Distribution

 

a. Statistically significant probabilities are reported as either p50.05 or 1030.001.
b. Proportion data are not included in this category.
c. Test for homogeneity of variance.

 2?19

Adult data was evaluated With the individual rat as the unit measured. Litter values were
used in evaluation of pup data, as appropriate.

Variables with interval or ratio scales of measurement, such as body weights, feed
consumption values, latency and errors per trial scores in behavioral tests and percent
mortality per litter were analyzed as described under the Parametric heading of the
schematic. Bartlett?s Test of Homogeneity of Variances<13 was used to estimate the
probability that the dosage groups have different variances. A non-significant result
(p>0.001) indicated that an assumption of homogeneity of variance was not
inappropriate, and the data was compared using the Analysis of Variance?). If that test
was significant (p50.05), the groups ggiven the test substance were compared with the
control group using Dunnett?s Test(1 If Bartlett?s Test was significant (1950.001), the
Analysis of Variance Test was not appropriate, and the data was analyzed as described
under the Nonparametric heading of the schematic. When 75% or fewer of the scores in
all the groups were tied, the Kruskal-Wallis Test(l6) was used to analyze the data, and in
the event of a significant result (p50.05), Dunn?s Testm) was used to compare the groups
given the test substance with the control group. When more than 75% of the scores in
any dosage group were tied, Fisher?s Exact Testug) was used to compare the proportion of
ties in the groups.

Data from the motor activity test, with measurements recorded at intervals (Blocks)
throughout each test session, were analyzed using an Analysis of Variance with Repeated
Measures?), as described under that heading in the schematic. A significant result
(p30.05) in that test could have appeared as effect of Dosage (differences among dosage
groups in the totals of all measurements in a session) or as an interaction between Dosage
and Block (differences in the patterns of dosage group values across the measurement
periods). If the Dosage effect was significant, the totals for the control group and the
groups given the test substance were compared using Dunnett?s Test(15 If the Dosage 
Block interaction was significant, an Analysis of Variance?) was used to evaluate the
data at each measurement period, and a significant result (p50.05) was followed by a
comparison of the dosage groups using Dunnett?s test(15 

Variables that had graded or count scores, such as litter size, the number of trials to a
criterion in a behavioral test or the day a developmental landmark appeared, were
analyzed using the procedures described under the Nonparametric heading of the
schematic.

Clinical observation incidence data were analyzed using the Variance Test for
Homogeneity of the Binomial Distributionao).

 3-1

3. RESULTS - MALE RATS

3.1. Mortality, Clinical and Necropsy Observations
(Summaries Tables B1 and Individual Data - Tables B15 and B16)

3.1.1. Mortality
All male rats survived to scheduled sacrifice.
3.1.2. Clinical Observations

Signi?cant increases (1930.01) in the incidences of excess salivation, perioral substance
and urine?stained abdominal fur occurred in the 250 mg/kg/day dosage group.

All other clinical observations were considered unrelated to the test substance because:

1) the incidences were not dosage?dependent; and/or 2) the observation occurred in only
one or two male rats in any dosage group. These observations included chromorhinorrea,
soft or liquid feces, missing/broken incisors, chromodacryorrhea, scabs on right forelimb,
red substance on the penis and ulceration on right forelimb.

3.1.3. Necropsy Observations

All necropsy observations were considered unrelated to the test substance because: 1) the
incidences were not dosage-dependent; and/or 2) the observation occurred in only one
male rat (17636) in the 250 mg/kg/day dosage group. These observations included a tan,
firm, lobular mass (2the right hemisphere of the prostate and
a red ventral side of the same prostate gland. A cut surface of the mass revealed a tan
smooth surface. Histomorphologic diagnosis was suppurative prostatitis.

3.1.4. Histopathology

Treatment?related microscopic changes were observed in the liver of male rats in the 50
and 250 mg/kg/day dosage groups and in the stomach of male rats in the 250 mg/kg/day
dosage group.

. The treatment?related microscopic changes in, the liver consisted of minimal or mild
enlargement (hypertrophy) of centrilobular hepatocytes in most of the male rats in the
250 mg/kg/day dosage group and mg/kg/day dosage group. The
enlargement was due to an increased amount of finely granular, dense eosinophilic
cytoplasm. Also, in three of the affected rats in the 250 mg/kg/day dosage group,
necrosis of individual enlarged hepatocytes was seen in the centrilobular areas.

Microscopic examination of the stomach revealed focal erosions in the pyloric glandular
mucosa of two rats in the 250 mg/kg/day dosage group.

treatment-related microscopic changes were observed in any of the male rats given
10 mg/kg/day of the test substance.

 3-2

3.2. Terminal Body Weights and Organ Weights and Ratios of Organ
Weight to Terminal Body Weight and Brain Weight (Summaries -
Tables B3 through Individual Data Tables B17 and B18)

Terminal body weights of the male rats were significantly reduced (pS0.01) in the
250 mg/kg/day dosage group, as compared with control group values.

Absolute weights of the left and right kidneys were significantly increased or
in the 50 and 250 mg/kg/day dosage groups and the absolute weight of the liver
was significantly increased (1930.01) in the 250 mg/kg/day dosage group, as compared
with the control group value. The ratios of the weights of these organs to terminal body
weights were significantly increased ((930.05 or pS0.01) in the 50 and 250 mg/kg/day
dosage groups. Relative to the brain weight, only the liver weight in the 250 mg/kg/day
dosage group was significantly increased (pS0.0l).

3.3. Hematology and Clinical Chemistry (Summaries - Tables B6 through B7)

Dosages of the test substance as high as 250 mg/kg/day did not affect any hematology or
clinical chemistry values evaluated. Average values for red blood cells (RBC), white
blood cells (WBC), hemoglobin concentration (HGB), hematocrit (HCT), mean
corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular
hemoglobin concentration (MCHC), platelets, volume, prothrombin and activated partial
thromboplastin time (PT and APTT), mean platelet volume (MPV), nucleated red blood
cell count (NRBC), segmented neutrophils, bands, monocytes, eosinophils,
basophils and abnormal in male rats were comparable among the four
dosage groups and did not differ significantly.

Average values for total protein (TP), albumin (A), glucose (GLU), cholesterol (CHOL),
total bilirubin (TBILI), blood urea nitrogen (BUN), creatinine (CREAT), alanine
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALK),
calcium (CA), phosphorus (PHOS), triglycerides (TRIG), sodium (NA), potassium (K),
chloride (CL), globulin (G) and albumin/globulin ratio in male rats were
comparable among the four dosage groups and did not differ significantly.

3.4. Body Weights and Body Weight Changes
(Figure 1; Summaries - Tables B8 and Individual Data - Table B19)

Body weight gains were significantly reduced (1950.01) in the 250 mg/kg/day dosage
group on study days (DSs36. Body weight gains were also
significantly decreased (1930.05) in the 50 mg/kg/day dosage group on DSs 1 to 36.

Body weights were significantly reduced on DS 29 and 36 in the 250 mg/kg/day
dosage group. Body weights and body weight gains of the male rats were unaffected by
dosages of the test substance as high as 10 mg/kg/day.

 3?3

3.5. Absolute (g/day) and Relative (g/kg/day) Feed Consumption Values
(Summaries Tables B10 and Individual Data Table B20)

Absolute (g/day) feed consumption values were significantly reduced or pS0.01)
in the 50 and 250 mg/kg/day dosage groups on DSs 1 to 8 and significantly reduced
(pS0.0l) in the 250 mg/kg/day dosage groups 36. Absolute feed
consumption values during the recovery period were comparable between the 0 (Vehicle)
and 10 mg/kg/day dosage groups.

Relative (g/kg/day) feed consumption values were significantly reduced or
1730.01and 250 mg/kg/day dosage groups. Relative feed
consumption values of the male rats were unaffected by dosages of the test substance as
high as 10 mg/kg/day.

3.6. Mating and Fertility
(Summary Table Individual Data - Table B21)

A11 mating and fertility parameters (numbers of days in cohabitation, rats that mated,
fertility index, rats with confirmed mating dates during the first and second week of
cohabitation, rats pregnant per rats in cohabitation and the number of pregnant rats per
number of rats in cohabitation) were unaffected by dosages of the test substance as high
as 250 mg/kg/day.

3.7. Functional Observational Battery
(Summary - Table Individual Data Table B22)

There were no statistically significant or biologically important differences among the
four dosage groups in the measures of the functional observational battery (FOB). There
were no alterations in home cage behavior, autonomic functions (lacrimation, salivation,
palpebral closure, prominence of the eye, pupillary reaction to light, piloerection,
respiration, defecation and urination), sensorimotor functions [responses to Visual,
auditory, tactile and painful stimuli (reactivity and sensitivity)], excitability (reactions to
handling and behavior in the open field), gait and sensorimotor coordination (gait pattern
in the open field, severity of gait abnormalities, air righting reaction and landing foot
splay) and forelimb and hindlimb grip strength and abnormal clinical observations
including but not limited to: convulsions, tremors, unusual behavior, hypotonia or
hypertonia, emaciation, dehydration, unkempt appearance and deposits around the eyes,
nose or mouth.

Body weights recorded during the functional operational battery for the treated groups
were not significantly different than the control group for the male rats.

3.8. Motor Activity (Figure 3 and 4; Summary Table 
Individual Data - Table B23)

There were no statistically significant or biologically important differences among the
four dosage groups in the measures of motor activity on DS 8.

 4-1

4. RESULTS - Female Rats

4.1. Mortality, Clinical and Necropsy Observations
(Summaries - Tables C1 and Individual Data - Tables C27 and C28)

4.1.1. Mortality
All female rats survived to scheduled sacrifice.
4.1.2. Clinical Observations

All clinical observations were considered unrelated to the test substance because: 1) the
incidences were not dosage?dependent; and/or 2) the observation occurred in only one or
two female rats in any dosage group. These observations included perioral substance,
excess salivation, bent tail, chromodacryorrhea, corneal opacity of right eye, localized
alopecia on the limbs, underside or head, urine?stained abdominal fur, red perivaginal
substance, soft or liquid feces, missing/broken incisors and dehydration.

4.1.3. Necropsy Observations

All necropsy observations were considered unrelated to the test substance because: 1) the
incidences were not dosage-dependent; and/or 2) the observation occurred in only one
female rat in the 50 mg/kg/day dosage group and one female rat in the 250 mg/kg/day
dosage group. These observations included an absent right kidney in one 50 mg/kg/day
dosage group female rat (17706) and a small thymus in one 250 mg/kg/day dosage group
female rat (17696). The small thymus was not available for histomorphologic diagnosis.

4.1.4. Histopathology

Treatment?related microscopic changes were observed in the liver and thymus of female
rats in the 250 mg/kg/day dosage group.

The treatment-related microscopic changes in the liver consisted of minimal or mild
enlargement (hypertrophy) of centrilobular hepatocytes in most of the female rats in the
250 mg/kg/day dosage group. The enlargement was due to an increased amount of finely
granular, dense eosinophilic cytoplasm.

Microscopic examination of the thymus revealed an increased incidence and severity of
atrophy of the thymic lobules in female rats in the 250 mg/kg/day dosage group.

No treatment-related microscopic changes were observed in any of the female rats given
10 mg/kg/day of the test substance.

418-0272PAGE 4?2

4.2. Terminal Body Weights and Organ Weights and Ratios of Organ
Weight to Terminal Body Weight and Brain Weight (Summaries - Tables
C3 through Individual Data Tables C29 and C30)

Terminal body weights of the female rats were reduced albeit not significantly,
in the 250 mg/kg/day dosage group, as compared with control group values.

Absolute weights of the liver was significantly increased (1930.01) in the 250 mg/kg/day
dosage group, as compared with the control group value. The ratios of the weight of this
organ and the weight of the right kidney to terminal body weights were significantly
increased (1930.01) in the 250 mg/kg/day dosage group. Only the ratio of the liver weight
to brain weight in the 250 mg/kg/day dosage group was significantly increased (1930.01)
was considered treatment-related; the significantly increased ratio of the liver
weight to brain weight in the 10 mg/kg/day dosage group was not considered treatment-
related because it was not dosage dependent.

4.3. Hematology and Clinical Chemistry (Summaries - Tables C6 and C7)

Dosages as high as 250 mg/kg/day did not affect any hematology or clinical chemistry
values evaluated. Average values for red blood cells (RBC), white blood cells (WBC),
hemoglobin concentration (HGB), hematocrit (HCT), mean corpuscular volume (MCV),
mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration
(MCHC), platelets, prothrombin and activated partial thromboplastin time (PT and
APTT), mean platelet volume (MPV), nucleated red blood cell count (NRB C),
segmented neutrophils, bands, monocytes, eosinophils, basophils, abnormal
in female rats were comparable among the four dosage groups and did not
differ significantly.

Average values for total protein (TP), albumin (A), glucose (GLU), cholesterol (CHOL),
total bilirubin (TBILI), blood urea nitrogen (BUN), creatinine (CREAT), alanine
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALK),
calcium (CA), phosphorus (PHOS), triglycerides (TRIG), sodium (NA), potassium (K),
chloride (CL), globulin (G) and albumin] globulin ratio in female rats were
comparable among the four dosage groups and did not differ significantly.

4.4. Body Weights and Body Weight Changes (Figure 1; Summaries - Tables
C8 through Individual Data - Tables C31 through C33)

4.4.1. Precohabitation

Body weight gains were significantly reduced (pS0.05) during the precohabitation period
in the 250 mg/kg/day dosage group 15. Body weights were not
significantly affected by dosages of the test substance on any weight day during
precohabitation.

 4?3

4.4.2. Gestation

Body weights and body weight gains were not significantly affected by dosages of the
test substance during gestation.

Body weights gains were significantly reduced (1730.05 or 1930.01) during gestation on
days of gestation (DGsmg/kg/day dosage group and on
DGSs 12 to 15 in the 10 mg/kg/day dosage group. These significant reductions in body
weight gain were not considered treatment-related because they were not dosage-
dependent.

4.4.3. Lactation

Body weight gains were not significantly affected by dosages of the test substance during
lactation. Body weights were significantly reduced during lactation on day of
lactation (DL) 1 in the 250 mg/kg/day dosage group but was not considered treatment?
related because it did not persist.

4.5. Absolute (g/day) and, Relative (g/kg/day) Feed Consumption Values
(Summaries Tables C14 through Individual Data - Tables C34
through C36)

4.5.1. Precohabitation

Absolute (g/day) and relative (g/kg/day) feed consumption values were not significantly
affected by dosages of the test substance during the precohabitation period.

4.5.2. Gestation

Absolute (g/day) feed consumption values were not significantly affected by dosages of
the test substance during the gestation period.

Relative (g/kg/day) feed consumption values were significantly increased (pS0.0l) during
gestation on DGs 15 to 18 in the 250 mg/kg/day dosage group but was not considered
treatment-related because it did not persist.

4.5.3. Lactation

Absolute and relative feed consumption values were not significantly affected by dosages
of the test substance during lactation.

4.6. Estrous Cycling, Mating and Fertility (Summary - Table 
Individual Data - Table C37)

The average numbers of estrous stages per 14 days were comparable among the four
dosage groups and did not significantly differ. The number of rats with six or more
consecutive days of diestrus Or estrus did not differ significantly.

 4?4

All mating and fertility parameters (numbers of days in cohabitation, rats that mated,
Fertility Index, rats with confirmed mating dates during the first and second week of
cohabitation, rats pregnant per rats in cohabitation and the number of pregnant rats per
number of rats in cohabitation) were unaffected by dosages of the test substance as high
as 250 mg/kg/day.

4.7. Functional Observational Battery (Summary - Table Individual
Data - Table C38)

There were no statistically significant or biologically important differences among the
four dosage groups in the measures of the functional observational battery (FOB). There
were no alterations in home cage behavior, autonomic functions (lacrimation, salivation,
palpebral closure, prominence of the eye, pupillary reaction to light, piloerection,
respiration, defecation and urination), sensorimotor functions [responses to Visual,
auditory, tactile and painful stimuli (reactivity and sensitivity)], excitability (reactions to
handling and behavior in the open field), gait and sensorimotor coordination (gait pattern
in the open field, severity of gait abnormalities, air righting reaction and landing foot
splay) and forelimb and hindlimb grip strength and abnormal clinical observations
including but not limited to: convulsions, tremors, unusual behavior, hypotonia or
hypertonia, emaciation, dehydration, unkempt appearance and deposits around the eyes,
nose or mouth.

Body weights recorded during the functional operational battery for the treated groups
were not significantly different than the control group for the female rats.

4.8. Motor Activity (Figures 5 and 6; Summary Table 
Individual Data - Table C39)

There were no statistically significant or biologically important differences among the
four dosage groups in the measures of motor activity on DS 86.

4.9. Natural Delivery and Litter Observations (Summary Tables C23 and
Individual Data - Tables C40 through C43)

Pregnancy occurred in all 15 (100%) rats assigned to the 0 (Vehicle) and 50 mg/kg/day
dosage groups, 14 of the rats assigned to the 10 mg/kg/day dosage group and
13 of the rats assigned to the 250 mg/kg/day dosage group. All pregnant dams
delivered a litter of one or more liveborn pups. The number of liveborn pups was
significantly reduced (pS0.0l) in the 250 mg/kg/day dosage group. The number of
stillborn pups was significantly increased (1930.01) in the 250 mg/kg/day dosage group.
The number of pups found dead or presumed cannibalized on day 1 and days 2 to 5
postpartum was significantly increased in the 250 mg/kg/day dosage groups.
The viability index was significantly reduced (1930.01) in the 250 mg/kg/day
dosage group, compared to the control group value The number of pups
surviving per litter on postpartum day 5' was significantly reduced (pS0.05) in the

250 mg/kg/day dosage group. Pup body weights per litter were also reduced, albeit not
significantly, in the 250 mg/kg/day dosage group on postpartum days 1 and 5. These

 4-5

findings at 250 mg/kg/day were considered related to the test substance because they
were dosage dependent.

Values for the numbers of dams delivering litters, the duration of gestation, averages for
implantation sites per delivered litter, the gestation index (number of dams with one or
more liveborn pups/number of pregnant rats), the numbers of dams with stillborn pups,
dams with all pups dying, stillborn pups, surviving pups per litter on postpartum day 
and pup sex ratios were comparable among the four dosage groups and did not
significantly differ.

4.10. Pup Clinical and Necropsy Observations (Summary - Tables C25 and
Individual Data - Tables C44 and C45)

No clinical or necropsy observations in the F1 generation pups were attributable to
dosages of the test substance as high as 250 mg/kg/day because: 1) the incidences were
not dosage?dependent; and 2) the observation occurred in only one to three litters. These
clinical observations included: not nursing, not nesting, pale and bruise on head, back,
mouth, lower midline, chest and/or neck. Necropsy observations on postpartum day 5
was limited to slight dilation of the renal pelvis of one pup from a 10 mg/kg/day dosage
group litter.

 4?6

REFERENCES

1.

10.

11.

12.

Organisation for Economic Co?operation and Development (1996). OECD
Guideline for Testing of Chemicals. Section 4, o. 422: Combined Repeated
Dose Toxicity Study With the Reproduction/Developmental Toxicity Screening
Test, adopted 22 March 1996.

Organisation for Economic Co?operation and Development (1998). The Revised
OECD Principles of Good Laboratory Practices 

US. Food and Drug Administration. Good Laboratory Practice Regulations;
Final Rule. 21 CFR Part 58.

Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice
Standard for Safety Studies on Drugs, MHW Ordinance Number 21, March 26,
1997.

Christian, MS. and Voytek, RE. (1982). In Vivo Reproductive and Mutagenicity
Tests. Environmental Protection Agency, Washington, DC. National Technical
Information Service, US. Department of Commerce, Springfield, VA 22161.

Christian, MS. (1984). Reproductive toxicity and teratology evaluations of
naltrexone (Proceedings of Naltrexone Symposium, New York Academy of
Sciences, November 7, 1983), J. Clin. 

Lang, PL. (1988). Embryo and Fetal Developmental Toxicity (Teratology)
Control Data in the Charles River rl: Rat. Charles River Laboratories,
Inc., Wilmington, MA 01887?0630. (Data base provided by Argus Research
Laboratories, Inc.)

Institute of Laboratory Animal Resources (1996). Guide for the Care and Use of
Laboratory Animals. National Academy Press, Washington, DC.

Haggerty, G.C. (1989). Development of Tier I neurobehavioral testing
capabilities for incorporation into pivotal rodent safety assessment studies.
J. Amer. Col. Toxicol. 8:53-70.

Irwin, S. (1968). Comprehensive observational assessment: Ia. A systemic
quantitative procedure for assessing the behavioral and physiologic state of the
mouse. (Berlin) 13:222-257.

Moser, V.C. (1989). Screening approaches to neurotoxicity: A functional
observational battery. J. Amer. Col. Toxicol. 8:85?94.

O'Donoghue, .L. 1989). Screening for neurotoxicity using a neurologically
based examination and neuropathology. J. Amer. Col. Toxicol. 8:97-116.

13.

14.

15.

16.

17.

18.

19.

20.

418-0272PAGE 4-7

Sokal, RR. and Rohlf, (1969). Bartlett's test of homogeneity of variances.
Biometry, W.H. Freeman and Co., San Francisco, pp. 370-371.

Snedecor, G.W. and Cochran, W.G. (1967). Analysis of Variance. Statistical
Methods, 6th Edition, Iowa State University Press, Ames, pp. 25 8?275.

Dunnett, CW. (1955). A multiple comparison procedure for comparing several
treatments with a control. J. Amer. Stat. Assoc. 50:1096?1 121.

Sokal, RR. and Rohlf, El. (1969). Kruskal?Wallis Test. Biometry,
W.H. Freeman and Co., San Francisco, pp. 388-389.

Dunn, OJ. (1964). Multiple comparisons using rank sums. Technometrics


Siegel, S. (1956). Nonparametric Statistics for the Behavioral Sciences. Fisher?s
Exact. McGraw-Hill Co., New York, pp. 96-105.

SAS Institute, Inc. (1988). Repeated measures analysis of variance. 
User's Guide, Release 6.03 Edition, Cary, NC, pp. 602-609.

Snedecor, G.W. and Cochran, W.G. (1967). Variance test for homogeneity of the
binomial distribution. Statistical Methods, 6th Edition, Iowa State University
Press, Ames, pp. 240-241.

APPENDIX A

REPORT FIGURES

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

BODY WEIGHTS - MALE RATS

 

 

 

 

Figure 1
480
460 (VEHICLE*pS0.05 .

360 
a. Last value recorded
before cohabitation.
340 b. First value recorded
after cohabitation117

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

BODY WEIGHTS - FEMALE RATS
Figure 2

 

 

 

 

 

 

 

 

 

450 . I 
0 (VEHICLE) 
400 
10 

A350 50 
9
i?
I Org.?
L9
lg 250 
300 
$1330.05 
a. Last value recorded
250 before cohabitation.

1815a 123456
DAY OF STUDY DAY OF GESTATION DAY OF LACTATION

117

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

MOTOR ACTIVITY - NUMBER OF MOVEMENTS - MALE RATS

 

 

 

 

 

 

(D



Figure 3
80
. _7
70 (VEHICLE) 
wig/x?l4100
TIME (MINUTES)



418-0271PAGE 

awn

00L

 

 

 

093



09



0L



 

Ava/swam: 

 

 

 

 

 

?7 em?gj
Siva HWVW NI EIWLL 

(66911. HESWHN AGHLS .LSEJ. SNINEEHOS
AJJOIXOJ. EIH.L HJJM [6691. J. MIOIXOJ. EISOCI GENIEWOO (ESVAVS) 


0
L0

NI (SCINOOES) EWLL

00L

09L

093

NUMBER OF MOVEMENTS

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

MOTOR ACTIVITY - NUMBER OF MOVEMENTS - FEMALE RATS

 

 

 

 

    

 

 

 

Figure 5
90
(VEHICLE100
TIME (MINUTES)



 

(samNrwSLNEWEJAOW NI (SGNOOEIS) 

 

Ava/swamOOZ

 

Ava/swam (enema/0 0

 

 

 

 

 

093

9 SJHEH
Siva .LNEWEIAOW Ell/\lLL HOLOW

(66911. .LSEJ. ONINEHHOS
MIOIXOJ. 3H.L HJJM [6691 .L :10 AJJOIXOJ. HSOCI CIEINIEWOO (ESVAVO) 5130'8 L17 

APPENDIX 

REPORT TABLES F0 GENERATION MALE RATS

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE Bl (PAGE 1): CLINICAL OBSERVATIONS - SUMMARY - FO GENERATION MALE RATS

DOSAGE GROUP I II Iv
DOSAGE 0 (VEHICLE) 10 50 250
g??/ig 

MORTALITY 0 0 0 0
EXCESS SALIVATION 0/ 0 0/ 0 0/ 0 24/ 10Hr
RED, SLIGHT PERIORAL SUBSTANCE URINE- STAINED ABDOMINAL EUR 0/ 0/ 1/ 1 14 4 
CHROMORHINORRHEA LOCALIZED ALOPECIA: LIMBS CHROMODACRYORRHEA 0 0 0 1/ 5/ 2
SOFT OR LIQUID FECES RIGHT FORELIMB: SCAB (INCISORSPENIS: RED SUBSTANCE RIGHT FORELIMB: ULCERATION 0/ 0/ 0 1/ 1

STATISTICAL ANALYSES OF CLINICAL OBSERVATION DATA WERE RESTRICTED TO THE NUMBER OF RATS WITH OBSERVATIONS.
MAXIMUM POSSIBLE INCIDENCE (DAYS OF RATS EXAMINED PER GROUP.

TOTAL NUMBER OF OF RATS WITH OBSERVATION.

Significantly different from the vehicle control group value (p50.01) .

I17



PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE B2 (PAGE 1): NECROPSY OBSERVATIONS - SUMMARY F0 GENERATION MALE RATS

DOSAGE GROUP I II Iv
DOSAGE (VEHICLE) 10 50 250
RATS EXAMINED a 15 15 15 15
MORTALITY 0 
APPEARED NORMAL 15 15 15 14
PROSTATE:

RIGHT HEMISPHERE, TAN, FIRM,

LOBULAR MASS 1

VENTRAL RIGHT SIDE, RED 1

a. Refer to the individual clinical Observations table {Table B15) for external Observations confirmed at necropsy.





PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B3 (PAGE 1): TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS - SUMMARY - FO GENERATION MALE RATS

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLE) 10 50 250
RATS TESTED 15 15 15 15
TERMINAL BODY WEIGHT 447.1 1 34.7 439.0 21.3 428.6 i 32.2 412.3 16.0**
EPIDIDYMIS LEFT 0.74 i 0.06 0.72 i 0.09 0.72 i 0.08 0.71 i 0.06
TESTIS LEFT 1.76 i 0.14 1.64 i 0.29 1.73 i 0.15 1.74 0.13
EPIDIDYMIS RIGHT 0.76 i 0.06 0.74 i 0.10 0.73 i 0.09 0:70 i 0.06
TESTIS RIGHT 1.74 i 0.14 1.72 i 0.12 1.74 i 0.15 1.75 i 0.14
BRAIN 2.31 i 0.10 2.25 i 0.12 2.36 i 0.09 2.32 i 0.16

10]a 10]a 10]a 10]a
LIVER 13.51 i 1.26 13.79 i 1.74 14.06 i 1.51 18.31 i 2.27**
KIDNEY LEFT 1.94 i 0.16 1.96 i 0.16 2.12 i 0.18* 2.16 i 0.13**

10]a 10]a 10]a 10]a
KIDNEY RIGHT 2.00 i 0.09 2.02 i 0.21 2.16 i 0.18* 2.18 i 0.13*

10]a 10}a 10]a 10]a
ADRENAL LEFT 0.030 i 0.003 0.030 i 0.005 0.029 1 0.006 0.030 i 0.007

9]a,b 10]a 103a 10]a
ADRENAL RIGHT 0.028 1 0.004 0.032 0.005 0.029 1 0.002 0.028 1 0.004

10]a 10]a 10]a 101a
SPLEEN 0.89 i 0.09 0.79 i 0.12 0.85 i 0.12 0.83 i 0.10

10]a 10]a 10]a 10]a
THYMUS 0.54 i 0.14 0.43 i 0.13 0.43 i 0.14 0.40 i 0.12

10]a 10]a 10]a 10]a
HEART 1.51 i 0.13 1.49 i 0.20 1.46 i 0.16 1.45 i 0.17

10]a 10]a 10]a 10]a

ALL WEIGHTS WERE RECORDED IN GRAMS (G).

NUMBER OF VALUES AVERAGED.

a. Results did not warrant examination of the five additional rats.

b. Excludes a value for rat 17660, which had an organ damaged (weight affected).
Significantly different from the vehicle control group value (P50.05).

Significantly different from the vehicle control group value (p50.01).

H7

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B4 (PAGE 1): RATIOS OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT - SUMMARY - F0 GENERATION MALE RATS

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLE) 10 50 250
RATS TESTED 15 15 15 15
EPIDIDYMIS LEFT 0.165 1 0.016 0.165 1 0.019 0.167 0.023 0.173 1 0.018
TESTIS LEFT 0.395 i 0.050 0.373 i 0.066 0.406 1 0.048 0.422 0.038
EPIDIDYMIS RIGHT 0.169 i 0.019 0.167 1 0.025 0.171 0.0267 0.171 1 0.017
TESTIS RIGHT 0.392 i 0.046 0.393 i 0.027 0.409 1 0.047 0.425 1 0.041
BRAIN 0.521 i 0.039 0.512 1 0.032 0.547 0.033 0.555 0.050

10]a 10]a 103a 10]a
LIVER 3.043 1 0.144 3.133 i 0.278 3.275 1 0.166** 4.434 i 0.450**
KIDNEY LEFT 0.436 0.046 0.448 1 0.043 0.493 0.056* 0.517 i 0.033**

10]a 10]a 10]a 10]a
KIDNEY RIGHT 0.451 i 0.037 0.462 1 0.051 0.501 1 0.056* 0.521 1 0.031**

10]a 10]a 10]a 10]a

ADRENAL LEFT 6.562 i 0.570 6.737 1 1.213 6.690 i 1.451 7.069 i 1.568

9]a,c 10]a 10]a 10]a
ADRENAL RIGHT 6.325 1 0.938 7.215 1 1.194 6.826 1 0.724 6.598 i 1.005

10]a 10]a 10]a 10]a
SPLEEN 0.200 i 0.027 0.178 i 0.026 0.197 1 0.033 0.197 1 0.021

10]a 10]a 10]a 10]a
THYMUS 0.122 1 0.032 0.099 1 0.030 0.099 i 0.033 0.096 1 0.029

10]a 10]a 10]a 10]a
HEART 0.341 1 0.027 0.341 i 0.038 0.338 1 0.039 0.348 i 0.042

10]a 10]a 103a 10]a
ALL WEIGHTS WERE RECORDED IN GRAMS (G). RATIOS (ORGAN BODY WEIGHT) 100.

3 NUMBER OF VALUES AVERAGED.

a. Results did not warrant examination of the five additional rats.

b. Value was multiplied by 1000.

c. Excludes a value for rat 17660, which had an organ damaged (weight affected).
Significantly different from the vehicle control group value (p50.05).

Significantly different from the vehicle control group value (p50.01).

L308 117


-

17'8 

PROTOCOL 418~027z ORAL (SAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B5 (PAGE 1): RATIOS OF ORGAN WEIGHT TO BRAIN WEIGHT - SUMMARY - F0 GENERATION MALE RATS

DOSAGE GROUP I II IV

DOSAGE 0 (VEHICLE) 10 50 250
1} if); is; gag. is; 
BRAIN WEIGHT . 2.31 i 0.10 2.25 i 0.12 2.36 i 0.09 2.32 4 0.16
EPIDIDYMIS LEFT 31.28 i 2.24 32.08 i 3.44 29.98 4 3.37 29.86 i 2.87
TESTIS LEFT 75.14 i 6.24 75.90 i 4.98 73.00 i 8.32 73.95 4 10.60
EFIDIDYMIS RIGHT 31.97 i 2.81 32.63 i 3.73 30.38 i 3.16 29.72 i 3.60
TESTIS RIGHT 74.42 i 5.96 76.90 i 3.34 72.98 i 6.85 73.87 i 9.89
LIVER 594.63 4 42.79 620.48 1 81.18 603.91 4 53.24 807.37 4123.75**
KIDNEY LEFT 83.88 i 7.32 87.59 i 7.45 90.39 i 9.47 93.84 i 9.85
KIDNEY RIGHT 86.77 i 5.89 90.12 i 9.43 91.76 i 8.79 94.73 4 10.17
ADRENAL LEFT 1.18 i 0.30 1.32 i 0.27 1.22 i 0.25 1.29 i 0.38
ADRENAL RIGHT 1.;2 :1b0.16 1.42 i 0.29 1.25 i 0.11 1.19 i 0.18
ISPLEEN 38.72 i 5.38 35.15 i 4.75 36.13 4 5.76 35.99 i 6.32
THYMUS 23.18.HEART Results did not warrant examination of the five additional rats.
b. Excludes a value for rat 17660, which had an organ damaged (weight affected).
Significantly different from the vehicle control group value (p50.01) .

I17

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE B6 (PAGE 1): HEMATOLOGY - SUMMARY FO GENERATION MALE RATS
(See last page of this table for abbreviations)

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLE) 10 50 250
E. E, 
WBC MM) 14.7 i 3.61 18.9 i 2.96 15.3 i 3.36 19.3 i 7.90
RBC MM) 7.55 i 0.493 7.56 i 0.448 7.27 i 0.291 7.17 i 0.270
HGB 15.8 i 0.26 15.6 i 0.71 15.2 i 0.40 15.1 i 0.65
HCT 43.7 i 1.82 421.88
MCV (CU MICRONS) 57.9 i 2.09 56.3 i 0.84 56.9 i 1.94 56.5 i 1.44
MCH (PICO GRAMS) 21.0 i 1.15 20.7 i 0.42 20.9 i 0.70 . 21.1 i 0.88
MCHC 36.3 i 0.97 36.8 i 0.35 361.25
PLT MM) 1197 1 122.5 1172 i 54.0 1218 i 190.7 I 1283 i 138.9
PT (SECONDS) 14.4 i 0.66 13.7 i 0.39 14.7 i 0.70 14.6 i 0.96
APTT (SECONDS) 25.4 i 1.89 25.9 i 2.33 26.2 i 2.18 I 26.7 i 2.51

 

117

9'8 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B6 (PAGE 2): HEMATOLOGY - SUMMARY F0 GENERATION MALE RATS
(See the page of this table for abbreviations)

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLEMPV (CU MICRONSNRBC COUNT - MM) 12.6 i 3.67 15.8 i 3.21 13.3 i 3.24 14.1 i 4.01
Segmented MM) 1.9 i 0.26 2.8 i 0.87 1.8 i 0.41 5.0 i 7.38
Bands MMMonocytes MM) 0.1 i 0.07 0.2 i 0.20 0.1 i 0.09 0.1 i 0.13
Eosinophil MM) 0.1 i 0.05 0.2 i 0.11 0.2 i 0.15 0.1 i 0.14
Basophils MM) 0.0 i 0.00 0.0 i 0.00 0.0 i 0.00 0.0 i 0.00
Abnormal MM) 0.0 i 0.00 0.0 i 0.00 0.0 i 0.00 0.0 i 0.00
Other MM) 0.0 i 0.00 0.0 i 0.00 0.0 i 0.00 0.0 i 0.00



PROTOCOL 418*027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY

SCREENING TEST STUDY NUMBER:

T-7599)

TABLE B6 (PAGE 3): HEMATOLOGY - SUMMARY F0 GENERATION MALE RATS

HGB
HCT
MCV
MCH
MCHC
PLAT
MPV
PT
APTT
NRBC
Segmented

Abnormal 

White Blood Cells (Leukocytes)
Red Blood Cells 
Hemoglobin

Hematocrit (Packed Cell Volume)
Mean Corpuscular Volume

Mean Corpuscular Hemoglobin
Mean Corpuscular Hemoglobin Concentration
Platelets

Mean Platelet Volume
Prothrombin Time

Activated Partial Thromboplastin
Nucleated Red Blood Cell Count
Segmented Neutrophils

Abnormal 

Other Cells

8'8 I17

PROTOCOL 418w027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B7 (PAGE 1): CLINICAL CHEMISTRY SUMMARY F0 GENERATION MALE RATS
(See last page of this table for abbreviations)

DOSAGE GROUP I II Iv
DOSAGE 0 (VEHICLECHOL TBILI 0CREAT 0108.3

611 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B7 (PAGE 2): CLINICAL CHEMISTRY - SUMMARY - F0 GENERATION MALE RATS
(See last page of this table for abbreviations)

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLE11.1 i 0.37 11.4 i 38 11 4 i 0.29 11 3 i 0 14
PHOS 80.18 2.3 i 0.01'8 I17

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B7 (PAGE 3): CLINICAL CHEMISTRY SUMMARY - F0 GENERATION MALE RATS

ABBREVATION TERMINOLOGY
TpTotalproten
A Albumin
GLU Glucose
CHOL Cholesterol
TBILI Total Bilirubin
BUN Blood Urea Nitrogen
GREAT Creatinine
ALT Alanine Aminotransferase
AST Aspartate Aminotransferase
ALK Alkaline Phosphatase
CA Calcium
PHOS Phosphorus (inorganic)
TRI Triglycerides
NA Sodium
Potassium
CL Chloride
Globulin
Albumin/Globulin Ratio



PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B8 (PAGE 1): BODY WEIGHTS - SUMMARY - F0 GENERATION MALE RATS

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLE) 10 50 250
RATS TESTED 15 15 15 15

BODY WEIGHT (G)

DAY 1 342.7 i 9.4 341.9 i 9.4 343.8 i 13.1 339.5 i 9.4
DAY 8 384.8 i 16 3 38020.1 370.6 1 11 4
DAY 15a 411.6 1 24.8 40924.4 393.5 i 13 9
DAY 29b 458.3 i 32.5 450.8 i 20.8 440.7 i 31.7 428.8 1 l3.9STUDY

a. Last value recorded before cohabitation.

b. First value recorded after cohabitation.

Significantly different from the vehicle control group value .



PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599) 7

TABLE B9 (PAGE 1): BODY WEIGHT CHANGES - SUMMARY - FO GENERATION MALE RATS

DOSAGE GROUP I II IV
DOSAGE (VEHICLE) 10 50 250
RATS TESTED 15 15 15 15

BODY WEIGHT CHANGE (G)

DAYS 1 - 8 +42.1 i 9.1 +39.0 7.5 +35.2 i 9.8 +31.1 i 
DAYS 8 - 15a +26.8 i 10.1 +28.9 i 7.6 +23.4 i 6.8 +22.9 1 6.8
DAYS 1 7 15a +68.9 i 17.8 +67.9 i 12.8 +59.6 i 12.5 +53.9 
DAYS 29b- 36 +15.9 i 6.0 +15.5 i 5.4 +15.2 i 7.1 +14.7 i 3.7
DAYS 1 - 36 +131.5i 29.6 +124.4i 21.8 +112.1i 21.2* +103.9i 13.8**

DAYS DAYS OF STUDY
a. Last value recorded before cohabitation.
b. First value recorded after cohabitation.
Significantly different from the vehicle control group value (p50.05) .
Significantly different from the vehicle control group value (1350.01).

I17

El'? 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7S99)

TABLE B10 (PAGE 1): ABSOLUTE FEED CONSUMPTION VALUES SUMMARY - F0 GENERATION MALE RATS

DOSAGE GROUP I II IV
DOSAGE (VEHICLE) 10 50 250
RATS TESTED 15 15 15 .15

FEED CONSUMPTION (G)

DAYS 1 8 27.4 i 2.0 26.2 i 1.6 25.9 i 2.4* 24.7 i 
DAYS 8 - 15a 26.3 i 2.8 25.8 i 1.6 25.5 i 2.6 24.9 i 1.9
14]b
DAYS 1 - 15a 26.9 i 2.4 26.1 i 1.4 25.7 i 2.3 24.8 i 
14]b
DAYS 36 28.3 i 2.8 27.2 i 1.9 26.8 i 2.8 26.0 i 1.6
DAYS 1 - 36 27.3 i 2.4 26.4 i 1.5 26.1 i 2.3 25.2 i 

DAYS DAYS OF STUDY
NUMBER OF VALUES AVERAGED
a. Last value recorded before cohabitation.
b. Excludes values that were associated with spillage.
First value recorded after cohabitation.
Significantly different from the vehicle control group value (930.05).
Significantly different from the vehicle control group value (p50.01).

171'8 117

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B11 (PAGE 1): RELATIVE FEED CONSUMPTION VALUES - SUMMARY FO GENERATION MALE RATS

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLE) 10 50 250
RATS TESTED 15 15 15 15

FEED CONSUMPTION (G)

DAYS 1 8 75.1 i 3 8 72.4 3 2 71.4 i 4.9* 70.0 i 
DAYS 8 - 15a 66.0 i 4 5 65.1 i 3 4 65.2 i 4.4 65.2 i 3.7
14]b
DAYS 1 - 15a 70.4 i 3 9 68.6 i 2 7 68.2 i 3.6 67.5 i 2.7
. 14]b
DAYS 29C- 36 60.6 i 3.2 59.5 i 2.8 59.9 i 4.3 59.8 i 2.6
DAYS DAYS DAYS OF STUDY
NUMBER OF VALUES AVERAGED
a. Last value recorded before cohabitation.
b. Excludes values that were associated with spillage.
c. First value recorded after cohabitation.
Significantly different from the vehicle control group value (p50.05) .
Significantly different from the vehicle control group value (p50.01) .



PROTOCOL 418*027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B12 (PAGE 1): MATING AND FERTILITY - SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLE) 10 50 250
RATS IN COHABITATION 15 15 15 15
DAYS IN COHABITATION RATS THAT MATED 14( 93.3) 15(100.0) 13( 86.7) 13( 86.7)
FERTILITY INDEX c,d 14/14 14/15 13/13 12/13
(100.0) 93.3) (100.0) 92.3)
RATS WITH CONFIRMED
MATING DATES 14 15 13 13
MATED WITH FEMALE 
DAYS 1- 7 14(100.0) 15(100.0) 13(100.0) 13(100.0)
DAYS 8-14 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0)
RATS IN
COHABITATION 14/15 14/15 13/15 12/15
93.3) 93.3) 86.7) 80.0)

Restricted to rats with a confirmed mating date and rats that did not mate.

a
b. Includes only one mating for each male rat.

c. Number of pregnancies/number of rats that mated.


8

Includes only one pregnancy for each rat that impregnated more than one female rat.

Restricted to rats with a confirmed mating date.

I17

0
I



PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE 
TOXICITY SCREENING TEST STUDY NUMBER: T-7599)

 

 

TABLE 813 (PAGE 1): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - MALE RATS

DOSAGE GROUP I II IV
DOSAGE (VEHICLE) 10 50 250
RATS 5 5 5 5

HOME CAGE BEHAVIOR

 

1: Sleeping 0 0 
2: Awake, Immobile 5 5 5 5
3: Normal movement 0 
4: Unusual posture 0 0 
5: Unusual behavior 0 0
ALTERATIONS (HOME CAGE)
1 None 5 5 5
2: Stereotyped behavior 0 
3: Bizarre behavior 0
4: Limb twitches/tremor 0
5: Whole body tremor/spasm 0 0 
6: Unusual posture 0 
7: Tonic-clonic seizure 
REACTION TO REMOVAL
Sits quietly 5 5 5 5
(2) Vocalization 0 0 0
(3) Runs or freezes 0 0 0
(4) Tail or throat rattles 0
MEAN SCORE 1.0 1.0 1.0 1.0
REACTION TO HANDLING
(1) No resistance 5 5 5 5
(2) Vocalization 0 0 0
(3) Tense 0 0 0
(4) Squirming 0 
MEAN SCORE 1.0 1.0 1.0 1.0
n: Category number for descriptive test item.
Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score

and then dividing the sum of the products by the total number of rats



PROTOCOL 418-027: ORAL (SAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE 

 

 

 

TOXICITY SCREENING TEST STUDY NUMBER: 

TABLE 1313 (PAGE 2): FUNCTIONAL OBSERVATIONAL BATTERY SUMMARY MALE RATS

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLE) 10 50 250
RATS 5 5 5 5
HEARS IN OPEN FIELD 7DEFECATION IN OPEN FIELD

1: None 5 3
2: Feces normal 4 0 
3: Soft or liquid feces 0 

URINATION IN OPEN FIELD

(1) None 0 3

(2) Normal urination 5 2

(3) Excess urination 0 

MEAN SCORE 1.8 2 1.4 1.4

LEVEL OF AROUSAL

(1) Stuporous 0
(2) Sluggish 0 0 
(3) Apparently normal 5 5 5 5
(4) Sudden darting 0 
(5) Freezing, vocalization 0 0 

MEAN SCORE ALTERATIONS (OPEN FIELD)

1: None 5 5 5 5
2: Stereotyped behavior 0 
3: Bizarre behavior 0 0 
4: Limb twitches/tremor 0 0 0
5: Whole body tremor/spasm 0 0 0
5: Unusual posture 0 0 0
7: Tonic-clonic seizure 0 0 0
n: Category number for descriptive test item.
Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score

and then dividing the sum of the products by the total number of rats
a. Excludes a value that was incorrectly recorded.

81'8 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE 
TOXICITY SCREENING TEST STUDY NUMBER: T-7599)

TABLE B13 (PAGE 3): FUNCTIONAL OBSERVATIONAL BATTERY SUMMARY MALE RATS

 

 

DOSAGE GROUP I II IV
DOSAGE (VEHICLE) 10 50 250
RATS 5 5 5 5

GAIT PATTERN

 

1: Apparently normal 5 5 5 5
2: Ataxic 0 
3: Limbs splay or drag 0 0 0 
4: Spastic, tip?toe 0 0 0
5: Duck?walk 0 
6: Scissors gait 0 0 0
GAIT ABNORMALITY, SEVERI TY
(1) Normal gait 5 5 5 5
(2) Slight 0 0 
(3) Moderate 0 0 
(4) Extreme 0 0 0
MEAN SCORE 1.0 1.0 1.0 1.0
PALPEBRAL CLOSURE
(1) Wide open 5 5 5 5
(2) drooping 0
(3) Half?closed 0 0 0 
(4) Completely shut 0 0
MEAN SCORE 1.0 1.0 1.0 1.0
PROMINENCE OF THE EYE
1: Normal 5 5 5 5
2: Exophthalmos 0 0
3: Enophthalmos 0 0 0
n: Category number for descriptive test item.
Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score

and then dividing the sum of the products by the total number of rats

61'8 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE 
TOXICITY SCREENING TEST STUDY NUMBER: T-7599)

 

 

 

TABLE B13 (PAGE 4) FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY MALE RATS
DOSAGE GROUP I II IV
DOSAGE (VEHICLE) 10 50 250
RATS 5 5 5 5
LACRIMATION
(1) No excess 5 5 5 5
(2) Excess at eyelid margin 0 
(3) Margin persistently damp 0 0
(4) Extends beyond margin 0 0 0
MEAN SCORE 1.0 1.0 1.0 1.0
SALIVATION
(1) No excess 5 5 5 5
(2) Margin of mouth wet 0 0 0
(3) 1/4 to 1/2 submandibular 0 0 
(4) Entire submandibular 0
MEAN SCORE 1.0 1.0 1.0 1.0
PILOERECTION 0 0 0
ABNORMAL RESPIRATION 0 0 0
APPEARANCE
(1) Clean and groomed 5 5 5
(2) Unkempt 0 0 0 0
(3) Urine and/or fecal stain 0 0 0
MEAN SCORE 1.0 1.0 1.0 1.0
VISUAL REACTION
(1) None 0 0 
(2) Orienting 5 5 5 5
(3) Startle 0 0 0
(4) More energetic reaction 0 0 
(5) Attacks 0 0 0 0
MEAN SCORE 2.0 2.0 2.0 2.0
n: Category number for descriptive test item. .
Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score

and then dividing the sum of the products by the total number of rats



PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE 
TOXICITY SCREENING TEST STUDY NUMBER: T-7599)

 

 

 

TABLE 313 (PAGE 5): FUNCTIONAL OBSERVATIONAL BATTERY SUMMARY MALE RATS
DOSAGE GROUP DOSAGE 0 (VEHICLE) 10 50 250
RATS 5 5 5 
TACTILE REACTION
(1) None 
(2) Orienting 5 5 5 5
(3) Startle 0 0 0 0
(4) More energetic reaction 0 0 
(5) Attacks 0 0 0
MEAN SCORE 2.0 2.0 2.0 2.0
AUDITORY REACTION
(1) None 0 0 0
(2) Orienting 0 0 0
(3) Startle 5 5 5 5
(4) More energetic reaction 0 0 0
(5) Intense vocalization 0 0 
MEAN SCORE 3.0 3.0 3.0 3.0
TAIL-PINCH REACTION
(1) None 
(2) Orienting 5 5 5 5
(3) Startle 0 0 0
(4) More energetic reaction 0 
(5) Attacks 0 0 0
MEAN SCORE 2.0 2.0 2.0 2.0
VISUAL PLACING RESPONSE
(1) Early extension 5 5
(2) Extension after contact 0 
(3) No extension 0 
MEAN SCORE 1.0 1.0 1.0 1.0
n: Category number for descriptive test item.
Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score

and then dividing the sum of the products by the total number of rats



PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE 
TOXICITY SCREENING TEST STUDY NUMBER: T-7599)

 

 

TABLE 313 (PAGE 6): FUNCTIONAL OBSERVATIONAL BATTERY SUMMARY MALE RATS

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLE) 10 50 250
RATS 5 5 5 5

AIR RIGHTING RESPONSE

(1) All feet land on ground 5 5 5

(2) Lands on side 0 0

(3) Lands on back 0 0 0 0
MEAN SCORE 1.0 1.0 1.0 1.0

PUPIL RESPONSE TO LIGHT 5 5 5 5

FORELIMB GRIP TEST

 

Maximum (G) 375.0 1 120.9 423.0 1 55.0 404.0 1 110.4 293.0 1 114.2
Average (G) 337.6 1 112.8 393.4 1 50.4 329.0 i 98.1 275.4 1- 105.8
HINDLIMB GRIP TEST
Maximum (G) 387.0 i 123.0 341.0 1 66.8 420.0 1 99.7 354.0 1 104.0
Average (G) 355.0 1 105.3 309.0 1 55.1 382.8 1 96.0 315.0 1 97.8
LANDING FOOT SPLAY
Average (CMBODY WEIGHT (G) 464.6 1 37.3 457.5 i 19.9 438.6 i 28.4 422.4 1 12.3
n: Category number for descriptive test item.
Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score

and then dividing the sum of the products by the total number of rats




0



PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B14 (PAGE 1): MOTOR ACTIVITY - SUMMARY F0 GENERATION MALE RATS

 

 

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLE) 10 50 250
DAY 86

NUMBER OF RATS 5 5 5 5

NUMBER OF MOVEMENTS

BLOCK 1 MEAN 1 S.D. 65.4 1 9.9 67.0 1 10.0 64.0 1 4.1 65.6 1 5.3
BLOCK 2 MEAN 1 S.D. 72.0 1 7.6 67.8 1 9.0 63.2 1 15.3 72.2 1 12.2
BLOCK 3 MEAN 1 S.D. 69.8 1 4.1 70.4 1 15.1 66.8 1 11.6 62.0 1 9.0
BLOCK 4 MEAN 1 S.D. 58.0 1 18.9 62.4 1 14.6 54.6 1 14.5 61.2 1 10.8
BLOCK 5 MEAN 1 S.D. 29.8 1 29.2 63.4 1 19.9 42.8 1 30.9 25.6 1 29.2
BLOCK 6 MEAN 1 S.D. 31.2 1 28.8 51.6 1 30.9 28.4 1 24.5 16.0 1 22.4
BLOCK 7 MEAN 1 S.D. 35.0 1 35.3 41.4 1 28.8 22.4 1 29.7 10.8 1 21.4
BLOCK 8 MEAN 1 S.D. 44.8 1 27.6 50.2 1 31.9 25.4 1 22.4 8.2 1 13.1
BLOCK 9 MEAN 1 S.D. 35.0 1 34.2 41.4 1 23.7 32.2 1 31.3 1.4 1 1.7
BLOCK 10 MEAN 1 S.D. 18.8 1 23.7 36.4 1 30.2 44.4 1 27.2 10.8 1 20.9
BLOCK 11 MEAN 1 S.D. 20.0 1 27.0 33.0 1 22.8 35.8 1 31.7 25.0 1 24.2
BLOCK 12 MEAN 1 S.D. 31.8 1 38.6 24.6 1 19.5 22.4 1 22.3 22.6 1 27.8
BLOCK 13 MEAN 1 S.D. 26.0 1 31.5 22.8 1 29.9 19.4 1 27.6 7.4 1 7.7
BLOCK 14 MEAN 1 S.D. 14.8 1 25.5 27.2 1 26.2 19.8 1 24.1 3.8 1 6.3
BLOCK 15 MEAN 1 S.D. 11.2 1 21.8 18.6 1 24.3 15.4 1 23.9 8.0 1 12.5
BLOCK 16 MEAN 1 S.D. 14.8 1 22.6 18.0 1 21.1 22.0 1 21.0 16.2 1 24.2
BLOCK 17 MEAN 1 S.D. 13.8 1 25.9 4.8 1 5.3 13.4 1 23.0 3.8 1 6.9
BLOCK 18 MEAN 1 S.D. 12.4 1 23.9 3.8 1 5.0 7.6 1 14.8 3.4 1 4.7
TOTAL MEAN 1 S.D. 604.6 1 292.0 704.8 1 280.9 600.0 1 120.2 425.0 1 91.8

 

TOTAL SUM OF EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.





PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE 314 (PAGE 2): MOTOR ACTIVITY SUMMARY F0 GENERATION MALE RATS

 

 

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLE) 10 50 250
DAY 86

NUMBER OF RATS 5 5 5 5

TIME (SECONDS) SPENT IN MOVEMENT

BLOCK 1 MEAN 1 S.D. 178.6 1 20.7 204.8 1 16.2 188.4 1 19.3 179.6 1 22.4
BLOCK 2 MEAN 1 S.D. 170.8 1 18.0 167.4 1 10.1 135.0 1 31.2 152.6 1 29.4
BLOCK 3 MEAN 1 S.D. 140.8 1 42.6 140.2 1 23.4 123.4 1 20.5 111.6 1 23.8
BLOCK 4 MEAN 1 S.D. 77.8 1 18.5 101.8 1 22.4 101.6 1 30.8 109.2 1 52.2
BLOCK 5 MEAN 1 S.D. 41.8 1 54.5 101.4 1 39.2 56.2 1 43.7 32.2 1 38.2
BLOCK 6 MEAN 1 S.D. 51.0 1 62.5 85.4 1 50.9 33.2 1 28.1 24.0 1 45.5
BLOCK 7 MEAN 1 S.D. 45.2 1 49.3 66.4 1 61.9 33.4 1 50.3 13.6 1 30.4
BLOCK 8 MEAN 1 S.D. 64.8 1 43.6 70.4 1 48.2 26.8 1 31.0 5.0 1 9.1
BLOCK 9 MEAN 1 S.D. 56.4 1 59.5 75.0 1 46.2 38.2 1 39.3 0.6 1 0.9
BLOCK 10 MEAN 1 S.D. 27.8 1 47.1 47.0 1 39.9 72.6 1 55.4 14.2 1 28.0
BLOCK 11 MEAN 1 S.D. 30.6 1 42.4 40.0 1 36.4 60.4 1 64.3 32.8 1 34.1
BLOCK 12 MEAN 1 S.D. 39.6 1 52.6 35.8 1 35.6 26.2 1 27.9 30.6 1 43.0
BLOCK 13 MEAN 1 S.D. 35.6 1 47.6 30.0 1 39.9 21.8 1 31.0 5.8 1 8.0
BLOCK 14 MEAN 1 S.D. 24.2 1 49.7 27.8 1 28.4 22.6 1 30.9 2.2 1 4.9
BLOCK 15 MEAN 1 S.D. 20.4 1 45.6 20.2 1 29.9 19.4 1 34.8 6.6 1 11.3
BLOCK 16 MEAN 1 S.D. 21.8 1 43.8 22.2 1 30.4 26.4 1 28.4 28.0 1 40.6
BLOCK 17 MEAN 1 S.D. 17.2 1 37.4 4.0 1 6.2 20.0 1 36.4 4.0 1 8.9
BLOCK 18 MEAN 1 S.D. 14.8 1 32.0 2.6 1 4.3 12.2 1 26.2 1.2 1 2.7
TOTAL MEAN 1 S.D. 1059.2 1 547.0 1242.4 1 381.5 1017.8 1 181.4 753.8 1 146.0

 

TOTAL SUM OF BLOCKS: EACK BLOCK CONSISTS OF A 5 MINUTE PERIOD.





PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B15 (PAGE 1): CLINICAL OBSERVATIONS INDIVIDUAL DATA - F0 GENERATION MALE RATS

DOSAGE GROUP I VEHICLE 0 (VEHICLE) 
RAT DESCRIPTION
17601 NO ADVERSE FINDINGS
17602 NO ADVERSE FINDINGS
17603 35 CHROMORHINORRHEA
17604 NO ADVERSE FINDINGS
17607 NO ADVERSE FINDINGS
17608 NO ADVERSE FINDINGS
17618 NO ADVERSE FINDINGS
17630 NO ADVERSE FINDINGS
17631 11 SOFT OR LIQUID FECES
17639 14- 15) SOFT OR LIQUID FECES
34 CHROMORHINORRHEA
17648 NO ADVERSE FINDINGS
17652 NO ADVERSE FINDINGS
17656 NO ADVERSE FINDINGS
17658 NO ADVERSE FINDINGS
17660 34? 35) CHROMORHINORRHEA



PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B15 (PAGE 2): CLINICAL OBSERVATIONS - INDIVIDUAL DATA F0 GENERATION MALE RATS

DOSAGE GROUP II LOW DOSAGE 10 
RAT DESCRIPTION
17615 34 PENIS: RED SUBSTANCE
17616 34- 35) CHROMORHINORRHEA
17624 NO ADVERSE FINDINGS
17626 NO ADVERSE FINDINGS
17632 NO ADVERSE FINDINGS
17634 14 CHROMORHINORRHEA

35 CHROMORHINORRHEA
17635 NO ADVERSE FINDINGS
17638 NO ADVERSE FINDINGS
17642 NO ADVERSE FINDINGS
17643 14 CHROMORHINORRHEA
17645 10 SOFT OR LIQUID FECES

14 SOFT OR LIQUID FECES
17649 NO ADVERSE FINDINGS
17651 15 SOFT OR LIQUID FECES
17653 14 CHROMORHINORRHEA
17655 NO ADVERSE FINDINGS

93?8 

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599. 7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T- 7599)

TABLE B15 (PAGE 3): CLINICAL OBSERVATIONS - INDIVIDUAL DATA - F0 GENERATION MALE RATS

DOSAGE GROUP MIDDLE DOSAGE 50 
RAT DESCRIPTION
17605 NO ADVERSE FINDINGS
17610 14 CHROMORHINORRHEA
16 URINE-STAINED ABDOMINAL FUR
27 CHROMORHINORRHEA
17611 NO ADVERSE FINDINGS
17613 NO ADVERSE FINDINGS
17619 NO ADVERSE FINDINGS
17620 NO ADVERSE FINDINGS
17623 NO ADVERSE FINDINGS
17627 23 CHROMODACRYORRHEA
23 INCISORS: 
17628 10 PENIS: RED SUBSTANCE
17633 NO ADVERSE FINDINGS
17640 NO ADVERSE FINDINGS
17646 32- 37) LOCALIZED ALOPECIA: LIMBS a
17650 NO ADVERSE FINDINGS
17657 NO ADVERSE FINDINGS
17659 NO ADVERSE FINDINGS

DS DAY OF STUDY
a. Observation confirmed at necropsy.








PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B15 (PAGE 4): CLINICAL OBSERVATIONS - INDIVIDUAL DATA - F0 GENERATION MALE RATS

DOSAGE GROUP IV HIGH DOSAGE 250 
RAT DESCRIPTION
17606 10 EXCESS SALIVATION
12- 13) SALIVATION
17 RED, SLIGHT PERIORAL SUBSTANCE
23 EXCESS SALIVATION
30- 31) EXCESS SALIVATION
33 EXCESS SALIVATION
17609 12 CHROMORHINORRHEA
12- 13) CHROMODACRYORRHEA
14 CHROMORHINORRHEA
14- 22) INCISORS: 
16? 17) CHROMODACRYORRHEA
32 EXCESS SALIVATION
17612 30 RED, SLIGHT PERIORAL SUBSTANCE
35 PENIS: RED SUBSTANCE
17614 14? 15) CHROMORHINORRHEA
29 RED, SLIGHT PERIORAL SUBSTANCE
17617 1 EXCESS SALIVATION
14 RED, SLIGHT PERIORAL SUBSTANCE
14 URINE-STAINED ABDOMINAL FUR




16 RED, SLIGHT PERIORAL SUBSTANCE




29 EXCESS SALIVATION
32 EXCESS SALIVATION
37 URINE-STAINED ABDOMINAL FUR

83'8 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE B15 (PAGE 5): CLINICAL OBSERVATIONS - INDIVIDUAL DATA - F0 GENERATION MALE RATS

RED, SLIGHT PERIORAL SUBSTANCE
RED, SLIGHT PERIORAL SUBSTANCE
31 EXCESS SALIVATION





35 EXCESS SALIVATION
17622 16? 17 RED, SLIGHT PERIORAL SUBSTANCE
23- 31) RIGHT FORELIMB: (DID NOT EXCEED 2.5 CM 0.5 CM)
32 RIGHT FORELIMB: ULCERATION (1.0 CM IN DIAMETER)
32 RED, SLIGHT PERIORAL SUBSTANCE
33- 37) RIGHT FORELIMB: (DID NOT EXCEED 1.0 CM IN 
37 CHROMODACRYORRHEA a
37 LOCALIZED ALOPECIA: LIMBS a
17625 32 RED, SLIGHT PERIORAL SUBSTANCE
17629 6- 7) CHROMORHINORRHEA
14 URINE-STAINED ABDOMINAL FUR
19 RED, SLIGHT PERIORAL SUBSTANCE
24 RED, SLIGHT PERIORAL SUBSTANCE
30 EXCESS SALIVATIQN
31~ 35) URINE-STAINED ABDOMINAL FUR
37 URINE-STAINED ABDOMINAL FUR
17636 14 EXCESS SALIVATION
37 URINE-STAINED ABDOMINAL FUR
17637 15 EXCESS SALIVATION
17641 11 EXCESS SALIVATION
15 EXCESS SALIVATION
23- 37) LOCALIZED ALOPECIA: LIMBS a
31 EXCESS SALIVATION
33- 34) EXCESS SALIVATION
17644 17 RED, SLIGHT PERIORAL SUBSTANCE
32- 35) ABDOMINAL FUR
17647 3 SOFT OR LIQUID FECES

EXCESS SALIVATION
EXCESS SALIVATION
17654 3 SOFT OR LIQUID FECES
EXCESS SALIVATION
RED, SLIGHT PERIORAL SUBSTANCE
DS DAY OF STUDY
a. Observation confirmed at necropsy.



.


63'8 

PROTOCOL 418~027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B16 (PAGE 1): NECROPSY OBSERVATIONS - INDIVIDUAL DATA - F0 GENERATION MALE RATS

DOSAGE GROUP RAT DAY OF DOSES
DOSAGE NUMBER NECROPSY ADMINISTERED OBSERVATIONS a
I
0 (VEHICLE) 17601 DS 37 36 ALL TISSUES.APPEARED NORMAL.
17602 DS 37 36 ALL TISSUES APPEARED NORMAL.
17603 DS 37 36 ALL TISSUES APPEARED NORMAL.
17604 DS 37 36 ALL TISSUES APPEARED NORMAL.
17607 DS 37 36 ALL TISSUES APPEARED NORMAL.
17608 DS 37 36 ALL TISSUES APPEARED NORMAL.
17618 DS 37 36 ALL TISSUES APPEARED NORMAL.
17630 DS 37 36 ALL TISSUES APPEARED NORMAL.
17631 DS 37 36 ALL TISSUES APPEARED NORMAL.
17639 DS 37 36 ALL TISSUES APPEARED NORMAL.
17648 DS 37 36 ALL TISSUES APPEARED NORMAL.
17652 DS 37 36 ALL TISSUES APPEARED NORMAL.
17656 DS 37 36 ALL TISSUES APPEARED NORMAL.
17658 DS 37 36 ALL TISSUES APPEARED NORMAL.
17660 DS 37 36 ALL TISSUES APPEARED NORMAL.

DS DAY OF STUDY
3.. Refer to the individual clinical observations table (Table 3315) for external observations confirmed at necropsy.






098 

PROTOCOL 418-027:

TABLE B16 (PAGE 2):

DOSAGE GROUP
DOSAGE 

DAY OF STUDY

ORAL (GAVAGE)

COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER:

DAY

NECROPSY OBSERVATIONS 

OF

INDIVIDUAL DATA -

DOSES

NECROPSY ADMINISTERED



F0 GENERATION MALE RATS

TISSUES
TISSUES
TISSUES
TISSUES
TISSUES
TISSUES
TISSUES
TISSUES
TISSUES
TISSUES
TISSUES
TISSUES
TISSUES
TISSUES
TISSUES

APPEARED
APPEARED
APPEARED
APPEARED
APPEARED
APPEARED
APPEARED
APPEARED
APPEARED
APPEARED
APPEARED
APPEARED
APPEARED
APPEARED
APPEARED

Refer to the individual clinical observations table (Table B15) for external observations confirmed at necropsy.

117

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST (SPONSORTS STUDY NUMBER: 

TABLE B16 (PAGE 3): NECROPSY OBSERVATIONS - INDIVIDUAL DATA - FO GENERATION MALE RATS

DS DAY OF STUDY

a. Refer to the individual clinical observations table (Table B15) for external observations confirmed at necrOpsy.

DOSAGE GROUP RAT DAY OF DOSES
DOSAGE NUMBER NECROPSY ADMINISTERED OBSERVATIONS a

50 17605 DS 37 36 ALL TISSUES APPEARED NORMAL
17610 DS 37 36 ALL TISSUES APPEARED NORMAL
17611 DS 37 36 ALL TISSUES APPEARED NORMAL
17613 DS 37 36 ALL TISSUES APPEARED NORMAL
17619 DS 37 36 ALL TISSUES APPEARED NORMAL
17620 DS 37 36 ALL TISSUES APPEARED NORMAL
17623 DS 37 36 ALL TISSUES APPEARED NORMAL
17627 DS 37 36 ALL TISSUES APPEARED NORMAL
17628 DS 37 36 ALL TISSUES APPEARED NORMAL
17633 DS 37 36 ALL TISSUES APPEARED NORMAL
17640 DS 37 36 ALL TISSUES APPEARED NORMAL
17646 DS 37 36 ALL TISSUES APPEARED NORMAL
17650 DS 37 36 ALL TISSUES APPEARED NORMAL
17657 DS 37 36 ALL TISSUES APPEARED NORMAL.
17659 DS 37 36 ALL TISSUES APPEARED NORMAL.

H7

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B16 (PAGE 4): NECROPSY OBSERVATIONS INDIVIDUAL DATA - FO GENERATION MALE RATS

DOSAGE GROUP RAT DAY OF DOSES
DOSAGE NUMBER NECROPSY ADMINISTERED OBSERVATIONS a
IV
250 17606 DS 37 36 ALL TISSUES APPEARED NORMAL.

17609 DS 37 36 ALL TISSUES APPEARED NORMAL.

17612 DS 37 36 ALL TISSUES APPEARED NORMAL.

17614 DS 37 36 ALL TISSUES APPEARED NORMAL.

17617 DS 37 36 ALL TISSUES APPEARED NORMAL.

17621 DS 37 36 ALL TISSUES APPEARED NORMAL.

17522 DS 37 36 ALL TISSUES APPEARED NORMAL.

17625 DS 37 36 ALL TISSUES APPEARED NORMAL.

17629 DS 37 36 ALL TISSUES APPEARED NORMAL.

17636 DS 37 36 PROSTATE: RIGHT HEMISPHERE, TAN, FIRM, LOBULAR MASS
{2.8 CM 0.9 CM 0.7 CM), CUT SURFACE REVEALED A TAN, SMOOTH
VENTRAL RIGHT SIDE, RED.
ALL OTHER TISSUES APPEARED NORMAL.

17637 DS 37 36 ALL TISSUES APPEARED NORMAL.

17641 DS 37 36 ALL TISSUES APPEARED NORMAL.

17644 DS 37 36 ALL TISSUES APPEARED NORMAL.

17647 DS 37 36 ALL TISSUES APPEARED NORMAL.

17654 DS 37 36 ALL TISSUES APPEARED NORMAL.

DS DAY OF STUDY
a. Refer to the individual clinical observations table (Table B15) for external observations confirmed at necropsy.



PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B17 (PAGE 1): TERMINAL BODY WEIGHTS, ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT -
INDIVIDUAL DATA - F0 GENERATION MALE RATS

DOSAGE GROUP I VEHICLE 0 (VEHICLE) 
EPIDIDYMIS TESTIS EPIDIDYMIS TESTIS BRAIN LIVER

RAT TERMINAL BODY LEFT LEFT RIGHT RIGHT

NUMBER WEIGHT ABS. REL. ABS. REL. ABS. REL. ABSTBW

17601 439 0 82 0.19 1 70 0.39 0 79 0.2.82
17602 512 0.80 0.16 1.76 0.34 0 82 0.3.04
17603 446 0.74 0.16 1.80 0.40 0 76 0.3.11
17604 433 0.80 0.18 1.96 0.45 0.82 0.2.74
17607 418 0 73 0.17 1.78 0.42 0 81 0.19 1 73 41 12 97 3.10
17608 469 0.84 0.18 1.77 0.38 0 88 0.19 1 72 0 37 2.42 0.52 14 64 3.12
17618 422 0.71 0.17 1.69 0.40 0 76 0.18 1.61 0 38 2.32 0.55 13 24 3.14
17630 448 0.75 0.17 1.80 0.40 0 78 0.17 1 79 0.40 2.39 0.53 13 82 3.08
17631 439 0.67 0.15 1.68 0.38 0 64 0.14 1.78 0.40 2.28 0.52 13 55 3.09
17639 483 0.69 0.14 1.51 0.31 0 70 0.14 1.50 0 31 2.12 0.44 14 04 2.91
17648 415 0.77 0.18 1.87 0.45 0.81 0.20 1.90 0 46 2.23 0.54 11 97 2.88
17652 520 0.72 0.14 1.68 0.32 0.75 0.14 1 71 0 33 2.46 0.47 16 55 3.18
17656 428 0.71 0 16 2.02 0.47 0.69 0.16 1.92 0 45 2.36 0.55 13 25 3.10
17658 433 0.63 0.14 1.51 0.35 0.70 0.16 1.50 0 35 2.25 0.52 13 27 3.06
17660 401 0.74 0.18 1 84 0.46 0.68 0.17 1.77 0 44 2 29 0.57 13 17 3.28

ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN BODY WEIGHT) 100.



.


1788 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: TM7599)

TABLE B17 (PAGE 2): TERMINAL BODY WEIGHTS, ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT 
INDIVIDUAL DATA - F0 GENERATION MALE RATS

DOSAGE GROUP I VEHICLE 0 (VEHICLE) 
KIDNEY KIDNEY ADRENAL ADRENAL SPLEEN THYMUS

RAT TERMINAL BODY LEFT RIGHT LEFT RIGHT

NUMBER WEIGHT ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. RELTBW

17608 469 2.06 0.44 2.11 0.45 0.033 7.04 0 032 6.82 77 0.16 0.53 0.11
17618 422 2.09 0.50 2.02 0.48 0.031 7.34 0 034 8.06 0 87 0.21 0.49 0.12
17630 448 1.98 0.44 2.03 0.45 0.032 7.14 0 026 5.80 0.81 0.18 0.34 0.08
17631 439 1.81 0.41 1.92 0.44 0.027 6.15 0 029 6.60 1.01 0.23 0.59 0 13
17639 483 2.02 0.42 2.10 0.43 0.027 5.59 0 026 5.38 1 02 0.21 0.71 0 15
17648 415 1.89 0.46 2.00 0.48 0.025 6.02 0 030 7.23 0.84 0.20 0.50 0 12
17652 520 2.04 0.39 1.97 0.38 0.034 6.54 0 029 5.58 0.85 0.16 0.56 0 11
17656 428 1.69 0.39 1.84 0.43 0.028 6.54 0 024 5.61 0 86 0.20 0.35 0 08
17658 433 1.69 0.39 1.94 0.45 0.029 6.70 0 030 6.93 1 02 0.24 0.82 0 19
17660 401 2.10 0.52 2.09 0.52 0.008b 2.00b 0 021 5.24 0 86 0.21 0.54 0 13

ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN BODY WEIGHT) 100.

a. Value was multiplied by 1000.
b. Damaged during processing (weight affected); values excluded from group averages and statistical analyses.

I17

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B17 (PAGE 3): TERMINAL BODY WEIGHTS, ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT -
INDIVIDUAL DATA - F0 GENERATION MALE RATS

DOSAGE GROUP I VEHICLE 0 (VEHICLE) 
HEART
RAT TERMINAL BODY
NUMBER WEIGHT ABS. REL.
WT TBW
17608 469 1.46 0.31
17618 422 1.43 0.34
17630 448 1.51 0.34
17631 439 1.61 0.37
17639 483 1.63 0.34
17648 415 1.66 0.40
17652 520 1.64 0.32
17656 428 1.36 0.32
17658 433 1.52 0.35
17660 401 1.28 0.32
ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN BODY WEIGHT) 100.

H7

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B17 (PAGE 4): TERMINAL BODY WEIGHTS, ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT -
INDIVIDUAL DATA - F0 GENERATION MALE RATS

DOSAGE GROUP II LOW DOSAGE 10 
EPIDIDYMIS TESTIS EPIDIDYMIS TESTIS BRAIN LIVER

RAT TERMINAL BODY LEFT LEFT RIGHT RIGHT

NUMBER WEIGHT ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. RELTBW

17615 424 0 66 0.16 1.76 0.42 0 70 0.17616 437 0 83 0.19 1.71 0.39 0 91 0.21 73 0 40 14.57 3 33
17624 417 0.65 0.16 0.69 0.16 0 68 0.17626 456 0 74 0 16 1.68 0.37 0 69 0.3.18
17632 457 0 68 0 15 1.76 0.38 0 71 0.2.98
17634 433 0.64 0.15 1.51 0.35 0 70 0.16 1 60 0 37 2.29 0.53 13 01 3 00
17635 440 0 83 0.19 1.69 0.38 0 87 0.20 1 80 0 41 2.31 0.52 14 06 3 20
17638 452 0.80 0.18 1.88 0.42 0 79 0.17 1 88 0.42 2.45 0.54 14 20 3 14
17642 413 0.72 0.17 1.70 0.41 0.76 0.18 1 72 0.42 2.21 0.54 12 00 2 90
17643 494 0.79 0.16 1 86 0.38 0.80 0.16 1 84 0.37 2.26 0.46 18 47 3 74
17645 440 0.90 0.20 1.91 0.43 0.86 0.20 1.91 0.43 2.40 0.54 16 04 3 64
17649 440 0.57 0.13 1.47 0.33 0.59 0.13 1.47 0.33 2.02 0.46 12 55 2 85
17651 434 0.69 0.16 1.58 0.36 0.68 0.16 1 68 0.39 2.20 0.51 11 98 2 76
17653 442 0.60 0.14 1.76 0.40 0.55 0.12 1 70 0.38 2.18 0.49 14 34 3 24
17655 406 0.69 0.17 1.70 0.42 0 75 0.18 1 69 0.42 2.15 0.53 12 82 3 16

ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN BODY WEIGHT) 100.

813741308117

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
7 SCREENING TEST STUDY NUMBER: Tw7599)

TABLE B17 (PAGE 5): TERMINAL BODY WEIGHTS, ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT 
INDIVIDUAL DATA - F0 GENERATION MALE RATS

DOSAGE GROUP II LOW DOSAGE 10 
KIDNEY KIDNEY ADRENAL ADRENAL SPLEEN THYMUS

RAT TERMINAL BODY LEFT RIGHT LEFT RIGHT

NUMBER WEIGHT ABS. REL. ABS. REL. ABSWT. TBW WT. TBW

17634 433 1.97 0.45 1.89 0.0.69 0.16 0.53 0.12
17635 440 2.10 0.48 2.21 0.0.84 0.19 0.61 0.14
17638 452 1.87 0.41 1.97 0.44 0 029 6.42 0 032 7 08 0.75 0.16 0.53 0.12
17642 413 1.82 0.44 1.89 0.46 0 026 6.30 0 032 7 75 0.85 0.20 0.48 0.12
17643 494 2.10 0 42 2.26 0.46 0 028 5.67 0 034 6 88 0.94 0.19 0.53 0.11
17645 440 2.14 0.49 2.14 0.49 0 026 5.91 0 029 6.59 0.99 0.22 0.37 0.08
17649 440 1.83 0.42 1.81 0.41 0 037 8 41 0 041 9.32 0.58 0.13 0.24 0.05
17651 434 1.72 0.40 1.78 0.41 0 038 8.76 0 040 9.22 0.70 0.16 0.24 0.06
17653 442 1.91 0.43 1.90 0.43 0 022 4.98 0 027 6.11 0.74 0.17 0.36 0.08
17655 406 2.19 0 54 2.37 0.0.83 0.20 0.45 0.11

ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN BODY WEIGHT) 100.

a. Value was multiplied by 1000.

898 117

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B17 (PAGE 6): TERMINAL BODY WEIGHTS, ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT -
INDIVIDUAL DATA - F0 GENERATION MALE RATS

DOSAGE GROUP II LOW DOSAGE 10 
HEART
RAT TERMINAL BODY
NUMBER WEIGHT ABS. REL.
WT TBW
17634 433 1.59 0.37
17635 440 1.40 0.32
17638 452 1.57 0.35
17642 413 1.37 0.33
17643 494 1.82 0.37
17645 440 1.72 0.39
17649 440 1.28 0.29
17651 434 1.56 0.36
17653 442 1.18 0.27
17655 406 1.45 0.36
ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN BODY WEIGHT) 100.

I17

.
I

65?8 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599. 7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T- 7599)

TABLE B17 (PAGE 7): TERMINAL BODY WEIGHTS, ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT -
INDIVIDUAL DATA - FO GENERATION MALE RATS

DOSAGE GROUP MIDDLE DOSAGE 50 
EPIDIDYMIS TESTIS EPIDIDYMIS TESTIS BRAIN LIVER

RAT TERMINAL BODY LEFT LEFT RIGHT RIGHT

NUMBER WEIGHT ABS. REL.I ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. RELTBW

17605 392 0 73 0.19 1.66 0.42 0 75 0.19 1.62 0 41 12 49 3.19
17610 467 0.74 0.16 1.73 0.37 0 71 0.15 1.77 0 38 15 99 3.42
17611 422 0.64 0.15 1 65 0.39 0.64 0.15 1.67 0 40 12 49 2.96
17613 411 0.92 0.22 1.94 0.47 0 97 0.3.16
17619 410 0.70 0.17 1.88 0.46 76 0.18 1.82 0.44 14 61 3.56
17620 475 0.70 0.15 1.63 0.34 0 65 0.14 1.67 0.35 2.48 0.52 16 22 3.41
17623 426 0.70 0.16 1.64 0.38 0 71 0.17 1.64 0 38 2 46 0.58 13 91 3.26
17627 415 0 67 0.16 1 61 0.0.40 2.39 0.58 12 79 3.08
17628 389 0 80 0.20 86 0.48 0.80 0 20 1 77 0.46 2.24 0.58 12 94 3.33
17633 484 0.74 0.15 1 94 0.40 0.74 0.15 1.92 0.40 2 38 0.49 16 89 3.49
17640 398 0.69 0.17 1 76 0.44 0.72 0.18 1.82 0 46 2 21 0.56 12 58 3.16
17646 423 0.64 0.15 1.66 0.39 0.0.54 13 15 3.11
17650 482 0.73 0.15 1.58 0.33 0.0.50 15 87 3.29
17657 417 0.57 0.14 1.49 0.36 0.62 0 15 1.54 0 37 2 34 0.56 13 85 3.32
17659 418 0 81 0 19 1.98 0.47 0 80 19 1.88 0 45 2 34 0.56 14 18 3.39

ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN BODY WEIGHT) 100.

0178 117

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST (SPONSORTS STUDY NUMBER: 

TABLE B17 (PAGE 8): TERMINAL BODY WEIGHTS, ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT 
INDIVIDUAL DATA F0 GENERATION MALE RATS

DOSAGE GROUP MIDDLE DOSAGE 50 
KIDNEY KIDNEY ADRENAL ADRENAL SPLEEN THYMUS

RAT TERMINAL BODY LEFT RIGHT LEFT RIGHT

NUMBER WEIGHT ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. RELTBW

17620 475 2.30 0.48 2.37 0.50 0 027 5.68 0 026 5.47 0.83 0.17 0.24 0 05
17623 426 2.00 0.47 2.09 0 49 0 029 6.81 0 031 7.28 0.68 0.16 0.62 0.14
17627 415 1.82 0.44 1.92 0.46 0 035 8.43 0 033 7.95 0.77 0.18 0.49 0.12
17628 389 2.30 0.59 2.29 0.59 0 032 8.23 0 030 7.71 1.05 0.27 0.23 0 06
17633 484 2 36 0.49 2.37 0 49 0 033 6.82 0 031 6.40 1.02 0 21 0.55 0 11
17640 398 2.26 0.57 2.29 0.58 0 030 7.54 0 028 7.04 0.70 0.18 0.31 0 08
17646 423 2.08 0.49 2.00 0.47 0 014 3.31 0 028 6.62 0.83 0.20 0.62 0.15
17650 482 1.93 0.40 1.92 0.40 0 031 6.43 0 033 6.85 0.85 0.18 0.40 0.08
17657 417 2.00 0.48 2.09 0.50 0 027 6.47 026 6.24 0.81 0.19 0.45 0.11
17659 418 2.19 0 52 2.23 0.53 0 030 7.18 0 028 6.70 0.95 0 23 0.38 0 09

ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN BODY WEIGHT) 100.

a. Value was multiplied by 1000.

117

[7'8 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B17 (PAGE 9): TERMINAL BODY WEIGHTS, ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT -
INDIVIDUAL DATA - F0 GENERATION MALE RATS

DOSAGE GROUP MIDDLE DOSAGE 50 
HEART
RAT TERMINAL BODY
NUMBER WEIGHT ABS. REL.
WT TBW
17620 475 1.62 0 34
17623 426 1.46 0 34
17627 415 1.08 0 26
17628 389 1.43 37
17633 484 1.54 32
17640 398 1.37 34
17646 423 1.52 0.36
17650 482 1.40 0.29
17657 417 1.57 0 38
17659 418 1.58 38
ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN BODY WEIGHT) 100.





PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: Tu7599)

TABLE B17 (PAGE 10): TERMINAL BODY WEIGHTS, ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT -
INDIVIDUAL DATA - F0 GENERATION MALE RATS

DOSAGE GROUP IV HIGH DOSAGE 250 
EPIDIDYMIS TESTIS EPIDIDYMIS TESTIS BRAIN LIVER

RAT TERMINAL BODY LEFT LEFT RIGHT RIGHT

NUMBER WEIGHT ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. RELTBW: WT TBW

17606 390 0 71 0.18 1.81 0.46 0 71 0.18 1.81 46 14 69 3.77
17609 407 0.84 0.21 1.80 0.44 0.77 0.19 1 92 0 47 15.67 3.85
17612 388 0.76 0.20 1.88 0.48 0.78 0 20 1.89 0 49 16.48 4.25
17614 428 0.76 0.18 1.80 0.42 0 74 0.17 1.80 0 42 23.34 5.45
17617 394 0.67 0.17 1.80 0.46 0.69 0.18 1.87 0 47 19.20 4.87
17621 417 0.70 0.17 1.80 0.43 0.67 0.16 1 81 0 43 2.52 0.60 16.80 4.03
17622 407 0.66 0.16 66 0.41 0 76 0.19 1 72 0 42 2.47 0.61 18 75 4.61
17625 431 0.69 0.16 1 53 0.35 0.64 0.15 1.48 0 34 2.20 0.51 18 98 4.40
17629 414 0.73 0.18 66 0.40 0.67 0.16 1.70 0 41 2.44 0.59 18.26 4.41
17636 445 0.67 0.15 1 96 0.44 0.72 0.16 1.96 0 44 2.01 0.45 21.64 4.86
17637 427 0.64 0.15 1.63 0.38 0.65 0.15 1.65 0 39 2.23 0.52 19 80 4.64
17641 416 0.73 0.18 1.56 0.38 0.73 0.18 1.54 0.37 2.33 0.56 18 99 4.56
17644 407 0.70 0.17 1 67 0.41 0 71 0.17 1.64 0.40 2.27 0.56 17 54 4.31
17647 400 0.74 0.18 1.93 0.48 0 72 0.18 1 85 0 46 2.19 0.55 18 47 4.62
17654 413 0.62 0.15 1.60 0.39 0 57 0.14 1 65 0 40 2.50 0.60 16 03 3.88

ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN BODY WEIGHT) 100.



PROTOCOL 418~027z ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE B17 (PAGE 11): TERMINAL BODY WEIGHTS, ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT -
INDIVIDUAL DATA - F0 GENERATION MALE RATS

DOSAGE GROUP IV HIGH DOSAGE 250 
KIDNEY KIDNEY ADRENAL ADRENAL SPLEEN THYMUS

RAT TERMINAL BODY LEFT RIGHT LEFT RIGHT

NUMBER WEIGHT ABS REL ABS REL ABS REL. ABSTBW

17621 417 2.09 0.50 2 29 0.55 0 030 7 19 0.029 6.95 0.75 0.18 0.51 0 12
17622 407 2.17 0.53 2 05 0.50 0 031 7 62 0.028 6.88 0.70 0.17 0.43 0 10
17625 431 2.15 0.50 2 12 0.49 0 020 4 64 0.018 4.18 1.05 0.24 0.60 0 14
17629 414 1.94 0.47 2 02 0.49 0 023 5 56 0.027 6.52 0.80 0.19 0.36 0 09
17636 445 2.21 0.50 2.29 0.51 0 045 10 11 0.027 6 07 0.89 0.20 0.20 0 04
17637 427 2.11 0.49 2.19 0.51 0 032 7 49 0.029 6 79 0.84 0.20 0.37 0.09
17641 416 2.39 0.57 2 34 0.56 0 034 8.17 0.034 8.17 0.70 0.17 0.40 0.10
17644 407 2.34 0.57 2.35 0.58 0 022 5.40 0.028 6.88 0.82 0.20 0.25 0.06
17647 400 2.08 0 52 2.09 0.52 0 028 7 00 0.028 7.00 0.84 0.21 0.40 0.10
17654 413 2.13 0 52 2 07 0.50 0 031 7 51 0.027 6.54 0.87 0.21 0.49 0 12

ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN BODY WEIGHT) 100.

a. Value was multiplied by 1000.



PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B17 (PAGE 12): TERMINAL BODY WEIGHTS, ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT 
INDIVIDUAL DATA - F0 GENERATION MALE RATS 

DOSAGE GROUP IV HIGH DOSAGE 250 
HEART
RAT TERMINAL BODY
NUMBER WEIGHT ABS. REL.
WT TBW
17621 417 1.35 0.32
17622 407 1.41 0.35
17625 431 1.88 0.44
17629 414 1.29 0.31
17636 445 1.37 0.31
17637 427 1.37 0.32
17641 416 1.39 0.33
17644 407 1.38 0.34
17647 400 1.57 0.39
17654 413 1.53 0.37
ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN BODY WEIGHT) 100.

H7

.
0

S178 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B18 (PAGE 1): BRAIN WEIGHTS, ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO BRAIN WEIGHT INDIVIDUAL DATA 
FO GENERATION MALE RATS

DOSAGE GROUP I VEHICLE 0 (VEHICLE) 
EPIDIDYMIS TESTIS EPIDIDYMIS TESTIS LIVER KIDNEY
RAT BRAIN LEFT LEFT RIGHT RIGHT LEFT
NUMBER WEIGHT ABS REL ABS REL. ABS RELBRW
17608 2 42 0.0.88 36 36 1.2.06 85 12
17618 2.32 0.0.76 32 76 1.2.09 90 09
17630 2.39 0.0.78 32 64 1.1.98 82 84
17631 2.28 0.0.64 28 07 1.1.81 .79 38
17639 2.12 0.0.70 33 02 1.2.02 95 28
17648 2 23 0.0.81 36 32 1.1.89 84 75
17652 2 46 0.0.75 30 49 1.2.04 82 93
17656 2.36 0.0.69 29 24 1.1.69 71 61
17658 2.25 0.0.70 31 11 1.1.69 75 11
17660 2.29 0.0.68 29 69 1.2.10 91 70
ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN WEIGHT) 100.

917'8 

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B18 (PAGE 2): BRAIN WEIGHTS, ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA -
F0 GENERATION MALE RATS

DOSAGE GROUP I VEHICLE 0 (VEHICLE) 
KIDNEY ADRENAL ADRENAL SPLEEN THYMUS HEART

RAT BRAIN RIGHT LEFT RIGHT

NUMBER WEIGHT ABS REL ABS RELBRW

17608 2.0.032 1.21.90 1 46 60 33
17618 2.32 2 02 87 07 031 1.34 0.034 1.17630 2.39 2 03 84 94 0 032 1.34 0.026 1.17631 2.28 1 92 84 21 0 027 1.18 0.029 1.17639 2.0.026 17648 2.0.030 1.17652 2.46 97 80 08 0 034 1.38 0.029 1.17656 2.36 84 77 97 0 028 1.19 0.024 1.17658 0.030 1.17660 008a 0 35a 0.021 ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN WEIGHT) 100.

a. Damaged during processing (weight affected); values excluded from group averages and statistical analyses.

L178 I17

PROTOCOL 418~027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE Bl8 (PAGE 3): BRAIN WEIGHTS, ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA -
F0 GENERATION MALE RATS

DOSAGE GROUP II LOW DOSAGE 10 
EPIDIDYMIS TESTIS EPIDIDYMIS TESTIS LIVER KIDNEY
RAT BRAIN LEFT LEFT RIGHT RIGHT LEFT
NUMBER WEIGHT ABS REL ABS REL. ABS. REL. ABS. REL. ABS. RELBRW
17634 2.29 0.17635 2.31 0.17638 2.45 0.17642 2.21 0.17643 2.26 0.17645 2.40 0.17649 2.02 0.17651 2.20 0.17653 2.18 0.17655 2.15 0.ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN WEIGHT) 100.

H7

8?7?3 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B18 (PAGE 4): BRAIN WEIGHTS, ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA -
F0 GENERATION MALE RATS

DOSAGE GROUP II LOW DOSAGE 10 
KIDNEY ADRENAL ADRENAL SPLEEN THYMUS HEART
RAT BRAIN RIGHT LEFT RIGHT
NUMBER WEIGHT ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. REL.
WT. BRW WT. BRW WT. BRW WT. BRW WT. BRW WT. BRW
17634 2.29 1.89 82 53 0 027 1.18 0 029 1.27 0.69 30 13 0.53 23 14 1.59 69 43
17635 2.31 2.21 95 67 0 031 1.34 0 029 1.26 0.84 36 36 0.61 26 41 1.40 60 61
17638 2.45 1.97 80 41 0 029 1.18 0 032 1 31 0.75 30 61 0.53 21 63 1.57 64 08
17642 2.21 1.89 85 52 026 1.18 0 032 1 45 0.85 38 46 0.48 21 72 1.37 61 99
17643 2 26 2.26 100 00 0 028 1.24 0 034 1 50 0.94 41 59 0.53 23 45 1.82 80 53
17645 2 40 2.14 89 17 0 026 1.08 0 029 1.21 0.99 41 25 0.37 15 42 1.72 71 67
17649 2.02 1.81 89 60 0 037 1.83 0 041 2.03 0.58 28 71 0.24 11 88 1.28 63 37
17651 2.20 1.78 80 91 0 038 1.73 0 040 1.82 0.70 31 82 0.24 10 91 1.56 70 91
17653 2.18 1.90 87 16 0 022 1.01 0 027 1.24 0.74 33 94 0.36 16 51 1.18 54 13
17655 2.15 2.37 110 23 031 1.44 0 024 1.12 0.83 38 60 0.45 20 93 1.45 67 44
ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW WEIGHT) 100.

617'8 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE B18 (PAGE 5): BRAIN WEIGHTS, ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA 
F0 GENERATION MALE RATS

DOSAGE GROUP MIDDLE DOSAGE 50 
EPIDIDYMIS TESTIS EPIDIDYMIS TESTIS LIVER . KIDNEY
RAT BRAIN LEFT LEFT RIGHT RIGHT LEFT
NUMBER WEIGHT ABS. REL. ABS REL ABS REL ABSBRW
17620 2.65.72 0 65 26 21 1.17623 1.17627 1.17628 2.1.17633 2.1.17640 1.17646 2.1.17650 2.1.17657 2.1.17659 2.1.ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN WEIGHT) 100.

I17

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE B18 (PAGE 6): BRAIN WEIGHTS, ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO BRAIN WEIGHT INDIVIDUAL DATA -
FO GENERATION MALE RATS

DOSAGE GROUP MIDDLE DOSAGE 50 
KIDNEY ADRENAL ADRENAL SPLEEN THYMUS HEART
RAT BRAIN RIGHT LEFT RIGHT 
NUMBER WEIGHT ABS REL ABS RELBRW
17620 2.48 2 37 95 56 0.027 1.09 0 026 1.05 0.17623 2.46 2 O9 84 96 0.029 1.18 0 031 1.26 0.17627 2 39 1 92 80 33 0.035 1.46 0 033 1.38 0.17628 2.24 2 29 102 23 0.032 1.43 0 030 1.34 1.17633 2.38 2 37 99 58 0.033 1 39 0 031 1 30 1.17640 2.21 2 29 103 62 0.030 1 36 0 028 1.27 0.17646 2.29 2 00 87 34 0.014 0.61 0 028 1.22 0.17650 2.42 1 92 79 34 0.031 1.28 0 033 1.36 0.17657 2 34 2 09 89 32 0.027 1.15 0 026 1.11 0.17659 2 34 2 23 95 30 0.030 1.28 0 028 1.20 0.WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN WEIGHT) 100.

117

[9'8 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE B18 (PAGE 7): BRAIN WEIGHTS, ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA -
F0 GENERATION MALE RATS

DOSAGE GROUP IV HIGH DOSAGE 250 
EPIDIDYMIS TESTIS EPIDIDYMIS TESTIS LIVER KIDNEY
RAT BRAIN LEFT LEFT RIGHT RIGHT LEFT
NUMBER WEIGHT ABS REL ABS REL ABS REL ABS REL ABS REL ABS REL
BRW
17621 2.52 70 27 78 1.80 71.43 0 67 26 59 1.81 71 82 16.80 666 67 2.09 82 94
17622 2.47 0 66 26 72 1.66 67 21 0 76 30.77 1.72 69 64 18.75 759 11 2.17 87 85
17625 2.20 0 69 31 36 1.53 69 54 64 29.09 1.48 67 27 18.98 862 73 2.15 97 73
17629 2.44 0 73 29 92 1.1.70 69 67 18.26 748 36 1.94 79 51
17636 2.01 0 67 33 33 1.1.96 97 51 21 64 1076 62 2.21 109 95
17637 2.23 0 64 28 70 1.63 73.09 0 65 29.15 1.2.11 94 62
17641 2.33 0 73 31 33 1.56 66.95 0 73 31.33 1.2.39 102 58
17644 2.27 0 70 3O 84 1.67 73 57 71 31.28 1.2.34 103 08
17647 2.19 0 74 33 79 1.1.2.08 94 98
17654 2.50 0 62 24 80 1.1.2.13 85 20
ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN WEIGHT) 100.




-



PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B18 (PAGE 8): BRAIN WEIGHTS, ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO BRAIN WEIGHT INDIVIDUAL DATA -
FO GENERATION MALE RATS

DOSAGE GROUP IV HIGH DOSAGE 250 
KIDNEY ADRENAL ADRENAL SPLEEN THYMUS HEART

RAT BRAIN RIGHT LEFT RIGHT

NUMBER WEIGHT ABS REL ABS RELBRW

17621 2.52 2 29 90 87 0.030 1.19 0.029 1.15 0 75 29 76 0.17622 2 47 2 05 83 00 0.031 1.26 0.028 1.13 0 70 28 34 0.17625 2 20 2 12 96 36 0.020 0.91 0.018 0.82 1 05 47 73 0.17629 2 44 2 02 82 79 0.023 0.94 0.027 1.11 0 80 32 79 0.17636 2 01 2 29 113 93 0.045 2.24 0.027 1.34 0 89 44 28 0.17637 2.23 2 19 98 21 0.032 1.43 0.029 1.30 0 84 37 67 0.17641 2.33 2 34 100 43 0.034 1.46 0.034 1.46 0 70 30 04 0.17644 2.27 2 35 103 52 0.022 0.97 0.028 1.23 0 82 36 12 0.25 11 01 38 60 79
17647 2.19 2 09 95 43 0.028 1.28 0.028 1.28 0 84 38 36 0.17654 2.50 2 O7 82 80 0.031 1.24 0.027 1.08 0 87 34 80 0.ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN WEIGHT) 100.

{9?8 H7

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599. 7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T- 7599)

TABLE B19 (PAGE 1): BODY WEIGHTS - INDIVIDUAL DATA - FO GENERATION MALE RATS

RAT DOSAGE GROUP I VEHICLE 0 (VEHICLE17601 333 331 340 348 367 365 375 383 380 388 384 396 398 401 409 403
17602 362 371 380 389 400 401 410 419 425 431 436 441 449 458 463 458
17603 342 350 357 364 369 373 379 383 391 395 398 406 408 413 417 412
17604 349 353 363 368 377 376 386 389 399 396 402 403 412 414 418 413
17607 330 333 341 348 354 358 360 364 365 369 372 377 379 382 385 382
17608 353 364 367 379 379 388 393 396 402 404 410 412 421 423 428 433
17618 343 347 351 361 366 374 376 383 379 384 390 396 394 394 398 404
17630 347 352 357 366 374 381 384 387 395 402 408 412 416 424 421 418
17631 332 337 346 355 360 364 370 376 374 380 372 389 393 394 394 398
17639 350 356 358 364 371 380 385 395 397 404 407 414 421 425 425 427
17648 333 340 350 354 359 363 374 372 370 381 384 389 390 390 395 391
17652 349 362 370 380 386 391 399 410 415 425 430 438 445 450 456 454
17656 342 348 352 359 364 371 373 380 379 380 388 386 391 393 398 392
17658 345 356 360 363 368 372 374 381 378 384 384 387 391 392 393 390
17660 331 338 344 343 350 353 355 354 362 360 363 367 368 374 374 375

DAY DAY OF STUDY
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
a. Last value recorded before cohabitation.



.


1798 

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B19 (PAGE 2): BODY WEIGHTS - INDIVIDUAL DATA - FO GENERATION MALE RATS

RAT DOSAGE GROUP I VEHICLE (VEHICLE17601 414 416 421 416 418 427 428 433 434 444 438 444 455 453 466 460
17602 464 468 476 479 479 484 490 493 496 504 514 514 522 516 532 533
17603 424 428 432 434 439 444 448 447 453 458 459 468 471 473 465 470
17604 418 417 421 423 420 427 433 436 430 435 438 438 449 450 447 457
17607 388 395 398 402 401 405 407 410 408 415 417 418 427 425 424 429
17608 436 438 442 445 444 448 454 452 456 458 463 467 474 474 477 480
17618 408 405 413 414 413 420 416 424 428 430 428 436 439 434 439 440
17630 423 429 434 436 439 441 446 446 451 454 456 459 459 464 468 469
17631 401 406 413 418 423 428 426 433 436 440 437 449 454 454 457 467
17639 431 432 438 440 446 446 452 452 462 463 465 475 481 482 489 490
17648 397 391 396 397 404 410 405 412 412 416 413 422 426 426 432 438
17652 459 464 475 473 479 485 487 '497 497 506 509 511 524 526 531 540
17656 394 400 401 406 409 412 411 416 418 423 427 429 435 438 440 444
17658 400 400 402 408 414 413 418 429 425 434 440 444 448 448 449 451
17660 379 379 382 379 382 388 393 394 392 399 399 402 410 404 409 414

DAY DAY OF STUDY
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
a. First value recorded after cohabitation.

H7



PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B19 (PAGE 3): BODY WEIGHTS - INDIVIDUAL DATA - F0 GENERATION MALE RATS

RAT DOSAGE GROUP I VEHICLE (VEHICLE17601 458 467. 465 473 439
17602 533 541. 545 544 512
17603 473 471. 471 476 446
17604 450 459. 462 461 433
17607 433 438 439 436 418
17608 484 490 495 493 469
17618 443 443. 446 446 422
17630 475 475. 476 474 448
17631 458 466 467 469 439
17639 495 496. 503 504 483
17648 436 436. 437 440 415
17652 537 540. 547 550 520
17656 446 451. 454 457 428
17658 449 457 462 463 433
17660 417 420 426 427 401

DAY DAY OF STUDY
ALL WEIGHTS WERE RECORDED IN GRAMS (G).

998 [17

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B19 (PAGE 4): BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS

RAT DOSAGE GROUP II LOW DOSAGE 17615 328 332 334 342 339 350 348 354 363 362 367 368 381 383 389 391
17616 354 361 365 374 380 385 390 396 403 403 409 410 413 416 420 419
17624 336 339 343 352 358 360 370 374 375 381 378 382 385 388 394 387
17626 344 350 360 370 376 382 391 390 390 394 403 404 407 409 415 414
17632 334 341 348 356 364 373 381 387 391 399 401 414 416 422 428 422
17634 357 362 366 371 378 380 386. 390 392 398 399 402 407 410 416 406
17635 337 341 350 353 360 368 374. 373 373 385 381 387 392 396 404 397
17638 347 350 358 368 373 376 385 390 393 398 400 405 405 406 417 409
17642 328 331 336 342 339 351 352 360 364 363 370 375 376 380 386 386
17643 350 358 362 374 385 392 399 402 410 419 422 435 436 432 449 446
17645 336 339 342 352 362 366 372 376 384 382 384 388 400 392 401 391
17649 340 348 353 360 364 369 372. 378 383 393 396 398 401 408 411 406
17651 336 341 344 348 367 370 376. 375 370 381 381 388 392 394 395 397
17653 353 356 363 368 374 378 385 390 393 404 404 408 413 420 420 415
17655 349 348 355 361 370 365 377 379 380 388 390 393 395 396 402 386

DAY DAY OF STUDY
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
a. Last value recorded before cohabitation.

117

L98 

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B19 (PAGE 5): BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS

RAT DOSAGE GROUP II LOW DOSAGE 17615 393 399 399 406 411 414 408 414 415 417 423 424 430 425 435 438
17616 427 422 424 424 428 427 428 432 436 436 445 443 447 447 450 454
17624 396 405 403 409 413 412 419 420 423 423 426 432 432 431 430 441
17626 414 415 424 429 434 438 446 445 443 451 456 462 463 471 469 473
17632 435 425 434 434 436 443 444 451 450 457 461 464 471 473 470 484
17634 415 415 420 425 421 430 429 438 440 445 440 443 454 449 456 460
17635 401 404 408 411 416 419 419 429 428 436 438 447 451 445 456 453
17638 407 416 409 423 427 429 429 432 436 442 447 446 455 457 467 473
17642 388 393 399 403 408 410 410. 416 417 420 424 423 427 424 423 425
17643 456 451 455 459 466 472 476. 486 484 489 496 502 506 511 512 516
17645 401 402 410 415 416 419 417 426 424 431 440 441 453 452 450 458
17649 407 410 414 410 416 424 425 430 430 433 439 441 452 446 451 455
17651 406 410 409 412 413 417 417 425 430 434 441 440 447 450 455 456
17653 426 425 427 432 431 430 437 442 443 447 452 455 455 460 461 465
17655 397 386 398 400 400 403 409 413 416 408 418 415 419 423 422 426

DAY DAY OF STUDY
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
a. First value recorded after cohabitation.



85"8 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE B19 (PAGE 6): BODY WEIGHTS - INDIVIDUAL DATA - FO GENERATION MALE RATS

RAT DOSAGE GROUP II LOW DOSAGE 17615 440 444. 448 452 424

17616 458 460. 461 461 437

17624 440 436. 444 443 417

17626 473 467. 478 476 456

17632 484 484. 486 488 457 

17634 455 453. 460 460 433

17635 457 456. 459 466 440

17638 470 475. 479 482 452

17642 423 431 438 440 413

17643 513 522. 521 529 494

17645 454 463. 465 464 440

17649 452 455. 463 464 440

17651 453 461. 459 464 434

17653 464 464. 466 468 442

17655 420 430 431 438 406

DAY DAY OF STUDY
ALL WEIGHTS WERE RECORDED IN GRAMS (G).



698 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B19 (PAGE 7): BODY WEIGHTS - INDIVIDUAL DATA - F0 GENERATION MALE RATS

RAT DOSAGE GROUP MIDDLE DOSAGE 17605 325 324 330 334 339 342 346 353 356 353 352 360 359 365 367 364
17610 363 373 381 385 388 394 401 406 416 419 416 423 425 432 438 431
17611 339 346 354 363 367 375 377 386 386 390 394 398 398 401 405 396
17613 346 350 353 366 374 377 385 396 392 396 396 406 407 412 415 412
17619 330 334 336 343 348 350 355 357 360 362 367 368 373 378 380 374
17620 358 364 373 379 386 395 404 412 416 417 424 429 430 436 435 441
17623 342 346 356 356 368 372 373 380 381 388 389 393 397 402 409 407
17627 340 337 342 345 347 352 358 363 363 370 373 375 386 388 391 396
17628 328 332 341 345 342 350 353 356 352 359 362 366 365 371 369 371
17633 356 366 374 382 393 402 408 404 400 415 418 422 425 427 435 435
17640 338 344 345 352 358 361 367 371 371 375 376 382 380 384 388 388
17646 349 354 363 368 373 379 381 384 386 376 386 387 395 395 402 387
17650 370 369 376 386 389 389 398 401 408 414 418 422 425 431 437 431
17657 337 338 349 359 362 367 368 365 373 374 382 389 378 380 388 386
17659 336 344 346 349 359 359 362 366 370 373 376 383 384 389 392 391

DAY DAY OF STUDY
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
a. Last value recorded before cohabitation.



09"8 

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B19 (PAGE 8): BODY WEIGHTS - INDIVIDUAL DATA - F0 GENERATION MALE RATS

RAT DOSAGE GROUP MIDDLE DOSAGE 17605 367 376 381 381 385 389 390. 394 391 399 403 406 407 406 408 415
17610 435 439 444 448 450 457 462 465 464 465 471 473 484 482 490 489
17611 403 400 411 408 407 408 410 415 415 415 420 424 433 429 432 434
17613 417 418 420 419 419 417 421 422 419 418 422 422 432 433 426 435
17619 384 388 389 390 394 398 401 399 404 411 416 413 425 420 420 430
17620 443 446 452 455 451 457 464 466 471 473 481 481 485 487 489 491
17623 411 411 413 413 415 414 422 423 421 426 430 432 438 440 444 446
17627 402 400 409 406 406 408 402 415 413 418 418 421 421 424 424 430
17628 378 374 379 384 385 386 389 392 391 393 390 397 388 399 401 403
17633 445 443 442 450 456 460 462 468 467 472 478 484 488 489 492 502
17640 387 388 391 391 395 395 399 402 402 405 407 408 416 412 416 420
17646 399 400 402 408 410 414 407 417 422 420 430 432 437 437 437 444
17650 448 452 459 460 459 462 464 472 469 478 480 480 491 496 496 504
17657 391 393 396 403 400 402 405 410 412 418 419 422 433 431 435 439
17659 397 402 399 405 406 412 412 416 422 424 422 423 432 431 436 442

DAY DAY OF STUDY
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
a. First value recorded after cohabitation.

H7


0

[9?8 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B19 (PAGE 9): BODY WEIGHTS - INDIVIDUAL DATA FO GENERATION MALE RATS

RAT DOSAGE GROUP MIDDLE DOSAGE 17605 412 414. 421 423 392
17610 484 487 490 488 467
17611 437 441 439 445 422
17613 431 427 434 433 411
17619 428 434 433 435 410
17620 496 503 505 498 475
17623 444 446. 447 454 426
17627 429 430. 434 438 415
17628 400 404. 409 413 389
17633 499 505. 509 510 484
17640 417 420 420 426 398
17646 446 452 454 454 423
17650 498 504. 509 515 482
17657 440 446. 452 457 417
17659 437 443. 443 449 418

DAY OF STUDY
ALL WEIGHTS WERE RECORDED IN GRAMS (G).

117

Z98 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B19 (PAGE 10): BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS

RAT DOSAGE GROUP IV HIGH DOSAGE 250 

DAY 17606 321 328 321 332 338 343 348 351 355 358 365 365 366 369 373 370
17609 358 358 360 373 375 382 383 388 392 394 397 400 398 392 400 409
17612 340 340 345 349 354 356 357 365 369 369 374 374 374 378 379 384
17614 348 343 338 355 360 371 376 382 389 396 394 398 404 408 413 403
17617 330 329 332 340 344 354 352 354 358 359 362 366 365 367 370 363
17621 347 349 351 361 370 373 380 387 386 392 392 395 398 401 403 394
17622 336 336 327 349 353 364 367 370 380 379 385 389 389 392 394 380
17625 338 342 338 350 357 366 369 376 389 388 390 392 398 405 408 393
17629 332 336 341 348 349 361 361 368 372 380 379 380 387 390 396 388
17636 350 350 350 357 366 368 377 380 386 396 402 401 407 411 414 403
17637 342 346 352 358 362 367 370 377 374 382 382 387 389 393 402 390
17641 342 340 344 350 354 362 365 369 368 373 378 381 383 392 396 392
17644 328 320 316 328 331 341 346 355 353 360 363 367 368 373 380 376
17647 343 349 345 354 360 362 361 366 363 370 371 375 378 377 384 381
17654 338 345 341 352 360 364 370 371 381 374 379 379 382 385 390 388

DAY DAY OF STUDY
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
a. Last value recorded before cohabitation.

{9?8 117

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B19 (PAGE 11): BODY WEIGHTS INDIVIDUAL DATA - F0 GENERATION MALE RATS

RAT DOSAGE GROUP IV HIGH DOSAGE 250 

DAY 17606 379 384 385 391 388 394 396 395 399 398 404 403 405 402 410 408
17609 395 407 401 416 414 416 417 421 427 424 422 432 427 426 432 433
17612 385 384 389 390 390 393 398 399 401 401 406 406 408 406 411 410
17614 415 418 418 420 426 425 430 432 436 434 432 431 442 437 430 449
17617 363 363 368 371 380 379 384 381 389 392 400 404 409 412 412 411
17621 401 402 403 408 411 407 416 417 413 423 424 421 428 432 432 437
17622 389 393 399 410 410 411 405 412 411 418 418 421 424 423 424 423
17625 407 411 413 418 422 424 426 430 430 438 447 453 450 442 445 456
17629 402 405 406 416 412 412 421 423 426 425 426 432 430 436 436 436
17636 412 408 417 422 425 429 429 432 437 439 442 445 443 446 463 466
17637 409 400 403 406 413 416 415 424 430 428 437 435 442 446 447 449
17641 396 395 402 401 404 409 412 423 412 420 426 430 442 435 438 442
17644 376 386 385 389 390 399 396 406 400 405 407 418 421 420 427 428
17647 384 390 394 392 396 403 398 404 408 408 412 419 425 422 420 430
17654 391 392 398 404 414 409 407 415 418 419 426 431 436 433 438 439

DAY DAY OF STUDY
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
a. First value recorded after cohabitation.

117

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B19 (PAGE 12): BODY WEIGHTS - INDIVIDUAL DATA - FO GENERATION MALE RATS

RAT DOSAGE GROUP IV HIGH DOSAGE 250 
DAY 33 34 35 36 37
17606 413 415 416 421 390
17609 430 433 438 438 407
17612 412 414 413 418 388
17614 447 452 449 453 428
17617 412 416. 422 427 394
17621 437 436. 442 449 417
17622 428 436. 433 438 407
17625 447 462. 466 469 431
17629 437 440. 440 444 414
17636 460 460 470 462 445
17637 452 452. 459 458 427
17641 439 445. 449 453 416
17644 422 430. 431 436 407
17647 425 428. 436 434 400
17654 446 445STUDY
ALL WEIGHTS WERE RECORDED IN GRAMS (G).





PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE B20 (PAGE 1): FEED CONSUMPTION VALUES - INDIVIDUAL DATA - FO GENERATION MALE RATS

17601 192. 189 194
17602 220. 219 230
17603 201. 200 196
17604 195. 193 202
17607 181. 167 170
17608 196. 190 205
17618 183. 176 175
17630 206. 201 190
17631 189. 177 207
17639 194. 184 220
17648 184. 164 186
17652 216. 218 240
17656 177. 159 180
17658 178. 156 180
17660 169. 172 194

DAYS DAYS OF STUDY

ALL WEIGHTS WERE RECORDED IN GRAMS (G).

a. Last value recorded before cohabitation.
b. First value recorded after cohabitation.






99'8 

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B20 (PAGE 2): FEED CONSUMPTION VALUES - INDIVIDUAL DATA - FO GENERATION MALE RATS

RAT DOSAGE GROUP II LOW DOSAGE 10 
DAYS 1? 8 8- 15a 29b-36
17615 158 183 189
17616 190 184 186
17624 177. 165 178
17626 189. 176 188
17632 200 208 209
17634 186 180 196
17635 191 184 196
17638 181 169 201
17642 171 168
17643 202. 196 220
17645 181. 172 190
17649 173. 179 191
17651 181. 172 169
17653 188 183 188
17655 186 180 192

DAYS DAYS OF STUDY

ALL WEIGHTS WERE RECORDED IN GRAMS (G).

a. Last value recorded before cohabitation.

b. First value recorded after cohabitation.

c. Spilled feed precluded the calculation of this value.

117

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B20 (PAGE 3): FEED CONSUMPTION VALUES - INDIVIDUAL DATA - FO GENERATION MALE RATS

RAT DOSAGE GROUP MIDDLE DOSAGE 50 
DAYS 1- 8 8- 15a 29b-36
17605 184. 169 187
17610 195. 207 199
17611 184. 170 169
17613 198. 183 169
17619 154. 157 166
17620 214. 215 229
17623 184. 168 179
17627 164. 177 165
17628 165 181 197
17633 207. 200 216
17640 175. 162 171
17646 186. 155 187
17650 173. 196 210
17657 170. 171 191
17659 167. 171 182

DAYS DAYS OF STUDY

ALL WEIGHTS WERE RECORDED IN GRAMS (G).

a. Last value recorded before cohabitation.
b. First value recorded after cohabitation.

[17

89?8 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B20 (PAGE 4): FEED CONSUMPTION VALUES - INDIVIDUAL DATA - F0 GENERATION MALE RATS

RAT DOSAGE GROUP IV HIGH DOSAGE 200 
DAYS 1- 8 8- 15a 29b-36
17606 163 165 157
17609 179 171 177
17612 163 157 164
17614 186 209 190
17617 165 162 178
17621 195 179 188
17622 168. 185 179
17625 178. 187 192
17629 180 167 176
17636 164. 190. 189
17637 178. 167 185
17641 178. 170 186
17644 164. 165 180
17647 169. 176 197
17654 166. 169 194

DAYS DAYS OF STUDY

ALL WEIGHTS WERE RECORDED IN GRAMS (G).

a. Last value recorded before cohabitation.
b. First value recorded after cohabitation.

It

6911 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B21 (PAGE 1): MATING AND FERTILITY - INDIVIDUAL DATA - FO GENERATION MALE RATS

DOSAGE GROUP I VEHICLE 0 (VEHICLE) 
DAYS IN FEMALE PREGNANCY
RAT COHABITATION MATING STATUS MATING DATE STATUS
17601 3 P(l7662)
17602 4 P(l7672)
17603 1 P(l7673)
17604 1 P(l7674)
17607 3 P(l7680)
17608 3 P(l7681)
17618 3 
17630 1 
17631 2 P(l7695)
17639 3 P(l7703)
17648 3 P(l7713)
17652a 4 
17652b 2 
17656 4 P(l7716)
17658 1 P(l77l7)
17660 7 DID NOT MATE - -(17719)
MATED FEMALE RAT NUMBER
CONFIRMED

PREGNANT NP NOT PREGNANT
Result of first cohabitation period.
Male rat mated early in the first cohabitation period and was cohabited with a second female rat.


ll



01:8 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE B21 (PAGE 2): MATING AND FERTILITY INDIVIDUAL DATA FO GENERATION MALE RATS

DOSAGE GROUP II LOW DOSAGE 1o 
DAYS IN FEMALE PREGNANCY

RAT COHABITATION MATING STATUS MATING DATE STATUS

17615 3 
17616 3 P(l7665)
17624 1 
17626 3 
17632 3 P(l767l)
17634 2 P(l7675)
17635 3 P(l7679)
17638 4 P(l7684)
17642 3 
17643 3 
17645 1 P(l7702)
17649 2 P(177o4)
17651 4 P(l7707)
17653 1 P(l7708)
17655 4 

MATED FEMALE RAT NUMBER
CONFIRMED
PREGNANT NP NOT PREGNANT





PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B21 (PAGE 3): MATING AND FERTILITY - INDIVIDUAL DATA - FO GENERATION MALE RATS

DOSAGE GROUP MIDDLE DOSAGE 50 
DAYS IN FEMALE PREGNANCY

RAT COHABITATION MATING STATUS MATING DATE STATUS

17605 2 P(l7661)
17610 2 P(l7667)
17611 3 
17613 4 P(l7670)
17619 2 
17620 4 
17623 1 P(l7693)
17627 3 
17628a 3 P(l7700)
l7628b 6 P(l7709)
17633 3 P(l7701)
17640 3 P(l7705)
17646 4 P(l7706)
17650 7 DID NOT MATE - -(17709)
17657 7 DID NOT MATE - ?(l7718)
17659a 4 P(l7720)
17659b 6 P(l77l8)

MATED FEMALE RAT NUMBER

CONFIRMED

PREGNANT NP NOT PREGNANT

a Result of first cohabitation period.

Male rat mated early in the first cohabitation period and was cohabited with a second female rat.





PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B21 (PAGE 4): MATING AND FERTILITY INDIVIDUAL DATA - Fo GENERATION MALE RATS

DOSAGE GROUP IV HIGH DOSAGE 250 
DAYS IN FEMALE PREGNANCY

RAT COHABITATION MATING STATUS MATING DATE STATUS

17606 7 DID NOT MATE ?(17664)
176o9a 4 P(l7677)
17609b 6 
17612 4 
17614 7 DID NOT MATE ~(17682)
17617 3 P(l7683)
17621 1 
17622 1 
17625 1 P(l7689)
17629 4 
17636 1 
17637 1 
17641a 3 P(l7699)
17641b 7 DID NOT MATE ~(17664)
17644 1 P(177ll)
17647 1 
17654 3 P(l7714)

MATED FEMALE RAT NUMBER

CONFIRMED

PREGNANT NP NOT PREGNANT

a Result of first cohabitation period.

Male rat mated early in the first cohabitation period and was cohabited with a second female rat.

117

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE 
TOXICITY SCREENING TEST STUDY NUMBER: T-7599)

 

 

 

TABLE B22 (PAGE 1): FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - MALE RATS
DOSAGE GROUP I 0 (VEHICLE) 
RAT 17601 17602 17603 17604 17607
HOME CAGE BEHAVIOR 2 2 2 2 2
ALTERATIONS (HOME CAGE) 1 1 1 1 1
REACTION TO REMOVAL 1 1 1 1
REACTION TO HANDLING 1 1 1
REARS IN OPEN FIELD 8 9 9 2 8
DEFECATION IN OPEN FIELD 1 2 3 2 1
URINATION IN OPEN FIELD 2 2 2 1 2
LEVEL OF AROUSAL 3 3 3 3 3
ALTERATIONS (OPEN FIELD) 1 1 1 1 1
GAIT PATTERN 1 1 1 
GAIT ABNORMALITY, SEVERITY 1 1 1 1
PALPEBRAL CLOSURE 1 1
PROMINENCE OF THE EYE 1 1 1
LACRIMATION 1 1 1 1
SALIVATION 1 1 1 1 1
PILOERECTION 0 0 0 0 0
ABNORMAL RESPIRATION 0 0 0 0 0
APPEARANCE 1 1 1 1
VISUAL REACTION 2 2 2 2 2
TACTILE REACTION 2 2 2 2 2
AUDITORY REACTION 3 3 3 3 3
TAIL-PINCH REACTION 2 2 2 2 2
VISUAL PLACING RESPONSE 1 1 1 1 1
AIR RIGHTING RESPONSE 1 1 1 1 
PUPIL RESPONSE TO LIGHT 1 1 1 1 
FORELIMB GRIP TEST #1 345 510 190 355 370
FORELIMB GRIP TEST #2 450 405 125 350 275
HINDLIMB GRIP TEST #1 445 375 310 200 360
HINDLIMB GRIP TEST #2 555 375 430 215 285
LANDING FOOT SPLAY #1 8.7 7.5 9.5 7.7 7.5a
LANDING FOOT SPLAY #2 8.9 7.6 12.6 9.6 6.9
BODY WEIGHT (G) 455 525 469 449 425

 

VALUES ARE THE QUANTITY, CATEGORY NUMBER) QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY.
a. Soft or liquid feces were observed during during landing foot splay testing.

H7

171:8 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE 
TOXICITY SCREENING TEST STUDY NUMBER: T-7599)

 

 

 

TABLE B22 (PAGE 2): FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - MALE RATS

DOSAGE GROUP II 10 
RAT 17615 17616 17624 17626 17632

HOME CAGE BEHAVIOR 2 2 2

ALTERATIONS (HOME CAGE)
REACTION TO REMOVAL
REACTION TO HANDLING
REARS IN OPEN FIELD
DEFECATION IN OPEN FIELD
URINATION IN OPEN FIELD
LEVEL OF AROUSAL
ALTERATIONS (OPEN FIELD)
GAIT PATTERN

GAIT ABNORMALITY, SEVERITY
PALPEBRAL CLOSURE
PROMINENCE OF THE EYE
LACRIMATION

SALIVATION

PILOERECTION

ABNORMAL RESPIRATION
APPEARANCE

VISUAL REACTION

TACTILE REACTION
AUDITORY REACTION
TAIL-PINCH REACTION
VISUAL PLACING RESPONSE
AIR RIGHTING RESPONSE







PUPIL RESPONSE TO LIGHT 1 1 1
FORELIMB GRIP TEST #1 330 425 420 405 445
FORELIMB GRIP TEST #2 325 470 290 450 370
HINDLIMB GRIP TEST #1 410 335 345 205 365
HINDLIMB GRIP TEST #2 275 355 245 230 325
LANDING FOOT SPLAY #1 7.0 8.1 11.2 12.5 7.8
LANDING FOOT SPLAY #2 9.8 8.5 11.3 12.7 7.2
BODY WEIGHT (G) 433 450 441a 470 477

 

VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY.
a. Value appeared incorrectly recorded and was excluded from group averages and statistical analyses.

117



PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE 
TOXICITY SCREENING TEST STUDY NUMBER: T-7599)

TABLE B22 (PAGE 3): FUNCTIONAL OBSERVATIONAL BATTERY INDIVIDUAL DATA - MALE RATS

 

DOSAGE GROUP 

RAT 

HOME CAGE BEHAVIOR
ALTERATIONS (HOME CAGE)
REACTION TO REMOVAL
REACTION TO HANDLING
REARS IN OPEN FIELD
DEFECATION IN OPEN FIELD
URINATION IN OPEN FIELD
LEVEL OF AROUSAL
ALTERATIONS (OPEN FIELD)
GAIT PATTERN

GAIT ABNORMALITY, SEVERITY
PALPEBRAL CLOSURE
PROMINENCE OF THE EYE
LACRIMATION

SALIVATION

PILOERECTION

ABNORMAL RESPIRATION
APPEARANCE

VISUAL REACTION

TACTILE REACTION
AUDITORY REACTION
REACTION
VISUAL PLACING RESPONSE
AIR RIGHTING RESPONSE
PUPIL RESPONSE TO LIGHT
FORELIMB GRIP TEST #1
FORELIMB GRIP TEST #2
HINDLIMB GRIP TEST #1
HINDLIMB GRIP TEST #2
LANDING FOOT SPLAY #1
LANDING FOOT SPLAY #2
BODY WEIGHT (G)

VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY.

17605
2

l?I






205
270
285
360
7.2
7.1
415

17610



395
575
560
465
7.2
7.4
488

17611
2





315
410
405
480
9.9
9.7
432

17613





380
400
390
345
7.0
6.5
430

17619





195
365
310
230
8.1
9.3
428

50 

H7

a




PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE 
TOXICITY SCREENING TEST STUDY NUMBER: T-7599)

 

 

 

TABLE B22 (PAGE 4): FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA MALE RATS
DOSAGE GROUP IV 250 
RAT 17606 17609 17612 17614 17617
HOME CAGE BEHAVIOR 2 2 2 2 2
ALTERATIONS (HOME CAGE) 1 1 1 1 1
REACTION TO REMOVAL 1 1 1 1 1
REACTION TO HANDLING 1 1 1 1 1
REARS IN OPEN FIELD 13 19 12 9 0
DEFECATION IN OPEN FIELD 1 2 1 1 3
URINATION IN OPEN FIELD 2 1 1 2
LEVEL OF AROUSAL 3 3 3 3 3
ALTERATIONS (OPEN FIELD) 1 1 1 1 1
GAIT PATTERN 1 1 1 1 1
GAIT ABNORMALITY, SEVERITY 1 1 1 1
PALPEBRAL CLOSURE 1 1 1 1 1
PROMINENCE LACRIMATION 1 1 1 1 1
SALIVATION 1 1 1 1 1
PILOERECTION 0 0 0 0
ABNORMAL RESPIRATION 0 0 0 0 0
APPEARANCE 1 1 1 la 1
VISUAL REACTION 2 2 2 2 2
TACTILE REACTION 2 2 2 2 2
AUDITORY REACTION 3 3 3 3 3
REACTION 2 2 2 2 2
VISUAL PLACING RESPONSE 1 1 1 1 1
AIR RIGHTING RESPONSE 1 1 1 1 1
PUPIL RESPONSE TO LIGHT 1 1 1 1 1
FORELIMB GRIP TEST #1 210 275 400 170 285
FORELIMB GRIP TEST #2 200 310 465 140 310
HINDLIMB GRIP TEST #1 190 385 400 180 290
HINDLIMB GRIP TEST #2 410 405 460 205 225
LANDING FOOT SPLAY #1 8.0 7.6 6.6 6.9 8.7
LANDING FOOT SPLAY #2 10.2 7.8 6.5 6.7 10.0
BODY WEIGHT (G) 410 434 411 436 421

 

VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY.
a . Chromorhinorrhea .

U7

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY

SCREENING TEST STUDY NUMBER: T-7599)

TABLE B23 (PAGE 1): MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS

 

 

 

DOSAGE GROUP I 0 (VEHICLE) 
RAT NUMBER 17601 17602 17603 17604 17607
DAY 86

NUMBER OF MOVEMENTS

BLOCK 1 76 58 75 54
BLOCK 2 79 70 81 65
BLOCK 3 72 63 70 70
BLOCK 4 63 33 76 74
BLOCK 5 35 0 7 74
BLOCK 6 1 6 41 72
BLOCK 7 2 79 62
BLOCK 8 2 55 72 61
BLOCK 9 0 81 6 57
BLOCK 10 0 26 9 57
BLOCK 11 28 4 3 64
BLOCK 12 77 1 6 71
BLOCK 13 67 3 7 53
BLOCK 14 9 2 3 60
BLOCK 15 0 0 6 50
BLOCK 16 4 2 14 54
BLOCK 17 3 1 5 60
BLOCK 18 1 0 6 55
TOTAL 518 407 566 1113

.5



 

TOTAL SUM OF EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.

[17

SEE HDVJ

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B23 (PAGE 2): MOTOR ACTIVITY - INDIVIDUAL DATA F0 GENERATION MALE RATS

 

 

 

DOSAGE GROUP I 0 (VEHICLE) 
RAT NUMBER 17601 17602 17603 17604 17607
DAY 86

TIME (SECONDS) SPENT IN MOVEMENT

BLOCK 1 186 196 147 169 195
BLOCK 2 161 149 180 168 196
BLOCK 3 79 146 120 180 179
BLOCK 4 84 54 104 78 69
BLOCK 5 33 0 9 136 31
BLOCK 6 0 2 53 154 46
BLOCK 7 0 0 107 86 33
BLOCK 8 0 85 88 109 42
BLOCK 9 0 123 1 114 44
BLOCK 10 0 25 3 110 1
BLOCK 11 45 8 1 99 0
BLOCK 12 103 0 2 91 2
BLOCK 13 101 0 5 72 0
BLOCK 14 7 1 0 113 0
BLOCK 15 0 0 102 0
BLOCK 15 2 0 7 100 0
BLOCK 1? 0 0 2 84 0
BLOCK 18 0 2 72 0
TOTAL 801 789 831 2037 838

 

TOTAL SUM OF EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.

H7






PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B23 (PAGE 3): MOTOR ACTIVITY - INDIVIDUAL DATA Fo GENERATION MALE RATS

 

 

 

DOSAGE GROUP II 10 
RAT NUMBER 17615 17616 17624 17626 17632
DAY 86

NUMBER OF MOVEMENTS

BLOCK 1 52 66 78 65 74
BLOCK 2 59 76 77 58 69
BLOCK 3 57 91 75 S4 75
BLOCK 4 48 74 73 45 72
BLOCK 5 31 85 70 63 68
BLOCK 6 0 81 59 67 51
BLOCK 7 0 71 27 64 45
BLOCK 8 0 64 50 50 87
BLOCK 9 0 43 55 55 54
BLOCK 10 1 72 9 48 52
BLOCK 11 0 27 3O 60 48
BLOCK 12 2 44 17 14 46
BLOCK 13 0 65 0 5 44
BLOCK 14 0 58 0 44 34
BLOCK 15 0 37 0 52 4
BLOCK 16 2 6 0 41 41
BLOCK 17 1 3 0 13 7
BLOCK 18 0 5 12 0 2
TOTAL 253 968 632 798 873

 

TOTAL SUM OF EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.

117






PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B23 (PAGE 4): MOTOR ACTIVITY - INDIVIDUAL DATA Fo GENERATION MALE RATS

 

 

 

DOSAGE GROUP II 10 
RAT NUMBER 17615 17616 17624 17626 17632
DAY 86

TIME (SECONDS) SPENT IN MOVEMENT

BLOCK 1 233 196 195 196 204
BLOCK 2 182 154 164 170 167
BLOCK 3 135 169 160 120 117
BLOCK 4 85 122 94 79 129
BLOCK 5 45 136 127 123 76
BLOCK 6 0 107 78 119 123
BLOCK 7 0 143 12 112 65
BLOCK 8 0 94 55 73 130
BLOCK 9 0 86 77 127 85
BLOCK 10 0 74 7 74 80
BLOCK 11 0 28 20 93 59
BLOCK 12 1 68 15 15 80
BLOCK 13 0 91 0 9 50
BLOCK 14 0 66 0 42 31
BLOCK 15 0 29 0 69 3
BLOCK 16 1 5 0 70 35
BLOCK 17 0 0 0 14 6
BLOCK 18 0 3 10 0 0
TOTAL 682 1571 1014 1505 1440

 

TOTAL SUM OF EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.



[8?8 

PROTOCOL 418 - 027 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599 . 7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B23 (PAGE 5): MOTOR ACTIVITY - INDIVIDUAL DATA F0 GENERATION MALE RATS

 

 

 

DOSAGE GROUP 50 
RAT NUMBER 17605 17610 17611 17613 17619
DAY 86

NUMBER OF MOVEMENTS

BLOCK 1 66 64 63 69 58
BLOCK 2 67 37 64 75 73
BLOCK 3 64 51 81 63 75
BLOCK 4 7O 40 43 50 70
BLOCK 5 69 22 0 52 71
BLOCK 6 41 0 11 28 62
BLOCK 7 41 2 1 2 66
BLOCK 8 2 52 29 3 41
BLOCK 9 4 34 43 2 78
BLOCK 10 1 68 66 48 39
BLOCK 11 0 40 80 48 11
BLOCK 12 0 37 51 1 23
BLOCK 13 1 31 63 0 2
BLOCK 14 0 55 34 0 10
BLOCK 15 5 57 14 1 0
BLOCK 16 54 31 11 0 14
BLOCK 17 14 53 0 0 0
BLOCK 18 1 34 0 2 1
TOTAL 500 708 654 444 694

 

TOTAL SUM OF EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.

H7



PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B23 (PAGE 6): MOTOR ACTIVITY - INDIVIDUAL DATA - F0 GENERATION MALE RATS

 

 

 

DOSAGE GROUP 50 
RAT NUMBER 17605 17610 17611 17613 17619
DAY 86

TIME (SECONDS) SPENT IN MOVEMENT

BLOCK 1 177 181 221 190 173
BLOCK 2 119 134 166 164 92
BLOCK 3 144 98 135 135 105
BLOCK 4 145 88 67 88 120
BLOCK 5 108 25 0 64 84
BLOCK 6 59 0 8 39 60
BLOCK 7 54 0 0 0 113
BLOCK 8 0 71 17 0 46
BLOCK 9 6 35 53 0 97
BLOCK 10 0 112 137 77 37
BLOCK 11 0 71 160 64 7
BLOCK 12 0 66 39 0 26
BLOCK 13 0 40 68 0 
BLOCK 14 0 71 36 0 6
BLOCK 15 4 81 12 0 0
BLOCK 16 58 56 4 0 14
BLOCK 17 16 84 0 0 0
BLOCK 18 0 59 1 1
TOTAL 890 1272 1123 822 982

 

TOTAL SUM OF EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.



?68?8 

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B23 (PAGE 7): MOTOR ACTIVITY - INDIVIDUAL DATA F0 GENERATION MALE RATS

 

 

 

DOSAGE GROUP IV 250 
RAT NUMBER 17606 17609 17612 17614 17617
DAY 86

NUMBER OF MOVEMENTS

BLOCK 1 61 60 65 72 70
BLOCK 2 70 54 76 88 73
BLOCK 3 48 64 63 73 62
BLOCK 4 54 60 48 73 71
BLOCK 5 1 52 1 12 62
BLOCK 6 2 6 0 18 54
BLOCK 7 3 1 0 1 49
BLOCK 8 1 8 1 0 31
BLOCK 9 0 2 0 1 4
BLOCK 10 2 0 48 0 4
BLOCK 11 1 32 47 50 0
BLOCK 12 3 56 1 50 3
BLOCK 13 4 20 0 9 4
BLOCK l4 1 1 1 16 0
BLOCK 15 10 0 1 29 0
BLOCK 16 57 2 0 20 2
BLOCK 17 1 0 0 16 2
BLOCK 18 1 5 0 11 0
TOTAL 320 423 352 539 491

 

TOTAL SUM OF EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.





PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE B23 (PAGE 8): MOTOR ACTIVITY - INDIVIDUAL DATA F0 GENERATION MALE RATS

 

 

 

DOSAGE GROUP IV 250 
RAT NUMBER 17606 17609 17612 17614 17617
DAY 86

TIME (SECONDS) SPENT IN MOVEMENT

BLOCK 1 192 197 181 187 141
BLOCK 2 163 173 108 180 139
BLOCK 3 82 114 95 142 125
BLOCK 4 122 146 44 167 67
BLOCK 5 70 0 14 77
BLOCK 6 0 5 0 10 105
BLOCK 7 0 0 0 0 68
BLOCK 8 0 4 0 0 21
BLOCK 9 0 1 0 0 2
BLOCK 10 0 0 64 0 7
BLOCK 11 0 33 79 52 0
BLOCK 12 1 92 0 60 0
BLOCK 13 1 19 8 1
BLOCK 14 0 0 0 11 0
BLOCK 15 7 0 0 26 0
BLOCK 16 89 0 0 51 0
BLOCK 17 0 0 0 20 0
BLOCK 18 0 0 0 6 0
TOTAL 657 4 571 3

 

TOTAL SUM OF EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.

H7

98?8 

APPENDIX 

REPORT TABLES F0 GENERATION FEMALE RATS

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE Cl (PAGE 1): CLINICAL OBSERVATIONS - SUMMARY - F0 GENERATION FEMALE RATS

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLE) 10 50 250
MORTALITY 0 0 

PRECOHABITATION (DAY 1 OF STUDY TO THE DAY OF COHABITATION):

MAXIMUM POSSIBLE INCIDENCE 225/ 15 225/ 15 225/ 15 225/ 15
RED, SLIGHT PERIORAL SUBSTANCE 1 1 0 3 3
EXCESS SALIVATION 1 1 0/ I 4 2
TAIL BENT 0/ 0/ 0/ 0 13/ 1
CHROMODACRYORRHEA 1 1 0 1/ 1
RIGHT EYE CORNEAL OPACITY 0 0 12 1 0 0
LOCALI ZED ALOPECIA: LIMBS 9/ 2 1/ 1 0 

STATISTICAL ANALYSES OF CLINICAL OBSERVATION DATA WERE RESTRICTED TO THE NUMBER OF RATS WITH OBSERVATIONS.
MAXIMUM POSSIBLE INCIDENCE (DAYS OF RATS EXAMINED PER GROUP.
TOTAL NUMBER OF OF RATS WITH OBSERVATION.

[10?8117

HDVJ

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE Cl (PAGE 2): CLINICAL OBSERVATIONS - SUMMARY - F0 GENERATION FEMALE RATS

DOSAGE GROUP I II IV
DOSAGE (VEHICLE) 10 50 250
MORTALITY 0 

PRESUMED GESTATION: a

MAXIMUM POSSIBLE INCIDENCE 330/ 15 335/ 15 331/ 15 316/ 14
EXCESS SALIVATION 0/ 0 0/ 0 0/ 0 25/ 
RED, SLIGHT OR MODERATE PERIORAL SUBSTANCE 0/ 0 0/ 0 0/ 0 16/ 
LOCALIZED ALOPECIA: TOTAL 43LIMBS 43UNDERSIDE HEAD ABDOMINAL FUR TAIL BENT RED PERIVAGINAL SUBSTANCE CHROMODACRYORRHEA INCISORSSOFT OR LIQUID FECES STATISTICAL ANALYSES OF CLINICAL OBSERVATION DATA WERE RESTRICTED TO THE NUMBER OF RATS WITH OBSERVATIONS.
MAXIMUM POSSIBLE INCIDENCE (DAYS OF RATS EXAMINED PER GROUP.

TOTAL NUMBER OF OF RATS WITH OBSERVATION.

a. Restricted to rats with a confirmed mating date.

Significantly different from the vehicle control group value (p50.01) .





PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C1 (PAGE 3): CLINICAL OBSERVATIONS - SUMMARY - Fo GENERATION FEMALE RATS

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLE) 10 50 250
MORTALITY 0 0 0 0
LACTATION:
MAXIMUM POSSIBLE INCIDENCE 90LOCALIZED ALOPECIA: TOTAL 12LIMBS 12UNDERSIDE EXCESS SALIVATION TAIL BENT DEHYDRATION -STATISTICAL ANALYSES OF CLINICAL OBSERVATION DATA WERE RESTRICTED TO THE NUMBER OF RATS WITH OBSERVATIONS.
MAXIMUM POSSIBLE INCIDENCE (DAYS OF RATS EXAMINED PER GROUP.
TOTAL NUMBER OF OF RATS WITH OBSERVATION.

[108117

90 HDVJ

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C2 (PAGE 1): NECROPSY OBSERVATIONS - SUMMARY - FO GENERATION FEMALE RATS

DOSAGE GROUP DOSAGE (VEHICLEMORTALITY 0 

APPEARED NORMAL 5 5 l4 1 4

KIDNEYS RIGHT ABSENT 

THYMUS SMALL 

a. Refer to the individual clinical observations table (Table C27) for external observations confirmed at necropsy.



?70 HDVJ

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE C3 (PAGE 1): TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS - SUMMARY - F0 GENERATION FEMALE RATS

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLE) 10 50 250
RATS TESTED 15 15 15 15
PREGNANT 15 14 15 13
INCLUDED IN ANALYSES 15 14 15 11a
TERMINAL BODY WEIGHT 299.1 i 24.7 304.0 1 18.9 296.0 1 25.0 284.8 1 11.1
BRAIN 2.20 i 0.08 2.19 i 0.07 2.19 i 0.07 2.20 i 0.08
10]b 10]b 10]b 9]b
LIVER 11.22 i 1.26 11.81 i 1.50 11.66 i 1.28 13.56 i 0.89**
KIDNEY LEFT 1.20 i 0.13 1.29 i 0.14 1.31 i 0.32 1.23 i 0.08
10]b 10]b 10]b 9]b
KIDNEY RIGHT 1.20 i 0.13 1.31 i 0.10 1.27 i 0.14 1.27 i 0.08
10]b 10]b 9]b,c 9]b
ADRENAL LEFT 0.042 i 0.004 0.046 1 0.008 0.041 1 0.008 0.045 1 0.008
10]b 10]b 10]b 9]b
ADRENAL RIGHT 0.041 i 0.006 0.043 1 0.006 0.038 i 0.008 0.040 i 0.006
10]b 10]b 10]b 9]b
SPLEEN 0.70 1 0.06 0.74 i 0.14 0.76 i 0.10 0.64 i 0.09
10]b 10]b 10]b 9]b
THYMUS 0.27 i 0.07 0.34 i 0.07 0.29 i 0.07 0.22 i 0.05
10]b 10]b 10]b 9]b
OVARY LEFT . 0.080 0.017 0.079 1 0.012 0.079 1 0.015 0.076 i 0.010
OVARY RIGHT 0.081 1 0.014 0.083 1 0.013 0.084 0.015 0.080 i 0.014
UTERUS WITH CERVIX 0.70 i 0.06
HEART 1.00 i 0.12
10]b 10]b 10]b 9]b

ALL WEIGHTS WERE RECORDED IN GRAMS (G).

NUMBER OF VALUES AVERAGED
a. Excludes values for dams that were sacrificed due to no surviving pups.
b. Results did not warrant examination of the five additional rats.

c. Excludes rat 17706, which had an absent right kidney.

Significantly different from the vehicle control group value (p50.01).




0

SO 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C4 (PAGE 1): RATIOS OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT - SUMMARY - Fo GENERATION FEMALE RATS

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLE) 10 50 250
RATS TESTED 15 15 15 15
PREGNANT 15 14 15 13
INCLUDED IN ANALYSES 15 14 15 11a
TERMINAL BODY WEIGHT 299.1 24.7 304.0 1 18.9 296.0 i 25.0 284.8 1 11.1
BRAIN 0.733 1 0 059 0.706 1 0.029 0.728 i 0.065 0.778 1 0.040
I 10]b lO]b lO]b 9]b
LIVER 3 753 i 0.336 3.871 1 0.318 3.935 i 0.233 4.763 i 0.284**
KIDNEY LEFT 0 397 i 0.029 0.416 1 0.042 0.432 1 0.096 0.434 1 0.034
10]b 10]b 10]b 91b
KIDNEY RIGHT 0 400 i 0.036 0.421 i 0.031 0.421 0.042 0.449 1 0.035**
10]b 10]b 9]b,d 9]b
ADRENAL LEFT 13.994 1 2.004 14.906 i 2.273 13.476 i 1.549 15.943 i 3.030
101b 10]b 10]b 91b
ADRENAL RIGHT 13.767 i 2.449 13.951 i 1.699 12.481 1.930 14.297 i 2.379
lOIb 10]b 10]b 9]b
SPLEEN 0 234 i 0.021 0.236 1 0.037 0.255 1 0.047 0.227 i 0.031
10]b 10]b lO]b 9]b
THYMUS 0 092 i 0.019 0.107 i 0.019 0.094 0.020 0.076 i 0.019
10]b lOJb 10]b 91b
OVARY LEFT 26.915 6.046 25.976 1 4.034 26.551 1 3.476 26.802 i 3.440
OVARY RIGHT 27.215 1 4.339 27.123 1 3.255 28.301 1 4.894 28.246 1 4.797
UTERUS WITH CERVIX . 0.267 1 0 034 0.258 0.035 0.263 i 0.028 0 246 i 0 025
HEART 361 i 0 019 0.371 1 0.026 0.366 1 0.036 354 i 0 034
101b 10]b lOJb 9]b

[20?8 117


0

ALL WEIGHTS WERE RECORDED IN GRAMS (G). RATIOS (ORGAN BODY WEIGHT) 100.
NUMBER OF VALUES AVERAGED

Excludes values for dams that were sacrificed due to no surviving pups.

Results did not warrant examination of the five additional rats.

Value was multiplied by 1000.

Excludes rat 17706, which had an absent right kidney.

Significantly different from the vehicle control group value (p50.01).



9?3 

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C5 (PAGE 1): RATIOS OF ORGAN WEIGHT TO BRAIN WEIGHT - SUMMARY - F0 GENERATION FEMALE RATS

DOSAGE GROUP I II IV

DOSAGE 0 (VEHICLEPREGNANT 10 10 10 11

INCLUDED IN ANALYSES 10 10 10 9a

BRAIN WEIGHT MEAN1S.D. 2.20 1 0.08 2.19 1 0.07 2.19 1 0.07 2.20 1 0.08
LIVER MEAN1S.D. 521.53 1 59.00 564.65 1 40.68* 547.24 1 48.14 616.82 1 35.48**
KIDNEY LEFT MEAN1S.D. 54.44 1 5.35 59.07 1 5.87 59.77 1 14.09 55.99 1 2.45
KIDNEY RIGHT MEAN1S.D. 54.3.10
ADRENAL LEFT MEAN1S.D. 1.90 1 0.20 2.11 1 0.34 1.88 :1b0.36 2.04 1 0.34
ADRENAL RIGHT MEAN1S.D. 1.88 1 0.29 1.98 1 0.28 1.74 1 0.38 1.83 1 0.27
SPLEEN MEAN1S.D. 32.11 1 3.12 33.76 1 6.06 34.92 1 4.73 29.17 1 3.90
THYMUS MEAN1S.D. 12.42 1 3.30 15.40 1 2.84 13.18 1 3.13 9.85 1 2.66
OVARY LEFT MEAN1S.D. 3.69 1 0.86 3.66 1 0.59 3.82 1 0.73 3.42 1 0.44
OVARY RIGHT MEAN1S.D. 3.75 1 0.77 3.94 1 0.42 3.95 1 0.67 3.63 1 0.73
UTERUS WITH CERVIX MEAN1S.D. 36.63 1 5.32 36.42 1 4.93 36.07 1 2.57 32.66 1 2.24
HEART NUMBER OF VALUES AVERAGED
a. Excludes values for dams that were sacrificed due to no surviving pups.
b. Excludes rat 17706, which had an absent right kidney.

Significantly different from the vehicle control group value (1:50.05) .
Significantly different from the vehicle control group value (p50.01) .

117

L0 

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C6 (PAGE 1): HEMATOLOGY SUMMARY Fo GENERATION FEMALE RATS
(See last page of this table for abbreviations)

DOSAGE GROUP I II IV
DOSAGE (VEHICLE) 10 50 250
E, .1 
INCLUDED IN ANALYSES 4a 5 6 4

WBC MM) 20.2 i 2.70 14.9 i 1.92 20.2 i 2.71 21.6 i 2.83
RBC MM) 5.86 i 0.466 6.00 i 0.246 5.77 i 0.578 5.76 i 0.371
HGB 13.9 i 0.61 14.3 i 0.46 13.7 i 0.78 13.2 i 0.68
HCT 36.8 i 1.61 38.2 i 1.08 36.3 i 2.88 34.1 i 2.46
MCV (CU MICRONS) 63.0 i 2.88 63.6 i 2.77 63.0 i 1.87 59.2 i 1.38
MCH (PICO GRAMS) 23.8 i 1.21 23.8 i 1.08 23.8 i 1.26 22.9 i 0 46
MCHC 37.8 i 0.72 37.4 i 0.17 37.8 i 1.01 38.7 i 1.36
PLAT MM) 1534 i 140.4 947 i 531.0 1598 i 423.9 1547 1 236.6
PT (SECONDS) 13.3 i 0.40 13.3 i 0.34 13.2 i 0.16 13.2 i 0.22

41a 5] a
APTT (SECONDS) 21.2 i 2.32 18.2 i 1.95 22.0 i 3.70 19.8 i 4.39

NUMBER OF VALUES AVERAGED
a. Excludes values for rats that had clotted samples.

H7

80 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C6 (PAGE 2): HEMATOLOGY SUMMARY F0 GENERATION FEMALE RATS

(See last page of this table for abbreviations)

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLEINCLUDED IN ANALYSES 4a 5 6 4
MPV (CU MICRONS) 7.7 i 0.91 8.8 i 2.08 8.0 i 1.02 8.2 i 0.58
41a 51a
NRBC COUNT MM) 15.9 i 1.81 12.6 i 2.28 15.5 i 2.48 16.4 i 4.17
Segmented MM) 3.9 i 1.38 2.0 i 0.76 4.4 i 1.54 4.1 i 1.95
Bands MM) 0.0 i 0.00 0.0 i 0.00 0.0 i 0.00 0.1 i 0.12
Monocytes MM) 0.3 i 0.34 0.2 i 0.16 0.2 i 0.27 0.9 i 0.56
EOSinOphil MM) 0.1 i 0.12 0.0 i 0.00 0.1 i 0.17 0.0 i 0.00
Basophils MM) 0.0 i 0.00 0.0 i 0.00 0.0 i 0.00 0.0 i 0.00
Abnormal MM) 0.1 i 0.10 0.0 i 0.00 0.0 i 0.00 0.1 i 0.15
Other MM) 0.0 i 0.00 0.0 i 0.00 0.0 i 0.00 0.0 i 0.00

NUMBER OF VALUES AVERAGED

a. Excludes values for rats that had

clotted samples.

117

6?3 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY

SCREENING TEST STUDY NUMBER:

T-7599)

TABLE C6 (PAGE 3): HEMATOLOGY - SUMMARY Fo GENERATION FEMALE RATS

HGB
HCT
MCV
MCH
MCHC
PLAT
MPV
PT
APTT
NRBC
Segmented

Abnormal 

White Blood Cells (Leukocytes)
Red Blood Cells 
Hemoglobin

Hematocrit (Packed Cell Volume)
Mean Corpuscular Volume

Mean Corpuscular Hemoglobin
Mean Corpuscular Hemoglobin Concentration
Platelets

Mean Platelet Volume

Prothrombin Time

Activated Partial Thromboplastin
Nucleated Red Blood Cell Count
Segmented Neutrophils

Abnormal 

Other Cells

117

OK) 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C7 (PAGE 1): CLINICAL CHEMISTRY - SUMMARY FO GENERATION FEMALE RATS
(See last page of this table for abbreviations)

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLE0.0.CHOL TBILI 0CREAT 013.0 62 i 1318.8 117 i 20.0 120 i 23.8






I 10 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE C7 (PAGE 2): CLINICAL CHEMISTRY SUMMARY FO GENERATION FEMALE RATS
(See last page of this table for abbreviations)

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLE) 10 50 250
Sig??5413 11.8 i 0 37 11.7 i 54 11.5 i 31 11.9 i 66
PHOS 90.19 2.4 i 0.38 2.2 i 0.13 2.2 i 0.210 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C7 (PAGE 3): CLINICAL CHEMISTRY SUMMARY F0 GENERATION FEMALE RATS

ABBREVATION TERMINOLOGY
TpTotalpmten
A Albumin
GLU Glucose
CHOL Cholesterol
TBILI Total Bilirubin
BUN Blood Urea Nitrogen
CREAT Creatinine
ALT Alanine Aminotransferase
AST Aspartate Aminotransferase
ALK Alkaline Phosphatase
CA Calcium
PHOS Phosphorus (inorganic)
TRI Triglycerides
NA Sodium
Potassium
CL Chloride
Globulin
Albumin/Globulin Ratio




-

?10 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C8 (PAGE 1): BODY WEIGHTS - PRECOHABITATION SUMMARY - F0 GENERATION FEMALE RATS

DOSAGE GROUP I II IV
DOSAGE (VEHICLE) 10 50 250
RATS TESTED 15 15 15 15

BODY WEIGHT (G)

DAY 1 227.2 i 7.9 227.3 1 7.5 226.5 1 5.9 226.5 i 5.7
DAY 8 248.2 i 11.8 248.8 i 9.1 248.5 1 12.1 242.5 i 10.0
DAY 15a 262.3 1 14.7 262.3 i 13.5 260.7 i 14.6 252.9 1 12.8

DAY DAY OF STUDY
a. Last value recorded before cohabitation.

117

Hi) 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C9 (PAGE 1): BODY WEIGHT CHANGES - PRECOHABITATION - SUMMARY - F0 GENERATION FEMALE RATS

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLE) 10 50 250
RATS TESTED 15 15 15 15

BODY WEIGHT CHANGE (G)

DAYS 1 - 8 +21.0 i 6.2 +21.5 i 4.4 +21.9 i 7.5 +16.0 i 6.5*
DAYS 8 - 15a +14.1 i 5.2 +13.5 i 6.0 +12.2 5.3 +10.3 i 4.1
DAYS 1 - 15a +35.1 i 10.0 +34.9 8.4 +34.1 i 10.4 +26.3 i 8.9*

DAYS DAYS OF STUDY
a. Last value recorded before cohabitation.
Significantly different from the vehicle control group value (p50.05) .

117



.PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C10 (PAGE 1): MATERNAL BODY WEIGHTS - GESTATION SUMMARY - F0 GENERATION FEMALE RATS

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLE) 10 50 250
RATS TESTED 15 15 15 15
PREGNANT 15 14 15 I 13

MATERNAL BODY WEIGHT (G)

DAY 0 268.5 1 13.4 272.9 1 13.0 272.1 i 17.0 262.0 i 16.2
DAY 1 276.3 i 14.5 277.6 1 14.8 276.8 1 16.8 268.2 1 13.1
DAY 2 281.8 i 15.5 282.7 1 15.0 280.6 i 17.7 272.5 i 14.2
DAY 3 284.4 i 15.6 286.5 i 17.4 282.5 i 17.6 273.7 i 14.8
DAY 4 288.0 1 15.0 289.4 i 15.9 287.6 i 19.0 278.3 1 16.6
DAY 5 292.1 1 16.4 291.9 1 17.3 289.8 i 18.5 280.9 1 16.4
DAY 6 295.8 1 17.9 295.8 1 17.7 292.0 1 18.4 283.1 i 15.7
DAY 7 299.7 i 18.4 298.7 i 16.5 296.8 1 19.3 285.5 1 17.2
DAY 8 303.5 i 18.9 301.9 i 17.4 299.0 1 20.6 288.3 1 17.5
DAY 9 306.0 i 20.0 306.8 i 19.2 302.4 i 21.2 292.8 i 18.0
DAY 10 312.5 i 20.6 311.8 i 20.1 308.1 i 21.9 298.7 1 17.1
DAY 11 319.3 i 21.8 318.4 1 19.6 315.3 1 22.2 304.8 1 17.3
DAY 12 325.3 i 22.7 327.1 1 21.6 322.9 i 24.1 311.5 i 16.7
DAY 13 329.8 i 24.6 329.2 1 21.8 324.9 1 24.1 315.2 i 16910 

PROTOCOL ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: Tr7599)

TABLE C10 (PAGE 2): MATERNAL BODY WEIGHTS - GESTATION SUMMARY - FO GENERATION FEMALE RATS

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLE) 10 50 250
RATS TESTED 15 15 15 15
PREGNANT 15 14 15 13

MATERNAL BODY WEIGHT (G)

24.5 338.8

DAY 15 345.4 i 25.9 341.4 i i 24.0 328.3 1 17.0
DAY 16 355.7 1 25.5 354.2 i 25.9 350.5 i 23.4 340.9 i 16.5
DAY 17 368.6 i 27.4 368.8 i 26.5 363.9 i 24.5 353.2 i 16.4
DAY 18 386.9 i 29.4 387.1 i 29.6 380.1 i 24.1 366.2 i 17.6
DAY 19 400.6 i 29.7 400.9 i 30.7 395.7 i 24.2 381.2 1 15PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C11 (PAGE 1): MATERNAL BODY WEIGHT CHANGES - GESTATION - SUMMARY Fo GENERATION FEMALE RATS

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLE) 10 50 250
RATS TESTED 15 15 15 15
PREGNANT 15 14 15 13

MATERNAL BODY
WEIGHT CHANGE (G)

DAYS 0 3 +15.9 i 4.8 +13.6 i 5.7 +10.4 i 5.7* +11.7 i 5.4
DAYS 3 - 6 +11.4 5.5 +9.4 1 4.9 +9.5 i 4.2 +9.4 i 3.7
DAYS 6 - 9 +10.2 4.5 +11.0 3.8 +10.4 i 5.2 +9.7 i 4.3
DAYS 9 - 12 +19.3 i 4.9 +20.3 i 5.3 +20.5 i 4.2 +18.7 i 6.5
DAYS 12 15 +20.1 i 4.6 +14.3 i +15.9 i 5.2* +16.8 i 4.1
DAYS 15 - 18 +41.5 i 6.2 +45.7 i 9 2 +41.3 i 5 5 +37.9 i 6.0
DAYS 18 - 20 +31.2 i 8.6 +29.4 i 6.7 +31.3 i 6.3 +29.4 i 5.6
DAYS 0 - 20 +149.6i 24.8 +143.6? 23.0 +139.3i 17.1 +133.6i 12.8

DAYS DAYS OF GESTATION
Significantly different from the vehicle control group value .
Significantly different from the vehicle control group value .



81-3 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C12 (PAGE 1): MATERNAL BODY WEIGHTS - LACTATION - SUMMARY - F0 GENERATION FEMALE RATS

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLEPREGNANT 15 14 15 13
DELIVERED A LITTER 15 14 15 13

MATERNAL BODY WEIGHT (G)

DAY 1 321.2 i 24.7 319.8 i 20.8 316.5 i 25.0 296.3 i 25.7*

DAY 2 320.9 1 27.2 324.6 i 25.7 318.7 i 26.1 308.2 1 14.1
ll]a

DAY 3 320.9 1 26.5 326.4 i 24.7 322.7 i 25.9 308.4 1 15.0
ll]a

DAY 4 324.1 1 27.6 329.1 i 25.0 320.6 1 25.8 310.6 1 14.6
ll]a

DAY 5 327.5 i 29.4 339.1 i 21.6 327.9 i 27.5 317.4 i 12.3
ll]a

DAY 6 299.1 i 24.7 304.0 i 18.9 296.0 1 25.0 284.8 i 11.1
ll]a

DAY DAY OF LACTATION

NUMBER OF VALUES AVERAGED

. Excludes values for dams that were sacrificed due to no surviving pups.
Significantly different from the vehicle control group value (p50.05).

l?I
I?l
I

117

610 

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C13 (PAGE 1): MATERNAL BODY WEIGHT CHANGES - LACTATION - SUMMARY - F0 GENERATION FEMALE RATS

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLEPREGNANT 15 14 15 13
DELIVERED A LITTER 15 14 15 13

MATERNAL BODY
WEIGHT CHANGE (G)

DAYS 1 - 2 i 9.3 +4.7 i 8.2 +2.2 i 7.2 +3.1 i 4.6
ll]a

DAYS 2 - 3 ?0.1 i 8.0 +1ll]a

DAYS 3 - 4 +3.3 i 6.4 +2ll]a

DAYS 4 5 . +3.4 i 9.0 +l0.0 i 6.9 +7.3 1 4 3 +6.8 1 7 7
ll]a

DAYS 5 6 ?28.4 i 8.6 -35.1 i 8.5 ?31.9 i 5 8 -32.6 i 8 0
ll]a

DAYS 1 6 ?22.1 i 9.6 -l5.8 i 6.5 ?20.5 i 9 7 -20.3 i 13 3
ll]a

DAYS DAYS OF LACTATION
NUMBER OF VALUES AVERAGED
a. Excludes values for dams that were sacrificed due to no surviving pups.

0Z0 H7

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C14 (PAGE 1): ABSOLUTE FEED CONSUMPTION VALUES PRECOHABITATION SUMMARY - FO GENERATION FEMALE RATS

DOSAGE GROUP I II IV
DOSAGE (VEHICLE) 10 50 250
RATS TESTED 15 15 15 15

FEED CONSUMPTION 

DAYS 1 - 8 1919DAYS 8 - 15a 2020l4]b

DAYS 1 15a 1920l4]b

DAYS DAYS OF STUDY

NUMBER OF VALUES AVERAGED

a. Last value recorded before cohabitation.

b. Excludes values that were associated with spillage.



PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C15 (PAGE 1): RELATIVE FEED CONSUMPTION VALUES - PRECOHABITATION SUMMARY - F0 GENERATION FEMALE RATS

DOSAGE GROUP I II IV
DOSAGE (VEHICLE) 10 50 250
RATS TESTED 15 15 15 15

FEED CONSUMPTION 

DAYS 1 - 8 82DAYS 8 - 15a 7914]b

DAYS 1 15a 8014]b

DAYS DAYS OF STUDY

NUMBER OF VALUES AVERAGED

a. Last value recorded before cohabitation.

b. Excludes values that were associated with spillage.

117

Z30 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C16 (PAGE 1): MATERNAL ABSOLUTE FEED CONSUMPTION VALUES - GESTATION - SUMMARY - F0 GENERATION FEMALE RATS

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLE) 10 50 250
RATS TESTED 15 15 I 15 15
PREGNANT 15 14 15 13

MATERNAL FEED
CONSUMPTION 

DAYS 0 - 7 23.3 i 1.9 23.3 i 2.7 22.6 i 3 2 22.2 i 2 3
12]a
DAYS 7 - 10 25.1 i 2.4 25.2 i 2.7 23.7 i 3.6 24.2 i 2.7
DAYS 10 12 25.4 i 2.9 25.6 i 4.0 25.0 i 3 2 26.5 i 3 4
DAYS 12 - 15 26.4 i 2.9 26.5 i 3.8 25.7 i 4 2 26.4 i 2 3
DAYS 15 - 18 26.8 i 3.1 28.3 i 3.2 26.9 i 3 7 28.1 i 3 2
DAYS 18 - 2O 25.7 i 3.7 25.3 i 3.4 25.8 i 2.8 25.0 i 2.8
DAYS DAYS DAYS OF GESTATION
NUMBER OF VALUES AVERAGED
a. Excludes values that were associated with spillage.

[10% H7


a

?20 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C17 (PAGE 1): MATERNAL RELATIVE FEED CONSUMPTION VALUES - GESTATION SUMMARY FO GENERATION FEMALE RATS

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLE) 10 50 250
RATS TESTED 15 15 15 15
PREGNANT 15 14 15 13

MATERNAL FEED
CONSUMPTION 

DAYS 0 7 . 81.6 i 4.0 80.9 i 5.7 79.0 i 7.1 80.8 i 6.6
12]a
DAYS 7 - 10 82.1 i 5.0 82.4 i 6.2 78.4 i 8 3 83.2 i 8 1
DAYS 10 - 12 79.5 i 5.7 80.0 i 9.5 79.3 i 8 9 86.8 i 10 3
DAYS 12 - 15 78.8 i 4.9 79.1 i 7.2 77DAYS 15 - 18 73.6 i 5.5 77.9 i 5.1 75.0 i 8 1 81.2 i 9 
DAYS 18 - 20 64.0 i 7.4 62.9 i 6.2 65.1 i 4.7 65.8 i 7.5
DAYS DAYS DAYS OF GESTATION

NUMBER OF VALUES AVERAGED

a. Excludes values that were associated with spillage.

Significantly different from the vehicle control group value (p50.01).

117

W0 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE C18 (PAGE 1): MATERNAL ABSOLUTE FEED CONSUMPTION VALUES - LACTATION - SUMMARY - FO GENERATION FEMALE RATS

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLEPREGNANT 15 14 15 13
DELIVERED A LITTER 15 14 15 13

MATERNAL FEED CONSUMPTION 

DAYS 1 - 5 31.4 i 5.6 36.4 i 4.2 33.0 i 5.6 30.8 i 7.4

DAYS DAYS OF LACTATION

NUMBER OF VALUES AVERAGED

a. Excludes values that were associated with spillage.

b. Excludes values for dams that were sacrificed due to no surviving pups.



PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C19 (PAGE 1): MATERNAL RELATIVE FEED CONSUMPTION VALUES - LACTATION - SUMMARY - Fo GENERATION FEMALE RATS

DOSAGE GROUP I II IV
DOSAGE (VEHICLEPREGNANT 15 14 15 13
DELIVERED A LITTER 15 14 15 13

MATERNAL FEED
CONSUMPTION 

DAYS 1 - 5 97.0 i 13.4 110.9 i 8.4 103.3 1 13.2 99.2 i 22.8

DAYS DAYS OF LACTATION

NUMBER OF VALUES AVERAGED

a. Excludes values that were associated with spillage.

b. Excludes values for dams that were sacrificed due to no surviving pups.

I17

9Z0 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE C20 (PAGE 1): MATING AND FERTILITY, ESTROUS CYCLING AND DAYS IN COHABITATION - SUMMARY Fo GENERATION FEMALE RATS

DOSAGE GROUP . I II IV
DOSAGE (VEHICLE) 10 50 250

ESTROUS CYCLING OBSERVATIONS

 

RATS EVALUATED 15 15 15 15
PRECOHABITATION ESTROUS CYCLING

ESTROUS 3DAYS

RATS WITH 6 OR MORE
CONSECUTIVE
DAYS OF DIESTRUS 1 1 

RATS WITH 6 OR MORE
CONSECUTIVE
DAYS OF ESTRUS 0

117

LEO 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C20 (PAGE 2): MATING AND FERTILITY, ESTROUS CYCLING AND DAYS IN COHABITATION - SUMMARY FO GENERATION FEMALE RATS

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLE) 10 50 250

MATING OBSERVATIONS

 

RATS IN COHABITATION 15 15 15 15

DAYS IN COHABITATION 4.2

RATS THAT MATED 15(100.0) 15(100.0) 15(100.0) l4( 93.3)

FERTILITY INDEX 15(100.0) 93.3) (100.0) 92.8)

RATS WITH CONFIRMED
MATING DATES 15 15 15 14

MATED BY FIRST MALE 
DAYS 1-7 14( 93.3) 15(100.0) 13( 86.7) 13( 92.8)

MATED BY SECOND MALE 

DAYS 7-14 1( 6.7) 0( 0.0) 2( 13.3) 1( 7.1)

RATS IN
COHABITATION 15(100.0) 93.3) (100.0) 86.7)

a. Restricted to rats with a confirmed mating date and rats that did not mate.
b. Number of pregnancies/number of rats that mated.
c. Restricted to rats with a confirmed mating date.

H7




8Z0 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE 
TOXICITY SCREENING TEST STUDY NUMBER: T-7599)

 

 

TABLE C21 (PAGE 1) FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - FEMALE RATS

DOSAGE GROUP DOSAGE (VEHICLE) 10 50 250
RATS 5 4 5 5

HOME CAGE BEHAVI OR

 

l: Sleeping 3 2 2
2: Awake, Immobile 2 2 5 3
3: Normal movement 0 0
4: Unusual posture 0
5: Unusual behavior 0 0 0
ALTERATIONS (HOME CAGE)
1: None 5 4 5 5
2: Stereotyped behavior 0 0 0
3: Bizarre behavior 0 0 
4: Limb twitches/tremor 
5: Whole body tremor/spasm 0 0
6: Unusual posture 0 
7: Tonic?clonic seizure 0 0 
REACTION TO REMOVAL
Sits quietly 5 4 5 5
(2) Vocalization 0 0 0 
(3) Runs or freezes 0 0 
(4) Tail or throat rattles 0 0
MEAN SCORE 1.0 1.0 1.0 1.0
REACTION TO HANDLING
(1) No resistance 5 4 5 5
(2) Vocalization 0 
(3) Tense 0 
(4) Squirming 
MEAN SCORE 1.0 1.0 1.0 1.0
n: Category number for descriptive test item.
Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score

and then dividing the sum of the products by the total number of rats

620 H7

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE 
TOXICITY SCREENING TEST STUDY NUMBER: T-7599)

 

 

TABLE C2 1 (PAGE 2) FUNCTIONAL OBSERVATIONAL BATTERY SUMMARY FEMALE RATS

DOSAGE GROUP DOSAGE 0 (VEHICLE) 10 50 250

RATS 5 4 5 5

REARS IN OPEN FIELD 7.8 i 1.8 10.3 i 1.7 10DEFECATION IN OPEN FIELD
1: None 5 3 5 5
2: Feces normal

2





3: Soft or liquid feces 0 

URINATION IN OPEN FIELD

(1) None 5 3 5 5
(2) Normal urination 0 1 
(3) Excess urination 0 0 0

MEAN SCORE 1.0 1.3 1.0 1.0

LEVEL OF AROUSAL

 

Stuporous 0 0 
(2) Sluggish 0 0
(3) Apparently normal 5 4 5 5
(4) Sudden darting 0 
(5) Freezing, vocalization 0 
MEAN SCORE 3.0 3.0 3.0 3.0
ALTERATIONS (OPEN FIELD)
1 None 4 4 5 5
2 Stereotyped behavior 0 0 0 
3 Bizarre behavior 0 0
4 Limb twitches/tremor 0 0 0
5: Whole body tremor/spasm 0 0 
6 Unusual posture 0 0 
7 Tonic-clonic seizure 0
Category number for descriptive test item.
Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score

and then dividing the sum of the products by the total number of rats

H7

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE 
TOXICITY SCREENING TEST STUDY NUMBER: T-7599)

 

 

TABLE C2 1 (PAGE 3 FUNCTIONAL OBSERVAT IONAL BATTERY SUMMARY FEMALE RATS

DOSAGE GROUP I II IV
DOSAGE (VEHICLE) 10 50 250
RATS 5 4 5 5

GAIT PATTERN

 

l: Apparently normal 5 4 5 5
2: Ataxic 
3: Limbs splay or drag 0 
4: Spastic, tip?toe 0 0
5: Duck?walk 
6: Scissors gait 0 
GAIT ABNORMALITY, SEVERITY

(1) Normal gait 4 5 5
2) Slight 
(3) Moderate 0 
(4) Extreme 0 

MEAN SCORE 1.0 1.0 1.0 1.0

PALPEBRAL CLOSURE

(1) Wide open 5 4 5 5
(2) drooping 0 0 0
(3) Half?closed 0 0 0
(4) Completely shut 0 0 0 0

MEAN SCORE 1.0 1.0 1.0 1.0

PROMINENCE OF THE EYE

1: Normal 5 4 5 5
2: Exophthalmos 0 0 0
3: Enophthalmos 
n: Category number for descriptive test item.
Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score

and then dividing the sum of the products by the total number of rats

[17

ISO 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE 

TOXICITY SCREENING TEST STUDY NUMBER: 

TABLE C21 (PAGE 4): FUNCTIONAL OBSERVATIONAL BATTERY SUMMARY FEMALE RATS

 

DOSAGE GROUP

I

 

 

II IV
DOSAGE (VEHICLE) 10 50 250
RATS 5 4 5 5
LACRIMATION
(1) No excess 5 4 5 5
(2) Excess at eyelid margin 0 0 0
(3) Margin persistently damp 0 0 0 0
(4) Extends beyond margin 0 0
MEAN SCORE 1.0 1.0 1.0 1.0
SALIVATION
(1) No excess 5 4 4 5
(2) Margin of mouth wet 1 0
(3) 1/4 to 1/2 submandibular 0 
(4) Entire submandibular 0 
MEAN SCORE 1.0 1.0 1.2 1.0
PILOERECTION 0 0
ABNORMAL RESPIRATION 0
APPEARANCE
(1) Clean and groomed 5 4 5 5
(2) Unkempt 
(3) Urine and/or fecal stain 0 - 
MEAN SCORE 1.0 1.0 1.0 1.0
VISUAL REACTION
(1) None 0 0 0 0
(2) Orienting 5 4 5 5
(3) Startle 0 0 0 
(4) More energetic reaction 0 0 0
(5) Attacks 0 
MEAN SCORE 2.0 2.0 2.0 2.0
n: Category number for descriptive test item.
Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score

and then dividing the sum of the products by the total number of rats

[108117


0



PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE 
TOXICITY SCREENING TEST STUDY NUMBER: T-7599)

 

 

TABLE C21 (PAGE 5): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY FEMALE RATS

DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLE) 10 50 250
RATS 5 4 5 5

TACTILE REACTION

 

(1) None 0 0
(2) Orienting 5 4 5 5
(3) Startle 0 
(4) More energetic reaction 0 0 
(5) Attacks 0 0 
MEAN SCORE 2.0 2.0 2.0 2.0
AUDITORY REACTION
(1) None 0 0 
(2) Orienting 0 0 
(3) Startle 5 4 5 5
(4) More energetic reaction 0
(5) Intense vocalization 0 0 
MEAN SCORE 3.0 3.0 3.0 3.0
REACTION
(1) None 0 
(2) Orienting 5 4 5 5
(3) Startle 
(4) More energetic reaction 0 
(5) Attacks 0 
MEAN SCORE 2.0 2.0 2.0 2.0
VISUAL PLACING RESPONSE
(1) Early extension 5 4 5 5
(2) Extension after contact 
(3) No extension 0 0 0 0
MEAN SCORE 1.0 1.0 1.0 1.0
n: Category number for descriptive test item.
2 Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score

and then dividing the sum of the products by the total number of rats

[10"8117

?93 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE 
TOXICITY SCREENING TEST STUDY NUMBER: T-7599)

 

 

 

TABLE C21 (PAGE 6): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY FEMALE RATS
DOSAGE GROUP I II IV
DOSAGE 0 (VEHICLE) 10 50 250
RATS 5 4 5 5
AIR RIGHTING RESPONSE
(1) All feet land on ground 4 5
(2) Lands on side 0 
(3) Lands on back 0 0
MEAN SCORE 1.0 1.0 1.0 1 0
PUPIL RESPONSE TO LIGHT 5 4 5 5
FORELIMB GRIP TEST
Maximum (G) 316.0 i 53.4 303. i 105.5 260.0 i 40.8 381.0 i 114.9
Average (G) 296.2 i 43.2 276. 1 101.7 240.6 1 23.2 358.0 1 108.7
HINDLIMB GRIP TEST
Maximum (G) 298.0 1 90.7 321. i 65.4 258.0 i 44.2 359.0 i 106.5
Average (G) 274.0 i 85.3 306. i 58.2 221.2 i 38.6 328.8 i 119.0
LANDING FOOT SPLAY
Average (CMBODY WEIGHT (G) 332.8 24.7 322. i 26.9 321.2 1 23.8 313.8 i 25.9
n: Category number for descriptive test item.



Score assigned to graded test items; mean score was calculated by

multiplying each score by the number of rats with that score

and then dividing the sum of the products by the total number of rats

117

1791) 

PROTOCOL 418?027:

TABLE C22 (PAGE 1): MOTOR ACTIVITY - SUMMARY F0 GENERATION FEMALE RATS

SCREENING TEST STUDY NUMBER:



ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY

 

 

 

DOSAGE GROUP I II IV

DOSAGE 0 (VEHICLE) 10 50 250

DAY 86

NUMBER OF RATS 5 4 5 5

NUMBER OF MOVEMENTS

BLOCK 1 MEAN 1 S.D. 75.0 1 8.5 73.0 1 4.7 66.8 1 12.8 77.0 1 13.0
BLOCK 2 MEAN 1 S.D. 80.8 1 12.8 78.2 1 6.7 72.0 1 16.8 77.6 1 23.7
BLOCK 3 MEAN 1 S.D. 69.8 1 17.3 77.8 1 9.1 54.8 1 38.4 75.2 1 13.7
BLOCK 4 MEAN 1 S.D. 58.0 1 29.8 62.5 1 33.3 46.4 1 41.6 74.6 1 16.5
BLOCK 5 MEAN 1 S.D. 65.4 1 30.3 51.8 1 27.7 47.4 1 37.8 69.2 1 20.8
BLOCK 6 MEAN 1 S.D. 65.0 1 33.3 56.0 1 39.0 51.6 1 29.8 64.0 1 16.8
BLOCK 7 MEAN 1 S.D. 63.6 1 28.6 61.5 1 44.4 72.4 1 8.2 63.6 1 23.8
BLOCK 8 MEAN 1 S.D. 38.4 1 30.4 52.8 1 35.0 54.2 1 10.1 63.4 1 31.0
BLOCK 9 MEAN 1 S.D. 46.8 1 32.4 65.5 1 9.1 45.4 1 39.6 39.8 1 30.4
BLOCK 10 MEAN 1 S.D. 56.0 1 30.4 69.5 1 12.9 52.4 1 13.0 47.0 1 32.1
BLOCK 11 MEAN 1 S.D. 60.2 1 39.1 53.0 1 11.0 52.6 1 23.6 61.6 1 23.4
BLOCK 12 MEAN 1 S.D. 47.6 1 36.6 41.0 1 32.3 33.8 1 25.0 73.2 1 17.7
BLOCK 13 MEAN 1 S.D. 50.2 1 25.2 34.2 1 23.3 35.0 1 27.1 50.0 1 27.4
BLOCK 14 MEAN 1 S.D. 60.4 1 17.9 29.5 1 28.5 43.2 1 25.8 34.8 1 27.6
BLOCK 15 MEAN 1 S.D. 55.2 1 10.1 49.5 1 32.3 54.4 1 30.2 42.4 1 37.8
BLOCK 16 MEAN 1 S.D. 53.4 1 14.3 54.5 1 35.9 46.6 1 29.1 39.0 1 27.3
BLOCK 17 MEAN 1 S.D. 69.8 1 28.0 25.2 1 32.6 55.4 1 29.1 38.4 1 32.9
BLOCK 18 MEAN 1 S.D. 54.4 1 13.4 31.5 1 30.6 39.2 1 29.7 50.2 1 27.7
TOTAL MEAN 1 S.D. 1070.0 1 277.2 967.0 1 219.2 923.6 1 256.7 1041.0 1 192.9
TOTAL SUM OF EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.

I17

0


990 

PROTOCOL 418?027:

SCREENING TEST STUDY NUMBER:

TABLE C22 (PAGE 2):

T-7599)

MOTOR ACTIVITY - SUMMARY Fo GENERATION FEMALE RATS

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICTY

 

 

 

DOSAGE GROUP I II IV

DOSAGE 0 (VEHICLE) 10 50 250

DAY 86

NUMBER OF RATS 5 4 5 5

TIME (SECONDS) SPENT IN MOVEMENT

BLOCK 1 MEAN 1 S.D. 190.2 1 37.2 183.2 1 29.5 220.4 1 29.9 178.6 1 28.4
BLOCK 2 MEAN 1 S.D. 178.8 1 47.1 150.8 1 22.8 141.6 1 54.2 154.2 1 29.9
BLOCK 3 MEAN 1 S.D. 130.4 1 61.0 137.2 1 43.1 84.2 1 72.6 124.6 1 33.6
BLOCK 4 MEAN 1 S.D. 91.8 1 61.6 103.8 1 71.5 62.8 1 62.9 110.0 1 38.5
BLOCK 5 MEAN 1 S.D. 99.4 1 51.8 81.5 1 62.8 77.2 1 80.6 107.4 1 40.2
BLOCK 6 MEAN 1 S.D. 86.4 1 49.0 76.0 1 50.8 77.0 1 48.4 89.2 1 30.8
BLOCK 7 MEAN 1 S.D. 87.8 1 42.3 85.0 1 57.7 110.8 1 17.4 96.2 1 35.6
BLOCK 8 MEAN 1 S.D. 67.6 1 55.4 84.2 1 64.3 87.6 1 49.7 81.0 1 43.6
BLOCK 9 MEAN 1 S.D. 74.6 1 57.8 119.0 1 23.8 72.0 1 71.9 62.4 1 56.7
BLOCK 10 MEAN 1 S.D. 88.0 1 55.3 107.8 1 20.2 64.2 1 36.6 61.0 1 43.3
BLOCK 11 MEAN 1 S.D. 75.4 1 54.6 104.0 1 73.8 82.6 1 46.8 89.8 1 46.8
BLOCK 12 MEAN 1 S.D. 71.8 1 56.4 74.2 1 80.8 45.2 1 39.6 114.8 1 15.0
BLOCK 13 MEAN 1 S.D. 83.0 1 54.6 45.5 1 40.1 56.8 1 48.8 68.8 1 44.3
BLOCK 14 MEAN 1 S.D. 85.8 1 21.9 48.2 1 65.4 69.0 1 39.3 42.6 1 38.6
BLOCK 15 MEAN 1 S.D. 92.4 1 17.7 69.0 1 53.1 87.6 1 48.4 65.0 1 62.0
BLOCK 16 MEAN 1 S.D. 78.2 1 32.9 77.0 1 54.6 68.6 1 52.8 49.8 1 39.2
BLOCK 17 MEAN 1 S.D. 89.0 1 46.3 44.2 1 74.1 86.6 1 47.4 52.4 1 47.0
BLOCK 18 MEAN 1 S.D. 70.2 1 27.2 55.5 1 69.8 56.2 1 50.4 66.4 1 40.0
TOTAL MEAN 1 S.D. 1740.8 1 585.8 1646.2 1 621.4 1550.4 1 528.7 1614.2 1 357.2
TOTAL SUM OF EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.

117

990 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY

SCREENING TEST

STUDY NUMBER:

TABLE C23 (PAGE 1): NATURAL DELIVERY OBSERVATIONS - SUMMARY - F0 GENERATION FEMALE RATS

DOSAGE GROUP
DOSAGE 

RATS ASSIGNED TO

NATURAL DELIVERY 
PREGNANT 
DELIVERED A LITTER 

DURATION OF GESTATION a 

IMPLANTATION SITES 
PER DELIVERED LITTER 

DAMS WITH STILLBORN PUPS 

DAMS WITH NO LIVEBORN PUPS 

GESTATION INDEX 

WITH ALL PUPS DYING
DAYS 1-5 POSTPARTUM 

15
15(100.0)

15(100.0)

22.7 i 0.

l( 6.7)
0.0)

100.0
15/ 15

15

l4( 93.

14(100.

22.5 i

226
16.1 

0( O.
0( O.

100.

14/

15
15(100.0)
15(100.0)

22.8 i

2( 13.3)

0( 0.0)

15

13( 86.

13(100.

22.9 i

204
15.7 

4( 30.
0( O.

100Calculated as the time (in days) elapsed between confirmed mating (arbitrarily defined as day 0) and the time (in days)

the first pup was delivered.

b. Number of rats with live of pregnant rats.
Significantly different from the vehicle control group value (p50.01).

[10"81?7

LEO HDVJ

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C24 (PAGE 1): LITTER OBSERVATIONS (NATURALLY DELIVERED PUPS) - SUMMARY - Fl GENERATION LITTERS

MATERNAL DOSAGE GROUP I II IV
MATERNAL DOSAGE 0 (VEHICLE) 10 50 250
DELIVERED LITTERS WITH
ONE OR MORE LIVEBORN PUPS 15 14 15 13
PUPS DELIVERED (TOTAL) 236 215 231 183
15.7 i 2.3 15.4 i 2.6 15.4 i 1.2 14.1 i 2.8
LIVEBORN 15.7 i 2.2 15.4 i 2.6 15.1 i 0.9 13.3 i 3.3
235( 99.6) 215(100.0) 227( 98.3) 173( 
STILLBORN 00.4) 0( 0.0) 4( 1.7) 6( 
UNKNOWN VITAL STATUS 0 0 0 4
PUPS FOUND DEAD OR PRESUMED CANNIBALIZED
DAY 1 2/235( 0.8) o/215( 0.0) 0/227( 0.0) 4/173( 
DAYS 2- 5 o/233( 0.0) 2/215( 0.9) 2/227( 0.9) 28/169( 
VIABILITY INDEX a 99.1 99.1 99.1 81.5**
233/235 213/215 225/227 141/173

POSTPARTUM
a. Number of live pups on day 5 postpartum/number of liveborn pups on day postpartum.
Significantly different from the vehicle control group value (p50.01) .

117


0

89C) 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C24 (PAGE 2): LITTER OBSERVATIONS (NATURALLY DELIVERED PUPS) - SUMMARY - F1 GENERATION LITTERS

MATERNAL DOSAGE GROUP I II IV
MATERNAL DOSAGE 0 (VEHICLE) 10 50 250

DELIVERED LITTERS WITH
ONE OR MORE LIVEBORN PUPS 15 14 15 13

SURVIVING a

DAY lb 15.7 i 2.2 15.4 i 2.6 15.1 i 0.9 13.3 i 3.3
DAY 5 15.5 i 2.1 15.2 i 2.4 15.0 i 1.0 10.8 i 6.3*
PERCENT MALE PUPS PER
NUMBER OF PUPS SEXED
DAY 1b 53.0 i 9.2 52.7 i 12.2 52.2 i 17.0 44.2 i 16.2
DAY 5 53.1 i 9.7 52.9 i 12.2 52.8 i 17.4 47.0 i 17.4
lO]c

DAY DAY POSTPARTUM
NUMBER OF VALUES AVERAGED
a. Average number of live pups per litter, including litters with no surviving pups.
b. Includes pups born alive, found dead day postpartum.
c. Excludes values for dams that were sacrificed due to no surviving pups.
Significantly different from the vehicle control group value (p50.05).






680 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C24 (PAGE 3): LITTER OBSERVATIONS (NATURALLY DELIVERED PUPS) - SUMMARY Fl GENERATION LITTERS

MATERNAL DOSAGE GROUP I II IV
MATERNAL DOSAGE 0 (VEHICLE) 10 50 250

DELIVERED LITTERS WITH
ONE OR MORE LIVEBORN PUPS 15 14 15 13

LIVE LITTER SIZE AT WEIGHING

DAY 1 15.5: 2.1 15.4: 2.6 15.1: 0.9 14.1: 1.8
12]a

DAY 5 15.5: 2.1 15.2: 2.4 15.0: 1.0 14.1: 1.7
101a

PUP (GRAMS)

6.4: 07 63:04 6.5: 03 59:08
12]a

DAYS 9.6: 10 100: 08 100: 10 93:13
101a

DAY DAY POSTPARTUM
NUMBER OF VALUES AVERAGED
Excludes values for dams that were sacrificed due to no surviving pups.






0170 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C2 5 (PAGE 1) CLINICAL OBSERVATIONS FROM BIRTH To DAY 5 - SUMMARY Fl GENERATION PUPS
i ii ii; ix} 
MATERNAL DOSAGE KG 0 (VEHICLE) 10 5 250
LITTERS EXAMINED (N) 15 14 15 13
21311;; 1213;?; 
COLD TO TOUCH 0/0 0/0 0/0 2/1
NOT NESTING 0/0 0/0 0/0 2/1
NOT NURSING 0/0 0/0 0/0 2/1
PALE 0/0 2/1 0/0 0/0
BRUISE 2/1 9/1 2/1 9/3

STATISTICAL ANALYSES WERE RESTRICTED TO THE NUMBER OF LITTERS WITH OBSERVATIONS.
a. Tabulation restricted to adverse observations; all other pups appeared normal.
b. Head, back, mouth, lower midline, chest, and/or neck.

H7

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C26 (PAGE 1): NECROPSY OBSERVATIONS SUMMARY - F1 GENERATION PUPS

MATERNAL DOSAGE GROUP MATERNAL DOSAGE (VEHICLE) 10 50 250
LITTERS EXAMINED (N) 15 14 15 13

TOTAL PUPS STILLBORN

OR FOUND DEAD a,b 2 0 4 5
STILLBORN 1 0 4 3
FOUND DEAD 1 0 2

NO MILK IN STOMACH 1(100.0) 0.0) 0( 0.0) 1( 50.0)

PUPS SACRIFICED AND NECROPSIED ON DAY 5 POSTPARTUM 

LITTERS EVALUATED 1 5 14 1 5 1 
PUPS EVALUATED APPEARED NORMAL

LITTER INCIDENCE 15(100 0) 14(100.0) 15(100.0) 10(100.0)
PUP INCIDENCE 233(100 0) 212( 99.5) 225(100.0) 141(100.0)
KIDNEYS: 
BILATERAL, PELVIS, SLIGHT DILATION
LITTER INCIDENCE 0( 0.0) 1( 7.1) o( 0.0) o( 0.0)
PUP INCIDENCE 0( 0.0) 1( 0.5) 0( 0.0) 0( 0.0)

a. Restricted to pups in which complete necropsies were performed. Complete necropsies were not performed on pups in which
autolysis or cannibalization precluded evaluation.

b. Refer to the individual pup clinical observations table (Table C44) for external clinical observations confirmed at necropsy.

c. Analysis restricted to pups found dead and necropsied.



PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE C27 (PAGE 1): CLINICAL OBSERVATIONS - INDIVIDUAL DATA - FO GENERATION FEMALE RATS

DOSAGE GROUP I VEHICLE (VEHICLE) 
RAT DESCRIPTION
17662 NO ADVERSE FINDINGS
17672 14 EXCESS SALIVATION
17673 NO ADVERSE FINDINGS
17674 3 CHROMODACRYORRHEA
17680 14 RED, SLIGHT PERIORAL SUBSTANCE
17681 NO ADVERSE FINDINGS
17690 NO ADVERSE FINDINGS
17694 NO ADVERSE FINDINGS
17695 11- 16) LOCALIZED ALOPECIA: LIMBS
0- 20) LOCALIZED ALOPECIA: LIMBS
1? 6) LOCALIZED ALOPECIA: LIMBS a
17703 NO ADVERSE FINDINGS
17713 NO ADVERSE FINDINGS
17715 NO ADVERSE FINDINGS
17716 NO ADVERSE FINDINGS
17717 12- 15) LOCALIZED ALOPECIA: LIMBS
0- 21) LOCALIZED ALOPECIA: LIMBS
1- 6) LOCALIZED ALOPECIA: LIMBS a
17719 NO ADVERSE FINDINGS
DS DAY OF STUDY DG DAY OF PRESUMED GESTATION DL DAY OF LACTATION

a. Observation confirmed at necropsy.

[10% 117

?170 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE C27 (PAGE 2): CLINICAL OBSERVATIONS - INDIVIDUAL DATA - FO GENERATION FEMALE RATS

DOSAGE GROUP II LOW DOSAGE 10 

RAT DESCRIPTION

17663 0 SOFT OR LIQUID FECES

17665 NO ADVERSE FINDINGS

17666 NO ADVERSE FINDINGS

17668 NO ADVERSE FINDINGS

17671 9- 21) LOCALIZED ALOPECIA: LIMBS
1- 6) LOCALIZED ALOPECIA: LIMBS a

17675 NO ADVERSE FINDINGS

17679 14 INCISORS: 

17684 NO ADVERSE FINDINGS

17688 NO ADVERSE FINDINGS

17698 13 LOCALIZED ALOPECIA: LIMBS
12- 19) LOCALIZED ALOPECIA: LIMBS

17702 NO ADVERSE FINDINGS

17704 NO ADVERSE FINDINGS

17707 3- 21) LOCALIZED ALOPECIA: LIMBS
1- 5) LOCALIZED ALOPECIA: LIMBS

17708 5- 6) LOCALIZED ALOPECIA: LIMBS a

17710 NO ADVERSE FINDINGS

DS DAY OF STUDY DG DAY OF PRESUMED GESTATION
a. Observation confirmed at necropsy.



17170 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C27 (PAGE 3): CLINICAL OBSERVATIONS - INDIVIDUAL DATA - FO GENERATION FEMALE RATS
DOSAGE GROUP MIDDLE DOSAGE 50 
RAT DESCRIPTION
17661 20- 21) CHROMODACRYORRHEA
17667 NO ADVERSE FINDINGS
17669 18- 21) LOCALIZED ALOPECIA: LIMBS
1? 6) LOCALIZED ALOPECIA: LIMBS a

17670 16 URINE-STAINED ABDOMINAL FUR

17676 NO ADVERSE FINDINGS

17687 3- 13) RIGHT EYE: CORNEAL OPACITY
15? 16) RIGHT EYE: CORNEAL OPACITY

17693 NO ADVERSE FINDINGS

17697 NO ADVERSE FINDINGS

17700 NO ADVERSE FINDINGS

17701 NO ADVERSE FINDINGS

17705 NO ADVERSE FINDINGS

17706 NO ADVERSE FINDINGS

17709 17- 27) LOCALIZED ALOPECIA: LIMBS
0- 21) LOCALIZED ALOPECIA: LIMBS
1- 6) LOCALIZED ALOPECIA: LIMBS a

17718 NO ADVERSE FINDINGS

17720 16 URINE-STAINED ABDOMINAL FUR

DS DAY OF STUDY DG DAY OF PRESUMED GESTATION DL DAY OF LACTATION

a. Observation confirmed at necropsy.

H7

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C27 (PAGE 4): CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS

DOSAGE GROUP IV HIGH DOSAGE 250 
RAT DESCRIPTION
17664 21- 28) INCISORS: 
50 RED, SLIGHT PERIORAL SUBSTANCE
17677 16- 18) URINE-STAINED ABDOMINAL FUR
0- 2) URINE-STAINED ABDOMINAL FUR
17678 17 RED, SLIGHT PERIORAL SUBSTANCE
1 EXCESS SALIVATION
13 RED, SLIGHT PERIORAL SUBSTANCE
20 EXCESS SALIVATION
17682 23- 25) EXCESS SALIVATION
3 RED, SLIGHT PERIORAL SUBSTANCE
15 RED, SLIGHT PERIORAL SUBSTANCE
17683 5- 21) LOCALIZED ALOPECIA: LIMBS
18? 21) LOCALIZED ALOPECIA: UNDERSIDE
1- 6) LOCALIZED ALOPECIA: LIMBS a
1- 6) LOCALIZED ALOPECIA: UNDERSIDE a
17685 12 EXCESS SALIVATION
14- 15) EXCESS SALIVATION
0- 7) EXCESS SALIVATION
13- 16) EXCESS SALIVATION
19- 20) EXCESS SALIVATION
1 EXCESS SALIVATION
3 EXCESS SALIVATION
5 EXCESS SALIVATION
17686 15 RED, SLIGHT PERIORAL SUBSTANCE
0 RED, SLIGHT PERIORAL SUBSTANCE
3 URINE-STAINED ABDOMINAL FUR
6 RED, SLIGHT PERIORAL SUBSTANCE
7~ 14) URINE-STAINED ABDOMINAL FUR
8- 9) RED, SLIGHT PERIORAL SUBSTANCE
15 RED, SLIGHT PERIORAL SUBSTANCE
16 EXCESS SALIVATION
20- 22) LOCALIZED ALOPECIA: HEAD
21 EXCESS SALIVATION
DS DAY OF STUDY DG DAY OF PRESUMED GESTATION DL DAY OF LACTATION

a. Observation confirmed at necropsy.



9?7'0 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C27 (PAGE 5): CLINICAL OBSERVATIONS - INDIVIDUAL DATA FO GENERATION FEMALE RATS

RAT DESCRIPTION
17689 NO ADVERSE FINDINGS
17691 3 CHROMODACRYORRHEA
11 EXCESS SALIVATION
17692 3 RED, SLIGHT PERIORAL SUBSTANCE
7 RED, SLIGHT PERIORAL SUBSTANCE
17696 13 EXCESS SALIVATION
1 RED, SLIGHT PERIORAL SUBSTANCE
5 EXCESS SALIVATION
9 EXCESS SALIVATION
13 EXCESS SALIVATION
16 EXCESS SALIVATION
2 SACRIFICED DUE T0 N0 SURVIVING PUPS
17699 NO ADVERSE FINDINGS
17711 14 RED, SLIGHT PERIORAL SUBSTANCE
RED, SLIGHT PERIORAL SUBSTANCE
RED, SLIGHT PERIORAL SUBSTANCE
RED, SLIGHT PERIORAL SUBSTANCE
RED, SLIGHT PERIORAL SUBSTANCE
14 RED PERIVAGINAL SUBSTANCE
15 RED, MODERATE PERIORAL SUBSTANCE
17 EXCESS SALIVATION
1 DEHYDRATION a
2 SACRIFICED DUE T0 N0 SURVIVING PUPS
17712 3- 15) TAIL BENT
15 RED, SLIGHT PERIORAL SUBSTANCE
0- 21) TAIL BENT

1- 21)
14 

LOCALIZED ALOPECIA: LIMBS
EXCESS SALIVATION

1 EXCESS SALIVATION
1 LOCALIZED ALOPECIA: LIMBS
1- 6) TAIL BENT a

17714 17 RED, SLIGHT PERIORAL SUBSTANCE

DS DAY OF STUDY DG DAY OF PRESUMED GESTATION DL DAY OF LACTATION
a. Observation confirmed at necropsy.



L170 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY

SCREENING TEST STUDY NUMBER: T-7599)

TABLE C28 (PAGE 1): NECROPSY OBSERVATIONS INDIVIDUAL DATA - FO GENERATION FEMALE RATS
DOSAGE GROUP RAT DAY OF PREGNANCY DOSES
DOSAGE NUMBER NECROPSY STATUS ADMINISTERED OBSERVATIONS a
I
0 (VEHICLE) 17662 DL 6 44 ALL TISSUES APPEARED
17672 DL 6 45 ALL TISSUES APPEARED
17673 DL 6 42 ALL TISSUES APPEARED
17674 DL 6 42 ALL TISSUES APPEARED
17680 DL 6 44 ALL TISSUES APPEARED
17681 DL 6 44 ALL TISSUES APPEARED
17690 DL 6 44 ALL TISSUES APPEARED
17694 DL 6 42 ALL TISSUES APPEARED
17695 DL 6 41 ALL TISSUES APPEARED
17703 DL 6 42 ALL TISSUES APPEARED
17713 DL 6 44 ALL TISSUES APPEARED
17715 DL 6 45 ALL TISSUES APPEARED
17716 VDL 6 45 ALL TISSUES APPEARED
17717 DL 6 42 ALL TISSUES APPEARED
17719 DL 6 49 ALL TISSUES APPEARED
II
10 17663 DG 25 NP 42 ALL TISSUES APPEARED
17665 DL 6 43 ALL TISSUES APPEARED
17666 DL 6 42 ALL TISSUES APPEARED
17668 DL 6 44 ALL TISSUES APPEARED
17671 DL 6 44 ALL TISSUES APPEARED
17675 DL 6 43 ALL TISSUES APPEARED
17679 DL 6 44 ALL TISSUES APPEARED
17684 DL 6 45 ALL TISSUES APPEARED
17688 DL 6 43 ALL TISSUES APPEARED
17698 DL 6 43 ALL TISSUES APPEARED
17702 DL 6 42 ALL TISSUES APPEARED
17704 DL 6 43 ALL TISSUES APPEARED
17707 DL 6 45 ALL TISSUES APPEARED
17708 DL 6 42 ALL TISSUES APPEARED
17710 DL 6 45 ALL TISSUES APPEARED
DS DAY OF STUDY DG DAY OF PRESUMED GESTATION DL DAY OF LACTATION

PREGNANT NP NOT PREGNANT

Refer to the individual clinical observations table (Table C27) for external observations

NORMAL.
NORMAL.
NORMAL.
NORMAL.
NORMAL.
NORMAL.
NORMAL.
NORMAL.
NORMAL.
NORMAL.
NORMAL.
NORMAL.
NORMAL.
NORMAL.
NORMAL.

confirmed at necropsy.



8170 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C28 (PAGE 2): NECROPSY OBSERVATIONS - INDIVIDUAL DATA - F0 GENERATION FEMALE RATS

DOSAGE GROUP RAT DAY OF PREGNANCY DOSES
DOSAGE NUMBER NECROPSY STATUS ADMINISTERED OBSERVATIONS a

50 17661 DL 6 43 ALL TISSUES APPEARED NORMAL.
17667 DL 6 43 ALL TISSUES APPEARED NORMAL.
17669 DL 6 44 ALL TISSUES APPEARED NORMAL.
17670 DL 6 45 ALL TISSUES APPEARED NORMAL.
17676 DL 6 43 ALL TISSUES APPEARED NORMAL.
17687 DL 6 45 ALL TISSUES APPEARED NORMAL.
17693 DL 6 42 ALL TISSUES APPEARED NORMAL.
17697 DL 6 44 ALL TISSUES APPEARED NORMAL.
17700 DL 6 43 ALL TISSUES APPEARED NORMAL.
17701 DL 6 44 ALL TISSUES APPEARED NORMAL.
17705 DL 6 44 ALL TISSUES APPEARED NORMAL.
17706 DL 6 45 KIDNEYS: RIGHT, ABSENT.
ALL OTHER TISSUES APPEARED NORMAL.
17709 DL 6 53 ALL TISSUES APPEARED NORMAL.
17718 DL 6 53 ALL TISSUES APPEARED NORMAL.
17720 DL 6 45 ALL TISSUES APPEARED NORMAL.
IV
250 17664 DS 54 NP 53 ALL TISSUES APPEARED NORMAL
17677 DL 6 46 ALL TISSUES APPEARED NORMAL
17678 DL 6 45 ALL TISSUES APPEARED NORMAL
17682 DL 6 53 ALL TISSUES APPEARED NORMAL
17683 DL 6 44 ALL TISSUES APPEARED NORMAL
17685 DL 6 42 ALL TISSUES APPEARED NORMAL
17686 DG 25 NP 40 ALL TISSUES APPEARED NORMAL
17689 DL 6 41 ALL TISSUES APPEARED NORMAL
17691 DL 6 45 ALL TISSUES APPEARED NORMAL
17692 DL 6 42 ALL TISSUES APPEARED NORMAL
DS DAY OF STUDY DG DAY OF PRESUMED GESTATION DL DAY OF LACTATION

PREGNANT NP NOT PREGNANT

a. Refer to the individual clinical observations table (Table C27) for external observations

confirmed at necropsy.



6170 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE C28 (PAGE 3): NECROPSY OBSERVATIONS - INDIVIDUAL DATA Fo GENERATION FEMALE RATS
DOSAGE GROUP RAT DAY OF PREGNANCY DOSES
DOSAGE NUMBER NECROPSY STATUS ADMINISTERED OBSERVATIONS a
IV
250 17696 DL 2 39 SACRIFICED DUE T0 N0 SURVIVING PUPS ON DAY 2 OF LACTATION.
cont. THYMUS: SMALL.

ALL OTHER TISSUES APPEARED NORMAL.
17699 DL 6 44 ALL TISSUES APPEARED NORMAL.

17711 DL 2 39 SACRIFICED DUE T0 N0 SURVIVING PUPS ON DAY 2 OF LACTATION.
ALL TISSUES APPEARED NORMAL.

17712 DL 6 42 ALL TISSUES APPEARED NORMAL.
17714 DL 6 44 ALL TISSUES APPEARED NORMAL.
DS DAY OF STUDY DG DAY OF PRESUMED GESTATION DL DAY OF LACTATION

PREGNANT NP NOT PREGNANT
a. Refer to the individual clinical observations table (Table C27) for external observations confirmed at necropsy.

117

090 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C29 (PAGE 1): TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT -
INDIVIDUAL DATA - Fo GENERATION FEMALE RATS

DOSAGE GROUP I VEHICLE 0 (VEHICLE) 
BRAIN LIVER KIDNEY KIDNEY ADRENAL ADRENAL
. RAT TERMINAL BODY LEFT RIGHT LEFT RIGHT
NUMBER WEIGHT ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. REL17662 303 9.58 3.16

17672 319 12 34 3.87

17673 271 10 17 3.75

17674 282 10 10 3.58

17680 303 11 66 3.85

17681 303 2.04 0.67 11 10 3.66 1.13 0.37 1.19 0.17690 345 2.27 0.66 12 40 3.59 1.28 0.37 1.31 0.17694 291 2.28 0.78 11 10 3.81 1.21 0.42 1.33 0.17695 271 2.16 0.80 10 63 3.92 1.08 0.40 1.00 0.17703 339 2.27 0.67 13 19 3.89 1.51 0.44 1.43 0.17713 292 2.26 0.77 9 91 3.39 1.03 0.35 1.03 0.17715 328 2.22 0.68 11 72 3.57 1.24 0.38 1.17 0.17716 298 2.15 0.72 13 55 4.55 1.19 0.40 1.21 0.17717 274 2.15 0.78 9 57 3.49 1.15 0.42 1.15 0.17719 268 2.16 0.80 11 30 4.22 1.14 0.42 1.17 0.ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN BODY WEIGHT) 100.

PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
a. Value was multiplied by 1000.

ISO 117

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C29 (PAGE 2): TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT -
INDIVIDUAL DATA - Fo GENERATION FEMALE RATS

DOSAGE GROUP I VEHICLE (VEHICLE) 
SPLEEN THYMUS OVARY OVARY UTERUS HEART
RAT TERMINAL BODY LEFT RIGHT WITH CERVIX
NUMBER WEIGHT ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. RELTBW
17662 303 089 0.23
17672 319 0.26
17673 271 0.71 0.26
17674 282 0.77 0.27
17680 303 0.31
17681 303 0.76 0.25 0.33 0.0.24 1.04 0 34
17690 345 0.70 0.20 0.38 0.1.17 0 34
17694 291 0.66 0.23 0.23 0.08 0 081 27 84 0.070 24 05 0 77 0 26 1.11 0 38
17695 271 0.70 0.26 0.24 0.09 0 103 38 01 0.090 33 21 0 96 0.35 0.94 0 35
17703 339 0.79 0.23 0 37 0.11 0 111 32 74 0.113 33 33 0 95 0.28 1.25 0 37
17713 292 0.65 0.22 0.31 0.11 0 044 15 07 0.057 19 52 0.74 0 25 1.02 0 35
17715 328 0.76 0.23 0.25 0.08 0 066 20 12 0.096 29 27 0.98 0.30 1.24 0 38
17716 298 0.70 0.23 0.20 0.07 0 080 26 84 0.071 23 82 0.68 0.23 1.00 0 34
17717 274 0.73 0.27 0.27 0.10 0 068 24 82 0.071 25 91 0.62 0.23 1.08 0 39
17719 268 0.59 0.22 0.15 0.06 0 083 30 97 0.079 29 48 0 77b 0 29 0.99 0 37
ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN BODY WEIGHT) 100.

PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
a. Value was multiplied by 1000.
b. Damaged during processing (weight not affected).

H7

Z90 

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE C29 (PAGE 3): TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT 
INDIVIDUAL DATA - FO GENERATION FEMALE RATS

DOSAGE GROUP II LOW DOSAGE 10 
BRAIN LIVER KIDNEY KIDNEY ADRENAL ADRENAL
RAT TERMINAL BODY LEFT RIGHT LEFT RIGHT
NUMBER WEIGHT ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. REL17663 NP 267. 7 49 2.80
17665 308 10 81 3.51
17666 289 12 16 4.21
17668 299. 10 54 3.52
17671 256. 8 16 3.19
17675 297 2.18 0.73 12 27 4.13 1.31 0.44 1.34 0.45 0.044 14 81 0 039 13 13
17679 295 2.13 0.72 11 54 3.91 1.35 0.46 1.30 0.44 0.037 12 54 0 036 12 20
17684 317 2.15 0.68 12.17 3.84 1.30 0.41 1.37 0.43 0.042 13 25 0 042 13 25
17688 311 2.21 0.71 11.60 3.73 1.02 0.33 1.20 0.38 0.054 17 36 0 049 15 76
17698 299 2.24 0.75 11 43 3.82 1.38 0.46 1.41 0.47 0.047 15 72 0 036 12 04
17702 307 2.05 0.67 11 83 3.85 1.14 0.37 1.23 0.40 0.041 13 36 0 040 13 03
17704 327 2.26 0.69 13 36 4.08 1.41 0.43 1.41 0.43 0.049 14 98 0 049 14 98
17707 296 2.18 0.74 11 40 3.85 1.15 0.39 1.10 0.37 0.047 15 88 045 15 20
17708 328 2.29 0.70 14 27 4.35 1.49 0.45 1.35 0.41 0.039 11 89 0 042 12 80
17710 327 2.20 0.67 13 78 4.21 1.39 0.42 1 40 0.43 0.063 19 27 0 056 17 12
ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN BODY WEIGHT) 100.

PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
a. Value was multiplied by 1000.

[108117

?90 

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C29 (PAGE 4): TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT -
INDIVIDUAL DATA - F0 GENERATION FEMALE RATS

DOSAGE GROUP II LOW DOSAGE 10 
SPLEEN THYMUS OVARY OVARY UTERUS HEART
RAT TERMINAL BODY LEFT RIGHT WITH CERVIX
NUMBER WEIGHT ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. RELTBW
17663 NP 267 0 053 19 85 0.062 23 22 0 48 0.18
17665 308 0 078 25 32 0.094 30 52 0 62 0.20
17666 289 0 067 23 18 0.076 26 30 0 91 0.31
17668 299 0 082 27 42 0.073 24 41 80 0.27
17671 256 0 073 28 52 0.053 20 70 0 74 0.29
17675 297 0.75 0.25 0.36 0.12 0 078 26 26 0.086 28 96 0 89 0.30 1.13 0 38
17679 295 0.55 0.19 0.29 0.10 0 063 21 36 0.071 24 07 0 71 0.24 1.00 0 34
17684 317 0 74 0.23 0.36 0.11 0 080 25 24 0.090 28 39 0 84 0 26 1.19 0 38
17688 311 0 64 0.20 0.26 0.08 0 090 28 94 0.086 27 65 0.76 0 24 1.23 0 40
17698 299 0 66 0.22 0 30 0.10 0 110 36 79 0.092 30 77 0.70 0.23 1.26 0 42
17702 307 0.71 0.23 0.29 0.09 0 071 23 13 0.082 26 71 0.92 0.30 1.16 0 38
17704 327 0.98 0.30 0.37 0.11 0 074 22 63 0.100 30 58 0.95 0.29 1.18 36
17707 296 0.60 0.20 0.29 0.10 0 077 26 01 0.086 29 05 0 66 0.22 1.08 0 36
17708 328 0 82 0.25 0.50 0.15 0 069 21 04 0.072 21 95 0 78 0.24 1.10 0 34
17710 327 0 95 0.29 0.0.097 29 66 0 75 0.23 1.16 0 35
ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN BODY WEIGHT) 100.

PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
a. Value was multiplied by 1000.

117

1790 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C29 (PAGE 5): TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT 
INDIVIDUAL DATA FO GENERATION FEMALE RATS

DOSAGE GROUP MIDDLE DOSAGE 50 
BRAIN LIVER KIDNEY KIDNEY ADRENAL ADRENAL
RAT TERMINAL BODY LEFT RIGHT LEFT RIGHT
NUMBER WEIGHT ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. REL17661 280 10 84 3.87
17667 311 13 45 4.32
17669 296 10 92 3.69
17670 268. 10 80 4.03
17676 265. 9 21 3.48
17687 337 2.13 0.63 13 22 3.92 1.25 0.37 1.33 0.39 0.045 13 35 0.042 12 46
17693 274 2.15 0.78 10 76 3.93 1.05 0.38 1.16 0.42 0.033 12 04 0.033 12 04
17697 268 2.17 0.81 10 23 3.82 1.11 0.41 1.10 0.41 0.030 11 19 0.026 9 70
17700 310 2.13 0.69 10 96 3.54 1.35 0 44 1.46 0.47 0.043 13 87 0.043 13 87
17701 311 2.26 0.73 12 74 4.10 1.12 0.36 1.19 0.38 0.047 15 11 0.042 13 50
17705 330 2.11 0.64 12 94 3.92 1.19 0.36 1.19 0.36 0.053 16 06 0.047 14 24
17706 315 2.22 0.70 12 79 4.06 2.15 0 68 0.043 13 65 0.039 12 38
17709 262 2.13 0.81 11 06 4.22 1.12 0 43 1.12 43 0.031 11 83 0.029 11 07
17718 295 2.27 0.77 12 17 4.12 1.46 49 1.45 0 49 0.038 12 88 0.029 9 83
17720 318 2.29 0.72 12 75 4.01 1.28 0 40 1.41 0 44 0.047 14 78 0.050 15 72
ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN BODY WEIGHT) 100.

PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
a. Value was multiplied by 1000.
b. Dam 17706 had an absent right kidney. See the individual necropsy observations table (Table C28) .

90 H7

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C29 (PAGE 6): TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT -
INDIVIDUAL DATA - Fo GENERATION FEMALE RATS

DOSAGE GROUP MIDDLE DOSAGE 50 
SPLEEN THYMUS OVARY OVARY UTERUS HEART
RAT TERMINAL BODY LEFT RIGHT WITH CERVIX
NUMBER WEIGHT ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. RELTBW
17661 280 0.63 0.22
17667 311 94b 0.30
17669 296 0.89 0.30
17670 268 0.67 0.25
17676 265 0.67 0.25
17687 337 0.78 0.23 0.37 0.0.22 1.05 0.31
17693 274 0.79 0.29 0.18 0.72b 0.26 0.99 0.36
17697 268 0.66 0.25 0.19 0.0.32 0.98 0.36
17700 310 0.62 20 0.35 0.0.82 0.26 1.12 0.36
17701 311 0.74 0 24 0.32 0.0.86 0 28 1.17 0.38
17705 330 0.73 0.22 0.27 0.1.38 0.42
17706 315 0.84 0.27 0.31 0.0.26 1.11 0.35
17709 262 0.90 0 34 0.31 0.0.27 0.91 0.35
17718 295 0.92 0.31 0.23 0.1.28 0.43
17720 318 0.65 0.20 0.35 0.0.24 1.10 0.34
ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN BODY WEIGHT) 100.

PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
a. Value was multiplied by 1000.
b. Damaged during processing (weight not affected) .

[10% 

990 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE C29 (PAGE 7): TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT -
INDIVIDUAL DATA - FO GENERATION FEMALE RATS

DOSAGE GROUP IV HIGH DOSAGE 250 
BRAIN LIVER KIDNEY KIDNEY ADRENAL ADRENAL

RAT TERMINAL BODY LEFT RIGHT LEFT RIGHT

NUMBER WEIGHT ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. REL17664 NP 11 51 
17677 287 13 06 4.55
17678 293 2 23 0.76 13 68 4.0.050 17 06 0 038 12 97
17682 300 14 07 4.69
17683 259 2.19 0.84 12 48 4.82 1 17 0.45 1.28 0.17685 277 2 31b 0.83 13 29 4.80 1 37 0.49 1.40 0.17686 NP 284 2 10 0.74 12 31 4.33 30 0.46 1.31 0.17689 285 2.27 0.80 14 32 5.02 1 30 0.46 1.27 0.17691 286 2.02 0.71 11 62 4.06 1 12 0.39 1.21 0.17692 277 1.17696 2 17 14 77 1 28 1.24 0 053 0 041 
17699 283 0.46 1.40 0.17711 2 10 12 56 1 38 1.38 0 059 0 052 
17712 292 0.41 1.22 0.17714 294 0.39 1.22 0.ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN BODY WEIGHT) 100.

PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)

a Value was multiplied by 1000.

b. Damaged during processing (weight not affected).

Dam was sacrificed due to no surviving pups on day 2 of lactation; values excluded from group averages and statistical
analyses.

117


0

L90 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C29 (PAGE 8): TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT -
INDIVIDUAL DATA - F0 GENERATION FEMALE RATS 

DOSAGE GROUP IV HIGH DOSAGE 250 
SPLEEN THYMUS OVARY OVARY UTERUS HEART

RAT TERMINAL BODY LEFT RIGHT WITH CERVIX

NUMBER WEIGHT ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. RELTBW

17664 NP 0 068 0.081 0 51b 
17677 287 0 072 25 09 0.083 28 92 0 68 0.24
17678 293 0 81 0.0.100 34 13 0 76 0.26 1.21 0 41
17682 300 0 092 30 67 0.086 28 67 0 58 0.19
17683 259 0.60 0.23 0 23 0.09 0 074 28 57 0.074 28 57 0 68 0.26 0.90 0.35
17685 277 0.54 0.19 20 0.07 0 079 28 52 0.072 25 99 0 70 0.25 0.94 0.34
17686 NP 284 0.48 0.17 43 0.15 0 058 20 42 0.053 18 66 0 42 0 15 1.09 0.38
17689 285 0.70 0.24 0 19 0.07 0 072 25 26 0.066 23 16 0.82 0 29 0.99 0.35
17691 286 0.54 0.19 0 29 0.10 0 066 23 08 0.074 25 87 0.67 0 23 0.94 0.33
17692 277 0 66 0.0.076 27 44 0 71 0 26 0.84 0 30
17696 49 0 06d 0 070 0.083 1 71 0.85 
17699 283 0 67 0.24 0 23 0.08 0 090 31 80 0.102 36 O4 0 64 0.23 1.00 0.35
17711 0 39 0 23 0 062 0.086 2 15 1.04 
17712 292 0 69 0.24 0 20 0.07 0 088 30 14 0.095 32 53 0 77 0.26 1.18 0.40
17714 294 0 56 0.19 15 0.05 0 076 25 85 0.057 19 39 0 71 0.24 1.05 0.36

ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN BODY WEIGHT) 100.

PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)

a. Value was multiplied by 1000.

b. Damaged during processing (weight not affected).

c. Dam was sacrificed due to no surviving pups on day 2 of lactation; values excluded from group averages and statistical
analyses.

d. Dam 17696 had a small thymus. See the individual necropsy observations table (Table C28).

89%) 

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE C30 (PAGE 1): ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - F0 GENERATION FEMALE RATS

DOSAGE GROUP I VEHICLE 0 (VEHICLE) 
LIVER KIDNEY KIDNEY ADRENAL ADRENAL SPLEEN

RAT BRAIN LEFT RIGHT LEFT RIGHT

NUMBER WEIGHT ABS REL ABS REL. ABS RELBRW
17681 0.034 1.67 034 1.67 0 76 37 25
17690 0.047 17694 0.041 1 80 0 042 1.84 66 28 95
17695 0.039 1 80 0 033 1.53 70 32 41
17703 0.042 17713 0.037 17715 0.041 17716 0.044 2.17717 0.049 2.17719 0.044 2.THYMUS OVARY OVARY UTERUS HEART

RAT BRAIN LEFT RIGHT WITH CERVIX

NUMBER WEIGHT ABS REL. ABS REL. ABS REL. ABS REL. ABS RELBRW

17681 2.04 0 33 16.18 0 080 3.92 0.096 4.70 0.74 36.27 1.04 50.98
17690 2.27 0 38 16.74 0 094 4.14 0.078 3.44 0.84 37.00 1.17 51.54
17694 2.28 0 23 10 09 081 3.55 0.070 3.07 0.77 33 77 1.11 48 68
17695 2.16 0 24 11.11 0 103 4 77 0.090 4.17 0.96 44 44 0.94 43 52
17703 2.27 0 37 16.30 0 111 4 89 0.113 4.98 0.95 41 85 1.25 55 07
17713 2.0.057 2.52 0.74 32 74 1.02 45 13
17715 2.22 0 25 11.26 0 066 2.97 0.096 4.32 0.98 44.14 1.24 55 86
17716 2.15 0 20 9.30 0 080 3.72 0.071 3.30 0.68 31 63 1.00 46 51
17717 2.15 27 12 56 068 3.16 0.071 3.30 0.62 28 84 1.08 50 23
17719 2.16 0 15 6.94 083 3 84 0.079 3.66 0.77a 35 65 0.99 45 83

ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN WEIGHT) 100.

PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
a. Damaged during processing (weight not affected).

H7

690 

 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C30 (PAGE 2): ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - FO GENERATION FEMALE RATS

DOSAGE GROUP II LOW DOSAGE 10 
LIVER KIDNEY KIDNEY ADRENAL ADRENAL SPLEEN

RAT BRAIN LEFT RIGHT LEFT RIGHT

NUMBER WEIGHT ABS REL ABS RELBRW
17675 61.47 0.044 2 02 0 039 1.79 0 75 34.40
17679 61.03 0.037 1 74 0 036 1.69 0 55 25 82
17684 0.042 1.95 0 042 1.95 0 74 34 42
17688 0.054 2.44 0 049 2.22 0 64 28 96
17698 0.047 2.10 0 036 1.61 0 66 29 46
17702 0.041 2.00 0 040 1.95 0 71 34 63
17704 0.049 2.17 0 049 2.17 0 98 43 36
17707 0.047 2.16 0 045 2.06 0 60 27 52
17708 0.039 1.70 0 042 1.83 0 82 35 81
17710 0.063 2 86 0 056 2.54 0 95 43 18
THYMUS OVARY OVARY UTERUS HEART

RAT BRAIN LEFT RIGHT WITH CERVIX

NUMBER WEIGHT ABS REL ABS REL ABS REL ABS REL. ABS RELBRW

17675 2.18 0 36 16 51 0.078 3.58 0.086 3.51.83
17679 2.13 0 29 13 62 0.063 2.96 0.071 3.46.95
17684 2.15 0 36 16 74 0.080 3.72 0.090 4.17688 2.21 26 11 76 0.090 4 07 0.086 3.17698 2.24 30 13 39 0.110 4 91 0.092 4.17702 2.05 0 29 14 15 0.071 3.46 0.082 4.17704 2.26 0 37 16 37 0.074 3.27 0.100 4.17707 2.18 0 29 13 30 0.077 3 53 0.086 3.17708 2.29 0 50 21 83 0.069 3.01 0.072 3.17710 2.20 0 36 16 36 0.091 4.14 0.097 4.ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN WEIGHT) 100.

PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)

I17

090 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C30 (PAGE 3): ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - F0 GENERATION FEMALE RATS

DOSAGE GROUP MIDDLE DOSAGE 50 
LIVER KIDNEY KIDNEY ADRENAL ADRENAL SPLEEN

RAT BRAIN LEFT RIGHT LEFT RIGHT

NUMBER WEIGHT ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. RELBRW
17687 1.33 62 44 0 045 2.11 0 042 1.97 0.78 36 62
17693 1.16 53 95 0 033 1.53 0 033 1.53 0.79 36 74
17697 1.10 50 69 0 030 1.38 0 026 1.20 0.66 30 41
17700 1.46 68 54 0 043 2.02 043 2.02 0.62 29 11
17701 49.56 1.19 52.65 0 047 2.08 0 042 1.86 0.74 32.74
17705 56.40 1.19 56.40 0 053 2.51 0 047 2.23 0.73 34 60
17706 96.85 a a 043 1.94 039 1.76 0.84 37 84
17709 1.12 52 58 0 031 1.46 0 029 1.36 0.90 42 25
17718 1.45 63 88 0 038 1.67 0 029 1.28 0.92 40 53
17720 1.41 61 57 0 047 2.05 0 050 2.18 0.65 28 38
THYMUS OVARY OVARY UTERUS HEART

RAT BRAIN LEFT RIGHT WITH CERVIX

NUMBER WEIGHT ABS REL ABS. REL ABS REL ABS RELBRW

17687 2.13 0.37 17.37 0.101 4.74 0 101 4.74 74 34 74 1.05 49.30
17693 2.15 0.18 8.37 0.062 2.88 0 081 3.77 0 72b 33 49 0.99 46.05
17697 2.17 0.19 8.76 0.071 3.27 0 093 4.28 0 85 39 17 0.98 45 16
17700 2.13 0.35 16 43 0.082 3.85 0 077 3.62 0 82 38 50 1.12 52 58
17701 2.26 0.32 14 16 0.072 3.18 0 064 2.83 86 38 05 1.17 51 77
17705 2.11 0.27 12 80 0.097 4 60 0 075 3.55 0 83 39 34 1.38 65 40
17706 2.22 0.31 13 96 0.108 4.86 0 111 5.00 0 82 36 94 1.11 50 00
17709 2.13 0.31 14 55 0.066 3.10 0 090 4.22 0 72 33 80 0.91 42 72
17718 2.27 0.23 10 13 0.082 3 61 0 074 3.26 0 76 33 48 1.28 56 39
17720 2.29 0.35 15 28 0.093 4 06 0 097 4.24 0 76 33 19 1.10 48 03

ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN WEIGHT) 100.

PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
a. Dam 17706 had an absent right kidney. See the individual necropsy observations table (Table C28) .
b. Damaged during processing (weight not affected) .

I90 117

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C30 (PAGE 4): ORGAN WEIGHTS AND RATIOS OF ORGAN WEIGHT TO BRAIN WEIGHT INDIVIDUAL DATA - FO GENERATION FEMALE RATS

DOSAGE GROUP IV HIGH DOSAGE 250 
LIVER KIDNEY KIDNEY ADRENAL ADRENAL SPLEEN

RAT BRAIN LEFT RIGHT LEFT RIGHT

NUMBER WEIGHT ABS REL ABS REL. ABS RELBRW
17678 050 2.24 0.038 1.70 0.81 36 32
17683 054 2.46 0.048 2.19 0.60 27 40
17685 043 1.86 0.034 ?1.47 0.54 23 38
17686 037 1.76 0.036 1.71 0.48 22 86
17689 045 1.98 0.043 1.89 0.70 30 84
17691 037 1.83 0.036 1.78 0.54 26 73
17692 031 1.43 0.033 1.52 0.66 30 41
17696b 053 2.44 0.041 1.89 0.49 22 58
17699 055 2.52 0.050 2.29 0.67 30 73
17711b 059 2.81 0.052 2.48 0.39 18 57
17712 041 1.87 0.039 1.78 0.69 31 51
17714 049 2.21 0.042 1.89 0.56 25 22
THYMUS OVARY OVARY UTERUS HEART

RAT BRAIN LEFT RIGHT WITH CERVIX

NUMBER WEIGHT ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. RELBRW

17678 2.23 0 30 13.45 0 074 3.32 0 100 4.48 0.76 34.08 1 21 54 26
17683 2.19 0 23 10.50 0 074 3.38 0 074 3.38 0.68 31.05 0 90 41 10
17685 2.31a 0 20 8.66 0 079 3.42 0 072 3.12 0.70 30 30 94 40 69
17686 NP 2.10 0 43 20.48 0 058 2.76 0 053 2.52 0.42 20.00 1 09 51 90
17689 2.27 0 19 8.37 0 072 3.17 0 066 2.91 0.17691 2.02 0 29 14.36 0 066 3.27 0 074 3.66 0.17692 2.17 0 15 6.91 0 057 2.63 0 076 3.50 0.17696b 2.17 0 06C 2.76 0 070 3.22 0 083 3.82 1.17699 2.18 0.23 10.55 0 090 4.13 0 102 4.68 0.17711b 2.10 0.23 10.95 0 062 2.95 0 086 4.10 2.17712 2.19 0 20 9.13 0 088 4.02 0 095 4.34 0.77 35.16 1 18 53 88
17714 2.22 0 15 6.76 0 076 3.42 0 057 2.57 0.ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. ORGAN WEIGHT. REL. TBW (ORGAN WEIGHT) 100.

PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)

a. Damaged during processing (weight not affected).

b. Dam was sacrificed due to no surviving pups on day 2 of lactation; values excluded from group averages and statistical
analyses.

c. Dam 17696 had a small thymus. See the individual necropsy observations table (Table C28).

H7

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE C31 (PAGE 1): BODY WEIGHTS - PRECOHABITATION - INDIVIDUAL DATA - F0 GENERATION FEMALE RATS

RAT DOSAGE GROUP I VEHICLE (VEHICLE15a

17662 222 221 229 231 234 234 238. 241 243 239 246 247 249 247 252
17672 237 241 240 243 254 250 253. 262 266 264 267 276 279 279 275
17673 225 225 224 229 232 234 228. 239 237 241 236 238 245 247 246
17674 229 230 237 240 242 243 251. 254 261 264 261 270 271 277 270
17680 222 220 229 232 233 229 235. 245 246 243 247 251 256 250 257
17681 239 235 242 245 244 247 252 257 253 256 260 262 265 263 267
17690 224 226 234 237 242 242 248. 258 253 261 262 262 269 271 275
17694 226 226 230 232 237 243 245. 243 249 251 253 251 257 264 265
17695 216 220 227 224 226 231 237 234 233 241 244 239 244 254 250
17703 240 238 248 248 256 252 260. 268 266 266 273 279 283 278 292
17713 230 229 239 239 240 237 245. 252 249 249 253 257 252 254 260
17715 237 238 247 249 246 247 258. 259 261 262 270 273 271 269 274
17716 221 222 224 227 227 229 231. 233 238 235 233 240 242 242 244
17717 224 227 232 229 234 240 246. 250 256 262 260 264 270 270 271
17719 216 217 221 219 219 224 228 228 227 230 233 238 238 234 237

DAY DAY OF STUDY
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
a. Last value recorded before cohabitation.

117

S90 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C31 (PAGE 2): BODY WEIGHTS - PRECOHABITATION INDIVIDUAL DATA - FO GENERATION FEMALE RATS

RAT DOSAGE GROUP II LOW DOSAGE 15a

17663 221 220 224 222 229 223 235. 235 237 237 240 243 246 247 247
17665 234 232 238 244 242 238 245 250 247 247 251 256 256 257 262
17666 223 226 233 234 240 244 248. 248 256 259 259 259 263 269 268
17668 224 225 231 235 233 233 236. 240 241 240 244 247 248 246 252
17671 215 215 222 222 224 220 224. 236 230 226 231 235 235 232 235
17675 233 236 238 238 238 241 246. 250 248 256 254 253 253 259 260
17679 221 225 231 234 236 236 240. 249 246 248 254 257 257 260 262
17684 228 234 236 239 243 245 247. 251 259 260 261 264 266 268 264
17688 225 226 229 232 234 235 240. 246 246 250 255 258 256 261 265
17698 237 230 239 246 246 242 250. 258 258 255 262 264 267 266 272
17702 223 230 227 233 240 246 244. 250 263 263 254 259 270 269 261
17704 233 232 236 240 246 248 250. 255 261 268 271 267 273 278 280
17707 218 224 220 226 227 230 232. 237 235 234 236 238 243 242 245
17708 239 238 245 252 254 254 260. 266 270 272 271 278 283 286 285
17710 236 238 239 249 246 251 256STUDY
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
a. Last value recorded before cohabitation.

H7




1790 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE C31 (PAGE 3): BODY WEIGHTS PRECOHABITATION INDIVIDUAL DATA Fo GENERATION FEMALE RATS

RAT DOSAGE GROUP MIDDLE DOSAGE 15a

17661 218 220 226 222 222 229 230 226 228 234 235 233 232 237 239
17667 232 240 247 249 244 252 258 257 256 263 268 264 262 270 272
17669 231 231 241 242 244 242 253. 257 258 258 265 268 267 267 271
17670 228 226 229 234 238 238 238. 249 247 245 247 249 258 254 249
17676 217 218 218 223 226 227 225 231 232 235 236 234 238 243 246
17687 238 238 248 252 255 256 262. 270 268 276 281 288 289 287 289
17693 222 226 230 234 237 237 238. 249 249 250 248 246 256 255 253
17697 225 225 230 235 233 232 237. 243 241 240 244 250 249 253 252
17700 225 229 233 238 242 244 249. 256 254 255 261 263 266 266 273
17701 236 235 244 248 249 249 255. 261 262 264 269 269 271 272 278
17705 225 225 230 235 239 240 242. 255 253 248 263 262 268 261 271
17706 227 231 234 238 243 244 246. 253 257 259 259 266 266 262 266
17709 222 220 223 224 228 223 229. 232 233 230 236 240 243 240 245
17718 228 231 230 234 235 237 236. 243 244 248 246 250 254 253 249
17720 224 226 222 229 233 235 245 245 253 258 259 264 278 269 257

DAY DAY OF STUDY
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
a. Last value recorded before cohabitation.

IV

990 

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE C31 (PAGE 4): BODY WEIGHTS - PRECOHABITATION INDIVIDUAL DATA - FO GENERATION FEMALE RATS

RAT DOSAGE GROUP IV HIGH DOSAGE 250 
DAY 15a

17664 217 219 214 219 225 227 223. 232 233 235 232 241 244 244 242
17677 236 239 244 240 249 255 257. 256 251 263 264 273 271 270 268
17678 228 227 229 231 236 238 234. 244 243 246 242 249 251 248 250
17682 224 233 234 235 237 242 247. 248 252 253 256 256 256 256 260
17683 222 220 226 226 228 226 228. 234 233 236 240 241 240 241 243
17685 233 233 235 230 236 241 239. 241 246 251 250 246 253 257 258
17686 227 225 227 228 229 230 228. 237 237 235 235 242 241 243 244
17689 226 226 229 235 238 238 241. 247 248 250 252 256 256 256 260
17691 229 222 215 223 233 234 235. 243 244 245 243 249 248 253 252
17692 222 224 225 224 231 235 235 236 241 244 243 241 246 247 246
17696 218 219 218 225 228 225 223. 232 233 236 234 236 241 235 234
17699 232 234 239 243 247 248 254. 256 257 256 260 260 264 260 267
17711 223 222 223 224 232 234 233. 234 239 239 238 240 243 243 241
17712 227 228 221 228 234 237 226. 234 238 239 236 235 243 244 246
17714 234 235 242 248 252 252 258 264 264 264 270 278 280 278 282

DAY DAY OF STUDY
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
a. Last value recorded before cohabitation.

[17




990 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE C32 (PAGE 1): MATERNAL BODY WEIGHTS - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS

RAT DOSAGE GROUP I VEHICLE (VEHICLE) 

PREGNANCY

STATUS DAY 17662 255 263 270 270 276 281 287 288 293 300 303 310 315
17672 289 298 299 301 304 312 316 323 326 324 336 348 346
17673 248 253 261 265 267 269 275 276 283 284 286 296 300
17674 272 284 290 293 294 302 304 308 315 316 321 329 338
17680 268 272 286 281 285 288 289 297 300 304 312 320 328
17681 277 284 286 287 292 298 301 306 309 312 320 328 334
17690 281 289 301 300 307 312 324 328 330 340 343 351 361
17694 265 274 277 278 284 286 295 292 299 300 309 312 319
17695 254 259 262 268 270 278 280 284 280 281 292 293 305
17703 286 296 309 313 316 319 327 331 336 341 347 354 362
17713 260 269 274 276 283 279 281 292 293 293 302 304 317
17715 288 298 300 310 308 316 316 320 327 328 337 344 352
17716 253 264 265 271 276 280 277 283 285 292 295 303 307
17717 269 276 279 282 284 286 288 285 291 292 297 306 305
17719 262 266 268 271 274 275 277 282 286 283 287 291 291

DAY 17662 316. 323 329 342 354 367 380 392 406
17672 354. 360 372 380 394 408 424 442 464
17673 304. 308 316 326 336 351 364 380 393
17674 341. 352 360 371 385 407 429 453 461
17680 332. 341 352 360 377 397 412 438 458
17681 334. 346 348 358 370 391 403 414 427
17690 371. 380 386 400 413 440 454 476 512
17694 325. 338 344 354 367 383 399 417 437
17695 299. 307 319 332 341 362 372 380
17703 370. 387 389 400 419 439 448 477
17713 318. 331 333 345 355 376 380 392 413
17715 360. 364 373 377 392 410 423 444 469
17716 313. 316 327 337 352 361 379 392 410
17717 310. 318 324 332 339 357 367 381 387
17719 300. 304 309 321 335 354 375 393 415

PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAY DAY OF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G).



L90 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C32 (PAGE 2): MATERNAL BODY WEIGHTS - PRESUMED GESTATION - INDIVIDUAL DATA FO GENERATION FEMALE RATS

RAT DOSAGE GROUP II LOW DOSAGE 10 
PREGNANCY

STATUS DAY 17663 NP 258 253 250 256 261 261 259 260 262 267 271 268 266
17665 267 271 274 280 284 286 295 296 297 300 308 315 324
17666 272 275 279 284 286 278 283 288 289 293 292 298 303
17668 263 261 269 276 280 279 291 290 294 298 306 314 324
17671 244 251 255 249 258 260 263 265 271 273 280 281 292
17675 266 267 272 277 278 282 283 291 291 298 299 306 313
17679 271 277 282 279 284 284 286 291 290 294 298 306 316
17684 283 286 294 294 298 304 303 309 311 314 324 333 339
17688 275 281 285 288 293 298 303 305 310 316 324 329 336
17698 278 284 298 300 305 309 314 309 317 321 334 336 342
17702 273 284 286 291 292 289 296 299 300 309 306 316 319
17704 277 291 294 299 298 304 306 313 316 324 329 336 348
17707 264 261 265 270 271 278 275 279 283 283 286 299 304
17708 288 290 294 301 303 310 312 320 323 328 332 334 349
17710 300 308 311 323 322 326 332 327 335 345 347 354 371

DAY 17663 NP 268 269 270 272 269 268 267 269 277 279 281 279 267
17665 326 336 339 354 368 390 396 417 434
17666 307 309 314 326 339 355 371 387 400
17668 322 338 337 353 373 382 391 405 426
17671 289 294 300 310 322 334 346 359 371
17675 317 317 321 335 353 377 395 411 434
17679 313 323 323 330 343 348 362 375 383
17684 348 351 361 373. 388 404 425 441 468
17688 332 351 344 366. 387 406 419 432
17698 340 356 353 364 376 397 402 413
17702 329 332 345 357 370 389 404 416 436
17704 349 356 372 382 399 425 445 459 468
17707 313 315 320 328 340 363 377 389 408
17708 350 355 363 378 389 414 431 456 472
17710 374 384 388 403 416 436 449 471 498

PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAY DAY OF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G).

I17

890 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C32 (PAGE 3): MATERNAL BODY WEIGHTS - PRESUMED GESTATION - INDIVIDUAL DATA - F0 GENERATION FEMALE RATS

RAT DOSAGE GROUP MIDDLE DOSAGE 50 

PREGNANCY

STATUS DAY 17661 243 251 248. 253 259 258 265 276 275 279 286 293 302
17667 273 287 290. 296 295 299 301 308 313 316 321 327 335
17669 282 288 290. 290 294 295 293 301 305 307 309 317 325
17670 262 262 265. 262 269 275 274 275 279 287 292 295 305
17676 247 250 253. 253 255 260 261 265 262 265 270 274 282
17687 305 305 311. 313 322 326 326 333 336 337 348 356 366
17693 255 262 265. 268 272 275 279 281 283 283 288 298 302
17697 258 262 274. 274 271 274 275 275 277 280 286 297 298
17700 277 280 285. 288 293 296 297 300 305 310 312 321 328
17701 293 298 299. 301 311 311 312 322 324 331 341 346 354
17705 280 288 297. 297 303 299 311 316 320 325 330 338 352
17706 276 282 283. 286 294 301 302 301 306 314 317 324 337
17709 273 272 276. 278 284 286 286 293 291 287 296 301 300
17718 288 292 297. 294 299 298 301 304 305 306 311 320 324
17720 269 273 27617661 306. 312 326 340 355 376 391 402 424
17667 337. 342 353 361 378 395 412 419 440
17669 325. 330 338 348 367 386 403 416 436
17670 306. 315 320 337 346 362 380 394 416
17676 284. 291 298 308 324 334 350 358 373
17687 370. 370 376 388 403 417 434 450 476
17693 301. 306 312 327 330 351 369 385 405
17697 300. 310 318 326 344 361 373 386 405
17700 333. 341 352 361 375 390 405 416
17701 355. 365 366 383 388 410 423 442 466
17705 350. 359 367 377 394 407 418 443 467
17706 340. 339 351 359 377 377 401 423 443
17709 304. 308 307 324. 331 352 362 379 391
17718 326. 335 344 352. 367 386 402 423
17720 336. 346 354 366 380 397 413 435 454

PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAY DAY OF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G).

If?

0
.



PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C32 (PAGE 4): MATERNAL BODY WEIGHTS PRESUMED GESTATION - INDIVIDUAL DATA - F0 GENERATION FEMALE RATS

RAT DOSAGE GROUP IV HIGH DOSAGE 250 
PREGNANCY

STATUS DAY 17664 NP MATING NOT CONFIRMED
17677 268. 276. 278. 281. 288. 290. 286. 289. 296. 297. 303. 313. 317.
17678 263. 269. 274. 283. 284. 289. 292. 297. 299. 303. 309. 320. 327.
17682 288. 284. 288. 290. 293. 292. 293. 299. 299. 303. 308. 310. 319.
17683 250. 264. 265. 261. 264. 267. 270. 266. 278. 279. 293. 304. 315.
17685 262. 268. 270. 275. 280. 282. 288. 289. 290. 295. 299. 302. 305.
17686 NP 243. 251. 259. 265. 267. 268. 272. 271. 278. 284. 286. 302. 293.
17689 264. 268. 267. 268. 270. 272. 276. 282. 288. 290. 293. 302. 305.
17691 264. 268. 274. 277. 281. 288. 287. 295. 296. 304. 309. 316. 317.
17692 254. 260. 262. 264. 269. 269. 274. 278. 276. 283. 284. 291. 299.
17696 231. 244. 252. 252. 252. 255. 257. 256. 259. 261. 272. 274. 282.
17699 272. 275. 283. 282. 289. 292. 299. 295. 296. 302. 309. 312. 321.
17711 249. 254. 256. 256. 261. 264. 266. 268. 264. 271. 278. 282. 293.
17712 250. 261. 267. 264. 271. 274. 275. 276. 280. 285. 288. 295. 301.
17714 291. 296. 306. 305. 316. 318. 317. 322. 327. 333. 338. 341. 34817664 NP MATING NOT CONFIRMED
17677 319. 325. 332. 341. 358. 363. 373. 386. 398. 381.
17678 330. 332. 338. 347. 364. 373. 385. 405. 422.
17682 324. 331. 341. 355. 367. 371. 389. 401.
17683 318. 328. 326. 339. 348. 369. 380. 396. 417.
17685 313. 319. 328. 340. 351. 373. 389. 403. 409.
17686 NP 272. 277. 275. 266. 270. 278. 284. 294. 290. 296. 299. 298. 284.
17689 316. 324. 327. 350. 355. 369. 389. 409. 420.
17691 324. 324. 331. 340. 351. 359. 374. 381. 391.
17692 298. 307. 315. 329. 340. 357. 371. 395. 409.
17696 284. 290. 299. 311. 323. 338. 356. 369. 377. 370.
17699 326. 333. 340. 352. 366. 380. 396. 403. 415.
17711 295. 300. 305. 319. 332. 337. 355. 366. 364. 354.
17712 304. 309. 320. 333. 350. 366. 385. 399. 408.
17714 347. 358. 366. 376. 387. 406. 414. 430. 443.

PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAY DAY OF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G).

0L0 117

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C33 (PAGE 1): MATERNAL BODY WEIGHTS - LACTATION - INDIVIDUAL DATA - F0 GENERATION FEMALE RATS

RAT DOSAGE GROUP I VEHICLE 0 (VEHICLE17662 304 315 321 328 328 303
17672 339 329 350 354 361 319
17673 304 287 290 301 295 271
17674 321 326 321 318 306 282
17680 331 331 332 339 338 303
17681 326 329 327 331 337 303
17690 360 381 366 372 388 345
17694 315 317 322 328 317 291
17695 294 293 286 298 299 271
17703 366 354 354 362 371 339
17713 312 305 311 302 321 292
17715 356 357 353 353 350 328
17716 305 306 302 298 307 298
17717 291 294 293 286 295 274
17719 294 290 285 292 300 268

DAY DAY OF LACTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G).

1L0 117

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C33 (PAGE 2): MATERNAL BODY WEIGHTS - LACTATION - INDIVIDUAL DATA - FO GENERATION FEMALE RATS

RAT DOSAGE GROUP II LOW DOSAGE 17663 NOT PREGNANT
17665 325. 324. 327. 326. 335. 308.
17666 297. 304. 299. 301. 309. 289.
17668 308. 312. 323. 329. 342. 299.
17671 276. 273. 270. 262. 290. 256.
17675 307. 313. 323. 325. 335. 297.
17679 322. 313. 307. 319. 328. 295.
17684 332. 345. 344. 339. 348. 317.
17688 332. 339. 337. 352. 355. 311.
17698 315. 318. 328. 339. 341. 299.
17702 328. 327. 333. 340. 344. 307.
17704 342. 350. 346. 349. 351. 327.
17707 299. 299. 309. 319. 330. 296.
17708 351. 357. 359. 344. 360. 328.
17710 344. 370. 364. 363. 379. 327.

DAY DAY OF LACTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G).



HDVJ

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C33 (PAGE 3): MATERNAL BODY WEIGHTS - LACTATION - INDIVIDUAL DATA - F0 GENERATION FEMALE RATS

RAT DOSAGE GROUP MIDDLE DOSAGE 17661 311 299 306 297 306 280
17667 331 329 332 329 341 311
17669 321 322 319 325 336 296
17670 294 297 294 292 294 268
17676 269 276 287 289 294 265
17687 351 354 359 354 364 337
17693 294 286 295 299 302 274
17697 295 297 311 295 304 268
17700 334 343 344 335 348 310
17701 351 348 350 345 348 311
17705 331 349 361 362 374 330
17706 337 337 337 341 340 315
17709 282 287 284 286 290 262
17718 314 323 320 318 326 295
17720 333 334 341 342 351 318

DAY DAY OF LACTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G).

117

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C33 (PAGE 4): MATERNAL BODY WEIGHTS - LACTATION - INDIVIDUAL DATA FO GENERATION FEMALE RATS

RAT DOSAGE GROUP IV HIGH DOSAGE 250 
DAY 1 2 3 4 5 6

17664 NOT MATING NOT CONFIRMED

17677 304. 298. 304. 304. 304. 287.

17678 327. 324. 332. 328. 330. 293.

17682 306. 310. 317. 321. 338. 300.

17683 298. 302. 296. 294. 304. 259.

17685 293. 304. 295. 294. 307. 277.

17686 NOT PREGNANT

17689 301. 302. 307. 312. 324. 285.

17691 303. 308. 310. 307. 315. 286.

17692 273. 279. 282. 291. 300. 277.

17696 248. SACRIFICED DUE T0 N0 SURVIVING PUPS ON DAY 2 OF LACTATION

17699 314. 318. 315. 320. 322. 283.

17711 248. SACRIFICED DUE T0 N0 SURVIVING PUPS ON DAY 2 OF LACTATION

17712 307. 313. 304. 310. 322. 292.

17714 330. 332. 331. 336. 326. 294.

DAY DAY OF LACTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G).

I17



PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C34 (PAGE 1): FEED CONSUMPTION VALUES - PRECOHABITATION INDIVIDUAL DATA FO GENERATION FEMALE RATS

RAT DOSAGE GROUP I VEHICLE 0 (VEHICLE) 
DAYS 1- 8 8- 15a
17662 138 132
17672 141 150
17673 103 110
17674 145 150
17680 133 145
17681 134 141
17690 127 146
17694 128 141
17695 141 139
17703 136 147
17713 129 130
17715 136 136
17716 196 192
17717 129 148
17719 123 124

DAY DAY OF STUDY
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
a. Last value recorded before cohabitation.

SLO H7

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C34 (PAGE 2): FEED CONSUMPTION VALUES PRECOHABITATION - INDIVIDUAL DATA - FO GENERATION FEMALE RATS

RAT DOSAGE GROUP II LOW DOSAGE 10 
DAYS 1- 8 8- 15a
17663 117 139
17665 156 149
17666 134 141
17668 126 131
17671 115 112
17675 128 143
17679 145 151
17684 140 156
17688 128 153
17698 142 141
17702 143 150
17704 139 162
17707 124 122
17708 151 160
17710 145 164

DAY DAY OF STUDY 
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
a. Last value recorded before cohabitation.

117

91:0 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C34 (PAGE 3): FEED CONSUMPTION VALUES - PRECOHABITATION INDIVIDUAL DATA F0 GENERATION FEMALE RATS

RAT DOSAGE GROUP MIDDLE DOSAGE 50 
DAYS 1? 8 8- 15a
17661 123 117
17667 130 132
17669 150 146
17670 138 132
17676 119 125
17687 187 191
17693 140 133
17697 129 136
17700 157 153
17701 160 167
17705 124 150
17706 140 146
17709 110 118
17718 124 133
17720 144 158

DAY DAY OF STUDY
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
a. Last value recorded before cohabitation.



PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C34 (PAGE 4): FEED CONSUMPTION VALUES - PRECOHABITATION - INDIVIDUAL DATA - FO GENERATION FEMALE RATS

RAT DOSAGE GROUP IV HIGH DOSAGE 250 
DAYS 1? 8 8- 15a
17664 125 134
17677 147 145
17678 123 129
17682 178 
17683 118 122
17685 133 149
17686 121 122
17689 135 139
17691 113 141
17692 126 137
17696 108 124
17699 138 141
17711 119 122
17712 109 122
17714 147 153

DAY DAY OF STUDY

ALL WEIGHTS WERE RECORDED IN GRAMS (G).

a. Last value recorded before cohabitation.

b. Spilled feed precluded the calculation of this value.

117

BLO 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE C35 (PAGE 1): MATERNAL FEED CONSUMPTION VALUES - PRESUMED GESTATION INDIVIDUAL DATA FO GENERATION FEMALE RATS

RAT DOSAGE GROUP I VEHICLE 0 (VEHICLE) 
PREGNANCY

STATUS DAYS 17662 159 80 50. 74 78 42
17672 171 75 55. 85 85 54
17673 138 64 45. 67 67 50
17674 171 83 53. 85 92 68
17680 165 79 55. 85 91 56
17681 159 77 53. 82 78 49
17690 190 89 61. 94 99 62
17694 168 76 44. 80 83 52
17695 161 72 52. 81 80 51
17703 183 84 55. 85 91 47
17713 154 74 49. 75 71 39
17715 176 77 58. 9O 75 56
17716 159 66 48. 75 69 52
17717 148 66 41. 65 75 44
17719 149 67 43. 66 74 50

PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAYS DAYS OF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G).

[10?8117

6L0 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C35 (PAGE 2): MATERNAL FEED CONSUMPTION VALUES - PRESUMED GESTATION - INDIVIDUAL DATA - FO GENERATION FEMALE RATS

RAT DOSAGE GROUP II LOW DOSAGE 10 
PREGNANCY

STATUS DAYS 17663 17665 168 75 56. 78 83 45
17666 135 59 39. 61 71 46
17668 157 83 55. 81 88 44
17671 139 69 41. 62 72 41
17675 152 71 47. 69 76 51
17679 164 75 52. 82 83 49
17684 170 76 57. 87 86 58
17688 165 80 43. 74 101 55
17698 168 81 55. 83 85 40
17702 166 71 42. 81 84 58
17704 179 82 60. 98 99 57
17707 139 63 51. 73 74 48
17708 172 87 52. 83 95 61
17710 207 84 67. 101 92 55

PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAYS DAYS OF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G).

117

080 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C35 (PAGE 3): MATERNAL FEED CONSUMPTION VALUES - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS

RAT DOSAGE GROUP MIDDLE DOSAGE 50 
PREGNANCY
STATUS DAYS 17661 140 71 58. 86 90 58
17667 154 73 47. 74 80 50
17669 155 70 52. 76 89 48
17670 129 60 44. 73 70 50
17676 126 58 47. 66 65 41
17687 207 87 58. 92 81 61
17693 146 65 40. 54 68 52
17697 146 64 48. 77 86 44
17700 169 81 54. 91 98 52
17701 188 83 53. 88 94 58
17705 167 84 56. 85 94 54
17706 178 78 53. 83 75 52
17709 143 52 38. 53 65 45
17718 152 62 45. 67 72 51
17720 172 79 57. 91 84 58

PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAYS DAYS OF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G).




0

{8?0 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C35 (PAGE 4): MATERNAL FEED CONSUMPTION VALUES - PRESUMED GESTATION - INDIVIDUAL DATA Fo GENERATION FEMALE RATS

RAT DOSAGE GROUP IV HIGH DOSAGE 250 
PREGNANCY

STATUS DAYS 17664 NP MATING NOT CONFIRMED

17677 153. 73. 52. 82. 72. 45.
17678 175. 73. 58. 79. 79. 55.
17682 170. 72. 68. 77. 80. 52.
17683 136. 82. 57. 85. 93. 46.
17685 174. 76. 42. 69. 86. 51.
17686 NP 148. 63. 34. 50. 48. 44.
17689 140. 78. 50. 76. 82. 51.
17691 a 74. 46. 76. 76. 42.
17692 152. 67. 47. 77. 84. 51.
17696 136. 60. 53. 72. 79. 47.
17699 162. 72. 58. 87. 97. 49.
17711 136. 55. 47. 71. 75. 50.
17712 174. 82. 54. 89. 106. 65.
17714 164. 82. 56. 90. 89. 47.

PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAYS DAYS OF PRESUMED GESTATION

ALL WEIGHTS WERE RECORDED IN GRAMS (G).

a. Spilled feed precluded the calculation of this value.

117

Z80 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C36 (PAGE 1): MATERNAL FEED CONSUMPTION VALUES - LACTATION - INDIVIDUAL DATA F0 GENERATION FEMALE RATS

17662 144
17672 143
17673 93
17674 97
17680 150
17681 129
17690 168
17694 126
17695 118
17703 127
17713 100
17715 138
17716 138
17717 94
17719 121

DAY DAY OF LACTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G).

117


0

E80 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C36 (PAGE 2): MATERNAL FEED CONSUMPTION VALUES - LACTATION - INDIVIDUAL DATA - FO GENERATION FEMALE RATS

17663 NOT PREGNANT
17665 133.
17666 131.
17668 158.
17671 117.
17675 153.
17679 118.
17684 156.
17688 147.
17698 a
17702 139.
17704 164.
17707 147.
17708 166.
17710 163.

DAY DAY OF LACTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
a. Spilled feed precluded the calculation of this value.

178'0 117

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C36 (PAGE 3): MATERNAL FEED CONSUMPTION VALUES LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS

17661 116
17667 110
17669 141
17670 109
17676 130
17687 154
17693 119
17697 110
17700 167
17701 126
17705 a
17706 150
17709 105
17718 141
17720 173

DAY DAY OF LACTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
a. Spilled feed precluded the calculation of this value.

H7

980 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C36 (PAGE 4): MATERNAL FEED CONSUMPTION VALUES - LACTATION INDIVIDUAL DATA FO GENERATION FEMALE RATS

17664 NOT MATING NOT CONFIRMED

17677 74.

17678 111.

17682 186.

17683 109.

17685 114.

17686 NOT PREGNANT

17689 141.

17691 133.

17692 106.

17696 SACRIFICED DUE T0 N0 SURVIVING PUPS ON DAY 2 OF LACTATION
17699 113.

17711 SACRIFICED DUE T0 N0 SURVIVING PUPS ON DAY 2 OF LACTATION
17712 155.

17714 113.

DAY DAY OF LACTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G).

117

980 

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C37 (PAGE 1): MATING AND FERTILITY, ESTROUS CYCLING AND DAYS IN COHABITATION INDIVIDUAL DATA - F0 GENERATION FEMALE RATS

PRECOHABITATION
ESTROUS DAYS IN MATING MATING PREGNANCY
RAT 14 DAYS COHABITATION STATUS DATE STATUS

NP

VM MATED CONFIRMED PREGNANT NP NOT PREGNANT
a Six or more consecutive days of diestrus were observed.

L80 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C37 (PAGE 2): MATING AND FERTILITY, ESTROUS CYCLING AND DAYS IN COHABITATION - INDIVIDUAL DATA - F0 GENERATION FEMALE RATS

PRECOHABITATION
ESTROUS DAYS IN MATING MATING PREGNANCY
14 DAYS COHABITATION STATUS DATE STATUS



14 DID NOT MATE







MATED CONFIRMED PREGNANT NP NOT PREGNANT
a Six or more consecutive days of diestrus were observed.

I17

880 

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE 
TOXICITY SCREENING TEST STUDY NUMBER: T-7599)

 

 

 

TABLE C38 (PAGE 1): FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - FEMALE RATS

DOSAGE GROUP I 0 (VEHICLE) 
RAT 17662 17672 17673 17674 17680

HOME CAGE BEHAVIOR 2 1

ALTERATIONS (HOME CAGE)
REACTION TO REMOVAL
REACTION TO HANDLING
REARS IN OPEN FIELD
DEFECATION IN OPEN FIELD
URINATION IN OPEN FIELD
LEVEL OF AROUSAL
ALTERATIONS (OPEN FIELD)
GAIT PATTERN

GAIT ABNORMALITY, SEVERITY
PALPEBRAL CLOSURE
PROMINENCE OF THE EYE
LACRIMATION

SALIVATION

PILOERECTION

ABNORMAL RESPIRATION
APPEARANCE

VISUAL REACTION

TACTILE REACTION
AUDITORY REACTION
REACTION
VISUAL PLACING RESPONSE
AIR RIGHTING RESPONSE







PUPIL RESPONSE TO LIGHT 1 1

FORELIMB GRIP TEST #1 310a 315 355 320b 225
FORELIMB GRIP TEST #2 355 325 255 285 220
HINDLIMB GRIP TEST #1 145 305 205 370 375
HINDLIMB GRIP TEST #2 190 325 215 220 390
LANDING FOOT SPLAY #1 6.6 6.1 7.2 6.7 6.7
LANDING FOOT SPLAY #2 7.7 6.8 5.5 6.8 6.8
BODY WEIGHT (G) 343 360 295 324 342

 

VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY.
a. Soft or liquid feces were observed during the forelimb grip testing.

125. Animal fell aproximately 3 feet to floor, animal appeared normal.

c. Value appeared incorrectly recorded and was excluded from group averages and statistical analyses.

117




680 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE 
TOXICITY SCREENING TEST STUDY NUMBER: 

 

 

 

TABLE C38 (PAGE 2): FUNCTIONAL OBSERVATIONAL BATTERY INDIVIDUAL DATA - FEMALE RATS
DOSAGE GROUP II 10 
RAT 17665 17666 17668 17671
HOME CAGE BEHAVIOR 1 2 2 1
ALTERATIONS (HOME CAGE) 1 1 1 1
REACTION TO REMOVAL 1 1 1 1
REACTION TO HANDLING 1 1 1 1
REARS IN OPEN FIELD 12 8 11 10
DEFECATION IN OPEN FIELD 1 2 1
URINATION IN OPEN FIELD 1 1 2 1
LEVEL OF AROUSAL 3 3 3 3
ALTERATIONS (OPEN FIELD) 1 1 1
GAIT PATTERN 1 1 1 1
GAIT ABNORMALITY, SEVERITY 1 1 1
PALPEBRAL CLOSURE 1 1 1 1
PROMINENCE LACRIMATION 1 1 1 1
SALIVATION 1 1 1 1
PILOERECTION 0 0
ABNORMAL RESPIRATION 0
APPEARANCE 1a 1 1 1c
VISUAL REACTION 2 2 2 2
TACTILE REACTION 2 2 2 2
AUDITORY REACTION 3 3 3 3
TAIL-PINCH REACTION 2 2 2 2
VISUAL PLACING RESPONSE 1 1 1 1
AIR RIGHTING RESPONSE 1 1 1
PUPIL RESPONSE TO LIGHT 1 1 1 1
FORELIMB GRIP TEST #1 210 385 175b 280
FORELIMB GRIP TEST #2 170 455 270 270
HINDLIMB GRIP TEST #1 285 370 335 220
HINDLIMB GRIP TEST #2 340 325 350 225
LANDING FOOT SPLAY #1 6.7 6.5 7.7 4.1
LANDING FOOT SPLAY #2 6.8 6.4 8.1 4.1
BODY WEIGHT (G) 335 310 353 292

 

VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY.
a. Localized alopecia: both forepaws (0.5 cm in diameter).

b. Animal fell apprroximately 3 to 4 feet and appeared normal.

0. Localized alopecia: both forepaws and forelimbs (2.0 cm 0.5 cm).

H7

060 HDVJ

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE 
TOXICITY SCREENING TEST STUDY NUMBER: T-7599)

 

 

 

TABLE C38 (PAGE 3): FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA FEMALE RATS
DOSAGE GROUP 50 
RAT 17661 17667 17669 17670 17676
HOME CAGE BEHAVIOR 2 2 2 2 2
ALTERATIONS (HOME CAGE) 1 1 1 1 1
REACTION To REMOVAL 1 1 1 1 1
REACTION TO HANDLING 1 1 1 1 1
REARS IN OPEN FIELD 9 9 15 8 9
DEFECATION IN OPEN FIELD 1 1 1 1 1
URINATION IN OPEN FIELD 1 1 1 1 1
LEVEL OF AROUSAL 3 3 3 3 3
ALTERATIONS (OPEN FIELD) 1 1 1 1 1
GAIT PATTERN 1 1 1 1 1
GAIT ABNORMALITY, SEVERITY 1 1 1 1 1
PALPEBRAL CLOSURE 1 1 1 1 1
PROMINENCE LACRIMATION 1 1 1 1 1
SALIVATION 2 1 1 1 1
PILOERECTION 0 0
ABNORMAL RESPIRATION 
APPEARANCE 1 1 1a 1 1
VISUAL REACTION 2 2 2 2 2
TACTILE REACTION 2 2 2 2 2
AUDITORY REACTION 3 3 3 3 3
REACTION 2 2 2 2 2
VISUAL PLACING RESPONSE 1 1 1 1 1
AIR RIGHTING RESPONSE 1 1 1 1 1
PUPIL RESPONSE TO LIGHT 1 1 1 1 1
FORELIMB GRIP TEST #1 190 200 245 275 230
FORELIMB GRIP TEST #2 310 200 245 240 270
HINDLIMB GRIP TEST #1 270 180 280 310 135
HINDLIMB GRIP TEST #2 170 235 215 220 195
LANDING FOOT SPLAY #1 8.7 6.1 6.0 6.7 5.7
LANDING FOOT SPLAY #2 6.8 7.7 5.8 6.6 6.7
BODY WEIGHT (G) 308 346 347 295 310

 

VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY.
a. Localized alopecia: both forepaws and forelimbs (2.0 cm 0.5 cm).



[6'0 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE 
TOXICITY SCREENING TEST STUDY NUMBER: T-7599)

 

 

 

TABLE C38 (PAGE 4): FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - FEMALE RATS
DOSAGE GROUP IV 250 
RAT 17677 17678 17682 17683 17691
HOME CAGE BEHAVIOR 1 2 2 1 2
ALTERATIONS (HOME CAGE) 1 1 1 1 1
REACTION TO REMOVAL 1 1 1 1 1
REACTION TO HANDLING 1 1 1 1 1
REARS IN OPEN FIELD 9 8 12 6 10
DEFECATION IN OPEN FIELD 1 1 1 1 1
URINATION IN OPEN FIELD 1 1 1 1 1
LEVEL OF AROUSAL 3 3 3 3 3
ALTERATIONS (OPEN FIELD) 1 1 1 1 1
GAIT PATTERN 1 1 1 1 1
GAIT ABNORMALITY, SEVERITY 1 1 1 1 1
PALPEBRAL CLOSURE 1 1 1 1 1
PROMINENCE LACRIMATION 1 1 1 1 1
SALIVATION 1 1 1 1 1
PILOERECTION 0
ABNORMAL RESPIRATION 
APPEARANCE 1 1 1 1a 1
VISUAL REACTION 2 2 2 2 2
TACTILE REACTION 2 2 2 2 2
AUDITORY REACTION 3 3 3 3 3
TAIL-PINCH REACTION 2 2 2 2 2
VISUAL PLACING RESPONSE 1 1 1 1 1
AIR RIGHTING RESPONSE 1 1 1 1 1
PUPIL RESPONSE TO LIGHT 1 1 1 1 1
FORELIMB GRIP TEST #1 405 200 455 350 455
FORELIMB GRIP TEST #2 330 190 410 290 495
HINDLIMB GRIP TEST #1 210 365 510 190 225
HINDLIMB GRIP TEST #2 345 360 535 270 280
LANDING FOOT SPLAY #1 5.5 6.3 6.2 7.6 6.5
LANDING FOOT SPLAY #2 6.8 7.4 5.2 8.6 7.6
BODY WEIGHT (G) 316 340 337 296 280

 

VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY.
a. Localized alopecia: right forelimb (1.5 cm 1.0 cm), right inguinal area (6.0 cm 2.0 cm) and right hindlimb (2.0 cm 2.0 cm).



Z60 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C39 (PAGE 1): MOTOR ACTIVITY - INDIVIDUAL DATA F0 GENERATION FEMALE RATS

 

 

 

DOSAGE GROUP I 0 (VEHICLE) 
RAT NUMBER 17662 17672 17673 17674 17680
DAY 86

NUMBER OF MOVEMENTS

BLOCK 1 7o 70 9o 71 74
BLOCK 2 78 84 92 9o 60
BLOCK 3 56 84 47 85 77
BLOCK 4 4o 51 26 103 70
BLOCK 5 25 77 92 91 42
BLOCK 6 14 50 91 93 77
BLOCK 7 42 76 27 98 75
BLOCK 8 47 5 8 72 60
BLOCK 9 75 29 1 78 51
BLOCK 10 76 64 4 79 57
BLOCK 11 37 77 3 90 94
BLOCK 12 7 74 8 74 75
BLOCK 13 4o 60 12 78 61
BLOCK 14 38 75 80 62 47
BLOCK 15 44 58 56 7o 48
BLOCK 16 46 44 41 75 61
BLOCK 17 28 63 71 104 83
BLOCK 18 34 61 62 48 67
TOTAL 797 1102 811 1461 1179

 

TOTAL SUM OF EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.

117


0

E60 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C39 (PAGE 2): MOTOR ACTIVITY - INDIVIDUAL DATA F0 GENERATION FEMALE RATS

 

 

 

DOSAGE GROUP I 0 (VEHICLE) 
RAT NUMBER 17662 17672 17673 17674 17680
DAY 86

TIME (SECONDS) SPENT IN MOVEMENT

BLOCK 1 179 180 139 231 222
BLOCK 2 172 172 113 193 244
BLOCK 3 135 157 27 146 187
BLOCK 4 58 69 20 164 148
BLOCK 5 16 105 105 159 112
BLOCK 6 9 97 75 113 138
BLOCK 7 55 119 30 118 117
BLOCK 8 89 10 7 108 124
BLOCK 9 158 50 0 90 75
BLOCK 10 146 126 2 83 83
BLOCK 11 38 113 1 92 133
BLOCK 12 7 129 17 91 115
BLOCK 13 42 137 9 116 111
BLOCK 14 63 115 95 65 91
BLOCK 15 95 112 68 105 82
BLOCK 16 114 77 26 78 96
BLOCK 17 28 82 67 146 122
BLOCK 18 47 96 62 44 102
TOTAL 1451 1946 863 2142 2302

 

TOTAL SUM OF EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.

H7


0

1760 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY

SCREENING TEST STUDY NUMBER: T-7599)

TABLE C39 (PAGE 3): MOTOR ACTIVITY - INDIVIDUAL DATA F0 GENERATION FEMALE RATS

 

 

 

DOSAGE GROUP II 10 
RAT NUMBER 17665 17666 17668 17671
DAY 86

NUMBER OF MOVEMENTS

 

BLOCK 1 66 75 75 76
BLOCK 2 85 72 83 73
BLOCK 3 69 87 84 71
BLOCK 4 96 17 74 63
BLOCK 5 76 37 20 74
BLOCK 6 71 60 1 92
BLOCK 7 108 68 1 69
BLOCK 8 74 57 2 78
BLOCK 9 56 61 77 68
BLOCK 10 76 71 80 51
BLOCK 11 45 62 42 63
BLOCK 12 2 27 65 70
BLOCK 13 28 4 54 51
BLOCK 14 14 33 3 68
BLOCK 15 74 58 2 64
BLOCK 16 83 65 2 68
BLOCK 17 12 16 0 73
BLOCK 18 7 3 57 59
TOTAL 1042 873 722 1231
TOTAL SUM OF EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.

117


0

S60 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C39 (PAGE 4): MOTOR ACTIVITY - INDIVIDUAL DATA Fo GENERATION FEMALE RATS

 

 

 

 

DOSAGE GROUP II 10 

RAT NUMBER 17665 17666 17668 17671

DAY 86

TIME (SECONDS) SPENT IN MOVEMENT
BLOCK 1 194 220 156 163
BLOCK 2 176 138 163 126
BLOCK 3 194 90 139 126
BLOCK 4 151 20 70 174
BLOCK 5 91 54 17 164
BLOCK 6 104 104 0 96
BLOCK 7 125 116 99
BLOCK 8 101 81 0 155
BLOCK 9 99 100 129 148
BLOCK 10 128 122 93 88
BLOCK 11 63 117 34 202
BLOCK 12 0 37 73 187
BLOCK 13 21 2 77 82
BLOCK 14 5 44 2 142
BLOCK 15 89 61 0 126
BLOCK 16 77 120 0 111
BLOCK 17 7 15 0 155
BLOCK 18 6 1 64 151
TOTAL 1631 1442 1017 2495
TOTAL SUM OF EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.

H7

960 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C39 (PAGE 5): MOTOR ACTIVITY - INDIVIDUAL DATA - F0 GENERATION FEMALE RATS

 

 

 

DOSAGE GROUP 50 
RAT NUMBER 17661 17667 17669 17670 17676
DAY 86

NUMBER OF MOVEMENTS

BLOCK 1 59 57 74 58 86
BLOCK 2 81 85 43 73 78
BLOCK 3 78 81 13 13 89
BLOCK 4 75 73 2 0 82
BLOCK 5 68 15 9 45 100
BLOCK 6 60 0 76 66 56
BLOCK 7 66 74 62 81 79
BLOCK 8 64 65 43 53 46
BLOCK 9 84 81 6 54 2
BLOCK 10 61 60 33 63 45
BLOCK 11 64 70 15 44 70
BLOCK 12 59 25 5 19 61
BLOCK 13 61 9 3 46 56
BLOCK 14 52 4 31 63 66
BLOCK 15 68 3 54 67 80
BLOCK 16 67 3 72 60 31
BLOCK 17 65 4 73 62 73
BLOCK 18 60 2 12 58 64
TOTAL 1192 711 626 925 1164

 

TOTAL SUM OF EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.

[10?8117

L6G 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE C39 (PAGE 6): MOTOR ACTIVITY - INDIVIDUAL DATA F0 GENERATION FEMALE RATS

 

 

 

DOSAGE GROUP 50 
RAT NUMBER 17661 17667 17669 17670 17676
DAY 86

TIME (SECONDS) SPENT IN MOVEMENT

BLOCK 1 242 251 196 231 182
BLOCK 2 190 177 54 128 159
BLOCK 3 179 116 12 10 104
BLOCK 4 140 67 0 0 107
BLOCK 5 193 17 8 39 129
BLOCK 6 96 104 123 62
BLOCK 7 122 86 121 126 99
BLOCK 8 134 144 45 79 36
BLOCK 9 136 154 3 66 1
BLOCK 10 82 67 23 114 35
BLOCK 11 127 118 10 68 90
BLOCK 12 99 27 2 25 73
BLOCK 13 107 10 1 7O 96
BLOCK 14 75 1 86 102 81
BLOCK 15 98 2 117 114 107
BLOCK 16 129 1 89 97 27
BLOCK 17 113 3 94 114 109
BLOCK 18 116 2 5 77 81
TOTAL 2378 1243 970 1583 1578

 

TOTAL SUM OF EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.



860 

PROTOCOL 418 - 027 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599 . 7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C39 (PAGE 7): MOTOR ACTIVITY - INDIVIDUAL DATA F0 GENERATION FEMALE RATS

 

 

 

DOSAGE GROUP IV 250 
RAT NUMBER 17677 17678 17682 17683 17691
DAY 86

NUMBER OF MOVEMENTS

BLOCK 1 71 88 59 76 91
BLOCK 2 49 91 57 105 86
BLOCK 3 55 88 69 77 87
BLOCK 4 64 80 80 96 53
BLOCK 5 48 51 80 98 69
BLOCK 6 76 50 73 79 42
BLOCK 7 88 31 82 69 48
BLOCK 8 87 9 77 73 71
BLOCK 9 61 3 12 52 71
BLOCK 10 68 27 0 68 72
BLOCK 11 74 79 21 63 71
BLOCK 12 79 78 90 43 76
BLOCK 13 4 74 67 55 50
BLOCK 14 1 44 11 65 53
BLOCK 15 3 60 77 72
BLOCK 16 5 61 14 53 62
BLOCK 17 5 50 2 73 62
BLOCK 18 81 62 6 54 48
TOTAL 919 1026 800 1276 1184

 

TOTAL SUM OF EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.

117




660 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C39 (PAGE 8): MOTOR ACTIVITY - INDIVIDUAL DATA F0 GENERATION FEMALE RATS

 

 

 

DOSAGE GROUP IV 250 
RAT NUMBER 17677 17678 17682 17683 17691
DAY 86

TIME (SECONDS) SPENT IN MOVEMENT

BLOCK 1 160 186 225 166 156
BLOCK 2 133 150 155 204 129
BLOCK 3 98 118 122 182 103
BLOCK 4 73 104 142 157 74
BLOCK 5 53 118 112 163 91
BLOCK 6 126 71 92 109 48
BLOCK 7 114 44 128 120 75
BLOCK 8 100 6 107 112 80
BLOCK 9 78 0 10 135 89
BLOCK 10 72 36 0 88 109
BLOCK 11 102 138 15 114 80
BLOCK 12 121 105 109 101 138
BLOCK 13 0 93 117 77 57
BLOCK 14 0 40 10 86 77
BLOCK 15 3 131 0 119 72
BLOCK 16 2 83 13 82 69
BLOCK 17 4 67 2 104 85
BLOCK 18 85 97 3 96 51
TOTAL 1324 1587 1362 2215 1583

 

TOTAL SUM OF EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.

117

0010 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C40 (PAGE 1): NATURAL DELIVERY, IMPLANTATION SITES, AND PUP VIABILITY AND SEX - INDIVIDUAL DATA 
FO GENERATION FEMALE GENERATION LITTERS

DURATION OF LITTER DELIVERED NUMBER OF LIVE PUPS AT TOTAL
GESTATION LIVE STILL- TOTAL COMPLETION OF DAY POSTPARTUM IMPLAN-
LITTER (DAYS) BORN BORN BORN 1 5 TATI ONS
NUMBER 
DOSAGE GROUP I VEHICLE (VEHICLE) 
17662 17672 17673 17674 17680 17681 17690 17694 22 16(17695 17703 22 20(17713 17715 17716 17717 17719 DOSAGE GROUP II LOW DOSAGE 10 
17663 NOT PREGNANT
17665 17666 17668 17671 17675 17679 17684 17688 17698 17702 17704 17707 17708 17710 MALE FEMALE
NUMBER OF PUPS DYING PRIOR TO WEIGHING ON DAY 1 POSTPARTUM.

117

1010 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE C40 (PAGE 2): NATURAL DELIVERY, IMPLANTATION SITES, AND PUP VIABILITY AND SEX - INDIVIDUAL DATA 
F0 GENERATION FEMALE GENERATION LITTERS

DURATION OF LITTER DELIVERED NUMBER OF LIVE PUPS AT TOTAL
GESTATION LIVE STILL- TOTAL COMPLETION OF DAY POSTPARTUM IMPLAN-
LITTER (DAYS) BORN BORN BORN 1 5 TATIONS
NUMBER 
DOSAGE GROUP MIDDLE DOSAGE 50 DAY
17661 17667 17669 17670 17676 17687 17693 17697 17700 17701 17705 17706 17709 17718 17720 DOSAGE GROUP IV HIGH DOSAGE 250 
17664 NOT MATING NOT CONFIRMED
17677 23 4(4) 0 7[3] - - - 13
17678 17682 17683 17685 17686 NOT PREGNANT
17689 17691 17692 17696 17699 17711 17712 17714 MALE FEMALE
NUMBER OF PUPS DYING PRIOR TO WEIGHING ON DAY 1 POSTPARTUM.
NUMBER OF PUPS IN WHICH CANNIBALIZATION AUTOLYSIS PRECLUDED THE DETERMINATION OF VIABILITY.

117




Z0 

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C41 (PAGE 1): PUP BODY WEIGHT LITTER AVERAGES FROM BIRTH TO DAY 5 POSTPARTUM INDIVIDUAL DATA F1 GENERATION LITTERS

RAT 
LITTER DAY 1 DAY 5
NUMBER 
MATERNAL DOSAGE GROUP I VEHICLE 0 (VEHICLE) 
17662 7.0 6.5 6.8 11.1 10.2 10.7
17672 6.4 6.2 6.4 10.9 9.7 10.4
17673 6.5 5.9 6.1 8.7 8.5 8.6
17674 6.7 6.5 6.6 9.2 8.7 9.0
17680 7.5 6.8 7.1 11.4 10.5 10.9
17681 6.1 5.8 6.0 9.8 9.5 9.6
17690 6.3 6.1 6.2 9.8 9.5 9.6
17694 6.2 5.7 6.0 10.0 9.2 9.8
17695 5.9 5.7 5.8 9.3 9.1 9.2
17703 5.5 5.2 5.4 8.7 7.9 8.2
17713 6.5 6.4 6.4 10.1 10.0 10.0
17715 8.1 8.5 8.3 11.8 12.4 12.0
17716 7.2 6.8 7.0 9.4 9.1 9.3
17717 6.3 6.0 6.1 8.8 8.8 8.8
17719 6.2 6.0 6.1 8.3 8.4 8.4
MATERNAL DOSAGE GROUP II LOW DOSAGE 10 
17663 NOT PREGNANT
17665 7.1 6.9 7.0 10 4 10.0 10.2
17666 6.3 5.9 6.0 10 0 9.4 9.5
17668 6.2 5.9 6.0 10.4 9.4 9.8
17671 6.5 6.4 6.4 9.5 9.3 9.4
17675 6.0 5.9 6.0 9.1 8.6 8.9
17679 7.3 7.1 7.2 12.1 12.0 12 0
17684 6.8 6.6 6.7 10 6 10.0 10 3
17688 6.0 5.7 5.9 10 6 10.4 10 5
17698 6.3 6.4 6.3 10.6 10.1 10.4
17702 6.2 5.7 6.0 9.8 9.0 9.5
17704 6.0 6.2 6.0 9.0 9.4 9.1
17707 6.0 5.9 6.0 10 2 10.2 10 2
17708 6.2 5.9 6.0 10.4 9.6 10 0
17710 6.6 6.2 6.5 10.5 9.8 10 3
MALE FEMALE TOTAL (SUM OF PUP OF LIVE PUPS) DAY DAY POSTPARTUM

ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS.

I 17

?010 

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C41 (PAGE 2): PUP BODY WEIGHT LITTER AVERAGES FROM BIRTH TO DAY 5 POSTPARTUM - INDIVIDUAL DATA - F1 GENERATION LITTERS


LITTER DAY 1 DAY 5

NUMBER 

MATERNAL DOSAGE GROUP MIDDLE DOSAGE 50 
17661 6.7 6.1 6.5 9.8 8.6 9.4
17667 7.1 6.9 7.0 10.8 10.2 10.5
17669 6.8 5.9 6.0 10.4 9.0 9.2
17670 7.0 6.8 6.8 9.5 9.1 9.2
17676 6.3 6.2 6.3 9.3 8.9 9.2
17687 6.8 6.4 6.6 12.0 11.8 11.9
17693 6.4 6.3 6.4 10.0 9.6 9.8
17697 6.5 6.2 6.4 10.0 9.3 9.7
17700 6.6 6.2 6.5 11.2 10.7 11.1
17701 7.1 6.8 6.9 11.0 9.9 10.2
17705 7.1 6.4 6.7 10.8 9.0 9.8
17706 7.1 6.6 6.9 11.9 11.5 11.8
17709 6.0 5.6 5.7 9.0 8.5 8.7
17718 6.5 6.2 6.4 9.6 9.8 9.7
17720 6.3 6.2 6.3 10.1 10.7 10 4

MATERNAL DOSAGE GROUP IV HIGH DOSAGE 250 
17664 NOT MATING NOT CONFIRMED
17677 NO SURVIVING PUPS ON DAY 1 OF LACTATION
17678 7.0 6.5 6.7 10.9 10.4 10.6
17682 6.8 6.8 6.8 11.5 11.2 11.3
17683 6.2 6.1 6.2 7.7 7.2 7.5
17685 5.5 5.4 5.4 7.4 7.7 7.7
17686 NOT PREGNANT
17689 5.8 5.8 5.8 9.2 9.2 9.2
17691 7.2 7.0 7.0 9.8 9.6 9.7
17692 5.7 5.5 5.6 8.1 8.0 8.1
17696 4.8 4.5 4.6 NO SURVIVING PUPS ON DAY 2 OF LACTATION
17699 5.8 5.5 5.7 9.0 8.8 8.9
17711 4.9 4.5 4.7 NO SURVIVING PUPS ON DAY 2 OF LACTATION
17712 6.5 6.0 6.3 11.0 9.9 10.5
17714 7.0 6.1 6.4 10.5 9.2 9.6

MALE FEMALE TOTAL (SUM OF PUP OF LIVE PUPS) DAY DAY POSTPARTUM

ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS.




I

V011) 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE C42 (PAGE 1): PUP BODY WEIGHTS FROM BIRTH TO DAY 5 POSTPARTUM INDIVIDUAL DATA - Fl GENERATION PUPS



0?

U1
L0
U1
Ch




3

ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS.
FIRST LETTER M-MALE, F-FEMALE, U-SEX UNDETERMINABLE

SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED)
NUMBER FOLLOWING INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED.

I17

HDVJ

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE C42 (PAGE 2): PUP BODY WEIGHTS FROM BIRTH TO DAY 5 POSTPARTUM INDIVIDUAL DATA F1 GENERATION PUPS

PUP LITTER MATERNAL DOSAGE GROUP II LOW DOSAGE 10 POSTPARTUM DAY 1
17663 NOT PREGNANT
17665 717666 6.3 6.4 6.3 6.2 5.6 5.9 6.2 6.1 5.5 5.9 6.1 6.0 5.9 5.9
17668 617671 6.8 6.5 6.0 6.9 6.3 6.4 6.2 6.6 6.5 6.3 6.2 6.5 6.5
17675 617679 7.4 7.3 7.2 7.4 7.4 6.8 6.9 7.6 6.9
17684 66.9
17688 6.3 6.0 6.1 6.1 6.2 6.4 6.4 5.0 5.3 5.7 5.9 5.7 5.3 5.8
17698 7.0 6.2 6.0 3.8 6.6 7.5 6.6 7.0 5.8 6.2 6.2 6.6 6.4 6.6 6.9 6.0
17702 6.0 6.0 6.1 6.5 6.4 6.0 6.2 6.5 5.5 6.2 5.4 5.6 5.9 6.2 5.1
17704 617707 6.6 6.4 5.8 6.0 6.1 5.3 6.1 5.5 6.1 5.3 5.8 6.2 5.9 6.3 6.0
17708 6.1 6.1 6.2 5.9 5.6 6.6 6.5 6.3 6.4 5.8 6.2 5.4 6.0 5.7 5.9 6.2
17710 6ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS.

FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE
SECOND LETTER -- A-ALIVE, S-STILLBORN, M-MISSING (PRESUMED CANNIBALIZED)
NUMBER FOLLOWING INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED.



90H) 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C42 (PAGE 3): PUP BODY WEIGHTS FROM BIRTH TO DAY 5 POSTPARTUM - INDIVIDUAL DATA - F1 GENERATION PUPS

PUP LITTER MATERNAL DOSAGE GROUP MIDDLE DOSAGE 50 POSTPARTUM DAY 1
17661 617667 6.9 6.8 6.5 8.7 6.5 7.5 6.9 6.5 5.6 7.8 6.7 6.4 8.3
17669 6.6 7.1 5.7 5.6 5.4 6.1 6.1 6.0 6.1 6.1 6.2 6.1 6.1 5.5 6.2 5.9
17670 6.9 6.2 7.1 7.5 6.6 7.4 6.7 7.5 6.8 7.4 6.1 6.9 5.1 6.9 7.0 7.1
17676 6.6 6.5 6.6 5.8 5.0 6.7 6.2 6.0 6.7 6.8 6.4 6.0 6.4 6.2 6.1
17687 6.6 6.8 6.5 6.0 6.9 7.0 7.2 7.2 6.2 6.7 6.1 6.7 6.5 6.0 6.5
17693 517697 6.7 6.7 6.5 6.5 6.7 6.7 6.1 6.6 6.2 5.7 6.5 6.4 5.3 6.5 6.8
17700 6.2 6.9 7.0 6.5 6.6 6.9 5.8 7.0 6.8 6.1 6.2 6.2 6.0 6.4
17701 7.2 6.7 7.5 7.0 7.3 6.5 6.7 6.7 6.7 7.0 6.7 7.3 6.6 6.3
17705 617706 7.3 7.4 7.4 6.9 7.3 6.7 6.9 7.1 6.6 7.6 6.6 6.6 6.6 6.4 6.7
17709 5.9 5.8 5.8 5.7 6.4 6.0 6.1 6.0 5.1 5.6 5.6 5.5 5.8 5.5 5.8 5.2
17718 7.1 6.6 6.1 6.1 6.0 7.0 6.7 6.6 6.1 6.5 6.5 6.1 5.9 6.1 6.6 6.5
17720 6.0 6.5 4.4 6.5 6.9 6.9 6.4 6.7 6.5 6.0 6.9 6.1 6.3 5.7 6.6 5.8
ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS.

FIRST LETTER M-MALE, U-SEX UNDETERMINABLE
SECOND LETTER -- U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED)
NUMBER FOLLOWING INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED.

117

L010 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C42 (PAGE 4): PUP BODY WEIGHTS FROM BIRTH TO DAY 5 POSTPARTUM - INDIVIDUAL DATA F1 GENERATION PUPS

PUP LITTER MATERNAL DOSAGE GROUP IV HIGH DOSAGE 250 POSTPARTUM DAY 1
17664 NOT MATING NOT CONFIRMED
17677 17678 6.9 7.4 7.0 7.0 6.5 6.9 6.2 6.7 5.8 6.1 7.1 6.7
17682 66.6
17683 617685 517686 NOT PREGNANT
17689 517691 76.5 6.9 7.4 7.3
17692 617696 417699 5.8 5.5 6.2 5.5 5.4 6.2 5.4 6.5 5.4 5.2 5.8 5.4 5.5 5.6
17711 5.0 4.9 4.8 4.9 4.8 MS 4.5 4.7 4.3 4.5 4.5 4.4 4.8
17712 6.1 6.5 6.3 6.8 6.6 6.8 6.3 6.5 5.9 6.4 5.8 6.1 5.8
17714 7ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS.

FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE
SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, (PRESUMED CANNIBALIZED)
NUMBER FOLLOWING INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED.

117




8010 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C42 (PAGE 5): PUP BODY WEIGHTS FROM BIRTH TO DAY 5 POSTPARTUM - INDIVIDUAL DATA F1 GENERATION PUPS

PUP LITTER MATERNAL DOSAGE GROUP I VEHICLE 0 (VEHICLE) POSTPARTUM DAY 5
17662 11.6 11.1 10.2 10 5 11.7 11.1 11.2 11.7 11 6 8.2 10.2 10.5 10.3 10.4
17672 9.8 10.8 11.2 11.0 11.6 10.5 10.5 11.1 11.6 10.6 9.0 9.1 9.7 10.0 10.6 9.7
17673 8.4 7.7 8.8 9.0 9.8 8.2 9.3 8.9 8.8 8.7 8.0 8.4 8.0
17674 9.3 9.7 8.1 9.8 8.7 9.5 9.5 8.8 9.8 9.7 8.2 9.6 8.6 8.4 8.8 9.0 8.7 8.6
17680 11.8 11.6 10.8 11 9 11.7 10.8 11.4 11.0 10 8 10.9 10.6 11.4 9.7 10.1 11.7 9.7 10.0
17681 10.1 10.6 9.7 9 2 10.9 9 1 9.1 11.0 8.2 9.4 9.0 9.6 9.9 9.9 9.6 9.2
17690 10.7 10.2 10.5 10 5 7.0 10.5 9.2 10.2 9.5 1017694 10.9 10.5 9.9 10.4 10.0 9.5 8.6 10.1 11.0 9.5 1017695 9.7 8.9 9.7 9.0 9.4 9.1 9.0 9.5 9.2 9.0 8.9 9.5 8.9 8.7 9.8
17703 87.2
17713 10.1 10.4 9.5 9.3 10.9 10.4 10.0 9.8 9.6 10 6 10.1 10.0 10.2 9.5
17715 12.2 11.1 10.8 12.4 12.5 12.7 12.2 10.4 12.6 12 3 12.6 12.3 12 3
17716 9.6 9.9 9.7 8.5 9.7 8.9 9.6 9.4 8.2 9.5 9.4 10.0 8.4 9 2
17717 8.6 7.6 9.9 9.2 8.9 8.6 8.6 8.5 9.0 9.5 8.3 8.9 9.3
17719 9ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS.

FIRST LETTER -- F-FEMALE, U-SEX UNDETERMINABLE
SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED)
NUMBER FOLLOWING INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED.

[108117

6010 

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE C42 (PAGE 6): PUP BODY WEIGHTS FROM BIRTH TO DAY 5 POSTPARTUM - INDIVIDUAL DATA - F1 GENERATION PUPS

PUP LITTER MATERNAL DOSAGE GROUP II LOW DOSAGE 10 POSTPARTUM DAY 5
17663 NOT PREGNANT
17665 10.7 10.9 10.4 10 4 10.1 11.0 10.2 9.9 10.8 10.3 10.4 10.0 9.7 9.6 9 2
17666 10.2 9.4 9.7 10 5 9.1 9.6 9.1 9.4 9.1 9.3 10.7 8.9 9.8 8.8
17668 11.0 10.5 10.3 10.6 10.8 9.2 1017671 9.4 9.5 9.1 9.7 9.9 9.4 8.7 9.5 9.5 9.0 9.6 9.5 9.2
17675 9.1 9.7 8.1 9.7 8.1 9.2 9.1 1017679 12.5 11.8 12.2 11.9 12.8 12 1 11.6 11.4 12.1
17684 10.2 11.6 10.2 9.7 10.3 11 4 10.5 10.7 10.8 9.7 11.1 9.3 10.2 9.8 9.7 10.0
17688 11.2 7.3 10.5 10.9 11.4 11.7 11.4 9.7 11.4 10.8 9.9 10.6 10.4 10.4
17698 10.5 10.5 10.5 11.6 10.9 10.6 11.1 1110.7 9.2 10.1 FD 2
17702 10.4 10.3 10.0 9.4 9.2 9.2 10 3 10.0 10.4 8.6 9.4 8 2 8.4 9.2 9.2
17704 7.6 9.2 9.1 9.0 10.3 9.3 1010.7 10.0 9.0 8.9 9.4
17707 11.1 8.3 10.4 10 1 11.1 10 1 9.3 10.5 10.8 9.3 10.5 11 1 9.1 10.7 10.3
17708 10.4 11.5 10.6 10 1 10 9 10.5 10.2 10.1 9.0 8.5 9.9 10 6 9.9 9.3 9.2 9.7
17710 10.9 10.5 9.0 10 3 10 3 11.3 9.6 10.6 10.5 10 2 11ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS.

FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE
SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED)
NUMBER FOLLOWING INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED.

117

01 1'0 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C42 (PAGE 7): PUP BODY WEIGHTS FROM BIRTH TO DAY 5 POSTPARTUM - INDIVIDUAL DATA F1 GENERATION PUPS

PUP LITTER MATERNAL DOSAGE GROUP MIDDLE DOSAGE 50 POSTPARTUM DAY 5
17661 9.8 9.4 10.0 9.7 10.8 10 1 9.6 1017667 9.7 10 6 11.8 10.0 9.8 13.6 10.2 9.7 12.0 7.8 10.0 12.2 9.3
17669 10.4 10.5 8.5 7.6 9.2 9.0 8.6 9.8 9.3 9.0 9.5 8.2 9.5 9.6 9.6 8.2
17670 9.5 9.9 9.8 10.3 9.0 8.6 8.8 9.6 9.2 9.8 9.8 9.5 8.3 7.5 9.2 9.2
17676 9.3 9.8 10.0 9.2 9.8 9.8 8.6 7.9 9.2 9.6 9.1 9.6 9.0 9.1 7.8
17687 12.7 11.2 11.7 12 5 12.4 11.7 12.0 11.6 12.1 11.7 12.5 11.7 11.5 11.3 11.7
17693 10.4 10 3 9.6 10 6 10.1 10 3 9.0 10.1 9.3 MS 8 8 9.6 9.7 9.9 10.1 FM 3 FS
17697 9.9 9.8 9.9 10 2 10.1 9 7 9 8 10.3 9.9 10.0 9.2 9.2 9.5 10.5 7.5
17700 11.2 11.7 9.7 10.8 12.5 12 6 10.9 11.8 10.5 10.4 11.1 11.1 10.9 9.8
17701 10.6 10.5 11 3 11.8 10.4 11 0 8.7 10.2 10.6 10.8 10.3 9.5 9.5 8.4
17705 11.5 9.9 12.2 119.2 8.1 9.5 10.1 9.4 7.1 9.7 10.6 7.7 FS
17706 12.3 12.3 12.1 12.4 11.2 10.9 12.7 12.8 11.3 11.4 12.0 11.0 11.3 11.6 FD 5
17709 9.6 9.5 8.5 9.0 8.3 8.6 9.5 8.6 8.3 7.8 9.2 9.3 8.2 7.8 8.4 8.6
17718 8.3 10 7 10 1 9.9 9.7 9.4 9.9 10.5 10.6 9.6 7.1 10.3 10.1 9.0 9.9 9.5
17720 11.3 11.4 10 5 5.7 10.9 10.4 9.4 11.4 10.7 9.5 10.2 11.0 11.3 11.0 11.7 10.1
ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS.

FIRST LETTER -- F-FEMALE, UNDETERMINABLE
SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, (PRESUMED CANNIBALIZED)
NUMBER FOLLOWING INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED.

I17

UPC) 

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C42 (PAGE 8): PUP BODY WEIGHTS FROM BIRTH TO DAY 5 POSTPARTUM - INDIVIDUAL DATA F1 GENERATION PUPS

PUP LITTER MATERNAL DOSAGE GROUP IV HIGH DOSAGE 250 POSTPARTUM DAY 5
17664 NOT MATING NOT CONFIRMED
17677 17678 11.0 10.5 11.2 10.7 11.3 10.5 9.4 10 3 10.4 11 4 9.8 11.0
17682 11.7 11.6 11.9 11.4 11.4 10.8 11.0 11.9 11.5 10.6 11.4 11 4 10.9 10 5
17683 87.3 6.9
17685 717686 NOT PREGNANT
17689 917691 9.9 9.3 9.4 10.8 10.3 10.2 10.0 10.2 9.5 8.6 8.2 10.1
17692 817696 17699 8.9 9.0 8.4 8 9 9.0 8.9 1017711 17712 11.4 10.9 10.6 11 5 10.8 10.1 10.8 11.6 9.4 9.8 11.0 9.7 9.4
17714 10.7 9.9 10.3 10 8 11ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS.

FIRST LETTER -- M-MALE, F-FEMALE, UNDETERMINABLE
SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED)
NUMBER FOLLOWING INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED.

117

Z1 10 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C43 (PAGE 1): PUP VITAL STATUS AND SEX FROM BIRTH TO DAY 5 POSTPARTUM - INDIVIDUAL DATA Fl GENERATION PUPS

"1:1

'11
35

A A

3 

erxjuj'nujujuj


143533353whininjujujuju:



'12!
11>

FIRST LETTER -- F-FEMALE, UNDETERMINABLE
SECOND LETTER A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, (PRESUMED CANNIBALIZED)
NUMBER FOLLOWING INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED.

117

El 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: 

TABLE C43 (PAGE 2): PUP VITAL STATUS AND SEX FROM BIRTH TO DAY 5 POSTPARTUM - INDIVIDUAL DATA - F1 GENERATION PUPS
PUP LITTER MATERNAL DOSAGE GROUP II LOW DOSAGE NOT PREGNANT

17665 17666 17668 17671 17675 17679 17684 17688 17698 FAFD2

17702 17704 17707 17708 17710 MAMM2 FA FA FA FA FA FA

FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE
SECOND LETTER A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED)
NUMBER FOLLOWING INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED.

[17


0

17110 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C43 (PAGE 3): PUP VITAL STATUS AND SEX FROM BIRTH TO DAY 5 POSTPARTUM - INDIVIDUAL DATA - Fl GENERATION PUPS




'FIRST LETTER M-MALE, F-FEMALE, U-SEX UNDETERMINABLE
SECOND LETTER -- A-ALIVE, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED)
NUMBER FOLLOWING INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED.




0

91 1?0 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C43 (PAGE 4): PUP VITAL STATUS AND SEX FROM BIRTH TO DAY 5 POSTPARTUM - INDIVIDUAL DATA F1 GENERATION PUPS
PUP LITTER MATERNAL DOSAGE GROUP IV HIGH DOSAGE 250 

17664 NOT MATING NOT CONFIRMED

17677 17678 17682 17683 17685 17686 NOT PREGNANT

17689 17691 17692 17696 17699 17711 17712 17714 FIRST LETTER -- F-FEMALE, U-SEX UNDETERMINABLE
SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, M-MISSING (PRESUMED CANNIBALIZED)
NUMBER FOLLOWING INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED.

117

9110 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C44 (PAGE 1): CLINICAL OBSERVATIONS FROM BIRTH TO DAY 5 POSTPARTUM - INDIVIDUAL DATA - F1 GENERATION PUPS

MATERNAL DOSAGE GROUP LITTER 
MATERNAL DOSAGE NUMBER POSTPARTUM OBSERVATIONS a
I
0 (VEHICLE) 17690 1- 2 1/18 PUPS: HEAD, BRUISE (DID NOT EXCEED 0.8 CM 0.3 CM).
II
10 17688 1- 4 1/14 PUPS: BACK, BRUISE (DID NOT EXCEED 0.5 CM 1.0 CM).
1- 2 1/14 PUPS: LOWER MIDLINE, BRUISE (DID NOT EXCEED 1.5 CM
2.0 PALE.
3- 5 1/14 PUPS: LOWER MIDLINE, BRUISE (DID NOT EXCEED 1.5 CM
1.0 CM).

50 17720 1? 2 1/16 PUPS: NECK, BRUISE (DID NOT EXCEED 2.0 CM 2.5 CM).
IV
250 17683 1- 4 1/16 PUPS: BACK, BRUISE (DID NOT EXCEED 2.0 CM 1.5 CM).
17685 1 1/16 PUPS: CHEST AND NECK, BRUISE (1.0 CM IN DIAMETER).
2- 3 1/15 PUPS: CHEST AND NECK, BRUISE (1.0 CM IN DIAMETER).
17696 1 2/15 PUPS: MOUTH, BRUISE (0.2 CM 0.1 CM).
17699 4 2/13 PUPS: COLD TO NOT NESTING OR NURSING.

a. Tabulation restricted to adverse observations; all other pups appeared normal.

LI 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599) 

TABLE C45 (PAGE 1): NECROPSY OBSERVATIONS - INDIVIDUAL DATA - F1 GENERATION PUPS
MATERNAL DOSAGE GROUP LITTER DAY
DOSAGE NUMBER POSTPARTUM OBSERVATIONS a
I
(VEHICLE) 17662 5 14 PUPS: APPEARED NORMAL.
17672 5 16 PUPS: APPEARED NORMAL.
17673 5 13 PUPS: APPEARED NORMAL.
17674 5 18 PUPS: APPEARED NORMAL.
17680 5 l7 PUPS: APPEARED NORMAL.
17681 5 16 PUPS: APPEARED NORMAL.
17690 5 18 PUPS: APPEARED NORMAL.
17694 1 1 PUP: FOUND DEAD. ALL TISSUES APPEARED NORMAL.
5 15 PUPS: APPEARED NORMAL.
17695 5 15 PUPS: APPEARED NORMAL.
17703 1 1 PUP: STILLBORN. ALL TISSUES APPEARED NORMAL.
1 PUP: FOUND DEAD. NO MILK IN STOMACH.
5 19 PUPS: APPEARED NORMAL.
17713 5 14 PUPS: APPEARED NORMAL.
17715 5 13 PUPS: APPEARED NORMAL.
17716 5 14 PUPS: APPEARED NORMAL.
17717 5 13 PUPS: APPEARED NORMAL.
17719 5 18 PUPS: APPEARED NORMAL.

a. Complete necropsies were not performed on pups in which autolysis or cannibalization precluded evaluation.



8110 

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C45 (PAGE 2): NECROPSY OBSERVATIONS - INDIVIDUAL DATA - F1 GENERATION PUPS

MATERNAL DOSAGE GROUP LITTER DAY
MATERNAL DOSAGE NUMBER POSTPARTUM OBSERVATIONS a
II .
10 17665 5 15 PUPS: APPEARED NORMAL.
17666 5 l4 PUPS: APPEARED NORMAL.
17668 5 16 PUPS: APPEARED NORMAL.
17671 5 13 PUPS: APPEARED NORMAL.
17675 5 18 PUPS: APPEARED NORMAL.
17679 5 9 PUPS: APPEARED NORMAL.
17684 5 16 PUPS: APPEARED NORMAL.
17688 5 14 PUPS: APPEARED NORMAL.
17698 2 1 PUP: FOUND DEAD. AUTOLYSIS PRECLUDED FURTHER
EVALUATION.

5 15 PUPS: APPEARED NORMAL.
17702 5 15 PUPS: APPEARED NORMAL.

17704 5 1 PUP: KIDNEYS: BILATERAL, PELVIS, SLIGHT DILATION.

ALL OTHER TISSUES APPEARED NORMAL.

18 PUPS: APPEARED NORMAL.
17707 5 15 PUPS: APPEARED NORMAL.
17708 5 16 PUPS: APPEARED NORMAL.
17710 5 18 PUPS: APPEARED NORMAL.

a. Complete necropsies were not performed on pups in which autolysis or cannibalization precluded evaluation.

6110 H7

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C45 (PAGE 3): NECROPSY OBSERVATIONS INDIVIDUAL DATA - F1 GENERATION PUPS

MATERNAL DOSAGE GROUP LITTER DAY
MATERNAL DOSAGE NUMBER POSTPARTUM OBSERVATIONS a

50 17661 5 15 PUPS: APPEARED NORMAL.
17667 5 13 PUPS: APPEARED NORMAL.
17669 5 16 PUPS: APPEARED NORMAL.
17670 5 16 PUPS: APPEARED NORMAL.
17676 5 15 PUPS: APPEARED NORMAL.
17687 5 15 PUPS: APPEARED NORMAL.
17693 1 2 PUPS: STILLBORN. ALL TISSUES APPEARED NORMAL.
5 14 PUPS: APPEARED NORMAL.
17697 5 15 PUPS: APPEARED NORMAL.
17700 5 14 PUPS: APPEARED NORMAL.
17701 5 14 PUPS: APPEARED NORMAL.
17705 1 2 PUPS: STILLBORN. ALL TISSUES APPEARED NORMAL.
5 16 PUPS: APPEARED NORMAL.
17706 5 1 PUP: FOUND DEAD. AUTOLYSIS PRECLUDED FURTHER
EVALUATION.
14 PUPS: APPEARED NORMAL.
17709 5 16 PUPS: APPEARED NORMAL.
17718 5 16 PUPS: APPEARED NORMAL.
17720 5 16 PUPS: APPEARED NORMAL.

a. Complete necropsies were not performed on pups in which autolysis or cannibalization precluded evaluation. Refer to the
individual pup clinical observations table (Table C44) for external clinical observations confirmed at necropsy.

117

PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7 WITH THE TOXICITY
SCREENING TEST STUDY NUMBER: T-7599)

TABLE C45 (PAGE 4): NECROPSY OBSERVATIONS - INDIVIDUAL DATA - F1 GENERATION PUPS

MATERNAL DOSAGE GROUP LITTER DAY
MATERNAL DOSAGE NUMBER POSTPARTUM OBSERVATIONS a
IV
250 17677 1 1 PUP: FOUND DEAD. NO MILK IN STOMACH.
ALL TISSUES APPEARED NORMAL.
1 PUP: FOUND DEAD. ALL TISSUES APPEARED NORMAL.
2 PUPS: FOUND DEAD. NO MILK IN STOMACH.
AUTOLYSIS PRECLUDED FURTHER EVALUATION.
17678 5 12 PUPS: APPEARED NORMAL.
17682 5 14 PUPS: APPEARED NORMAL.
17683 5 16 PUPS: APPEARED NORMAL.
17685 1 1 PUP: STILLBORN. ALL TISSUES APPEARED NORMAL.
5 15 PUPS: APPEARED NORMAL.
17689 5 17 PUPS: APPEARED NORMAL.
17691 5 12 PUPS: APPEARED NORMAL.
17692 1 2 PUPS: STILLBORN. ALL TISSUES APPEARED NORMAL.
5 14 PUPS: APPEARED NORMAL.
17696 1 2 PUPS: STILLBORN. AUTOLYSIS PRECLUDED FURTHER
EVALUATION.
2 3 PUPS: FOUND DEAD. AUTOLYSIS PRECLUDED FURTHER
EVALUATION.
6 PUPS: FOUND DEAD. CANNIBALIZATION PRECLUDED FURTHER
EVALUATION.
17699 5 13 PUPS: APPEARED NORMAL.
17711 1 1 PUP: STILLBORN. AUTOLYSIS PRECLUDED FURTHER
EVALUATION.
2 11 PUPS: FOUND DEAD. AUTOLYSIS PRECLUDED FURTHER
EVALUATION.
17712 5 13 PUPS: APPEARED NORMAL.
17714 5 15 PUPS: APPEARED NORMAL.

a. Complete necropsies were not performed on pups in which autolysis or cannibalization precluded evaluation. Refer to the
individual pup clinical observations table (Table C44) for external clinical observations confirmed at necropsy.



.


1510 

APPENDIX 

PROTOCOL AND AMENDMENTS

 D?l



905 Sheehy om. Bldg. A ARGUS RESEARCH
Horsham, PA 19044 . .

Telephone: (215) 4433710 . Chades River Laboratones
Telefax: 443-8587 Discovery and Development Semces

PROTOCOL 418-027
STUDY NUMBER: T4599

STUDY TITLE: Oral (Gavage) Combined Repeated Dose Toxicity Study of 7599.7 with
the Reproduction/Developmental Toxicity Screening Test

PURPOSE: The purpose of this study is to provide information on the possible health
hazards that may result from repeated exposure of BR
male and female rats to a test substance beginning before
cohabitation, through mating and continuing for at least 28 days (male
rats) or through parturition until day 4 or 5 of lactation (female rats). This
repeated dose study incorporates a reproduction/developmental toxicity
screening test that can be used to provide initial information on possible
effects on male and female reproductive performance gonadal
function, mating behavior, conception, development of the conceptus and
parturition). The study also places emphasis on neurological effects as a
speci?c endpoint and should identify the neurotoxic potential of a test
substance, which may warrant further in-depth investigation.

Because of the selectivity of the endpoints and the short duration of the
study, the screening test will not provide evidence for de?nitive claims of
no reproduction/developmental effects. In particular, it offers only limited
means of detecting postnatal, manifestations of prenatal exposure or effects
that may be induced during postnatal exposure.

TESTING

FACILITY: Argus Research
905 Sheehy Drive, Building A
Horsham, 19044?1297
Telephone: (215) 4438710
Telefax: (215) 443-8587



DIRECTOR: Raymond G. York, DABT

Associate Director of Research
Address as cited above for Testing Facility.
Email: 

418-0272PAGE Dal

Protocol 41 8?027
Page 2

SPONSOR: 3M Corporate Toxicology
3M Center, Building 220-2E-02
St. Paul, Minnesota 55144-1000

STUDY
MONITOR: Paul H. Lieder, DABT
3M Corporate Toxicology
3M Medical Department
Telephone: (651) 737?2678
Telefax: (651) 733~1773
Email: phliederl 
REGULATORY CITATIONS:

 

Organisation for Economic Co?operation and Development (1996). GE CD Guideline for Testing
of Chemicals. Section 4, No. 422: Combined Repeated Dose Toxicity Study with the
Reproduction/Developmental Toxicity Screening Test, adopted 22 March 1996.

Organisation for Economic Co?operation and Development (1998). The Revised OECD
Principles of Good Laboratory Practices 

US. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule.
21 CFR Part 58.

Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice Standard for Safety
Studies on Drugs, MHW Ordinance Number 21, March 26, 1997.

REGULATORY COMPLIANCE:

This study will be conducted in compliance with the Good Laboratory Practice (GLP)
regulations cited above with the exception of analysis of blood and liver samples sent to
Southern Research Institute for metabolite analysis.

All changes or revisions of this protocol shall be documented, signed by the Study Director and
the Sponsor, dated and maintained with the protocol.

The Testing Facility's Quality Assurance Unit (QAU) will audit the protocol, the raw data and
the report, and will inspect critical phases of those portions of the study conducted at the Testing
Facility in accordance with the Standard Operating Procedures of the Testing Facility.

The ?nal report will include a compliance statement signed by the Study Director that the report
accurately re?ects the raw data obtained during the performance of the study and that all
applicable GLP regulations were followed in the conduct of the study. Should signi?cant
deviations from GLP regulations occur, each will be described in detail, together with how the
deviation might affect the quality or integrity of the study.

 D93

Protocol 418-027
Page 3

Should any portion of the study be conducted by a subcontractor or by the Sponsor, the Study
Director will ensure that a quali?ed Principal Investigator is identi?ed by the facility conducting
that portion of the study. The QAU for that facility will conduct critical phase inspections and
audit respective results and reports for that study portion according to the SOPs of that facility.
Such critical phase inspection reports and report audits will be submitted by that facility to the
Principal Investigator and the Study Director. The dates of the inspections and report
submissions will be incorporated into a QAU Statement generated by that facility and provided
to the Testing Facility for inclusion in the ?nal report. In addition, that facility will provide a

statement of GLP compliance, as described above, signed by the Principal Investigator for
inclusion in the ?nal report.

SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE:
See ATTACHMENT 1 to the protocol.

TEST SUBSTANCE AND VEHICLE:

Identi?cation:

Test Substance:

7599.7. Lot identi?cation to be documented in the raw data.

The Sponsor will provide to the Testing Facility documentation or certi?cation of the identity,
composition, method of strength and activity/purity of the test substance. This
documentation will be included in the ?nal report.

Vehicle:

Aqueous 0.5% (CMC) (medium viscosity) prepared using reverse
osmosis membrane processed deionized water (R.O. deionized water). Lot identi?cation to be
documented in the raw data.

Neither the Sponsor nor the Study Director is aware of any potential contaminants likely to be
present in the vehicle that would interfere with the results of this study. Therefore, no analyses
other than those mentioned in this protocol will be conducted.

Safety Precautions:

Gloves, mask, appropriate protection and uniform/lab coat to be

worn during formulation preparation and dosage. The Material Safety Data Sheet (MSDS) will
be included in the raw data.

41 8-0271PAGE D54
Protocol 418~027

Page 4
Storage:
Bulk Test Substance: Room temperature, protected from light.
Bulk Vehicle Components: Room temperature.
Prepared Test Substance and
Vehicle Formulations: Room temperature, protected from light.

All test substance shipments to the Testing Facility should be addressed to the attention of Julian

Gulbinski, Manager of Formulation Laboratory, at the previously cited address and telephone
number.

Shipments should include information concerning storage conditions and shipping cartons should
be labeled appropriately. The recipient should be noti?ed in advance of shipment.

FORMULATION:

Frequency of Preparation:

Formulations (suspensions) will be prepared weekly at the Testing Facility.
Detailed preparation procedures are attached to this protocol (ATTACHMENT 2).
Adiustrnent for Purity:

The test substance will be considered 100% pure for the purpose of dosage calculations.

Testing Facility Reserve Samples:

The Testing Facility will reserve a sample (approximately 1 g) of each lot of bulk test substance
and bulk vehicle components used during the course of the study. Samples will be stored under
the previously cited conditions.

ANALYSES:

Results of required analyses will be provided to the Testing Facility for inclusion in the study
report.

Samples additional to those described below may be taken if deemed necessary during the course
of the study. Additional analyses, if required, will be documented by protocol amendment.

41 

Protocol 418-027
Page 5

Bulk Test Substance Sampling:

A sample (approximately 1 g) of the test substance will be taken on the last day of treatment and

sent (ambient conditions, protected from light) to the Sponsor for analysis. This sample will be
sent to:

Principal Investigator: Gregory S. Gonnan, 
Staff Chemist

Bioanalytical Chemistry Group

Southem Research Institute

2000 Ninth Avenue South

Birmingham, Alabama 35255-5305

Telephone: (205) 581-2725
Telefax: (205) 581?2044
Email: gorman@sri.org

The recipient will be noti?ed in advance of sample shipment.
Analyses of Prepared Formulations:

Concentration and Homogeneity:

Concentration and homogeneity of the prepared formulations will be veri?ed during the course
of this study. Quadruplicate samples (2 mL each) will be taken from the top, middle and bottom
of each concentration on the ?rst day of preparation. Two samples from each quadruplicate set
will be shipped for analysis; the remaining samples will be retained at the Testing Facility as
backup samples. Quadruplicate samples will be taken from each concentration on the last day of
preparation. Two samples from each quadruplicate set will be shipped for analysis; the
remaining samples will be retained as backup samples. Backup samples will be stored under the
previously cited conditions and discarded at the Testing Facility upon the request of the Sponsor.

m1

Stability of the prepared formulations will be documented during this study. Two sets of
duplicate samples (2 mL each) from each concentration will be taken on the ?rst day of
preparation. One sample of each duplicate set will be shipped on the day of preparation. These
samples will be analyzed at the following time points: as soon a?er preparation as possible and
ten days after the ?rst analysis. The remaining samples will be retained at the Testing Facility as
backup samples. Backup samples will be stored under the previously cited conditions and
discarded at the Testing Facility upon the request of the Sponsor.

 

Protocol 4 8~027
Page 6

Shipping Instructions:
Samples to be analyzed will be shipped (ambient conditions) to:

Gregory S. German, 

Staff Chemist

Bioanalytical Chemistry Group
Southern Research Institute

2000 Ninth Avenue South
Birmingham, Alabama 35255?5305

Telephone: (205) 581-2725
Telefax: (205) 581?2044
Email: gonnan@sri.org

The recipient will be noti?ed in advance of sample shipment.

DISPOSITION:

Prepared formulations will be discarded at the Testing Facility. All remaining bulk test
substance will be returned to the Sponsor at the previously cited address.

TEST SYSTEM:
Species/Strain and Reason for Selection:

The BR rat was selected as the Test System because: 1) it is one
mammalian species accepted for use in toxicity studies and it has been widely used throughout
industry; 2) this strain of rat has been demonstrated to be sensitive to reproductive and
developmental toxins; and 3) historical data and experience exist at the Testing Facilityu's)?

Number:

Initial population acclimated: 70 male and 70 virgin female rats.

Population selected for study: 60 male and 60 virgin female rats (15 per sex per
dosage group).

Body Weight and Age:

 

Male rats will be ordered to weigh from 300 to 325 each at receipt, at which time they will be
expected to be at least 60 days of age. Female rats will be ordered to weigh from 200 to 225 
each at receipt, at which time they will be expected to be at least 60 days of age. Actual body
weights will be recorded the day after receipt and will be documented in the raw data. The
weight ranges will be included in the ?nal report. At study initiation, the weight variation of the
rats will not exceed i20% of the mean weight of each sex.

41 Dn7

Protocol 418-027
Page 7

gear
Both male and female rats will be evaluated.
Source:

Charles River Laboratories, Inc.

The rats will be shipped in ?ltered cartons by air freight and/or truck from Charles River
Laboratories, Inc., to the Testing Facility.

Identi?cation:

Rats are permanently identi?ed using Mone1? self-piercing ear tags (Gey Band and Tag Co.,
Inc, No. MSPT 20101). Male and female rats are assigned temporary numbers at receipt and
given unique permanent identi?cation numbers when assigned to the study before administration

of the ?rst dosage. Pups will not be individually identi?ed during lactation; all parameters will
be evaluated in terms of the litter.

ANIMAL HUSBANDRY:

All cage sizes and housing conditions are in compliance with the Guide for the Care and Use of
Laboratory Animals?).

Egan-cg:

F0 generation rats will be individually housed in stainless steel, wire?bottomed cages, except
during the cohabitation and postpartum periods. During cohabitation, each pair of rats will be
housed in the male rat's cage. Beginning no later than day 20 of presumed gestation,

F0 generation female rats will be individually housed in nesting boxes. Each dam and delivered
litter will be housed in a common nesting box during the postpartum period.

Nestin Material:

Nesting material will be provided.

Bedding will be changed as often as necessary to keep the animals dry and clean. Analyses for
possible contamination are conducted semi?annually and documented in the raw data.

Room Air. Temperature and Humidity:

The animal room is independently supplied with at least ten changes per hour of 100% fresh air
that has been paSsed through 99.97% HEPA ?lters. Room temperature will be maintained at
to to and monitored constantly. Room humidity will also be monitored
constantly and maintained at 30% to 70%.

 

Protocol 418?027
Page 8

Light:

An automatically controlled 12?hour light: 12-hour dark ?uorescent light cycle will be
maintained. Each dark period will begin at 1900 hours EST. The light cycle may be adjusted by
the Study Director or designee if deemed necessary to accommodate scheduled laboratory
activities. Any such adjustment will be documented in the raw data.

Diet:

Rats will be given Certi?ed Rodent Diet? #5002 (PMI Nutrition International), available ad
libitum from individual feeders except during fasting.

Water:

Water will be available ad libitum from individual bottles attached to the cages or from an
automatic watering access system. All water will be ?om a local source and passed through a
reverse osmosis membrane before use. Chlorine will be added to the processed water as a
bacteriostat; processed water is expected to contain no more than 1.2 chlorine at the time of

analysis. Water is analyzed for possible bacterial contamination and twice annually for
possible chemical contamination.

Contaminants:

Neither the Sponsor nor the Study Director is aware of any potential contaminants likely to be
present in the certi?ed diet, in the drinking water or in the nesting materials at levels that would
interfere with the results of this study. Therefore, no analyses other than those routinely
performed by the feed supplier or those mentioned in this protocol will be conducted.

DAY NUMBERING SYSTEM:

Gestation day 0 is de?ned as the day spermatozoa are observed in a smear of the vaginal
contents and/or a copulatory plug observed in situ.

The day of birth is designated lactation day 0 (postpartum day 0) in the Health Effects Test
Guidelines - Reproduction and Fertility Effects (Of?ce of Prevention, Pesticides and Toxic
Substances 870.3800, August, 1998) and in the OECD Guideline for the Testing of Chemicals -
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity
Screening Test (Section 4, No. 422, 22 March 1966). This same day is designated day 1
postpartum (day of lactation) in the Standard Operating Procedures of the Testing Facility.
Throughout this protocol, the day of birth will be designated day postpartum (day 1 of
lactation) and all subsequent ages of the F1 generation rats and days of the lactation period will
be determined and cited accordingly.

 

Protocol 4 1 8-027
Page 9

RANDOMIZATION AND COHABITATION:

Upon arrival, rats will be assigned to individual housing on the basis of computer-generated
random units. After an acclimation period of at least ?ve days, male andrfemale rats will be
selected for study on the basis of physical appearance and body weights recorded during

acclimation. The rats will be assigned to dosage groups based on computer?generated
(weight-ordered) randomization procedures.

Within each dosage group, consecutive order will be used to assign rats to cohabitation, one male
rat per female rat. The cohabitation period will consist of a maximum of 14 days. Female rats
with spermatozoa observed in a smear of the vaginal contents and/or a copulatory plug observed
in situ will be considered to be at day 0 of presumed gestation and assigned to individual
housing. Female rats not mated within the ?rst seven days of cohabitation will be assigned

alternate male rats that have mated (same dosage group) and will remain in cohabitation for a
maximum of seven additional days.

Day 1 of lactation (postpartum) is de?ned as the day of birth and is also the ?rst day on which all

pups in a litter are individually weighed (pup body weights will be recorded after all pups in a
litter are delivered and groomed by the dam).

Within each dosage group, consecutive order will be used to assign the ?rst ?ve male and the
?rst ?ve female rats to a functional observational battery (FOB) and motor activity assessment.
The next ?ve rats per sex in each group will be assigned to hematology and clinical biochemistry
evaluations. The last ?ve rats per sex in each group will be assigned to metabolite analysis.
Histological evaluations will be performed on the last ten rats per sex in each group.

ADMINISTRATION:

Route and Reason for Choice:

The oral (gavage) route was selected for use because: 1) in comparison with the dietary route,
the exact dosage can be accurately administered; and 2) it is one possible route of human
exposure.

Method and Frequency:

Dosages will be adjusted daily for body weight changes and given at approximately the same
time each day.

Male rats will be given the test substance and/or the vehicle once daily beginning 14 days before
cohabitation (maximum 14 days) and continuing until sacri?ce, after completion of the
cohabitation period, after a minimum of 28 days of dosage.

418-0272PAGE 

Protocol 418?027
Page 10

Female rats will be given the test substance and/or the vehicle once daily beginning, 14 days
before cohabitation (maximum 14 days) and continuing until the day before scheduled sacri?ce
on day 6 of lactation.

Pups will not be directly given the test substance or the vehicle but may be possibly exposed to
the test substance during maternal gestation (in utero exposure) or via maternal milk during the
lactation period.

Rationale for Dosage Selection:

Dosages will be selected by the Sponsor based on previous studies conducted with the test
substance, taking into account possible differences in sensitivity between pregnant and
nonpregnant rats. The highest dosage will be expected to cause toxic effects but not mortality or
obvious suffering. The descending sequence of the lower dosage levels will be selected for the
purpose of demonstrating any dosage?related response, with no adverse effects expected at the
lowest level.

Dosage Levels, Concentrations and Volumes:

 

 

 

 

 

Number Dosage
Dosage Of Rats Dosage Concentration Volume
Group Per Sex (mg/kg/day) (mgmL) (Iii/kg; Argus Batch Number
I 15 0 (VehicleB-4The test substance will be considered 100% pure for the purpose of dosage calculations.
TESTS. ANALYSES AND MEASUREMENTS - F0 GENERATION:
Viability - Male and Female Rats:

All Periods: At least twice daily.

Clinical Observations and/or General Appearance - Male? and Female Rats:

Acclimation Period: Weekly.

 D?ll

Protocol 418?027
Page 11

Dosage Period: Daily before dosage. On the ?rst day of dosage,
postdosage observations will be recorded at approximately
hourly intervals after administration for the ?rst four hours
and at the end of the normal working day. Postdosage
observations for subsequent days of dosage will be
recorded at intervals determined appropriate by the Study
Director and/or Study Monitor after determination of the
onset of peak pharmacologic/toxicologic effects.

Postdosage Period: Before sacri?ce.
Maternal Behavior: Days 1 and 5 postpartum. Observed abnormal behavior
recorded daily.

Clinical observations may be recorded more frequently than cited above, if deemed appropriate
by the Study Director and/or Study Monitor.

Detailed Clinical Observations Male and Female Rats:

Once before the ?rst dosage and at least once weekly thereafter, detailed clinical observations
will be conducted for all male and female rats. These observations will be made outside the cage
in a standard arena at the same time each day of conduct. Effort will be made to ensure that
variations in the test conditions are minimal and that observations are conducted by observers
unaware of treatment groups. Signs noted should include, but not be limited to: changes in skin,
fur, eyes, mucous membranes, occurrence of secretions and excretions and autonomic activity
lacrimation, piloerection, pupil size, unusual respiratory pattern). Changes in gait, posture
and response to handling as well as the presence of clonic or tonic movements, stereotypic
behavior excessive grooming, repetitive circling), dif?cult or prolonged parturition or
bizarre behavior self-mutilation, walking backwards) should also be recorded.

Body Weights - Male and Female Rats:

Acclimation Period: Weekly.
Dosage Period: Daily.
Sacri?ce: Terminal weight.

Feed Consumption Values - Male Rats (recorded and tabulated):

Dosage Period: Weekly. Feed left recorded on the day before sacri?ce.
Rats will be fasted overnight before sacri?ce.

418-0272PAGE 

Protocol 418?027
Page 12?

Feed Consumption Values Female Rats (recorded and tabulated):

Dosage Period: Weekly to cohabitation.

Days (if necessary) of
presumed gestation and days 1 and 5 postpartum. Feed left
will be recorded on the day before sacri?ce. Rats will be
fasted overnight, before sacri?ce.

Feed Consumption Values - Male and Female Rats:

Feed consumption values may be recorded more frequently than cited above if it is necessary to
replenish the feed. During cohabitation, when two rats occupy the same cage with one feed jar,
replenishment of the feed jars will be documented. Individual values will not be recorded or
tabulated.

Estrous Cycling and Mating:

Betrous cycling will be evaluated by examination of vaginal cytology beginning with the day

after the ?rst administration and then until spermatozoa are observed in a smear of the vaginal
contents and/or a copulatory plug is observed in situ during the cohabitation period.

Natural Delivery:
Female rats will be evaluated for:
Adverse Clinical Signs Observed During Parturition.
Duration of Gestation (day 0 of presumed gestation to the time the ?rst pup is observed).
Litter Size (de?ned as all pups delivered).
Pup Viability at Birth.
Functional Observatitmal Battery:
On one occasion during the course of the study, a. functional observational battery (F will
be conducted on five male and ?ve female rats per group. For male rats, this assessment will be
conducted shortly before scheduled sacri?ce. Female rats should be tested during. the lactation
period, shortly before scheduled sacri?ce. To avoid hyperthermia of pups, dams will be

separated from their litters for no longer than 30 to 40 minutes.

The FOB, to be conducted by an observer unaware of the group assignment of the rat, will assess
the following parameters:

 3
Protocol 418-027

Page 13

1. Lacrimation, salivation, palpebral closure, prominence of the eye, pupillary
reaction to light, piloerection, respiration, and urination and defecation
(autonomic functions).

2. Sensorimotor responses to visual, auditory, tactile and painful stimuli (reactivity
and sensitivity).

3. Reactions to handling and behavior in the open ?eld (excitability).

4. Gait pattern in the open ?eld, severity of gait abnormalities, air righting reaction,
visual placing response and landing foot splay (gait and sensorimotor
coordination).

5. Forelimb and hindlimb grip strength.

6. Abnormal clinical signs including but not limited to convulsions, tremors and

other unusual behavior, hypotonia or hypertonia, emaciation, dehydration,
unkempt appearance and deposits around the eyes, nose or mouth.

Evidence of the ability of this battery to detect the effects of positive control substances will be
provided (Testing Facility Positive Control Data). Data will also be provided to document
interobserver reliability if more than one observer is, involved in the testing.

Motor Activity Test:

Motor activity will be evaluated on ?ve male and ?ve female rats per group once during the
course of the study. For male rats, this assessment will be conducted shortly before scheduled
sacri?ce. Female rats should be tested during the lactation period, shortly before scheduled
sacri?ce.

The movements of each rat will be monitored by a passive infrared sensor mounted outside a
stainless steel, Wire?bottomed cage (40.6 25.4 17.8 cm). Each test session will be 1.5 hours in
duration with the number of movements and time spent in movement tabulated at each
?ve?minute interval. The apparatus will monitor a rack of up to 32 cages and sensors during
each session, with each rat tested in the same location on the rack across test sessions. Groups
will be counterbalanced across testing sessions and cages.

Data will be provided to demonstrate that the test system is capable of detecting increases in
activity produced by positive control substances, (Testing Facility Positive Control Data).

 D-l4

Protocol 4 1 8-027
Page 14

HEMATOLOGY AND CLINICAL CHEMISTRY:

At scheduled sacri?ce, the ?ve male and ?ve female, rats per group assigned to hematology and
clinical chemistry sample collection will be exsanguinated from the inferior vena cava following
sacri?ce by carbon dioxide Rats will be fasted overnight before sacri?ce.
Approximately 5 mL of blood (fasted) will be collected and processed as described below.
Determinations additional to those described below may be conducted if the known properties of
the test substance may, or are suspected to, affect related metabolic pro?les calcium,
phosphate, fasting triglycerides and fasting glucose, speci?c hormones, and cholinesterase).

The tubes containing the samples will be labeled with the protocol number, Sponsor study
number, animal number, group number, dosage level, day of study, collection interval, date of
collection, species, generation and storage conditions.

Hematology:

Approximately 1 mL of blood will be collected into EDTA~coated tubes and maintained on wet
ice or refrigerated until shipment for analysis of the following hematologic parameters:

Count (RBC) Mean Corpuscular Volume (MCV)

Hematocrit (HCT) Leukocyte Count, Total (WBC)

Hemoglobin (HGB) Leukocyte Count, Differential

Mean Corpuscular Hemoglobin (MCH) Platelet Count (PLAT)

Mean Corpuscular Hemoglobin Mean Platelet Volume (MPV)
Concentration (MCHC) Cell Morphology

Two blood smear slides will be prepared at the Testing Facility for each sample for
measurements of differential leukocyte count. All samples (on wet ice) and slides (ambient

conditions) will be shipped on the day of collection, to Red?eld Laboratories at the following
address.

Approximately 1.8 mL of blood will be, added to a tube containing 0.2 mL of sodium citrate
(0.129 M). The contents will be mixed and maintained on wet ice until the tubes are centrifuged
(within 30 minutes of the collection time). The resulting plasma will be transferred to a transport
tube and immediately frozen. Plasma samples will be maintained on dry ice or in a freezer
until shipped on dry ice to Red?eld Laboratories at the following address, for
measurement of prothrombin time (PT) and activated partial thromboplastin time (APTT).

 

Protocol 4 8~027
Page 15

Clinical Chemistry:

Approximately 2 mL of blood will be collected into serum separator tubes and centrifuged. The 
resulting sera samples will be immediately frozen on dry ice and maintained frozen 
until shipment for analysis of the following parameters:

Total Protein (TP) Creatinine (GREAT)

Triglycerides (TRI) Alanine Aminotransferase (ALT)
Albumin (A) Aspartate Aminotransferase (AST)
Globulin (G) Alkaline Phosphatase (ALK)
Albumin/Globulin Ratio Calcium (CA)

Glucose (GLU) Phosphorus (PHOS)

Cholesterol (CHOL) Sodium (NA)

Total Bilirubin (TBILI) Potassium (K)

Urea Nitrogen (BUN) Chloride (CL)

Samples will be shipped (on dry ice) to arrive on Monday through Friday at Red?eld
Laboratories at the following address.

Shipping Instructions:
Samples will be shipped according to the conditions described above to:

Principal Investigator: Ms. Powell
Red?eld Laboratories

A Division of 

100 East Boone Street

PO. Box 308

Redfield, Arkansas 72132

Telephone: (501) 397?2540

Telefax: (501) 397-2002

The recipient will be noti?ed in advance of sample shipment.

URINALYSIS:

Urinalysis will not be conducted unless indicated based on expected or observed toxicity of the
test substance.

METHOD OF SACRIFICE:

F0 generation rats will be sacri?ced by carbon dioxide 

418-0271PAGE 

Protocol 4 1 8-027
Page 16

GROSS NECROPSY AND HISTOPATHOLOGY F0 GENERATION RATS:

Scheduled Sacri?ce:

Scheduled sacri?ce of male rats will be conducted on the day following the last, dosage

administration, a?er a minimum of 28 days of dosage. Scheduled sacri?ce of female rats will be
conducted on day 6 of lactation.

Gross necropsy of all male and female rats will include an initial physical examination of
external surfaces and all ori?ces, as well as the cranial, thoracic and abdominal cavities and their

contents. Special attention will be paid to the organs of the reproductive system. The number of
implantation sites and corpora lutea will be recorded.

Male and female rats will be examined for gross lesions. Gross lesions will be retained in neutral
buffered 10% formalin and examined histologically. Tissue trimming and histopathology will be
performed under the supervision of or by a BoardwCerti?ed Veterinary Pathologist.

The testes and epididymides of all male rats will be weighed, and the testes, epididymides,
seminal vesicles with coagulating gland and prostate will be retained in neutral buffered 10%
formalin. The testes will be ?xed in Bouin's solution for 48 to 96 hours before being retained in
neutral buffered 10% formalin. The ovaries and the uterus with cervix of each female rat will be
weighed, and ovaries, uterus, vagina and a mammary gland will be retained in neutral buffered
10% formalin. Uteri of apparently nonpregnant rats will be examined a?er being pressed

between glass plates to con?rm the absence of implantation sites, and retained in neutral
buffered 10% formalin.

Blood samples (approximately 3 mL) will be collected from the ?ve rats per sex per group
assigned to metabolite analysis. Blood will be collected from the vena cava. Each sample will
be divided into two aliquots. One aliquot of 2 mL will be transferred into an EDTA?coated
(purple top) tube and refrigerated. The second aliquot (approximately 1 mL) will be transferred
into a serum tube, allowed to clot and spun in a centrifuge. The resulting serum will be
transferred into polypropylene tubes labeled with the protocol number, Sponsor study number,
animal number, group number, dosage level, day of study, collection interval, date of collection,
species, generation and storage conditions. All samples will be immediately frozen on dry ice
and maintained frozen until shipment for analysis.

The liver will be excised and the organ weight recorded. One lobe (right lateral) will be placed
in a conical tube and ?ash frozen in an ice/alcohol bath. Liver samples will be maintained frozen
until shipment for analysis.

418-0272PAGE D-17

Protocol 418~027
Page 17

Shipping Instructions:

Liver and serum samples will be shipped on dry ice and. whole blood will be shipped on ice
packs. Samples to be analyzed will be shipped to:

Principal Investigator: Gregory S. Gorman, 
Staff Chemist

Bioanalytical Chemistry Group

Southern Research Institute

200 Ninth Avenue South

Birmingham, Alabama 35255-5305

Telephone: (205) 581-2725
Telefax: (205) 581?2044
Email: gonnan@sri .org

The recipient will be noti?ed in advance of sample shipment.

See ATTACHMENT 3 for additional tissues to be weighed and retained from the ten rats per sex
per group assigned to histological sample collection and evaluation.

All other tissues will be discarded.
Scheduled Sacri?ce of Female Rats that Do Not Deliver Litters:

Rats that do not deliver a litter will be sacri?ced on day 25 of presumed gestation. Gross

necropsy, examination and tissue retention will be conducted as described above for rats at
scheduled sacri?ce.

Dams with SurviviggPups:

Dams with no surviving pups will be sacri?ced after the last pup is found dead, missing or
presumed cannibalized. Gross necropsy, examination and tissue retention will be conducted as
described above for rats at scheduled sacri?ce.

Rats Found Dead or Moribugg:

Rats that die or are sacri?ced because of moribund condition, abortion or premature delivery will
be examined for the cause of death or moribund condition on the day the observation is made.
The rats will be examined for gross lesions. Testes and epididymides of male, rats will be
excised and paired organ weights will be recorded. The epididymides will be retained in neutral
buffered 10% formalin. The testes will be ?xed in Bouin's solution for 48 to 96 hours and then
retained in neutral buffered 10% formalin. Pregnancy status and uterine contents of female rats
will be recorded. Aborted fetuses and/or delivered pups will be examined to the extent possible.
Uteri of apparently nonpregnant rats will be examined after being pressed between glass plates to
con?rm the absence of implantation sites. Ovaries and uteri will be retained in neutral buffered

1 0% formalin.

 D-18

Protocol 41 8?027

 

Page 18
TESTS. ANALYSES AND MEASUREMENTS - Fl GENERATION:
Viability:
Preweaning Period: Litters will be observed for dead pups at least twice daily. The

pups in each litter will, be counted once daily.
Clinical Observations and/or General Appearance:

Preweaning Period: Once daily.

Clinical observations may be recorded more frequently than cited above, if deemed appropriate
by the Study Director and/or the Study Monitor.

Body Weights:

Preweaning Period: Days 1 (birth) and 5 postpartum.
Sacri?ce: Terminal weight.

Feed Consumption Values (recorded and tabulated):

Preweaning Period: Not recorded.

METHOD OF SACRIFICE Fl GENERATION PUPS:

F1 generation pups will be sacri?ced by carbon dioxide 

NECROPSY F1 GENERATION:

Gross lesions will be retained in neutral buffered 10% formalin for possible future eValuation.
Unless speci?cally cited below, all other tissues will be discarded.

Pups Found Dead on Day 1 Postpartum:

Pups that die before examination of the litter for pup viability will be evaluated for vital status at
birth. The lungs will be removed and immersed in water. Pups with lungs that sink will be
identi?ed as stillborn; pups with lungs that ?oat will be identi?ed as liveborn, and to have died

shortly after birth. Pups with gross lesions will be preserved in Bouin's solution for possible
future evaluation. -

Pups Found Dead or Moribund on Days 2 to 4 Postpartum:
Pups found dead or sacri?ced because of moribundity will be examined for gross lesions and for

the cause of death or the moribund condition. Pups with gross lesions will be preserved in
Bouin's solution for possible ?iture evaluation.

 D~l9

Protocol 418-027
Page 19

Scheduled Sacri?ce:

On day 5 postpartum, pups will be will be sacri?ced and examined for gross lesions; gross
lesions will be preserved in neutral buffered 10% formalin. Necropsy will include a single cross~
section of the head at the level of the frontal-parietal suture and examination of the cross?
sectioned brain for apparent hydrocephaly.

PROPOSED STATISTICAL TESTS:

When possible results will be evaluated by appropriate and acceptable statistical methods.
Because of the limited dimensions of the study, statistical analysis in the form of tests for
signi?cance are of limited value for many endpoints, particularly reproductive and neurological
endpoints. Some of the most widely used methods, especially parametric tests for measures of
central tendency, are inappropriate. If statistical analyses are to be conducted, the methods
selected will be appropriate for the distribution of the variable examined and added to the
protocol prior to ?nalization or by amendment.

DATA ACQUISITION. VERIFICATION AND STORAGE:

Data generated during the course of this study will be recorded either by hand or using the Argus
Automated Data Collection and Management System, the Vivarium Temperature and Relative
Humidity Monitoring System, the Coulboum Instruments Passive Infrared Motor Activity
System, the Coulboum Instruments Auditory Startle System, the Coulboum Instruments Spatial
Delayed Alternation System, and/or the passive avoidance software. All data will be tabulated,
summarized and/or statistically analyzed using the Argus Automated Data Collection and
Management System, the Vivarium Temperature and Relative Humidity Monitoring System,

Microsoft Excel [part of Microso? Of?ce 97 (version and/or The SAS System
(version 6.12).

Records will be reviewed by the Study Director and/or appropriate management personnel within
21 days a?er generation. All original records will be stored in the archives of the Testing
Facility. All original data will be bound and indexed. A copy of all raw data will be supplied to
the Sponsor upon request. Preserved tissues will be stored at the Testing Facility at no charge for

one year after mailing of the draft ?nal report, after which time the Sponsor will be contacted to
determine the disposition of these materials.

 

Protocol 418?027
Page 20

KEY PERSONNEL:

Executive Director of Research: Mildred S. Christian, Fellow, ATS

Director of Research: Alan M. Hobennan, DABT

Associate Director of Research and Study Director: Raymond G. York, DABT
Director of Operations and Compliance: Barbara J. Patterson, B.A.

Director of Laboratory Operations: John F. Barnett, B.S.

Director of Study Management: Valerie A. Sharper, M.S.

Manager of Animal Operations: Dena C. Lebo, V.M.D.

Chairperson, Institutional Animal Care and Use Committee: Douglas B. Learn, 
Consultant, Veterinary Pathology: W. Ray Brown, D.V.M., ACVP

RECORDS TO BE MAINTAINED:

Protocol and Amendments.

Test Substance, Vehicle and/or Reagent Receipt, Preparation and Use.
Animal Acquisition.

Randomization Schedules.

Mating History.

Treatment (if prescribed by Staff Veterinarian).
General Comments.

Clinical Observations and/or General Appearance.
Body Weights.

Feed Consumption Values.

Natural Delivery Observations.

FOB and Motor Activity Observations.

Blood Sample Collection, Processing and Shipment.
Gross Necropsy Observations.

Organ Weights.

Photographs (if required).

Study Maintenance (room and environmental records).
Feed and Water Analyses.

Packing and/or Shipment Lists.

 

. Protocol 418-027
Page 21

FINAL REPORT:

The Study Director will provide periodic updates of study progress to the Sponsor. Draft

summary tables of unaudited computer-recorded data may accompany these updates. Statistical
analyses will not be performed on these interim data.

A comprehensive draft ?nal report will be prepared on completion of the study and will be
?nalized following consultation with the Sponsor. The report will include the following:

Summary and Conclusion.
Experimental Design and Method.
Evaluation of Test Results.

Appendices: Figures, Summary and Individual Tables Summarizing the Above Data,
Protocol and Associated Amendments and Deviations, Study Director?s GLP Compliance
Statement, Reports of Supporting Data (if appropriate) and QAU Statement.

The Sponsor will receive one copy of the dra? report and two copies of the ?nal report.

Data will be hand? and/or computer-recorded. Records will be reviewed by the Study Director
and/or appropriate management personnel within 21 days after generation. All original records
will be stored in the archives of the Testing Facility. All original data will be bound and
indexed. A copy of all raw data will be supplied to the Sponsor upon request. Preserved tissues
will be stored at the Testing Facility at no charge for one year after mailing of the draft ?nal

report, after which time the Sponsor will be contacted to determine the disposition of these
materials.

INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE STATEMENT:

The procedures described in this protocol have been reviewed by the Testing Facility's
Institutional Animal Care and Use Committee. All procedures described in this protocol that

involve study animals will be conducted in a manner to avoid or minimize discomfort, distress or
pain to the animals.

The Sponsor's signature below documents the fact that information concerning the necessity for
conducting this study and the fact that this is not an unnecessarily duplicative study may be

obtained from the Sponsor. No alternative (in vitro) procedures were available for meeting the
stated purposes of the study.

1.



Protocol 418?027
Page 22

REFERENCES:

Christian, MS. and Voytek, RE. (1982). In Vivo Reproductive and Mutagenicily Tests.
Environmental Protection Agency, Washington, DC. National Technical Information
Service, US. Department of Commerce, Spring?eld, VA 22161.

Christian, MS. (1984). Reproductive toxicity and teratology evaluations of

naltrexone (Proceedings of Naltrexone Symposium, New York Academy of Sciences,
November 7, 1983), J. Clin. 

Lang, PL. (1988). Embryo and Fetal Developmental Toxicity (T eratology) Control Data
in the Charles River Rat. Charles River Laboratories, Inc., Wilmington,
MA 01887?0630. (Data base provided by Argus Research Laboratories, Inc.)

Institute of Laboratory Animal Resources (1996). Guide for the Care and Use of
Laboratory Animals. National Academy Press, Washington, DC.

Haggerty, G.C. (1989). Development of Tier I neurobehavioral testing capabilities for

incorporation into pivotal rodent safety assessment studies. J. Amer. Col. Toxicol. 8:53-
70.

Irwin, S. (1968). Comprehensive observational assessment: Ia. A systemic quantitative
procedure for assessing the behavioral and physiologic state of the mouse.
(Berlin) 13:222~257.

Moser, V.C. (1989). Screening approaches to neurotoxicity: A functional observational
battery. J. Amer. Col. Toxicol. 8:85-94.

O'Donoghue, .L. (1989). Screening for neurotoxicity using a neurologically based
examination and neuropathology. J. Amer. Col. Toxicol. 8197?116.

PROTOCOL APPROVAL:

FOR THE TESTING FACILITY 

 

 

Ali'iinM. {I/verman, 

irector of Research

    

 

 

 

Wand G. Yori, DABT
Associate Direct of Re earch
Study Director

Rebecca Altmann?Reilly, M.S.

Member, Institutional Animal Care
and Use Committee

OR THE SPONSOR



Paul H. Lieder, DABT
Study Monitor and
Sponsor's Representative

41 

Protocol 4 18-027
Page 23

rs??WL

Date

F478 ?2.62572,

 

 

Date
If) Feb 62002
Date
ZapZ
Date

 

ATTACHMENT 1

SCHEMATIC OF STUDY DESIGN AND STUDX SCHEDULE

 

Protocol 418?027
Page 1 of 3

ATTACHMENT 1

STUDY SCHEMATIC

COMBINED REPEAT DOSE AND TOXICITY

    

  

   

 


Fil?St Day Of Last Day of Test
$115333?? Substance
Dosage? Last Day of Test
Premating Cohabitation Substance
Male Dosage?
Rats
Natural
Motor Delivery
Activity/F01?
Presumed Postpartum
Gestation Period
Female
Rats
Day 5 Day 6
Motor
Activity/FOBjl

- Dosage Period

a For additional details see "Tests, Analyses and Measurements" section of the protocol.
b. FOB and motor activity evaluations conducted on ?ve males per group.
c. Male rats sacri?ced after completion of at least 28 days of dosage; necropsy and retention

of male reproductive organs. Hematology and clinical biochemistry samples (?ve male
and ?ve female rats per group) and histological samples (ten male and ten female rats per

group) collected.

(1. Five female rats per group assigned to FOB evaluation on day 5 postpartum and motor
activity evaluation on day 6 postpartum.

6. Last day of dosage for female rats is day 5 postpartum. Pups sacri?ced on day 5

postpartum. Female rats sacri?ced on day 6 postpartum; necropsy and retention of

female reproductive organs. Hematology, clinical biochemistry and histological samples
collected.

ATTACHMENT OSMAROZ
18MAR02


25 MAR 02





Protocol 418-027
Page 2 of 3



Animal Receipt - Acclimation Begins.

Start of Dosage Period Male Rats (14 days before
cohabitation and through a 14?day cohabitation

period until the of sacri?ce after at least 28 days of
dosage).

Dosage Period Female Rats (14 days before
cohabitation through Day 4 or Day 5 of lactation).

Dosage Period Estrous Cycle Evaluation.

Cohabitation Period (Maximum of 14 days).
Male 1 (7 days)
Male 2 (7 days)

First Possible Day 0 of Presumed Gestation.
Last Possible Day 0 of Presumed Gestation.

FOB and Motor Activity Evaluation - Five Male
Rats per Group

Scheduled Sacri?ce - Male Rats (Earliest possible
date). Hematology, Clinical Biochemistry and
Histological Sample Collection.

3. The start date of the study 1s the day the Study Director signs the protocol.

b. Throughout this schedule, the day of birth IS designated day postpartum (day 1 of
lactation) and all subsequent ages of the F1 generation rats and days of the lactation
period will be determined and cited accordingly, as described above the protocol section,

"Day Numbering System."

ATTACHMENT 31MAR02-17APR02



01 AUG 02



Protocol 418?027
Page 3 of 3

First Possible Delivery (Day 21 of presumed
gestation).

Last Possible Delivery (Day 25 of presumed
gestation).

First Possible Day 25 of Presumed Gestation
Female Sacri?ce.

Last Possible Day 25 of Presumed Gestation
Female Sacri?ce.
FOB Evaluation Five Female Rats per Group.

Day 5 Postpartum Pups Sacri?ced.

Motor Activity Evaluation - Five Female Rats per
Group.

Day 6 Postpartum Sacri?ce of Female Rats.
Hematology, Clinical Biochemistry and
Histological Sample Collection.

Draft Final Report

 D-ZS

ATTACHMENT 2

TEST SUBSTANCE PREPARATION PROCEDURE

 D-29

ATTACHMENT 2 Protocol 41 8-027

Version: 418~027(14 FEB 02)
- Page 1 of 2
TEST SUBSTANCE PREPARATION PROCEDURE

Test Substance: 7559.7
Vehicle: Aqueous 0.5% CMC (medium viscosity)

A. Purpose:

The purpose of this procedure is to provide a method for the preparation of
dosage suspensions of 7559.7 for oral (gavage) administration to rats on
Argus Research Study number 418-027.

B. General Information:

1.

All suspension containers will be labeled and colon-coded. Each label will
specify the protocol number, test substance identi?cation, Argus batch
number, concentration, dos-age level, preparation date, expiration date
and storage conditions.

Suspensions will be prepared: -
Daily Weekly For" days of use
Approximately every ten days By Sponsor



Suspensions will be administered at a ?nal dosage volume of .19., mL/kg.

Safety:

Gloves, uniform/lab coat, goggles or safety glasses with side
shields

Dust-mistlHEF?A??ltered Mask

Half-Face Respirator if not used in a chemical fume hood

Full~Face Respirator/Positive Pressure Hood

Tyvek Suit or tyvek apron and sleeves

Dosage suspensions adjusted for Activity/Purity or Correction Factor:
Yes No (Calculations based on 100%)
Activity Purity Correction Factor

Sampling requirements: Cited in protocol

Storage: Cited in protocol

 D-30

ATTACHMENT 2 Protocol 418-027
Version: 418-027(14 FEB 02)

Page 2 of 2
TEST SUBSTANCE PREPARATION PROCEDURE

NOTE: Prior to test substance preparation accurately measure the required
amount of the appropriate vehicle (R.O. deionized water should be used
for calibration purposes) in a graduated cylinder, pour the required
amount of vehicle into a beaker. Carefully mark each beaker at the
meniscus. This mark will be used during the preparation to bring the test
substance slurry up to volume.

C. Dosage Suspension Preparation:

1. Weigh the required amount of test substance on a piece of weigh paper or
into an appropriately sized mortar (see 
CALCULATION-S).

2. If' weigh paper is used, transfer the test substance to an appropriately

sized mortar. If necessary, grind the test substance into a ?ne powder.
Slowly add a small amount of vehicle! and grind. Continue to add vehicle
slowly and grind the vehicle and the test substance together to form a fine
slurry. Transfer the vehicle/test, substance slurry to a marked, beaker.

3. Rinse the mortar and pestle with additional vehicle to remove any
remaining test substance. Transfer rinse to beaker.

4. Add additional vehicle to the beaker to bring Volume up to the mark. Place
on magnetic stir plate and agitate prior to and during aliquotting,
administration and/or sampling.

5. Repeat steps through (4) for each concentration.

 

Clari?cation: No Yes [see attached clarification form]

lnitial/Date: gc .7 yer}

 

ATTACHMENT 3

TISSUES TO BE WEIGHED, RETAINED AND EXAMINED HISTOLOGICALLY

 

Protocol 418~027
Page 1 of 2

ATTACHMENT 3

TISSUES T0 WEIGHED AND RETAINED FOR POSSIBLE EXAMINATION
FROM TEN RATS PER SEX PER GRQUP

Ten rats per sex per group not assigned to functional observational battery and motor activity
tests will be assigned to histological evaluations.

Tissues to be Weighed:

The following organs will be excised, trimmed and individually weighed as soon as possible
after excision to avoid drying.

liver . spleen

kidneys brain

adrenals heart

thymus ovaries

testes uterus (with cervix)
epididymides

Tissues to be Retained:

The following tissues or representative samples will be retained in neutral buffered 10%
formalin.

brain (representative regions including cerebrum, cerebellum, pons)
small and large intestines (including Peyer?s patches)

lungs (perfused with neutral buffered 10% formalin)

nodes (submandibular and mediastinal)

peripheral nerve (sciatic)

gross lesions spinal cord (cervical, thoracic and lumbar)
stomach liver

kidneys adrenals

spleen heart

thymus thyroid/parathyroid

trachea uterus

urinary bladder bone marrow

testes* ovaries

epididymides uterus

seminal vesicles (with coagulating gland) vagina

prostate mammary gland (female rats only)

Testes will be ?xed in Bouin's solution for 48 to 96 hours before being retained in neutral
buffered 10% formalin.

 

Protocol 418-027
Page 2 of 2

ATTACHMENT 3

Histological Examination:

Histological examination of retained tissues, including reproductive organs, will be conducted
for the assigned ten rats per sex from the control and high dosage groups. If lesions attributed to
the test substance are observed in the rats exposed to the high test substance dosage, the same
tissues will be examined from the assigned ?ve rats per sex exposed to the lower test substance
dosages. Should results warrant examination of the lower dosage groups and conduct of
quantitative evaluation, scheduled report date and prices will be adjusted accordingly.

Shipping Instructions:

Tissues to be examined histologically will be shipped (ambient conditions) to:

Principal Investigator: W. Ray Brown, D.V.M., ACVP
Veterinary Pathologist

Research Pathology Services, Inc.
438 E. Butler Avenue

New Britain, 18901
Telephone: (215) 345-7070

The recipient will be noti?ed in advance of sample shipment.

 



905 sneehy um. Bldz- A ARGUS RESEARCH
Charles River Laboratories
Telcfax: (215) 443?5587 Discovery and Development Services

PROTOCOL 418-027
ORAL (GAVAGE) CONIBINED REPEATED DOSE TOXICITY STUDY
OF 7599.7 WITH THE 
TOXICITY SCREENING TEST
STUDY NUNIBER: T-7599

Amendment 1 15 March 2002

 

1. Purpose (page 1 of the protocol):

[Effective Date: 1 March 2002] The purpose of this study is to provide
information on the possible health hazards that may result from repeated exposure
of BR male and female rats to a test substance
beginning before cohabitation, through mating and continuing for at least 28 days

(male rats), or through parturition until day 5, rather than day 4 or 5, of lactation
(female rats).

Reason for Change:

This change corrects the protocol and is consistent with the method and frequency
of administration to female rats on page 10 of the protocol.

2. Vehicle (page 3 of the protocol):
[Effective Date: 22 February 2002] The vehicle will be aqueous 1.0%
(CMC) (medium viscosity), rather than aqueous 0.5%


Reason for Change:

This change was made because the test substance is precipitating out of
suspension during shipment for analysis and cannot be analyzed.

Any revisions to this ?nalized amendment must be made by subsequent amendment.

 

Protocol 418-027
Amendment 1
Page 2

3. Safety Precautions (page 3 of the protocol):

[Effective Date: 18 February 2002] A half-face respirator will be worn when the
bulk test substance is not being used in a chemical fume hood.

Reason for Change:

This addition was made so that safety precautions are consistent with the MSDS. I
4. Me (page 4 of the protocol):

[Effective Date: 18 February 2002] The prepared test substance and vehicle

fomiulations will be stored refrigerated, protected from light, rather than at room
temperature, protected from light.

Reason for Change:

This change was made at the request of the Sponsor based on the stability of the
test substance.

5. Analyses (page 4 of the protocol):
Additional analyses for concentration and homogeneity and stability will be

performed on samples taken from the second test substance preparation using

1.0% These samples will be taken and analyzed as
described in the protocol.

Reason for Change:

This change was made to provide an analysis of samples prepared using 1.0%
as the vehicle.

6. Bulk Test Substance Sampling (page 5 of the protocol)
[Effective Date: 25 February 2002] The 1 sample of the test substance taken on
the last day of treatment will be sent directly to Southern Research Institute at the

address in the protocol, rather than to the Sponsor, for analysis.

Reason for Change:

This change corrects the protocol to indicate that the sample will be sent to
Southern Research Institute, rather than to the Sponsor.

Any revisions to this finalized amendment must be made by subsequent amendment.

 D-36

Protocol 418?027
Amendment 1
Page 3

7. Bulk Test Substance Sampling(page 5 of the protocol) 

[Effective Date: .25 February 2002] A sample (approximately 5 g) of the test
substance will be taken and sent (ambient conditions, protected from light) for use
in the preparation of analytical standards and for possible spectrophotometric
analysis. The sample will be sent to:

Principal Investigator, Gregory S. Gonnan, 
Staff Chemist

Bioanalytical Chemistry Group

Southern Research Institute

2000 Ninth Avenue South

Birmingham, Alabama 35255-5305

Telephone: (205) 581-2725

Telefax (205) 581?2044
Email: gorman@sri.org
8. Shipping Instructions (page 6 of the protocol):

 

[Effective Date: 18 February 2002] The samples to be analyzed will be shipped
re?'igerated, protected from light, rather than at ambient conditions.

Reason for Change:

This change was made at the request of the Sponsor based on the stability of the
test substance.

9. Schedule (Page 2 of Attachment 1 to the protocol):

[Effective Date: 25 February 2002] The dosage period for female rats will be 14

days before cohabitation through Day 5 of lactation, rather than through Day 4 or
5 of lactation.

Reason for Change:

This change corrects the protocol and is consistent with the method and frequency
of administration to female rats on page 10 of the protocol.

10. Safety (Page 1 of Attachment 2 to the protocol):
[Effective Date: 18 February 2002] There should be an before ?Half-Face

Respirator if not used in a chemical fume hood? to indicate an additional safety
precaution.

Any revisions to this ?nalized amendment must be made by subsequent amendment.

 D-37

Protocol 4 1 8?027
Amendment 1
Page 4
Reason for Change:

This addition was made so that safety precautions are consistent with the MSDS.

64~ "?f??/lm?hmak -

Alan M. Hoberrnan, DABT Date:
Director of Research

 

 

Study Director

mars/AMP "abate; QMM am ?02:

 

Rebecca Altmann?Reilly, M.S. Date Paul H. Lieder, DABT Date
Member, Institutional Animal Care Study Monitor
and Use Committee Sponsor's Representative

Any revisions to this ?nalized amendment must be made by subsequent amendment.

418-0271PAGE D-38

v,

905 Shechy om, Bldg. A ARGUS RESEARCH
Horsham, PA I 9044 . .

(2 5) ?337,0 Charles RIVEF Laboratanes
Tdefax: (215) 443.3587 Discovery and Development Services

PROTOCOL 418-027
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY
OF 7599.7 WITH THE 
TOXICITY SCREENING TEST
STUDY NUMBER: 

Amendment 2 5 September 2002

 

1. Proposed Statistical Tests (page 19 of the protocol):

[Effective Date: 25 June 2002]: Attachment 1 to this amendment describes the
proposed statistical methods.

Body weight data, feed consumption values and organ weights will be analyzed as
described under the Parametric heading of the schematic. Bartlett's Test of
Homogeneity of Variances?g) will be used to estimate the probability that the
groups had different variances. A nonsigni?cant result (p>0.001) will indicate
that an assumption of homogeneity of variance is not inappropriate, and the data
will be compared using the Analysis of Variance Testm). If that test is signi?cant
the groups exposed to the test substance will be compared with the
control group using Dunnett's Testm). If Bartlett's Test is signi?cant (pS0.00l),
the Analysis of Variance Test is not appropriate, and the data will be analyzed as
described under the Nonparametric heading of the schematic. When 75 or
fewer of the scores in all the groups are tied, the Kruskal?Wallis Test?ui? will be
used to analyze the data. and in the event of a significant result Dunn's
Testm) will be used to compare the groups exposed to the test substance with the
control grou . When more than 75% of the scores in any group are tied, Fisher?s
Exact Test(I will-be used to compare the proportion of ties in the groups.

Data from the motor activity test, with repeated measurements within a session,
will be analyzed using an Analysis of Variance with Repeated Measures?), as
described under that heading in the schematic. A signi?cant effect (1930.05) in
that test can appear as effect of Concentration a difference between groups in the

total across all measurements in a session) or as an interaction between

Any revisions to this ?nalized amendment must be made by subsequent amendment.

 

Protocol 41 8?027
Amendment 2
Page 2
Concentration and Block (a difference between groups at specific measurement
periods). If the Concentration effect is signi?cant, the totals for the control group
and the groups given the test substance will be compared using, Dunnett's Test. If
the, Concentration Block interaction is signi?cant, an Analysis of Variance Test
will be used to evaluate the, data at each measurement period, and a significant
result 0130.05) will be followed by a comparison of the groups using Dunnett?s
Test.

Test items in the FOB having, graded or count scores will be analyzed using the
procedures described under the Nonparametric heading of the schematic.

Clinical observation incidence data will be analyzed as contingency tables using
the Variance Test for Homogeneity of the Binomial Distribution?16).

Alternate or additional statistical evaluations may be performed if deemed
necessary or appropriate.

Reason for Change:
The statistical methods were to be added by amendment.
2. References (page 22 of the protocol):

[Effective Date: 25 June 2002]: The following references are added to the
protocol.

9. Sokal, RR. and Rohlf, FJ. (1969). Bartlett's test of homogeneity of
variances. Biometry, W.H. Freeman and Co., San Francisco, pp. 370-371.

10. Snedecor, G.W. and Cochran, W.G. (1967). Analysis of Variance.
Statistical Methods, 6th Edition, Iowa State University Press, Ames, pp.
258275.11. Dunnett, CW. (1955). A multiple comparison procedure
for comparing several treatments with a control. J. Amer. Stat. Assoc.
50:1096~1 121.

11. Dunnett, CW. (1955). A, multiple comparison procedure for comparing
several treatments with a control. J. Amer. Stat. Assoc. 50:1096?1129.

12. Sokal, RR. and Rohlf, FJ. (1969). Kruskal~Wallis Test. Biometry,
W.l-l. Freeman and Co., San Francisco, pp. 388689.

Any revisions. to this ?nalized amendment must be made by subsequent amendment.

 D-40

Protocol 418-027
Amendment 2
Page 3

13. Dunn, DJ. (1964). Multiple comparisons using rank sums.
Technometrics 

l4. Siegel, S. (1956). Nonparametric Statistics for the Behavioral Sciences,
McGraw-Hill, New York, pp. 96?105.

15. SAS Institute, Inc. (1988). Repeated measures analysis of variance.
User's Guide, Release 6.03 Edition, Cary, NC, pp. 602-609.

16. Snedecor, G.W. and Cochran, (1967). Variance test for

homogeneity of the binomial distribution. Statistical Methods, 6th
Edition, Iowa State University Press, Ames, pp. 240241.

Reason for Change:
The proposed statistical tests cite these references.
3. Histological Examination (page 2 of Attachment 3 of the protocol):
[Effective Date: 4 June 2002]: If lesions attributed to the test substance are
observed in the rats exposed to the high: test substance dosage, the same tissues

will be examined from the assigned ten rats, rather than ?ve rats, per sex exposed
to the lower test substance dosages.

Reason for Change:

This change was made to correct the protocol. The Randomization and
cohabitation section of the protocol, page: 9, states that histological evaluations
will be performed on the last ten rats per sex in each group exposed to the lower
test substance dosages.

4. Histological Examination (page 2 of Attachment 3 of the protocol):
[Effective Date: 4 June 2002]: Histological evaluations will be performed on the

livers of ten male and ten female rats, the thymuses of ten female rats and the
stomachs of ten male rats exposed to each of the lower test substance dosages.

Any revisions to this ?nalized amendment must be made by subsequent amendment.

 

Protocol 41 8-027
Amendment 2
Page 4

Reason for Chan c:

This change was made: to clarify that additional histological evaluation would. be
performed because lesions of the livers, thymuses and stomachs were found in
male and/or female rats assigned to the 250 mg/kg/day dosage group.

d4 me



Alan M. Hoberman, DABT Date Ray

Director of Research Assocmte Director 0
Study Director

    

 

(MAMA CLO 9,151?, yaw/Z? 9??l/zoa7,

Rebecca Altmann~Reilly, M.S. Date Paul? H. Lieder, DABT Date
Member, Institutional Animal Care Study Monitor
and Use Committee Sponsor's, Representative

Any revisions to this ?nalized amendment must be made by subsequent amendment.

 D-42

Protocol 418-027

Attachment 1 to Amendment 2
Page 1

PROPOSED STATISTICAL 

The following schematic represents statistical analyses of the data.

eofTesta
ll. Nongaiameinc'?

i. Parametric

A. Kruskal-Wallis Test
(5 75% ties many mutation)

A. Bartlett's Test? 


i i i
Significant at 250.001 Not Significant Significant at Not Significant

Nonparametric Analysis of Variance Dunn's Test
B. Fisher's Exact Test on

Proportion of Ties
075% ties at any concentration)

Significant at ?5-05 Not Significant

Dunnett?s Test

B. Analysis of Variance? with Repeated Measures
i


Not Significant

i
Signi?cant 

(Dosage Block interaction)

(Dosage) .
Dunnett's Test One-way ANOVA for each block
1


Not Signi?cant

Significant at p50.05

Dunnett?s Test

Ill. Test for Proportion Data
Variance Tests for Homogeneity

of the Binomial Distribution

 

Statistically signi?cant probabilities are reponed as either p$0.05 011250.001.

a.
b. Proportion data are not included in this category.
c. Test for homogeneity of variance.

Any revisions to this ?nalized amendment must be made by subsequent amendment.

APPENDIX 

DEVIATIONS FROM THE PROTOCOL AND THE
STANDARD OPERATING PROCEDURES OF
THE TESTING FACILTY

 E?l

DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING
PROCEDURES OF THE TESTING FACILITY

On 25 March 2002, day 36 of study (DS 36), male rat 17632 in the 10 mg/kg/day
dosage group re?uxed approximately 1 mL of the 4.9 mL test substance that was
administered. This deviation did not adversely affect the outcome or
interpretation of the study because the rat was administered most of the dosage.

On 3 March 2002, DS 14, and on 26 March 2002, day 19 of presumed gestation
(DG 19), the postdosage observations for female rats 17716 in the

0 (Vehicle) mg/kg/day dosage group and 17683 in the 250 mg/kg/day dosage
group were performed one minute early from the range of 60 i 10 minutes. These
deviations did not adversely affect the outcome or interpretation of the study
because the extent of the deviation was minimal.

On 3 March 2002, DS 14, the postdosage observation for male rat 17630 in the

0 (Vehicle) mg/kg/day dosage group was not performed. This deviation did not
adversely affect the outcome or interpretation of the study because sufficient data
were available for evaluation of this parameter and it was a single event.

On 30 March 2002, DG 25, ovaries of female rat 17686 in the 250 mg/kg/day
dosage group were not retained after necropsy. This deviation did not adversely
affect the outcome or interpretation of the study because sufficient tissues were
saved from other rats in this dosage group to evaluate ovaries.

On 4 April 2002, plasma and serum samples from the following rats were
processed and immediately frozen on dry ice. On 5 April 2002, these samples
were found in a styrofoam box after they had thawed because of insufficient dry
ice to keep the samples frozen. Samples were immediately refrozen and
transferred to a -70? chest freezer for storage.

 

 

 

 

 

 

 

 

 

Dosage
Dosage Group (mg/kg/day) Rat Number Sample Type

I 0 17715 Serum

II 10 17684 Serum and Plasma
17707 Serum
17710 Serum

50 17687 Serum and Plasma
17706 Serum
17720 Serum
IV 250 17678 Serum

 

 

 

 

 

 

 

This deviation did not adversely affect the outcome or interpretation of the study
because sufficient samples were available for evaluation.

All deviations are documented in the raw data.

ZS 

G. Yor Ph. I., DABT Date
Associate Director 1 esearch
Study Director

 

 

 

APPENDIX 

CERTIFICATE OF ANALYSIS



Certificate of Analysis


41 ?2601~1878-5 L01 6

30 January 2002
Gibbes Bailie

Sample purity 95.55%.

This sample was analyzed using GC, and analyses
techniques. The results of these tests show the sample to contain the following composition:

CH 0.009 
0.63 
CH OC 0.14 

95.55 

0.002 

0.17 

1.80 

1.71 
0 0.0004 

30
7 
10

 




Additionally, the isomer distribution of the C4 alcohol was
determined using techniques and found to contain the following relative composition:

 

 

 

 

[linear] 98.8 

[iso- 0.97 
branch]

[alpha? 0.20 
branch]

 

 

 

Gibbes Bailie

APPENDIX 

ANALYTICAL REPORT

 G?l

FINAL REPORT

ANALYSIS OF DOSING SOLUTIONS USED AT ARGUS RESEARCH LABORATORY
FOR STUDY NUMBER (ARGUS RESEARCH LABORATORY
PROTOCOL NUMBER: 418?027), SOUTHERN RESEARCH INSTITUTE STUDY
A5362

STUDY ID: A5362

SPONSOR STUDY NO. (ARGUS RESEARCH LABORATORY PROTOCOL
NUMBER: 418?027)

Southern Research Institute
2000 Ninth Avenue South
PO. Box 55305
Birmingham, AL 35255?5305

Study Initiation Date: 3/15/02

Study Completion Date: 2/12/2003
Experimental Initiation Date: 3/11/02
Experimental Completion Date: 6/14/02

 

SUMMARY

All samples were analyzed according to analytical method A total of 8 formulated
dose samples including vehicles ranging in concentration from to 25 mg/mL were analyzed to
determine the 10 day stability of 1?Butanesu1fonamide, 
5 99.7) in the formulated mixture. A total of 8 formulated dose
samples including vehicles ranging in concentration from to 25 mg/ml were analyzed to
determine concentration of 99.7 in the formulated mixture. To test for homogeneity of dose
formulation a total of 24 formulated dose samples including vehicles ranging in concentration
from to 25 mg/ml were analyzed to determine concentration of 99.7 in the top, middle and
bottom of the formulated mixture. Samples were stored refrigerated as per sponsor?s shipping
recommendations. For the 10-day stability, study samples were found to be within i 11% of the
day 1 values except for the 5 mg/mL samples which were within i 15% of the expected dose
concentration but twice (204% and 196% of Day 1 values) that found on day 1. For the dose
analysis, 1 mg/ml dose formulation samples were found to be within i 15% of the reported
concentrations but the 5 and 25 mg/mL samples were lower than expected, ranging from 55% to
69% of the expected value. For the homogeneity samples the 1 mg/mL and 5 mg/mL samples
were lower than their expected concentrations ranging from 55 to 70%, but values between
top, middle, and bottom samples differed by less than i 16%. The 25 mg/mL dose samples were
within i 16% of expected values for both concentration and homogeneity between top, middle,
and bottom samples.

KEY PERSONNEL

Raymond G. York, D.A.B.T.
Study Director
Argus Research Laboratories

Gregory S. Gorman, 
Manager
Bioanalytical Chemistry Group

Lara Cook, M.S.
Research Associate II
Bioanalytical Chemistry Group

418-0271PAGE 

 G4

1.0 Objective

The objective of this study was to determine the stability, dose concentration, and homogeneity
of dose formulations (top, middle and bottom samples) of l-Butanesulfonamide,
99.7) in the supplied dosing
solutions received from the sponsor and to con?rm the identity of the test solution.

2.0 Safety

All necessary procedures to ensure safety of the were based on information contained in
the Material Safety and Data Sheets, provided by the producer of the test article and the stud
director. 

3.0 Compliance

The study described in this ?nal report was conducted in accordance with theF DA Good
Laboratory Practice Standards (21 CFR Part 58), OECD Principles of Good Laboratory Practices
and Japanese Ministry of Health and Welfare (MHW Ordinance Number 21,
March 26, 1997). The ?nal report accurately re?ects the raw data obtained during the
performance of the study. There were no adverse circumstances that affected the quality or
integrity of the study. -

4.0 Experimental
4.1 Analytical Procedures

The sample preparation and analysis procedures as described in the analytical method
were employed for all analyses. For the stability study each sample was
allowed to warm to room temperature, was sonicated for about 15 minutes and was then
vortexed well before being sampled. An aliquot was taken from each and diluted as
described in the method. For samples that were analyzed for the dose analysis and
homogeneity studies, samples were allowed to come to room temperature and sonicated
for 15 minutes, but would not go into solution. Samples were then run under hot Water
and sonicated further but would not go into solution and remained instead a suspension.
These samples were quantitatively transferred and diluted as described in the chemical
analysis sheets. Multiple calibration curves were prepared over a concentration range of
500 to 10,000 ng/mL and analyzed along with the samples as described in the method.
The correlation coef?cient for each curve was equal to or greater than 0.9991.

4.2 Results

The results of the identity testing con?rmed that the found spectra FT-IR and

13 NMR results) were consistent with the submitted substance, 99.7. The results of
the formulation analyses are presented (Tables I - VII) corresponding to the sponsor?s
study number at the end of the report.

 

4.3 Calculations

Calculations were performed using Turonuan (Version 1.0). The amount of analyte in
the diluted dose formulation samples (ng/mL) was back calculated using a calibration
curve generated ?om a set of calibration standards containing the equivalent amount of
carboxy methyl cellulose (CMC) as in the diluted samples. The calibration curve was
generated by a regression analysis to determine the best ?t curve linear, quadratic,
etc.) and amount of weighting. A quadratic ?t with weighting was determined to be

the best ?t 
ax2 bx 
where:
Peak area response of test article
Concentration of the test article in standards.
a, b, Constants derived from the regression analysis.
5.0 Storage

A copy of the ?nal report and all raw data will be stored in the, Southern Research Institute
archives.

6.0 Conclusion

A total of 40 dose formulation samples ranging in concentration from 0 to 25 mg/mL
were analyzed using method 5 92. For the 10-day stability study, samples were found to
be within i 11% of the Day 1 values except for the 5 mg/mL samples which were within i 15%
of the expected dose concentration but twice (204% and 196% of Day 1 values) that found on
Day 1. This may have been due to the low values found for the 5 mg/mL samples on Day 1
(52% of expected concentration). For the dose analysis, the 1 mg/ml dose formulation samples
were found to be Within 1 15% of the reported concentrations but the 5 and 25 mg/mL samples
were lower than expected, ranging from 5 5% to 69% of the expected value. For the
homogeneity samples the 1 mg/mL and 5 mg/mL samples were lower than their expected
concentrations, ranging from 55% to 70% but values between top, middle, and bottom samples
differed by less than i 15%. The 25 mg/mL dose samples were within i 16% of expected values
for both concentration and. homogeneity between top, middle, and bottom samples. The
variation in expected concentrations may have been due to the fact that samples were in a
suspension rather than in solution and instead of assisting in solubility the presence of the 1%
CMC made the samples very viscous and quantitative transfer dif?cult to perform.

Data presented in Tables I through VII are based on non?truncated numbers and may not be
reproducible based on rounded numbers displayed. Values for each measured concentration are
based on the average of two replicates per sample.

 

Table I 
Day 1 of the 10?Day Stability Study for a Dose Formulation Containing 599.7 1% CMC
Sponsor Study Number T-7599.7 (Argus Research Laboratory Protocol Number: 418?027)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Day 1
Nominal Target Measured Dose
Dose Dilution Conc. of
concentration (ug/mL) (ug/mL) Theoretical
(mg/mL) 
Sample 
0 (1 of 4) NA Not detected 
0 (2 of 4) NA Not detected 
3.0 3.0 25.2 101
25 (2 of 4) 3.0 2.8 23.1 93
Table II

Day 10 of the 10-Day Stability Study for a Dose Formulation Containing 1% CMC
Sponsor Study Number 599.7 (Argus Research Laboratory Protocol Number: 418?027)

 

 

 

 

 

 

 

 

 

 

Day 10*
Nominal Target Measured Dose
Dose Dilution Conc. of of Day 1

concentration (ug/mL) (ug/mL) Theoretical

(mg/mL) 

Sample 
0 (1 of 4) NA Not detected 
(2 of 4) NA Not detected 
3.0 2.9 243.0 3.0 24.7 99 107

 

 

 

 

 

 

 

 

 G-7

Table 
Dose Formulation Analysis of in 1% CMC
Sponsor Study Number T-7599.7 (Argus Research Laboratory Protocol Number: 418-027)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Nominal Target Measured Dose
Dose Dilution Concentration Concentration of
concentration (ug/mL) (ug/mL) (mg/mL) Theoretical
(mg/mL) 
Sample ID.
0 (1 of 4) NA not detected 
0 (2 of 4) NA not detected 
of43.0 1.8 14.9 60
25 (2 of 4) 3.0 1.7 13.7 55
Tables IV, V9 VI and VII

Homogeneity Dose Formulation Analysis of T-7599.7 in 1% CMC
Sponsor Study Number (Argus Research Laboratory Protocol Number: 418-027)
(In the sample ID, tOp, middle, and bottom)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table IV
Controls (0 mg/ml)
Nominal Target Measured Dose
Dose Dilution Concentration Concentration of
concentration (ug/mL) (ug/mL) (mg/mL) Theoretical
(mg/mL) 
Sample LB.
0 (1 of 12T) NA not detected 
0 (2 of 12T) NA not detected 
0 (5 of 12M) NA not detected 
0 (6 of 12M) NA not detected 
0 (9 of 128) NA not detected 
0 (10 of 128) NA not detected 
Table 
1 mg/ml
Nominal Target Measured Dose
Dose Dilution Concentration Concentration of
concentration (ug/mL) (ug/mL) (mg/mL) Theoretical
(mg/mL) 
Sample ID.
1 (1 of 12T12M12M12B128) 3.0 2.1 0.7 70

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table VI
5 mg/ml
Nominal Target Measured Dose
Dose Dilution Concentration Concentration of
concentration (ug/mL) (ug/mL) (mg/mL) Theoretical
(mg/mL) 
Sample ID.
5 (1 of 12T12T12M12M128128) 3.0 1.9 3.2 64
Table VII
25 mg/ml
Nominal Target Measured Dose
Dose Dilution Concentration Concentration of
concentration (ug/mL) (ug/mL) (mg/mL) Theoretical

Sample ID. 7 
25 (1 of 12T) 3.0 3.0 24.6 98
25 (2 of 12T) 3.0 3.1 25.6 103
25 (5 of 12M) 2.9 3.4 28.9 116
25? (6 of 12M) 3.0 2.7 22.5 90
25 (9 of 128) 3.0 2.9 23.9 96
25 (10 of 12B) 3.0 3.0 25.7 103

 

 

 

 

 

 

 

Calculated values are based upon non~truncated numbers and may not be
reproducible based on rounded numbers displayed in tables I through VII.

ma

7.0 Approvals

mam

Lara Cook, M.S.
Research Associate II
Bioanalytical Chemistry Group

Gregory 37605112111 Ph. D.
Manager
Bioanalytical Chemistry Group

?x 21 
Charles D. Hebert, D.A.B.T.

Director
Safety Assessment Department

6W0 ear

Ram?/rd York Ph ..B T.
Study Director
Argus Research Laboratories

(3?9

?~He03

Date



Date

2 

 

Date

26163
Date

418-0272PAGE 

my?; emery 9mm. . 
Qrigitmi in 1* Unif??ty Fi?
I?llilgisn?dlam e" 9?10?)

QUALITY ASSURANCE STATEMENT

Final Report On:

Analysis of Dosing Solutions Used at Argus Research Laboratory
For Sponsor?s Study Number (Argus Research Laboratory
Protocol Number: 418?027), SR1 Study A5362

Study N0.: A536.2

Listed below are the phases and/or procedures performed by Southern Research Institute that were inspected and
audited by the Quality Assurance Unit during the study described in the report. Findings were reported to the study
director and management periodically.

 

 

Inspection/ Date Management Date Study Director
PhaseS/medum Audit Date Noti?ed Noti?ed
Test Substance Characterizatlon: quu1d 6/18/02 1/23/03 1/24/03

Chromatography/Mass Spectrometry

 

1/7/03?1/9/03;

 

Final (Draft) Report Review . 1/23/03 1/24/03
And Data Audit 1/13/03, 1/21/03
Final Report Review 2/1 1/03 2/11/03 2/11/03

 

 

 

 

 

 

The results presented in this ?nal report accurately re?ect the raw data.

C?m #13

?K/elly?Crick, istant Manager, Quality?Assurance Date

APPENDIX 

TEMPERATURE AND RELATIVE HUMIDITY REPORT

ARGUS

H?l

 

Temperature and Relative Humidity Report
Location: Room 01

Protocol Number: 418-027

 

Range of Dates: 12-Feb?2002 13:35 to 13-Apr-2002 09:59

 

 

Target Range:
Species: Rat

Total Number of Days:
Total Number of Hours:
Total Number of Data Points:

Mean SD):

Maximum:
Median:
Minimum:

Number of Points in Range 
Number of Points High 
Number of Points Low 

70.6

73.3
70-8
66.6
1436

0
0

 

Temperature
to 

61
1436.0
1436

(14.1)

(100.0)
(0.0)
(0-0)

 

Relative Humidity
30% to 70%
61
1436.0
1436
54.5 4.4)
66.9
55.0
35.3
1436 (100.0)
0 (0.0)
0 (0.0)

 

 

Report Generated: 24-Jun-2002 at 14:03

COMMENTS:

 

 

 

 

/7 
REVIEWED BY: 
L0

umulative by Location (vMay-21~1999)

5 $56;

DATE:

APPENDIX I

POSITIVE CONTROL DATA

 I-?l

Historical Control Data

This Functional Observation Battery Standard Operating Procedure and Studies
conducted to document the training and competency of the technical staff and Motor
Activity Negative Control Data and Positive Control Data are available at the Testing
Facility.

Page 1

 

Summary Information for Functional Observation Battery

 

 

In?Life Test Dosage Information
Number of
Study Number Title Start Substance mg/kg mL/kg Dosages
012-006 Validation of Functional
Observational Battery and Motor Activity
Measure Using Positive Test Substances 12/89 acrylamide 50 7
physostigmine 0.75 1.5 
DDT 75 1 1
012-014 Neurotoxicity Evaluation of
Positive Control Substances in
Rats 9/91 acrylamide 40 9
IDPN 200 1 3
carbaryl 75 5 1
DDT 75 5 
triadimefon 200 5 1
0 12-0 15 Neurotoxicity Evaluation of
DDT in Rats 3/92 DDT 75 1 1
012-017 Neurotoxicity Evaluation of
Positive Control Substances in
Rats 5/92 acrylamide 40 9
IDPN 200 1 3V
carbaryl 40 5 
DDT 75 1 1
d-amphetamine 4.0 1 1
012-022 Neurotoxicity Evaluation of
Carbaryl in Rats 10/92 carbaryl 40, 200 5 1
012-031 Neurotoxicity Evaluation of
Positive Control Substances in
Rats 7/93 acrylamide 45 1 10
IDPN 250 1 4
carbaryl 4O 5 1
DDT 75 1 
d-amphetamine 4 1 1

 

Page 2

418-0272PAGE 1?3

 

012-056 Neurotoxicity Evaluation of
Positive Control Substances in

Rats 11/95 acrylamide 45 10
IDPN 250 1 5
carbaryl d-amphetamine 4.0 1

012-075 Neurotoxicity Evaluation of
Positive Control Substances in

Rats 3/98 acrylamide carbaryl 100 4 1
DDT 100 2 1

012?081 Neurotoxicity Evaluation of
Positive Control Substances in

Rats 1 1/01 acrylamide 30 10
IDPN 250 1
d-amphetamine 40 1 
carbaryl 100 4 1
DDT 100 2 5

 

Page 3

 14

Summary Information for Motor Activity

 

Dosage Information

 

In?Life Test
. Number of
Study Title Start Substance mg/kg mL/kg DosaggG
012-01 1 The Assessment of Motor
Activity in Neonatal and Adult Rodents
using Passive Infrared Sensors 5/91 d?amphetamine 0.75, 1.5, 4 1 1
Chlorpromazine 1, 2, 4 1 1
012-014 Neurotoxicity Evaluation of
Positive Control Substances in
Rats 9/91 acrylamide 40 9
IDPN 200 1 3
carbaryl triadimefon 200 5 1
012-016 Motor Activity Evaluation in
Rats
Administered Chlorpromazine and d? .
Amphetamine (Positive Control Study) d?amphetamme 05? 1? 4 1 1
Chlorpromazine l, 2, 4 1 1
012-058 Neurotoxicity Evaluation of
Positive Control Substances in
Rats 4/96 acrylamide 45 1 10
d-amphetamine 0.Page 4

APPENDIX 

HISTOPATHOLOGY REPORT

 -1

RESEARCH PATHOLOGY SERVICES, INC.

438 East Butler Avenue, New Britain, PA 18901
Phone: 215-345?7070 0 Fax: 215-345-4326

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY
OF 7599.7 WITH THE 
TOXICITY SCEENING TEST
PROTOCOL 418?027
STUDY NUMBER T-7599
HISTOPATHOLOGY REPORT

SUBMITTED TO:
Raymond G. York, D.A.B.T.
Argus Research
905 Sheehy Drive
Horsham, PA 19044

SUBMITTED BY:

M2194'ay Brown, D.V.M., 
Veterinary Pathologist

 

February 25, 2003

 1?2

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER 

 

 

HISTOPATHOLOGY REPORT
TABLE OF CONTENTS
REPORT
Page
Method I 1
Results 3
Summary 5
Quality Assurance Unit Statement 6
TABLE
1. Incidence and Degree of Severity of Histomorphologic Observations 7
APPENDIX

Histomorphologic Observations to M3
Key to Histomorphologic Observations l-1

Tables
l?1.Histomorphologic Observations - Group Male Rats 
l?2.Histomorphologic Observations Group II Male Rats l?4
 -3.Histomorphologic Observations Group Male Rats Is5
l-4.Histomorphologic Observations - Group IV Male Rats l?6
l-5.Histomorphologic Observations Group Female Rats IE8
l?6.Histomorphologic Observations - Group II Female Rats 
l?7.Histomorphologic Observations - Group Female Rats 
l?8.Histomorphologic Observations Group IV Female Rats 

ll. individual Animal Gross and Histomorphology Data ll-?1 TO ?-80

418-0272PAGE J-3

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418?027
STUDY NUMBER 

HISTOPATHOLOGY REPORT

 

METHOD

Microscopic examination was made of the specified tissues from 40 male and
40 female BR rats in an oral (gavage) combined
repeated dose toxicity study of 7599.7 with the reproduction/developmental toxicity
screening test. A brief outline of the study design showing the dose group identifica-
tion, dosage levels of the test and control substances and number of male and
female rats examined group are shown below.

 

 

 

 

 

 

NUMBER DOSE
DOSAGE OF RATS DOSAGE CONCENTRATION VOLUME
GROUP PER SEX (mg/kg/day) (mg/mu (mL/kg)
10 0 (VehicleThe test substance was considered to be 100% active for the purpose of dosage calculations.

The rats were given the test substance and/or vehicle beginning before
cohabitation, through mating and continued for at least 28 days (male rats), or
through parturition until Day 5 of lactation (female rats). Dosages were adjusted daily
for body weight changes and given at approximately the same time each day.
Scheduled sacrifice of male rats was on the day following the last dosage
administration, after a minimum of 28 days of dosage. Scheduled sacrifice of female
rats was on Day 6 of lactation.

All rats were necropsied and the specified tissues were collected and placed
in 10% neutral buffered formalin for fixation. The testes were fixed in Bouin?s solu-
tion for 48 to 96 hours and then retained in 10% neutral buffered formalin. The in-Iife
portion of the study, necropsies, and recording of the gross necropsy observations
were performed by the staff of Argus Research, Horsham, PA. The tissue process?-
ing, microscopic slide preparation and histopathologic evaluation were performed by
Research Pathology Services, Inc.

 

Research Pathology Services, Inc. -1

418-0272PAGE 1?4

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER 

HISTOPATHOLOGY REPORT

 

The tissues specified for microscopic evaluation from the male and female
rats of Groups I and IV included: brain, duodenum, jejunum, ileum, cecum, colon,
rectum, Peyer?s patch, lung, submandibular and mediastinal nodes, sciatic
nerve, stomach, kidneys, spleen, thymus, trachea, urinary bladder, testes, epididy?
mides, seminal vesicles, coagulating gland, prostate, spinal cord (cervical, lumbar
and thoracic), liver, adrenal glands, heart, thyroid, parathyroid, uterus, bone marrow
(sternum), ovaries, uterus, vagina, mammary gland (female rats) and all other
tissues with gross changes. In addition, the liver of male and female rats, stomach
of male rats and thymus of female rats were examined from the intermediate dosage
groups. Representative samples of these tissues were routinely processed, embed?
ded in paraffin, sectioned, and stained with hematoxylin and eosin for microscopic
evaluation.

Upon completion of the project, all raw data (remaining wet tissue, paraffin
blocks, microscopic slides and histology records) will be returned to Argus Research
for archiving.

 

Research Pathology Services, Inc. -2

 J-S

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER 

REPORT

 



The type, incidence and degree of severity of the histomorphologic changes
in the specified tissues for the male and female rats are presented in Table 1. The
microscopic observations in each rat are summarized in tabular form in Appendix I
(Tables to A key to the histomorphologic observations precedes Table M.
The gross necropsy observations, detailed descriptions of the microscopic observa-
tions, and a correlation of the microscopic findings with the gross changes in these
rats, when applicable, are contained in Appendix II.

No treatment?related microscopic changes were observed in any of the male
rats given 10 mg/kg/day or in female rats given 10 or 50 mg/kg/day of the test
substance.

Treatment?related microscopic changes were observed in the liver of male
rats of the 50 and 250 mg/kg/day dosage groups and female rats of the 250
mg/kg/day dosage group, thymus of female rats of the 250 mg/kg/day dosage group
and stomach of the male rats of the 250 mg/kg/day dosage group.

The treatment?related microscopic change in the liver consisted of minimal or
mild enlargement (hypertrophy) of centrilobular hepatocytes in most male and fe?
male rats of the 250 mg/kg/day dosage group and in 4/10 male rats of the 50
mg/kg/day dosage group. The enlargement was due to an increased amount of
finely granular, dense eosinophilic cytoplasm. The incidence and severity of the
change occurred in a dose-related manner. Also, in three of the affected high dose
male rats, necrosis of individual enlarged hepatocytes was seen in centrilobular
areas (Table 1).

The treatment?related effect in the thymus consisted of an increased inci?
dence and severity of atrophy of the thymic lobules in female rats of the 250
mg/kg/day dosage group. Single incidences of thymic atrophy occurred in female
rats of the control and lower dosage groups, but the increased incidence and
severity of this effect in the high dosage group was considered to be treatment-
related.

Microscopic examination of the stomach revealed focal erosions in the pyloric
glandular mucosa of two high dose male rats. Although the incidence was low, this

 

Research Pathology Services, Inc. -3

 1-6

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418?027
STUDY NUMBER 

HISTOPATHOLOGY REPORT

 

change may be treatment-related. Other changes observed in the stomach which
occurred at a somewhat varied and sporadic incidence in the control and compound-
treated male rats included edema with or without inflammation (infiltrations of
polymorphonuclear inflammatory cells) in the submucosa of the glandular and
nonglandular (forestomach) areas. The very slight increased incidence and severity
(Table 1) of these changes in these areas of the stomach of the high dose male rats
may also be treatment-related. However, these changes were not clearly associated
with the erosions.

All other microscopic changes were considered to have occurred spontane-
ously and to be incidental and unrelated to compound administration. The type, in?
cidence and severity of these changes were not influenced by compound admini?
stration. These changes also are listed in the attached histomorphology tables.

One high dosage group male rat had early in the spleen only.
There was no evidence of disseminated involvement. Although this is a Group IV
rat, it is still considered to have been incidental and a spontaneouslya-occurring
effect.

 

Research Pathology Services, Inc. -4

 J-7

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418?027
STUDY NUMBER Tu7599

HISTOPATHOLOGY REPORT

 

SUMMARY

Microscopic examination was made of the specified tissues from four groups
of 10 male and 10 female BR rats used in an oral
(gavage) combined repeated dose toxicity study of 7599.7 with the reproduc?
tion/developmental toxicity screening test. The four groups of rats had been given 0
(vehicle), or 10, 50 or 250 mg/kg/day of 7599.7, orally by gavage, once daily for
the protocol-?specified number of days.

No treatment-related microscopic changes were observed in the male rats
given 10 mg/kg/day or female rats given 10 or 50 mg/kg/day of the test substance.

Treatment-related microscopic changes were observed in the liver of male
rats of the 50 and 250 mg/kg/day dosage groups and female rats of the 250
mg/kg/day dosage group, thymus of female rats given 250 mg/kg/day and stomach
of male rats given 250 mg/kg/day of the test substance.

The treatment?related effect in the liver consisted of minimal to mild
hypertrophy of centrilobular hepatocytes in the mid and high dosage group male rats
and in the high dosage group female rats. A low incidence of high dose male rats
had individual-cell necrosis of affected centrilobular hepatocytes.

The treatment?related change in the thymus was an increased incidence and
severity of atrophy of the thymic Iobules in female rats of the high dosage group.
There were single incidences of atrophy in each of the control and lower dosage
groups, but this increased incidence in the 250 mg/kg/day dosage group was con!
sidered to be treatment-related.

The treatment?related change in the stomach in male rats of the high dosage
group consisted of a low incidence of focal erosions of the pyloric glandular mucosa.
A varied incidence of edema and. in?ammation of the submucosa of the
nonglandular and glandular areas also was observed in a few rats at a higher
incidence and severity in Group 4 and this may also be related to compound?related.

All other changes were considered to be spontaneous in origin and not
treatment?related. The type, incidence or severity of these changes were not
considered to be influenced by administration of 7599.7.

 

Research Pathology Services, Inc. -5

 1-8

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418?027
STUDY NUMBER T-7599

HISTOPATHOLOGY REPORT

 

QUALITY ASSURANCE UNIT STATEMENT

All aspects of the tissue processing, microscopic slide preparation, histo?
pathologic evaluation and report preparation for the study listed above have been
performed according to the Standard Operating Procedures of Research Pathology
Services, Inc. and were audited in accordance with the procedures established by
the Quality Assurance Unit of Research Pathology Services, Inc. in compliance with

the regulations as specified in the protocol.

Quality Assurance inspections were performed on 04/08/02, 04/12/02, 04/18/02,
04/19/02, 04/23/02, 04/24/02, 05/22/02, 06/05/02, 06/07/02, 07/10/02, 07/11/02,
07/12/02, and 02/25/03 and findings were reported to management on 04/30/02,
05/31/02, 06/28/02 and 02/25/03. There! were no deviations from the protocol,
Standard Operating Procedures and/or appropriate Good Laboratory Practice regu-
lations noted during the conduct of the study that had an impact on study integrity.
The summary report of QA inspections is included in the final report submitted to the
Study Director on February 25, 2003.

. 
78de (5
Karen W. Harkins, BS
Quality Assurance Unit

 

?2 ~225~ 0 3
Date

 

Research Pathology Services, Inc. ?6

 1-9

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST

PROTOCOL 418-027
STUDY NUMBER T-7599

TABLE 1

Incidence and Degree of Severity of HistomorphoTogic Observations

 

Dose Group:
Sex:
Number of AnimgTs/Group:

ADRENAL GLANDS:
NO. EXAMINED
NO. NORMAL

?infiTtration, mononucTear-ceIT,

minima]

?vacuoTation, cortex
minimaT
mde

BONE MARROW (STERNUM):
NO. EXAMINED
NO. NORMAL

BRAIN:
ND. EXAMINED
NO. NORMAL

CECUM:
N0. EXAMINED
NO. NORMAL

?inf1ammation, mucosa, chronic

mde


NO. EXAMINED
NO. NORMAL

COLON:
NO. EXAMINED
N0. NORMAL

DUODENUM:
NO. EXAMINED
N0. NORMAL

EPIDIDYMIDES:
NO. EXAMINED
NO. NORMAL

~infi1tration, mononucTear-ceTT, focaT

minima]

EXTREMITIES:
NO. EXAMINED
N0. NORMAL

-dermatitis, uIcerative, focaI

mde

HEART:
NO. EXAMINED
NO. NORMAL

muTtifocaT 
TotaT incidence of specified Tesion, a1] grades.

 1?10

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST

STUDY NUMBER T-7599

TABLE 1 (Continued)

Incidence and Degree of Severity of HistomorphoTogic Observations

 

Dose GroupSex: 
Number of AnimaIs/Groupz HEART (Continued):

-inf1ammation, subacute, focaT/muTtifocaI 
minimaT -pericarditis, chronic, focaT 
minimal 0 1 0 0 0

ILEUM:

NO. EXAMINED 10 10 lO 0 10

NO. NORMAL 10 0 10 IO 0 10

JEJUNUM:

N0. EXAMINED 10 0 10 10 10

NO. NORMAL 10 10 10 0 0 10

KIDNEYS:

NO. EXAMINED 10 10 10 0 10

NO. NORMAL 7 6 8 5

-cyst(s), meduTTa 0 0 2 0 0 0

-diTatation, pelvis 
miId 1 0 0 

'edema. Papi I I ary 
minimaT -infiTtration, mononucTear-ceTI, focaT 
minimaI 1 0 0 

?minera1ization, muTtifocaT 
minimaT -nephritis, chronic, focaT 
minimaT 1 

?pyeTitis, chronic 
minimai 0 0 0 1

?vacuoTation, corticaT tubuTar epitheTium 
mde 0 0 1

LIVER:

NO. EXAMINED NO. NORMAL 3 1 5 8 3 1

-hematopoiesis, extrameduTTary, muTtifocaT 
minimaT 0 0 0 1 

 

TotaT incidence of specified Tesion, grades.

 I -11

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

TABLE 1 (Continued)

Incidence and Degree of Severity of HistomorphoTogic Observations

 

 

 

 

Dose GroupSex: 
Number of AnimaIs/Groupz LIVER (Continued):

-hypertrophy, hepatoceIIuTar, centriTobuTar [10] 
minimaI 0 4 2 0 6
mi]d 8 2

?infTammation, chronic, focaI/muTtifocaT 
minimaI -Iipidosis, tension, focaT 1 0 1 0 0 

-necrosis, focaI 
minimaI -necrosis, individuaT hepatocytes 
minima] 2 
miId 1 

-vacuoTation, muItifocaI 
minimaT ?vacuoIation, hepatoceTIuTar, periporta] 
minima] 1 2 1

LUNG:

NO. EXAMINED 10 10 10 10

NO. NORMAL 9 9 8 10

-infTammation, interstitia], muItifocaT 
minima?macrophages, aTveoTi, focaT 
minima] 1 1 

NODE1 MEDIASTINAL:

NO. EXAMINED 9 10 9 9

NO. NORMAL 8 8 7 7


minimaT miId 1 2

-hyperpTasia, Iymphocytic/pIasmacytic 
minimal 0 1 

?macrophages, pigmented 
minimal NODE, 

NO. EXAMINED 10 10 10 0 10

NO. NORMAL 5 4 1 2

 

TotaI incidence of specified Iesion, grades.

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7

1?12

WITH THE TOXICITY SCREENING TEST

Incidence and Degree of Severity of HistomorphoIogic Observations

PROTOCOL 418-027
STUDY NUMBER T-7599

TABLE 1 (Continued)

 

Dose Group:
Sex:
Number of AnimaIs/Groupz

NODE. SUDMANDIBULAR (Continued):

-hyperpIasia, Iymphocytic/pTasmacytic
minimaI
miId
moderate

MAMMARY GLAND:
NO. EXAMINED
NO. NORMAL

?hyperpIasia, physioIogicaT

-ianammation, subacute
miId

NERVEI SCIATIC:

NO. EXAMINED
NO. NORMAL

OVARIES:
NO. EXAMINED
NO. NORMAL

PARATHYROID:
NO. EXAMINED
NO. NORMAL

PATCH:
NO. EXAMINED
N0. NORMAL

?mineraIization
minimaI

PROSTATE:
NO. EXAMINED
NO. NORMAL

?atrophy, focaI
minimaT

?inf1ammation, chronic, muItifocaI
minimaI

?prostatitis, suppurative
marked

RECTUM:
NO. EXAMINED
N0. NORMAL

l?I

COCO
i-l

CO











0





10

i?I

COCO
I?l







0

00

IV

10



Hid-bow
BI

10
10

I

10




I_l??I

C000


CO


0

CO

CO


0


10




0000

TotaT incidence of specified Iesion, grades.

-10

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7

1?13

WITH THE TOXICITY SCREENING TEST

Incidence and Degree of Severity of HistomorphoIogic Observations

PROTOCOL 418-027
STUDY NUMBER 

TABLE 1 (Continued)

 

 

 

 

Dose GroupSex: 

Number of AnimaIs/GroupRECTUM {Continued}:

?edema/inf1ammation, submucosa 
moderate 1 0 0 0 0 

-parasite(s) 0 0 2 0 0 

SEMINAL VESICLES:

NO. EXAMINED 10 0 10

NO. NORMAL 10 10

SPINAL CORD. CERVICAL:

NO. EXAMINED 10 10 10 10

N0. NORMAL ,10 0 10 10 0 10

SPINAL LUMBAR:

NO. EXAMINED IO 0 10 10 0 ID

NO. NORMAL 10 IO 10 10

SPINAL CORD, THORACIC:

NO. EXAMINED 10 10 10 0 10

NO. NORMAL 10 0 IO 10 10

SPLEEN:

N0. EXAMINED IO 0 10 10 10

NO. NORMAL -atr0phy 
miId 0 0 1

-hematopoiesis, extrameduIIary, increased 
minimaI 1 3
miId 0 3 

?Iymphosarcoma 0 0 1 

STOMACH:

NO. EXAMINED 10 10 10 10 10 10

NO. NORMAL 6 7 8 3 9 10

-diIatation, mucosaI gIands 
minimaI 3 2 2 
miId 1 1 

?edema/inf1ammation, submucosa, gTanduIar
area 
minimal 1 2 0 0 0
miId 1 1 0
moderate 0 2 0 

 

TotaT incidence of specified Tesion, grades.

-11

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7

1-14

WITH THE TOXICITY SCREENING TEST

Incidence and Degree of Severity of Histomorphoiogic Observations

PROTOCOL 418-027
STUDY NUMBER T-7599

TABLE 1 (Continued)

 

 

 

Dose GroupSex: 

Number of AnimaIs/GrouDSTOMACH (Continued):

-edema/infTammation, submucosa, nongTanduIar
area 
minimaI moderate 0 1 1 0 0

-erosion(s), gianduTar mucosa 
minimaT 0 1 0 0 0 0
miId 0 1 

TAIL:

NO. EXAMINED 1

NO. NORMAL 0 1

TESTES:

NO. EXAMINED 10 10

N0. NORMAL 10 10

THYMUS:

NO. EXAMINED 10 10 10 10 10 9

N0. NORMAL 10 10 9 9 9 4


minimaT moderate 1

THYROID:

NO. EXAMINED 10 10 10 10

NO. NORMAL 7 0 7 7 5

-hypertrophy, foTTicuTar epitheTium 
miId 1 0 

?uTtimobranchiaT body/cyst TRACHEA:

NO. EXAMINED 10 10 10 10

NO. NORMAL 9 10 10 10

-inf1ammation, chronic, focaT 
minimaI 1 0 0 0 0 0

URINARY BLADDER:

N0. EXAMINED 10 0 IO 10 0 10

NO. NORMAL 10 10 10 0 10

UTERUS:

NO. EXAMINED 10 0 10

NO. NORMAL 2 0 1

 

TotaT incidence of specified Iesion, grades.

-12

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7

1?15

WITH THE TOXICITY SCREENING TEST

Incidence and Degree of Severity of HistomorphoIogic Observations

PROTOCOL 418~027
STUDY NUMBER T-7599

TABLE 1 (Continued)

 

 

Dose GroupSex: 
Number of AnimaIs/GroupUTERUS {Continued}:

?distention, Iumen 
minimaI 0 0
moderate 0 0 0 1

?hemorrhage, endometrium 
miId 0 0 0 1

?inf1ammation, endometrium, diffuse 
miId 0 0 1

-macrophages, pigmented 
minimaI 1 0 2
miId 0 0 2
moderate 7 0 5

?thrombus 2 0 0 1

VAGINA:

N0. EXAMINED 10 0 10

N0. NORMAL 8 0 0 8

~inf1ammation, acute 
moderate 0 0 1

?mucification 
moderate 2 0 0 1
marked 0 0 1

 

TotaI incidence of specified Tesion, gradesw

-13

 



 



66911 HEIGINHN 
H7 
iSEi SNINEIEHOS 3HJ. 
[6694 .L AllOlXOi CIEINIEIWOO (HSVAVS) 



 1?17

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST

PROTOCOL 418?027
STUDY NUMBER 

HISTOPATHOLOGY REPORT

 

SS

KEY TO OBSERVATIONS

No change (not remarkable, within normal histologic limits or indicated
change not present).

Tissue not available (specified tissue missing, insufficient tissue
in plane of section, artifact precludes evaluation, or specified tissue
not present in section).

Microscopic finding(s) in tissue(s) with gross observation(s).

Within normal limits [no microscopic change(s) to correlate with the
gross 

Primary malignant neoplasm present.

Indicated change or lesion present

Minimal degree or amount of indicated change or lesion.
Mild degree or amount of indicated change or lesion.
Moderate degree or amount of indicated change or lesion.
Marked degree or amount of indicated change or lesion.

Scheduled Sacrifice

 1?18

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7

WITH THE TOXICITY SCREENING TEST
PROTOCOL 418?027
STUDY NUMBER T-7599

HistomorphoTogic Observations

TABLE 

 

Dose Group:
AnimaT Number:
Sex:

Death Tyne:

ADRENAL GLANDS:
-vacu01ation, cortex

BONE MARROW (STERNUM):
636.111.;

CECUM:
-1nf1ammation, mucosa, chronic

COAGULATING GLAND:

 

COLON:

 

DUODENUM:

EPIDIDYMIDES:
-1nf11tration, mononucTear?ceTT, focaI

HEART:
?inf1ammation, subacute, focaT/muTtifocaT

 

ILEUM:

 

JEJUNUM:

KIDNEYS:

?diTatation, peTvis

-edema, papiTIary

?inf11tration, mononucTear?ceTT, focaT

LIVER:
-infTammation, chronic, focaT/muTtifocaT
?vacuoTation, hepatoceTTuTar, periporta]

LUNG:
?1nfTammation, interstitiaT, muTtifocaT

NODE, MEDIASTINAL:


NODE, SUBMANDIBULAR:
~hyperp1asia, 

NERVEI SCIATIC:
PARATHYROID:
PATCH:

PROSTATE:
~atrophy, foca]

I
17608


SS

I
17618


SS

I

17630 17631


SS

I


SS

I
17639


SS

I
17648


SS

I
17652


SS

I
17656

SS

I
17658


SS

I
17660


SS

 

I-Z

 

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7

WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027

STUDY NUMBER 

TABLE (Continued)

HistomorphoTogic Observations

 

Dose Group:
AnimaI Number:
Sex:

Death Type:

PROSTATE (Continued):
?inf1ammation, chronic, muTtifocaT

RECTUM:
-edema/inf1ammation, submucosa

SEMINAL VESICLES:

 

SPINAL CORD, CERVICAL:

SPINAL CORDI LUMBAR:

SPINAL CORD, THORACIC:
SPLEEN:

STOMACH:

-diIatation, mucosaT gTands

-edema/inf1ammation, submucosa, gIanduTar
area

?edema/inf1ammation, submucosa,
nongTanduTar area

TESTES:

THYMUS:

THYROID:

-hypertrophy, foTTicuIar epitheTium
?uItimobranchiaT body/cyst

TRACHEA:
?inf1ammation, chronic, focaT

URINARY BLADDER:

I
17608


SS

I
17618


SS

I
17630


$8

I
17631


SS



I
17639


SS

I
17648


SS

I
17652


SS

I
17656


SS

I
17658


88

I
17660


SS

 

I-3

 

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST

STUDY NUMBER T-7599

TABLE I-2

HistomorphoIogic Observations

 

 

Dose GroupAnimaI Number: 17634 17635 17638 17642 17643 17645 17649 17651 17653 17655
Sex: 
Death TypeLIVER:
-inf1ammation, chronic, focaI/muItifocaT -Iipidosis, tension, focaT - - - - -
?vacuoTation, hepatoceTIuIar, periportaI 1 - - 1 
STOMACH:
?d11atation, mucosa] gIands 1 - 2 - -
?edema/inf1ammation, submucosa,

nongIanduIar area - - 3 - -

 

I-4

I

 1?21

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

TABLE I-3

HistomorphoIogic Observations

 

Dose Group:
AnimaI Number:
Sex:

Death Type:

LIVER:


17620 17623 17627 17628 17633 17640 17646 17650 17657 17659


?hypertrophy, hepatoceTIuIar, centriIobuIar ?inf1ammation, chronic, focaT/muItifocaT - 1 1 1 1 1 1

STOMACH:

~diIatation, mucosaI gIands 1 - 1 - -
?edema/1nf1ammation, submucosa, gIanduIar

area

 

I-5

418-0271PAGE 1-22

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7

WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027

STUDY NUMBER T-7599

TABLE I-4

HistomorphoIogic Observations

 

Dose Group:
AnimaT Number:
Sex:

Death Type:

ADRENAL GLANDS:
-vacuoTation, cortex

BONE MARROW (STERNUM):
BRAIN:

CECUM:

 

COAGULATING GLAND:

mm

COLON:
DUODENUM:

EPIDIDYMIDES:
-inf11tration, mononucIear?ceTI, focaT

EXTREMITIES:
-dermatitis, uTcerative, focaI

HEART:
-infTammation, subacute, focaI/muItifocaT

ILEUM:

 

JEJUNUM:

KIDNEYS:

?cyst(s), meduITa
-mineraTization, muTtifocaT
?nephritis, chronic, focal

LIVER:

. -hypertrophy, hepatoceTIuIar, centriIobuTar
-inf1ammation, chronic, focaT/muItifocaI
?Iipidosis, tension, focaI

~necrosis, focaT

-necrosis, individuaI hepatocytes

LUNG:
-infTammation, interstitia], muItifocaI
-macrophages, aTveoTi, focaI

NODE, MEDIASTINAL:


NODE, SUBMANDIBULAR:
?hyperp1asia, Iymphocytio/pTasmacytic

SCIATIC:

IV
17621


SS

IV

17622
M,
SS



IV
17625


SS

IV
17629


SS

IV
17636


SS

IV
17637


SS

IV
17641


SS



IV
17644

SS

IV
17647


SS

IV
17654


88

 

1-6

ORAL (SAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7

WITH THE TOXICITY SCREENING TEST
STUDY NUMBER T-7599

HistomorphoTogic Observations

PROTOCOL 418-027

TABLE 1-4 (Continued)

1-23

 

Dose Group:
AnimaT Number:
Sex:

Death Type:

PARATHYROID:

PATCH:
-mineraTization

PROSTATE:

-atrophy, focaT

?ianammation, chronic, muTtifocaT
-prostatitis, suppurative

RECTUM:
-parasite(s)

SEMINAL VESICLES:
SPINAL CORD, CERVICAL:

SPINAL LUMBAR:

SPINAL CORD. THORACIC:

SPLEEN:
~hematopoiesis, extrameduTTary, increased




-di1atation, mucosaI gTands

?edema/infTammation, submucosa, gIanduTar
area

~edema/inf1ammation, submucosa,
nongIanduTar area

-erosion(s), gIanduTar mucosa


THYMUS:

THYROID:
?uTtimobranchiaT body/cyst

TRACHEA:
URINARY BLADDER:

IV

17621
M,
SS



IV
17622


SS

IV
17625


SS

IV

17629 17636


SS

IV


SS

7:

IV
17637


SS

IV
17641


SS

IV
17644


SS

7%

IV
17647


53

IV

17654


SS

 

I-7

 1-24

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7

WITH THE TOXICITY SCREENING TEST
PROTOCOL 418~027
STUDY NUMBER T-7599

HistomorphoIogic Observations

TABLE 

 

Dose Group:
AnimaT Number:
Sex:

Death Type:

ADRENAL GLANDS:

~inf11tration, mononucTeareceIT, muTtifocaT

BONE MARROW (STERNUM):

 

 

DUODENUM:

BEBE
?pericarditis, chronic, focaT

ILEUM:
JEJUNUM:

KIDNEYS:
~mineraTization, muTtifocaT

LIVER:

~inf1ammation, chronic, focaT/muItifocaT
?necrosis, focaT

?vacu01ation, hepatoceIIuTar, muTtifocaI

LUNG:
?1nfTammation, interstitiaI, muTtifocaT
-macrophages, aTveoIi, focaI

NODE1 MEDIASTINAL:

-hyperpIasia, 
~macrophages, pigmented

NODE, SUBMANDIBULAR:
?hyperp1asia, 

MAMMARY GLAND:

~hyperp1asia, physioTogicaT
?infTammation, subacute

NERVE, SCIATIC:
OVARIES:
PARATHYROID:
PATCH:

I
17681


SS

I
17690


SS

I
17694


83

I

17695


33

I
17703


SS

I
17713

SS

I
17715


SS

I
17716


88

I
17717


SS

I
17719


SS



 

WK

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7

WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

TABLE (Continued)

HistomorphoIogic Observations

1?25

 

Dose Group:
AnimaI Number:
Sex:

Death Tyne:

SEEIIJILI

SPINAL CORD. CERVICAL:
SPINAL CORD, LUMBAR:
SPINAL CORD, THORACIC:

SPLEEN:
-hematopoiesis, extrameduTIary, increased

STOMACH:
?d11atation, mucosa] gIands

THYMUS:
?atrophy

THYROID:
?u1t1mobranchia1 body/cyst




UTERUS:

?distention, Iumen
-macrophages, pigmented
?thrombus

VAGINA:
?mucification

I
17681


SS

I
17690


SS

I
17694


SS



I

17695 17703


33

I


SS

I

17713 17715


33

I


53



I

17716 17717


$3

I


53

I
17719


35

 

418?027 1-26

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418~027
STUDY NUMBER T-7599

TABLE I-6

HistomorphoIogic Observations

 

 

Dose GroupAnimaI Number: 17675 17679 17684 17688 17698 17702 17704 17707 17708 17710
Sex: 
Death TypeLIVER:

?ianammation, chronic, focaI/muItifocaI - 

?necrosis, focaI

THYMUS:
-atrophy

 

 I ?27

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER 

TABLE I-7

HistomorphoTogic Observations

 

 

Dose Group: 
AnimaI Number: 17687 17693 17697 17700 17701 17705 17706 17709 17718 17720
Sex: 
Death TypeLIVER:

?inf1ammation, chronic, focaT/muItifocaT - 1 1 1 1 1 1
THYMUS:

~atrophy - - 1 - - - - -

 

 

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

TABLE I-8

Histomorph010g1c Observations

 

Dose GroupAnimaT Number: 17685 17686 17689 17691 17692 17696 17699 17711 17712 17714
Sex: 
Death TypeADRENAL GLANDS: - - - -

BONE MARROW (STERNUM): 

 

 

 

 

 

BRAIN: - 
CECUM: - 
COLON: - - - 
DUODENUM: - - -
HEART:

?inf1ammation, subacute, focaI/muTtifocaT 1 - 
ILEUM: - - - 
JEJUNUM: - -
KIDNEYS:

?mineraIization, muTtifocaI - 1 1 - - -
-pye11tis. chronic 1 - 
?vacu01ation, corticaT tubuTar epitheTium 2 - -
LIVER:

-hypertrophy, hepatoceTIuTar, centriTobuIar -infTammation, chronic, focaI/muItifocaT 1 1 - - 1 
-Tipidosis, tension, focaT - 
?vacuoTation, hepatoceTTuIar, periportaT - - - 1 -
LUNG: 
NODE. MEDIASTINALNODE, SUBMANDIBULAR:

?hyperp1asjaMAMMARY GLAND:

-hyperpTasia, physioTogicaT 
NERVE, SCIATIC: - - - - 
OVARIES: - - -

PARATHYROID: - - - - -
PATCH: - - - .. 
31291119.; - 
SPINAL CORD, CERVICAL418-027 1?29

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418?027
STUDY NUMBER T-7599

TABLE 1-8 (Continued)

HistomorphoTogic Observations

 

Dose GroupAnimaT Number: 17685 17686 17689 17691 17692 17696 17699 17711 17712 17714>
Sex: 
Death TvneSPINAL CORDI LUMBAR: - - - 
SPINAL CORD. THORACIC: - - 
SPLEEN:

-atrophy - - - - 2 
-hematopoiesis, extrameduTTary, increased - - 1 - - 1 1
5.19.11.69.11; - - - - - 


THYMUS:
?atrophy 2 1 3 1 2

THYROID:
~u1timobranchia1 body/cyst - 

- - - - - 
URINARY BLADDER: - - - - 

UTERUS:
?distention, Tumen - - 

3 
?hemorrhage, endometrium - 2 
?inf1ammation, endometrium, diffuse 2 - -
?macrophages, pigmented ?thrombus - - 
VAGINA:
-inf1ammation, acute - - 3 - 
-mucification 3 - 4 

 

 CINV SSOEIE) 



 



669121. HEIGWHN A0018 

SNINEEHOS AilOlXOi 
[6691 .L ALIOIXOL EISOCI Gal?s/EH38 CEINIEIWOO (ESVAVS) 



 

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER 

Appendix II
IndividuaT AnimaT Gross and HistomorphoIogy Data

 

 

 

ANIMAL NUMBER: 17608 DOSE GROUP: I

SEX: DEATH TYPE: Sacrifice-ScheduIed
GROSS OBSERVATIONIS): HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabTe

HISTOMORPHOLOGIC OBSERVATIONS:

ADRENAL GLANDS: vacuoTation, cortex (miId)

LIVER: ianammation, chronic, focaI/muTtifocaT (minimaT)
LUNG: infTammation, interstitia], muTtifocaI (minimaT)
THYROID: ultimobranchial body/cyst

TRACHEA: ianammation, chronic, focaT (minimaT)

THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:

BONE MARROW (STERNUM) BRAIN CECUM COAGULATING GLAND

COLON DUODENUM EPIDIDYMIDES HEART

ILEUM JEJUNUM KIDNEYS NODE, MEDIASTINAL
NODE, SUBMANDIBULAR NERVE, SCIATIC PARATHYROID PATCH

PROSTATE RECTUM SEMINAL VESICLES SPINAL CORD, CERVICAL
SPINAL CORD, LUMBAR SPINAL CORD, THORACIC SPLEEN STOMACH

TESTES THYMUS URINARY BLADDER

End of Record? 17608

 1-32

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaT AnimaT Gross and Histomorphology Data

 

 

 

ANIMAL NUMBER: 17618 DOSE GROUP: I

SEX: DEATH TYPE: Sacrifice?ScheduTed
GROSS OBSERVATIONTS): HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appTicabTe

HISTOMORPHOLOGIC OBSERVATIONS:

CECUM: infTammation, mucosa, chronic (mde)
LIVER: infTammation, chronic, focaT/muItifocaT (mde)
STOMACH: dilatation. mucosaT gTands (minimaT)

edema/inflammation, submucosa, gTanduTar area (minimaT)

THE FOLLOWING TISSUETS) WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN COAGULATING GLAND
COLON DUODENUM EPIDIDYMIDES HEART

ILEUM JEJUNUM KIDNEYS LUNG

NODE, MEDIASTINAL NODE, SUBMANDIBULAR NERVE, SCIATIC PARATHYROID
PATCH PROSTATE RECTUM SEMINAL VESICLES
SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR SPINAL CORD, THORACIC SPLEEN

TESTES THYMUS THYROID TRACHEA

URINARY BLADDER

End of Record- 17618

 1-33

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaI AnimaI Gross and HistomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17630 DOSE GROUP: I

SEX: DEATH TYPE: Sacrifice-ScheduIed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabTe

HISTOMORPHOLOGIC OBSERVATIONS:

ADRENAL GLANDS: vacuoIation, cortex (minimaI)
LIVER: ianammation, chronic, focal/muItifocaI (minimaI)
STOMACH: diIatation, mucosaI gIands (minimaT)

edema/ianammation, submucosa, nongTanduIar area (minimaT)

THE FOLLOWING WERE WITHIN NORMAL LIMITS:

BONE MARROW (STERNUM) BRAIN CECUM COAGULATING GLAND
COLON DUODENUM EPIDIDYMIDES HEART

ILEUM JEJUNUM KIDNEYS LUNG

NODE, SUBMANDIBULAR NERVE, SCIATIC PARATHYROID PATCH
PROSTATE RECTUM SEMINAL VESICLES SPINAL CORD, CERVICAL
SPINAL CORD, LUMBAR SPINAL CORD, THORACIC SPLEEN TESTES

THYMUS THYROID TRACHEA URINARY BLADDER



NOT AVAILABLE FOR EVALUATION:
NODE, MEDIASTINAL

End of Record? 17630

 J-34

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418?027
STUDY NUMBER T-7599

Appendix II
IndividuaT AnimaI Gross and HistomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17631 DOSE GROUP: I

SEX: DEATH TYPE: Sacrifice?ScheduTed
GROSS OBSERVATIONTS): HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appTicabTe

HISTOMORPHOLOGIC OBSERVATIONS:

KIDNEYS: diTatation, peris (miId)

LIVER: vacuoTation, hepatoceTIuTar, periportaT (minimaT)
infTammation, chronic, focaI/muTtifocaI (minimaI)

NODE, SUBMANDIBULAR: hyperpIasia, (mde)

PROSTATE: atrophy, focaT (minimaT)

THYROID: uItimobranchiaT body/cyst

hypertrophy, foITicuTar epitheTium (mde)

THE FOLLOWING WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM

COAGULATING GLAND COLON DUODENUM EPIDIDYMIDES

HEART ILEUM JEJUNUM LUNG

NODE, MEDIASTINAL NERVE. SCIATIC PARATHYROID PATCH
RECTUM SEMINAL VESICLES SPINAL CORD. CERVICAL SPINAL CORD, LUMBAR
SPINAL CORD, THORACIC SPLEEN STOMACH TESTES

THYMUS TRACHEA URINARY BLADDER

End of Record- 17631

 1-35

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER 

Appendix II
IndividuaI AnimaT Gross and HistomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17639 DOSE GROUP: I

SEX: DEATH TYPE: Sacrifice-Scheduled
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabIe

HISTOMORPHOLOGIC OBSERVATIONS:

EPIDIDYMIDES: infiTtration, mononucIear-ceTI, foca] (minimaT)
NODE, MEDIASTINAL: (minimaI)
NODE, SUBMANDIBULAR: hyperpIasia, Iymphocytic/pIasmacytic (minimaT)

THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM

COAGULATING GLAND COLON DUODENUM HEART

ILEUM JEJUNUM KIDNEYS LIVER

LUNG NERVE, SCIATIC PARATHYROID PATCH
PROSTATE RECTUM SEMINAL VESICLES SPINAL CORD, CERVICAL
SPINAL CORD, LUMBAR SPINAL CORD, THORACIC SPLEEN STOMACH

TESTES THYMUS THYROID TRACHEA

URINARY BLADDER

End of Record- 17639

 J-36

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418?027
STUDY NUMBER 

Appendix II
IndividuaT AnimaT Gross and HistomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17648 DOSE GROUP: I

SEX: DEATH TYPE: Sacrifice-ScheduIed
GROSS OBSERVATIONIS): HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabTe

HISTOMORPHOLOGIC OBSERVATIONS:

HEART: ianammation, subacute. focaI/muTtifocaI (miId)
KIDNEYS: infiTtration, mononucTear-ceII, focaT (minimaI)
LIVER: infTammation, chronic, focaI/muTtifocaI (minimaT)
NODE, SUBMANDIBULAR: hyperpTasia, Iymphocytic/pIasmacytic (mde)
STOMACH: diTatation, mucosaT gTands (minimaT)

THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM

COAGULATING GLAND COLON DUODENUM EPIDIDYMIDES

ILEUM JEJUNUM LUNG NODE, MEDIASTINAL
NERVE, SCIATIC PARATHYROID PATCH PROSTATE

RECTUM SEMINAL VESICLES SPINAL CORD. CERVICAL SPINAL CORD, LUMBAR
SPINAL CORD, THORACIC SPLEEN TESTES THYMUS

THYROID TRACHEA URINARY BLADDER

End of Record? 17648

 1-37

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418?027
STUDY NUMBER T-7599

Appendix II
IndividuaT AnimaI Gross and HistomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17652 DOSE GROUP: I

SEX: DEATH TYPE: Sacrifice?ScheduTed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appTicabIe

HISTOMORPHOLOGIC OBSERVATIONS:

LIVER: ianammation, chronic, focaI/muTtifocaT (minimaI)
RECTUM: edema/infTammation, submucosa (moderate)
STOMACH: edema/ianammation, submucosa, gTanduIar area (mde)

THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM
COAGULATING GLAND COLON DUODENUM EPIDIDYMIDES
HEART ILEUM JEJUNUM KIDNEYS

LUNG NODE, MEDIASTINAL NODE, SUBMANDIBULAR NERVE, SCIATIC
PARATHYROID PATCH PROSTATE SEMINAL VESICLES
SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR SPINAL CORD, THORACIC SPLEEN

TESTES THYMUS THYROID TRACHEA

URINARY BLADDER

End of Record- 17652

 1?38

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaT AnimaT Gross and HistomorphoTogy Data

ANIMAL NUMBER: 17656 DOSE GROUP: I
SEX: DEATH TYPE: Sacrifice-ScheduTed

 

GROSS OBSERVATIONS): HISTOMORPHOLOGIC OBSERVATION s;

   

GENERAL: No gross changes. Not appTicabTe

HISTOMORPHOLOGIC OBSERVATIONS:

EPIDIDYMIDES: infiTtration, mononucTear?ceTT, focaT (minimaT)
KIDNEYS: edema, papiTTary (minimaT)

NODE, SUBMANDIBULAR: hyperpTasia, (minimaT)
PROSTATE: infTammation, chronic, multifocaT (minimal)

THE FOLLOWING WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM

COAGULATING GLAND COLON DUODENUM HEART

ILEUM JEJUNUM LIVER LUNG

NODE1 MEDIASTINAL NERVE, SCIATIC PARATHYROID PATCH
RECTUM SEMINAL VESICLES SPINAL CORD, CERVICAL SPINAL CORD. LUMBAR
SPINAL CORD, THORACIC SPLEEN STOMACH TESTES

THYMUS THYROID TRACHEA URINARY BLADDER

End of Record- 17656

 

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER 

Appendix II
IndividuaI AnimaT Gross and Histomorphology Data

 

 

 

ANIMAL NUMBER: 17658 DOSE GROUP: I

SEX: DEATH TYPE: Sacrifice?ScheduIed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabIe

HISTOMORPHOLOGIC OBSERVATIONS:

THYROID: uItimobranchiaI body/cyst

THE FOLLOWING WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM

COAGULATING GLAND COLON DUODENUM EPIDIOYMIDES

HEART ILEUM JEJUNUM KIDNEYS

LIVER LUNG NODE, MEDIASTINAL NODE, SUBMANDIBULAR
NERVE, SCIATIC PATCH PROSTATE

RECTUM SEMINAL VESICLES SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR
SPINAL CORD, THORACIC SPLEEN STOMACH TESTES

THYMUS TRACHEA URINARY BLADDER



End of Record? 17658

 3?40

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaI AnimaI Gross and HistomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17660 DOSE GROUP: I

SEX: DEATH TYPE: Sacrifice-ScheduIed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabIe

HISTOMORPHOLOGIC OBSERVATIONS:
LIVER: ianammation, chronic, focaT/multifocaT (minimaI)
NODE, SUBMANDIBULAR: hyperpTasia, Iymphocytic/pIasmacytic (minimaI)

THE FOLLOWING WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM
COAGULATING GLAND COLON DUODENUM EPIDIDYMIDES
HEART ILEUM KIDNEYS

LUNG NODE, MEDIASTINAL NERVE, SCIATIC PARATHYROID
PATCH PROSTATE RECTUM SEMINAL VESICLES
SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR SPINAL CORD, THORACIC SPLEEN

STOMACH TESTES THYMUS THYROID

TRACHEA URINARY BLADDER

End of Record- 17660



 1-41

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaI AnimaI Gross and HistomorphoIogy Data

 

 

 

ANIMAL NUMBER: 17634 DOSE GROUP: II

SEX: DEATH TYPE: Sacrifice-ScheduIed
GROSS OBSERVATIONIS): HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabIe

THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:
STOMACH

End of Record? 17634

II-ll

418-0272PAGE J-42

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaI AnimaI Gross and HistomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17635 DOSE GROUP: II

SEX: DEATH TYPE: Sacrifice-ScheduIed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabIe

HISTOMORPHOLOGIC OBSERVATIONS:

LIVER: vacuoIation, periporta] (minimaT)
ianammation, chronic, focaI/muItifocaI (minimal)
STOMACH: diIatation, mucosa] gIands (minimaI)



End of Record? 17635



418?027 1?43

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaT AnimaT Gross and HistomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17638 DOSE GROUP: II

SEX: DEATH TYPE: Sacrifice-Scheduled
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not applicabTe

THE FOLLOWING WERE WITHIN NORMAL LIMITS:
STOMACH

End of Record- 17638

II-13

 1?44

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaI AnimaI Gross and HistomorphoIogy Data

 

 

 

ANIMAL NUMBER: 17642 DOSE GROUP: II

SEX: DEATH TYPE: Sacrifice-ScheduTed
GROSS OBSERVATIONIS): 
GENERAL: No gross changes. Not appTicabIe

THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:
STOMACH

End of Record- 17642

II-14

 1?45

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaI AnimaT Gross and HistomorphoIogy Data

 

 

 

ANIMAL NUMBER: 17643 DOSE GROUP: II

SEX: DEATH TYPE: Sacrifice?ScheduTed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabTe

HISTOMORPHOLOGIC OBSERVATIONS:

LIVER: ianammation, chronic, focaI/muTtifocaI (mde)
STOMACH: diIatation, mucosa] gIands (miId)



End of Record- 17643

II-15

 5?46

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER 

Appendix II
IndividuaT AnimaI Gross and HistomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17645 DOSE GROUP: II

SEX: DEATH TYPE: Sacrifice?ScheduTed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appTicabTe

THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:
STOMACH

End of Record- 17645

II-IG

 1-47

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaI AnimaI Gross and HistomorphoIogy Data

 

 

 

ANIMAL NUMBER: 17649 DOSE GROUP: II

SEX: DEATH TYPE: Sacrifice-ScheduTed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabTe

HISTOMORPHOLOGIC OBSERVATIONS:

LIVER: ianammation. chronic, focal/muItifocaT (minimaI)
STOMACH: edema/ianammation, submucosa, nongIanduTar area (moderate)

End of Record- 17649



418-0272PAGE L48

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaT AnimaT Gross and HistomorphoTogy Data

ANIMAL NUMBER: 17651
SEX: 

GROSS OBSERVATIONIS):

GENERAL: No gross changes.

End of Record- 17651

DOSE GROUP: II
DEATH TYPE: Sacrifice-ScheduTed

HISTOMORPHOLGGIC 

Not appTicabIe

II-18

418?027 I-49

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER 

Appendix II
IndividuaT AnimaT Gross and HistomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17653 DOSE GROUP: II

SEX: DEATH TYPE: Sacrifice-ScheduTed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appTicabTe

THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:
STOMACH



End of Record? 17653

11-19

 1-50

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaI AnimaI Gross and HistomorphoIogy Data

 

 

 

ANIMAL NUMBER: 17655 DOSE GROUP: II

SEX: DEATH TYPE: Sacrifice?ScheduIed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabTe

THE FOLLOWING WERE WITHIN NORMAL LIMITS:
STOMACH

End of Record- 17655

II-20

 1-51

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaI AnimaT Gross and HistomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17620 DOSE GROUP: 

SEX: DEATH TYPE: Sacrifice?ScheduTed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appTicabTe

HISTOMORPHOLOGIC OBSERVATIONS:

LIVER: hypertrophy, hepatoceTIuTar, centriIobuIar (minimaI)
STOMACH: edema/infTammation. submucosa, gTanduTar area (minimaT)
diTatation, mucosaI gIands (minimaI)

End of Record? 17620



 3?52

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418~027
STUDY NUMBER T-7599

Appendix II
Individua] AnimaI Gross and HistomorphoIogy Data

 

 

 

ANIMAL NUMBER: 17623 DOSE GROUP: 

SEX: DEATH TYPE: Sacrifice-ScheduIed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appTicabIe



THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:
STOMACH

End of Record? 17623

11-22

 1-53

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaT AnimaT Gross and HistomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17627 . DOSE GROUP: 

SEX: DEATH TYPE: Sacrifice-ScheduTed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appTicabIe

HISTOMORPHOLOGIC OBSERVATIONS:

LIVER: infTammation, chronic, focaT/muTtifocaT (minimaT)
hypertrophy, hepatoceITuTar, centriTobuIar (minimaI)

THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:
STOMACH

End of Record? 17627

II-23

 1-54

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaI AnimaT Gross and HistomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17628 DOSE GROUP: 111

SEX: DEATH TYPE: Sacrifice-ScheduIed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabTe

LIVER: inflammation, chronic, focaI/muTtifocaI (minimaI)

THE FOLLOWING WERE WITHIN NORMAL LIMITS:
STOMACH

End of Record? 17628



 

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaI AnimaI Gross and HistomorphoIogy Data

 

 

 

ANIMAL NUMBER: 17633 DOSE GROUP: 

SEX: DEATH TYPE: Sacrifice-ScheduTed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appTicabTe

THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:
STOMACH

End of Record? 17633

II-25

 

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418?027
STUDY NUMBER T-7599

Appendix II
IndividuaT AnimaT Gross and HistomorphoIogy Data

 

 

 

ANIMAL NUMBER: 17640 DOSE GROUP: 

SEX: DEATH TYPE: Sacrifice?ScheduTed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabTe

End of Record? 17640

II-26

 5-57

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaT AnimaT Gross and HistomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17646 DOSE GROUP: 

SEX: DEATH TYPE: Sacrifice-ScheduTed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appTicabTe

THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:
STOMACH

End of Record- 17646



 1?58

ORAL (SAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418?027
STUDY NUMBER T-7599

Appendix II
Individual AnimaI Gross and HistomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17650 DOSE GROUP: 

SEX: DEATH TYPE: Sacrifice-ScheduIed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabIe

HISTDMORPHOLOGIC OBSERVATIONS:

LIVER: hypertrophy, centriIobuIar (minimaI)
STOMACH: diIatation, mucosaI glands (minimaI)
edema/ianammation, submucosa, gIanduIar area (minimaI)

End of Record- 17650

11?28

 5-59

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER 

Appendix II
IndividuaI AnimaI Gross and HistomorphoIogy Data

 

 

 

ANIMAL NUMBER: 17657 DOSE GROUP: 

SEX: DEATH TYPE: Sacrifice?ScheduIed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabIe

THE FOLLOWING WERE WITHIN NORMAL LIMITS:
STOMACH 7

End of Record? 17657

11-29

 L60

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418~027
STUDY NUMBER T-7599

Appendix II
IndividuaI AnimaT Gross and HistomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17659 DOSE GROUP: 

SEX: DEATH TYPE: Sacrifice-ScheduTed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not app11cab1e

THE FOLLOWING WERE WITHIN NORMAL LIMITS:
STOMACH

End of Record? 17659



 3-61

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST

STUDY NUMBER T-7599

Appendix II
IndividuaT AnimaI Gross and HistomorphoIogy Data

 

 

 

ANIMAL NUMBER: 17621 DOSE GROUP: IV

SEX: DEATH TYPE: Sacrifice?ScheduIed
GROSS HISTOMORPHOLOGIC 
SPLEEN: NoduIe, 0.3cm (trimming observation). 

 

HISTOMORPHOLOGIC OBSERVATIONS:

ADRENAL GLANDS: vacuoIation, cortex (minimaT)

LIVER: infTammation, chronic, focal/multifocaT (miId)
hypertrophy, hepatoceIIuTar, centriIobuIar (miId)

NODE, SUBMANDIBULAR: hyperpIasia, Iymphocytic/pIasmacytic (minimaI)

RECTUM: parasite(s)

SPLEEN: Iymphosarcoma, maIignant

STOMACH: erosion(s), gIanduIar mucosa (minimal)

THE FOLLOWING HERE WITHIN NORMAL LIMITS:

BONE MARROW (STERNUM) BRAIN CECUM COAGULATING GLAND
COLON DUODENUM EPIDIDYMIDES HEART

ILEUM JEJUNUM KIDNEYS LUNG

NODE, MEDIASTINAL NERVE, SCIATIC PARATHYROID PATCH
PROSTATE SEMINAL VESICLES SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR
SPINAL CORD, THORACIC TESTES THYMUS THYROID

TRACHEA URINARY BLADDER

NEOPLASMS:

SPLEEN maIignant

End of Record? 17621



 I ?62

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaI AnimaT Gross and HistomorphoIogy Data

 

 

 

ANIMAL NUMBER: 17622 DOSE GROUP: IV

SEX: DEATH TYPE: Sacrifice?Scheduled
GROSS OBSERVATIONIS): HISTOMORPHOLOGIC 
EXTREMITIES: Right front Teg? scab. dermatitis, uTcerative, focaT

HISTOMORPHOLOGIC OBSERVATIONS:

EXTREMITIES: dermatitis, uIcerative, focaT (mde)

LIVER: hypertrophy, hepatoceITuIar, centriIobuTar (miId)
NODE, SUBMANDIBULAR: hyperpIasia, Iymphocytic/pIasmacytic (moderate)
PROSTATE: atrophy, focaI (minimaT)

STOMACH: erosion(s), gIanduIar mucosa (mde)

THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM

COAGULATING GLAND COLON DUODENUM EPIDIDYMIDES

HEART ILEUM JEJUNUM KIDNEYS

LUNG NODE, MEDIASTINAL NERVE, SCIATIC PARATHYROID

PATCH RECTUM SEMINAL VESICLES SPINAL CORD, CERVICAL
SPINAL CORD, LUMBAR SPINAL CORD, THORACIC SPLEEN TESTES

THYMUS THYROID TRACHEA URINARY BLADDER

End of Record? 17622

II-32

 1?63

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaT AnimaI Gross and HistomorphoTogy Data

 

 

ANIMAL NUMBER: 17625 DOSE GROUP: IV

SEX: DEATH TYPE: Sacrifice?ScheduTed
GROSS OBSERVATIONISI: HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabIe

HISTOMORPHOLOGIC OBSERVATIONS:

ADRENAL GLANDS: hypertrophy/vacuoIation, zona gIomerqusa (miId)
LIVER: necrosis, focaI (minimaI)

hypertrophy, centriIobuIar (miId)
NODE, SUBMANDIBULAR: hyperpIasia, Iymphocytic/plasmacytic (minimaI)



THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:

BONE MARROW (STERNUM) BRAIN CECUM COAGULATING GLAND
COLON DUODENUM EPIDIDYMIDES HEART

ILEUM JEJUNUM KIDNEYS LUNG

NODE, MEDIASTINAL NERVE, SCIATIC PARATHYROID PATCH
PROSTATE RECTUM SEMINAL VESICLES SPINAL CORD, CERVICAL
SPINAL CORD, LUMBAR SPINAL CORD, THORACIC SPLEEN STOMACH

TESTES THYMUS THYROID TRACHEA

URINARY BLADDER

End of Record- 17625

II-33

 1?64

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418~027
STUDY NUMBER 

Appendix II
IndividuaT AnimaI Gross and HistomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17629 DOSE GROUP: IV

SEX: DEATH TYPE: Sacrifice?ScheduIed
GROSS OBSERVATIONIS): HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabTe

HISTOMORPHOLOGIC OBSERVATIONS:

KIDNEYS: cyst(s), meduTTa

LIVER: hypertrophy, hepatoceTIuTar, centriIobuTar (miId)

LUNG: macrophages, aTveoTi, focaI (minimaT)
infTammation, interstitial, muTtifocaT (minimaT)

NODE, SUBMANDIBULAR: hyperpIasia, Iymphocytic/pTasmacytic (miId)

PROSTATE: ianammation, chronic, muTtifocaI (minimaT)

STOMACH: edema/ianammation, submucosa, nongIanduIar area (minimaI)
diTatation, mucosaI gTands (minimaT)

THYROID: uTtimobranchiaT body/cyst

THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM

COAGULATING GLAND COLON DUODENUM EPIDIDYMIDES

HEART ILEUM JEJUNUM NODE, MEDIASTINAL
NERVE, SCIATIC PARATHYROID PATCH RECTUM

SEMINAL VESICLES SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR SPINAL CORD, THORACIC
SPLEEN TESTES THYMUS TRACHEA

URINARY BLADDER

COMMENTS:

STOMACH The edema/infTammation is most prominent at the Iimiting
ridge.

End of Record- 17629



 

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER 

Appendix II
IndividuaI AnimaI Gross and HistomorphoIogy Data

 

 

 

ANIMAL NUMBER: 17636 DOSE GROUP: IV

SEX: DEATH TYPE: Sacrifice?ScheduIed
GROSS OBSERVATIONIS): HISTDMORPHOLOGIC 
PROSTATE: Right hemisphere- firm, IobuIar mass, prostatitis, suppurative

tan in coTor, measuring 2.80m 0.9cm 0.7cm,
cut surface reveaIs tan, smooth surface,
ventraI right side red in coIor.

HISTOMORPHOLOGIC OBSERVATIONS:

ADRENAL GLANDS: vacuoIation, cortex (minimaI)

KIDNEYS: cyst(s), meduIIa

LIVER: ianammation, chronic, focaI/muItifocaI (minimaI)
hypertrophy, centriIobuTar (minimaI)

NODE, MEDIASTINAL: (miId)

PROSTATE: prostatitis, suppurative (marked)

RECTUM: parasite(s)

STOMACH: edema/infTammation, submucosa, gIanduIar area (moderate)
edema/ianammation, submucosa, nongIanduIar area (miId)

THYROID: uItimobranchiaI body/cyst

THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:

BONE MARROW (STERNUM) BRAIN CECUM COAGULATING GLAND

COLON DUODENUM EPIDIDYMIDES HEART

ILEUM JEJUNUM LUNG NODE, SUBMANDIBULAR
NERVE, SCIATIC PATCH SEMINAL VESICLES SPINAL CORD, CERVICAL
SPINAL CORD, LUMBAR SPINAL CORD, THORACIC SPLEEN TESTES

THYMUS TRACHEA URINARY BLADDER

TISSUEIS) NOT AVAILABLE FOR EVALUATION:
PARATHYROID

End of Record? 17636

II-35

 1?66

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
Individual Animal Gross and Histomorphology Data

 

 

 

ANIMAL NUMBER: 17637 DOSE GROUP: IV

SEX: DEATH TYPE: Sacrifice-Scheduled
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not applicable

HISTOMORPHOLOGIC OBSERVATIONS:

LIVER: necrosis, individual hepatocytes (minimal)
hypertrophy, hepatocellular, centrilobular (mild)
PATCH: mineralization (minimal)
STOMACH: edema/inflammation, submucosa, nonglandular area (minimal)

edema/inflammation, submucosa, glandular area (mild)
dilatation, mucosal glands (minimal)
THYROID: ultimobranchial body/cyst

THE FOLLOWING WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM
COAGULATING GLAND COLON DUODENUM EPIDIDYMIDES
HEART ILEUM JEJUNUM KIDNEYS

LUNG NODE, MEDIASTINAL NODE, SUBMANDIBULAR NERVE, SCIATIC
PARATHYROID PROSTATE RECTUM SEMINAL VESICLES
SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR SPINAL CORD, THORACIC SPLEEN

TESTES THYMUS TRACHEA URINARY BLADDER

End of Record- 17637



 L67

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
Individua] Anima] Gross and HistomorphoIOQy Data

 

 

 

ANIMAL NUMBER: 17641 DOSE GROUP: IV

SEX: DEATH TYPE: Sacrifice?ScheduIed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not applicabIe

HISTOMORPHOLOGIC OBSERVATIONS:

KIDNEYS: mineraTization, muTtifocaT (minimaT)

LIVER: ianammation, chronic, focaI/muItTFOCaI (minimaI)
hypertrophy, hepatoceITuTar, centriTobuTar (miId)
necrosis, individuaI hepatocytes (minimaI)

NODE, MEDIASTINAL: (minimal)
NODE, SUBMANOIBULAR: hyperpIasia, Iymphocytic/pIasmacytic (minimaT)
STOMACH: diIatation, mucosaI gIands (mde)

THE FOLLOWING WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM

COAGULATING GLAND COLON DUODENUM EPIDIDYMIDES

HEART ILEUM JEJUNUM LUNG

NERVE, SCIATIC PARATHYROID PATCH PROSTATE

RECTUM SEMINAL VESICLES SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR
SPINAL CORD, THORACIC SPLEEN TESTES THYMUS

THYROID TRACHEA URINARY BLADDER

End of Record? 17641

11-37

 1?68

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418?027
STUDY NUMBER T-7599

Appendix II
IndividuaI AnimaI Gross and HistomorphoIogy Data

 

 

 

ANIMAL NUMBER: 17644 DOSE GROUP: IV 

SEX: DEATH TYPE: Sacrifice?ScheduIed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabTe

HISTOMORPHOLOGIC OBSERVATIONS:

ADRENAL GLANDS: vacuoIation, cortex (minimaT)

LIVER: hypertrophy, hepatoceITuIar, centriTobuIar (mde)
necrosis, individua] hepatocytes (miId)

NODE, SUBMANDIBULAR: hyperpTasia, (minimaI)

PROSTATE: infTammation, chronic, muTtifocaT (minimaI)

SPLEEN: hematopoiesis, extrameduTIary, increased (minimaT)

THE FOLLOWING WERE WITHIN NORMAL LIMITS:

BONE MARROW (STERNUM) BRAIN CECUM COAGULATING GLAND
COLON DUODENUM EPIDIDYMIDES HEART

ILEUM JEJUNUM KIDNEYS LUNG

NODE, MEDIASTINAL NERVE. SCIATIC PATCH RECTUM

SEMINAL VESICLES SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR SPINAL CORD, THORACIC
STOMACH TESTES THYMUS THYROID

TRACHEA URINARY BLADDER

NOT AVAILABLE FOR EVALUATION:
PARATHYROID

End of Record- 17644

II-38

 L69

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaI AnimaT Gross and Histomorphology Data

 

 

 

ANIMAL NUMBER: 17647 DOSE GROUP: IV

SEX: DEATH TYPE: Sacrifice?ScheduIed
GROSS OBSERVATIONIS): HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appTicabIe

HISTOMORPHOLOGIC OBSERVATIONS:

EPIDIDYMIDES: infiItration, mononucIear-ceTI, focal (minimaT)
LIVER: hypertrophy, centriIDbuTar (miId)
STOMACH: edema/infTammation, submucosa, nongIanduTar area (moderate)

edema/infTammation, submucosa, gIanduIar area (moderate)

THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM
COAGULATING GLAND COLON DUODENUM HEART

ILEUM JEJUNUM KIDNEYS LUNG

NODE, MEDIASTINAL NODE, SUBMANDIBULAR NERVE, SCIATIC PARATHYROID
PATCH PROSTATE RECTUM SEMINAL VESICLES
SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR SPINAL CORD, THORACIC SPLEEN

TESTES THYMUS THYROID TRACHEA

URINARY BLADDER

End of Record? 17647

11-39

 3?70

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER 

Appendix II
Individua] AnimaT Gross and HistomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17654 DOSE GROUP: IV

SEX: DEATH TYPE: Sacrifice-ScheduIed
GROSS OBSERVATIONIS): HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appTicabTe

HISTOMORPHOLOGIC OBSERVATIONS:

HEART: in?ammation, subacute, focaI/muTtifocaI (minimaT)
KIDNEYS: nephritis, chronic, facaI (minimaT)
LIVER: Iipidosis, tension, focaT

inflammation, chronic, focaT/muTtifocaT (minimaT)
hypertrophy, hepatoceTIuIar, centriTobuTar (minimaI)



THE FOLLOWING WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM

COAGULATING GLAND COLON DUODENUM EPIDIDYMIDES

ILEUM JEJUNUM LUNG NODE, MEDIASTINAL
NODE. SUBMANDIBULAR NERVE, SCIATIC PARATHYROID PATCH

PROSTATE RECTUM SEMINAL VESICLES SPINAL CORD, CERVICAL
SPINAL CORD, LUMBAR SPINAL CORD, THORACIC SPLEEN STOMACH

TESTES THYMUS THYROID TRACHEA

URINARY BLADDER

End of Record? 17654



 1-71

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418*027
STUDY NUMBER T-7599

Appendix II
Individua] AnimaT Gross and Histomorphology Data

 

 

 

ANIMAL NUMBER: 17681 DOSE GROUP: I

SEX: DEATH TYPE: Sacrifice?ScheduTed
GROSS OBSERVATIONIS): HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabTe

HISTOMORPHOLOGIC OBSERVATIONS:

KIDNEYS: mineraTization, muTtifocaT (minimaT)

NODE, SUBMANDIBULAR: hyperpTasia, Iymphocytic/pTasmacytic (moderate)
MAMMARY GLAND: hyperpTasia, physiologicaT

SPLEEN: hematopoiesis, extramedulIary, increased (mde)
THYROID: uItimobranchiaI body/cyst

VAGINA: mucification (moderate)

THE FOLLOWING WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM

COLON DUODENUM HEART ILEUM

JEJUNUM LIVER LUNG NODE, MEDIASTINAL
NERVE, SCIATIC OVARIES PARATHYROID PATCH

RECTUM SPINAL CORD. CERVICAL SPINAL CORD, LUMBAR SPINAL CORD, THORACIC
STOMACH THYMUS TRACHEA URINARY BLADDER

UTERUS

End of Record- 17681

II-41

 1-72

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER 

Appendix II
IndividuaI AnimaI Gross and HistomorphoIogy Data

 

 

 

ANIMAL NUMBER: 17690 DOSE GROUP: I

SEX: DEATH TYPE: Sacrifice?ScheduIed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabIe

HISTOMORPHOLOGIC OBSERVATIONS:

LIVER: ianammation, chronic, focaI/muItifocaI (minimaI)
NODE, SUBMANOIBULAR: hyperpIasia, Iymphocytic/pIasmacytic (minimaI)
MAMMARY GLAND: hyperpIasia. physioIogicaI

STOMACH: dilatation, mucosa] glands (minimaI)

VAGINA: mucification (moderate)

THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM

COLON DUODENUM HEART ILEUM

JEJUNUM KIDNEYS LUNG NODE, MEDIASTINAL
NERVE, SCIATIC OVARIES PARATHYROID PATCH

RECTUM SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR SPINAL CORD, THORACIC
SPLEEN THYMUS THYROID TRACHEA

URINARY BLADDER UTERUS

End of Record? 17690

II-4Z

 1-73

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
Individua] AnimaI Gross and HistomorphoIogy Data

 

 

 

ANIMAL NUMBER: 17694 DOSE GROUP: I

SEX: DEATH TYPE: Sacrifice-ScheduIed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabIe

HISTOMORPHOLOGIC OBSERVATIONS:

LUNG: macrophages, aIveoIi, focaI (minimaI)

NODE, MEDIASTINAL: macrophages, pigmented (minimal)
(minimaI)

NODE, SUBMANDIBULAR: hyperpIasia, Iymphocytic/pIasmacytic (miId)

MAMMARY GLAND: hyperpIasia, physioIogicaI

UTERUS: thrombus

macrophages, pigmented (minimaI)

THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM

COLON DUODENUM HEART ILEUM

JEJUNUM KIDNEYS LIVER NERVE1 SCIATIC
OVARIES PARATHYROID PATCH RECTUM

SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR SPINAL CORD. THORACIC SPLEEN

STOMACH THYMUS THYROID TRACHEA
URINARY BLADDER VAGINA

End of Record? 17694

II-43

 1?74

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix 11
Individual AnimaT Gross and HistomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17695 DOSE GROUP: I

SEX: DEATH TYPE: Sacrifice-ScheduIed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appTicabTe

HISTOMORPHOLOGIC OBSERVATIONS:

NODE, MEDIASTINAL: hyperpTasia, (minimaT)
macrophages, pigmented (minimaT)

MAMMARY GLAND: hyperplasia, physioTogicaT

SPLEEN: hematopoiesis1 extrameduITary, increased (mde)

UTERUS: macrophages, pigmented (moderate)

THE FOLLOWING WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM

COLON DUOOENUM HEART ILEUM

JEJUNUM KIDNEYS LIVER LUNG

NODE, SUBMANDIBULAR NERVE, SCIATIC OVARIES PARATHYROID

PATCH RECTUM SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR
SPINAL CORD, THORACIC STOMACH THYMUS THYROID

TRACHEA URINARY BLADDER VAGINA

End of Record? 17695

II-44

 

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaI AnimaI Gross and HistomorphoIogy Data

 

 

 

ANIMAL NUMBER: 17703 DOSE GROUP: I

SEX: DEATH TYPE: Sacrifice-ScheduIed
GROSS I HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabIe

HISTOMORPHOLOGIC OBSERVATIONS:

KIDNEYS: mineraIization, muTtifocaI (minimaI)

LIVER: ianammation, chronic, focaI/muItifocaI (minimal)
NODE, SUBMANDIBULAR: hyperpTasia, Iymphocytic/pIasmacytic (moderate)
MAMMARY GLAND: hyperpIasia, physioIogicaI

SPLEEN: hematopoiesis, extrameduTIary, increased (miId)
THYROID: uTtimobranchiaT body/cyst

UTERUS: macrophages, pigmented (moderate)

THE FOLLOWING WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM

COLON DUODENUM HEART ILEUM

JEJUNUM LUNG NODE, MEDIASTINAL NERVE, SCIATIC
OVARIES PARATHYROID PATCH RECTUM

SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR SPINAL CORD, THORACIC STOMACH

THYMUS TRACHEA URINARY BLADDER VAGINA

End of Record? 17703

II-45

 

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST

STUDY NUMBER Tn7599

Appendix II
IndividuaI AnimaT Gross and HistomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17713 DOSE GROUP: I

SEX: DEATH TYPE: Sacrifice~$cheduTed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not applicabTe

OBSERVATIONS:

HEART: pericarditis, chronic, focaT (minimaT)

LIVER: vacuoTation, muTtifocaI (minimaI)
NODE, SUBMANDIBULAR: hyperpTasia, Iymphocytic/pTasmacytic (minimaI)
MAMMARY GLAND: hyperpTasia, physiologicaI

UTERUS: macrophages, pigmented (moderate)

distention, Tumen (minimal)

THE FOLLOWING WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM

COLON DUODENUM ILEUM JEJUNUM
KIDNEYS LUNG NODE, MEDIASTINAL NERVE, SCIATIC
OVARIES PARATHYROID PATCH RECTUM

SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR SPINAL CORD, THORACIC SPLEEN

STOMACH THYMUS THYROID TRACHEA
URINARY BLADDER VAGINA

End of Record? 17713

II-46

 

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 
STUDY NUMBER 

Appendix II
IndividuaI AnimaT Gross and HistomorphoIogy Data

 

 

 

ANIMAL NUMBER: 17715 DOSE GROUP: I

SEX: DEATH TYPE: Sacrifice-ScheduIed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabTe

HISTOMORPHOLOGIC OBSERVATIONS:

ADRENAL GLANDS: infiItration, mononucTear-ceIT, muItifocaI (minimaI)
LIVER: ianammation, chronic, focaI/muTtifocaT (minimaI)
NODE, SUBMANDIBULAR: hyperpIasia, (miId)

MAMMARY GLAND: hyperpIasia, physioTogicaI

SPLEEN: hematopoiesis, extrameduTIary, increased (minimaT)
UTERUS: thrombus

macrophages, pigmented (moderate)

THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:

BONE MARROW (STERNUM) BRAIN CECUM COLON

DUODENUM HEART ILEUM JEJUNUM

KIDNEYS LUNG NODE, MEDIASTINAL NERVE, SCIATIC
OVARIES PARATHYROID PATCH RECTUM

SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR SPINAL CORD, THORACIC STOMACH

THYMUS THYROID TRACHEA URINARY BLADDER
VAGINA

End of Record? 17715

II-47

 3?78

ORAL (SAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaI AnimaI Gross and HistomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17716 DOSE GROUP: I

SEX: DEATH TYPE: Sacrifice?ScheduTed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appTicabIe

HISTOMORPHOLOGIC OBSERVATIONS:

LIVER: necrosis, focaT (minimal)

NODE. SUBMANDIBULAR: hyperpIasia, Iymphocytic/pIasmacytic (minimaI)
MAMMARY GLAND: hyperpIasia. physioIogicaT

UTERUS: macrophages, pigmented (moderate)

THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM

COLON DUODENUM HEART ILEUM

JEJUNUM KIDNEYS LUNG NODE, MEDIASTINAL
NERVE, SCIATIC OVARIES PARATHYROID PATCH

RECTUM SPINAL CORD, SPINAL CORD. LUMBAR SPINAL CORD, THORACIC
SPLEEN THYMUS THYROID

TRACHEA URINARY BLADDER VAGINA

End of Record- 17716

11-48

 J-79

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418~027
STUDY NUMBER T-7599

Appendix II

IndividuaI AnimaI Gross and Histomorphology Data

ANIMAL NUMBER: 17717
SEX: 

DOSE GROUP:
DEATH TYPE:

Sacrifice-ScheduIed

 

GROSS 

GENERAL: No gross changes.

HISTOMORPHOLOGIC 

Not appTicabIe

HISTOMORPHOLOGIC OBSERVATIONS:

LUNG: ianammation, interstitiaT, muItifocaT (minimaI)
NODE, SUBMANDIBULAR: hyperpIasia, Iymphocytic/pTasmacytic (mild)
MAMMARY GLAND: hyperpIasia, physioTogicaI

THYROID: uTtimobranchiaI body/cyst

UTERUS: macrophages, pigmented (moderate)

THE FOLLOWING WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM)
COLON DUODENUM

JEJUNUM KIDNEYS

NERVE, SCIATIC OVARIES

RECTUM SPINAL CORD, CERVICAL
SPLEEN STOMACH

URINARY BLADDER VAGINA

BRAIN

HEART

LIVER

PARATHYROID

SPINAL CORD, LUMBAR
THYMUS

CECUM

ILEUM

NODE, MEDIASTINAL
PATCH

SPINAL CORD, THORACIC
TRACHEA

End of Record- 17717

II-49

418-027 

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaT AnimaT Gross and HistomorphoIogy Data

 

 

 

ANIMAL NUMBER: 17719 DOSE GROUP: I

SEX: DEATH TYPE: Sacrifice~3chedu1ed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabIe

HISTOMORPHOLOGIC OBSERVATIONS:

NODE, SUBMANDIBULAR: hyperpIasia, (minimaI)
MAMMARY GLAND: inflammation; subacute?(m11d)
hyperpTasia, physioIogicaI
THYMUS: atrophy (minimaT)
UTERUS: macrophages, pigmented (moderate)

THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM

COLON DUODENUM HEART ILEUM

JEJUNUM KIDNEYS LIVER LUNG

NERVE, SCIATIC OVARIES PARATHYROID PATCH

RECTUM SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR SPINAL CORD, THORACIC
SPLEEN STOMACH THYROID TRACHEA

URINARY BLADDER VAGINA

NOT AVAILABLE FOR EVALUATION:
NODE, MEDIASTINAL

End of Record- 17719



 1?81

ORAL (SAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaI Animal Gross and HistomorphoIogy Data

 

 

 

ANIMAL NUMBER: 17675 DOSE GROUP: II

SEX: DEATH TYPE: Sacrifice?ScheduTed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appTicabIe

End of Recordr 17675



 1?82

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER 

Appendix II
IndividuaT AnimaT Gross and.HistomorphoTogy Data

ANIMAL NUMBER: 17679
SEX: 

GROSS 

GENERAL: No gross changes.

End of Record? 17679

DOSE GROUP: II
DEATH TYPE: Sacrifice?ScheduTed

HISTOMORPHOLOGIC 

Not appTicabTe

11-52

 1-83

ORAL (SAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaI AnimaI Gross and HistomorphoIogy Data

 

 

 

ANIMAL NUMBER: 17684 DOSE GROUP: II

SEX: DEATH TYPE: Sacrifice-ScheduIed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabIe

End of Record- 17684

II-53

418-0272PAGE 1-84

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418?027
STUDY NUMBER 

Appendix II
IndividuaT AnimaI Gross and HistomorphoIogy Data

ANIMAL NUMBER: 17688
SEX: 

GROSS 

GENERAL: No gross changes.

End of Record? 17688

DOSE GROUP: II
DEATH TYPE: Sacrifice-ScheduIed

HISTOMORPHOLOGIC 

Not appIicabIe

II-54

 J-85

ORAL (SAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaI AnimaI Gross and HistomorphoIogy Data

 

 

ANIMAL NUMBER: 17698 DOSE GROUP: II

SEX: DEATH TYPE: Sacrifice-Scheduled
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabTe

HISTOMORPHOLOGIC OBSERVATIONS:

THYMUS: atrophy (minimaI)

End of Record- 17698

II-55

 1-86

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 759947
WITH THE TOXICITY SCREENING TEST
PROTOCOLL418-OZ7
STUDY NUMBER 

Appendix II
IndividuaI AnimaT Gross and HistomorphoIogy Data

 

 

 

ANIMAL NUMBER: 17702 DOSE GROUP: II

SEX: DEATH TYPE: Sacrifice-ScheduIed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appTicabTe



End of Record- 17702



418?027 1-87

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaT AnimaT Gross and HistomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17704 DOSE GROUP: II

SEX: DEATH TYPE: Sacrifice-ScheduTed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appTicabTe

THE FOLLOWING TISSUETS) WERE WITHIN NORMAL LIMITS:
THYMUS

End of Record? 17704



 1-88

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaT AnimaT Gross and H13tomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17707 DOSE GROUP: II

SEX: DEATH TYPE: Sacrifice-ScheduIed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appTicabTe

HISTOMORPHOLOGIC OBSERVATIONS:

LIVER: necrosis, focaI (minimaT)
ianammation, chronic, focaT/muItifocaT (minimaT)

THE FOLLOWING WERE WITHIN NORMAL LIMITS:
THYMUS

End of Record? 17707

II-58

 I-89

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418+027
STUDY NUMBER 

Appendix II
IndividuaT AnimaT Gross and HistomorphoTogy Data

 

 

ANIMAL NUMBER: 17708 DOSE GROUP: II

SEX: DEATH TYPE: Sacrifice?ScheduTed
GROSS HISTOMORPHOLOGIC OBSERVATIONSS):
GENERAL: No gross changes. Not appTicabTe

End of Record~ 17708

11-59

 L90

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599;7
WITH THE TOXICITY SCREENING TEST

STUDY NUMBER T-7599

Appendix II
IndividuaT AnimaT Gross and HistomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17710 DOSE GROUP: II

SEX: DEATH TYPE: Sacrifice?ScheduTed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appTicabTe

End of Record- 17710

II-BO

 1-91

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL.418-027
STUDY NUMBER T-7599

Appendix II
IndividuaT AnimaT Gross and HistomorphoTogy Data

 

 

ANIMAL NUMBER: 17687 DOSE GROUP: 

SEX: DEATH TYPE: Sacrifice?ScheduTed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appTicabTe

End of Record? 17687

II-61

418-0271PAGE L92

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER 

Appendix II
IndividuaT AnimaT Gross and HistomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17693 DOSE GROUP: 

SEX: DEATH TYPE: Sacrifice?ScheduTed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appTicabTe

THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:
THYMUS

End of Record~ 17693

11-62

 1?93

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418~027
STUDY NUMBER T-7599

Appendix II
IndividuaI AnimaI Gross and HistomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17697 DOSE GROUP: 

SEX: DEATH TYPE: Sacrifice?ScheduIed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabIe

HISTOMORPHOLOGIC OBSERVATIONS:

THYMUS: atrophy (minimaI)

End of Record* 17697

11-63

 L94

ORAL (SAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 759947
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418*027
STUDY NUMBER T-7599

Appendix II
Individual AnimaI Gross and HistomorphoIogy Data

 

 

ANIMAL NUMBER: 17700 DOSE GROUP: 

SEX: DEATH TYPE: Sacrifice-ScheduTed
GROSS HISTOMORPHOLOGIC OBSERVATIONISZ:
GENERAL: No gross changes. Not appTicabIe

THE FOLLOWING WERE WITHIN NORMAL LIMITS:
THYMUS

End of Record? 17700

11-64

 

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418*027
STUDY NUMBER T-7599

Appendix II
IndividuaT AnimaT Gross and:HistomorphoIogy Data

 

 

 

ANIMAL NUMBER: 17701 DOSE GROUP: 

SEX: DEATH TYPE: Sacrifice-ScheduIed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not applicabTe

THE FOLLOWING WERE WITHIN NORMAL LIMITS:
THYMUS

End of Record- 17701

11-65

 L96

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaT AnimaT and HistomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17705 DOSE GROUP: 

SEX: DEATH TYPE: Sacrifice?Scheduled
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabTe

HISTOMORPHOLOGIC OBSERVATIONS:

MW

THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:
THYMUS

End of Record- 17705

II-66

 1?97

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
Individua] AnimaI Gross and HistomorphoIogy Data

 

 

 

ANIMAL NUMBER: 17706 DOSE GROUP: 

SEX: DEATH TYPE: Sacrifice-ScheduTed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appTicabTe

THE FOLLOWING WERE WITHIN NORMAL LIMITS:
THYMUS

End of Record? 17706

II-67

418-0271PAGE I ?98

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418*027
STUDY NUMBER T-7599

Appendix II
IndividuaT AnimaI Gross and HistomorphoIogy Data

 

 

ANIMAL NUMBER: 17709 DOSE GROUP: 

SEX: . DEATH TYPE: Sacrifice-ScheduIed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabIe

End of Record? 17709

11-68

 J-99

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaT AnimaT Gross and HistomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17718 DOSE GROUP: 

SEX: DEATH TYPE: Sacrifice-ScheduTed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appTicabTe

THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:
THYMUS

End of Record- 17718

11-69

 I-IOO

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 759947
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaI AnimaI Gross and Histomorphology Data

 

 

 

ANIMAL NUMBER: 17720 DOSE GROUP: 

SEX: DEATH TYPE: Sacrifice?Scheduled
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appTicabIe

THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:
THYMUS

End of Record? 17720



418-0271PAGE 

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 759947
WITH THE TOXICITY SCREENING TEST

STUDY NUMBER T-7599

Appendix II
Individua] AnimaT Gross and HistomorphoIogy Data

 

 

ANIMAL NUMBER: 17685 DOSE GROUP: IV

SEX: DEATH TYPE: Sacrifice?ScheduTed
GROSS OBSERVATIONTS): HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appTicabTe

HISTOMORPHOLOGIC OBSERVATIONS:

KIDNEYS: pyeTitis, chronic (minimaT)
LIVER: Tipidosis, tension, focal

hypertrophy. hepatoceIIular, centriTobuTar (minimaT)
SUBMANDIBULAR: hyperpTasia, (moderate)
MAMMARY GLAND: hyperpTasia, physioTogicaT
UTERUS: macrophages, pigmented (minimaT)

THE FOLLOWING WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM

COLON DUODENUM HEART ILEUM

JEJUNUM NODE, MEDIASTINAL NERVE, SCIATIC
OVARIES PARATHYROID PATCH RECTUM

SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR SPINAL CORD, THORACIC SPLEEN

STOMACH THYMUS THYROID TRACHEA
URINARY BLADDER VAGINA

End of Record- 17685



418-0271PAGE 

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaI AnimaT Gross and HistomorphoIogy Data

 

 

 

ANIMAL NUMBER: 17686 DOSE GROUP: IV

SEX: DEATH TYPE: Sacrifice-Scheduled
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appTicabIe

HISTOMORPHOLOGIC OBSERVATIONS:

LIVER: infTammation. chronic, focaI/muItifocaT (minimaI)
NODE, SUBMANDIBULAR: hyperpIasia, (moderate)
MAMMARY GLAND: hyperpTasia, physioTagjcaT

THYROID: uItimobranchiaT body/cyst

UTERUS: macrophages, pigmented (minimaI)

VAGINA: mucification (moderate)

THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM

COLON DUODENUM HEART ILEUM

JEJUNUM KIDNEYS LUNG NODE, MEDIASTINAL
NERVE, SCIATIC PARATHYROIO PATCH RECTUM

SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR SPINAL CORD, THORACIC SPLEEN

STOMACH THYMUS TRACHEA URINARY BLADDER

TISSUEIS) NOT AVAILABLE FOR EVALUATION:
OVARIES

End of Record- 17686



 I403

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418~027
STUDY NUMBER T-7599

Appendix II
IndividuaT AnimaT Gross and HistomorphoTogy Data

 

 

 

ANIMAL NUMBER: 17689 DOSE GROUP: IV

SEX: DEATH TYPE: Sacrifice?ScheduTed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appTicabIe

HISTOMORPHOLOGIC OBSERVATIONS:

LIVER: infTammation, chronic, focaT/muTtifocaT (minimaT)
hypertrophy, hepatoceTIuTar, centrilobular (minimaT)

NODE, MEDIASTINAL: (mde)

NODE, SUBMANDIBULAR: hyperpTasia, (mde)

MAMMARY GLAND: hyperpTasia, physioTogicaT

SPLEEN: hematopoiesis, extrameduITary, increased (minimaT)

UTERUS: macrophages, pigmented (mde)

THE FOLLOWING WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM

COLON DUODENUM HEART ILEUM

JEJUNUM KIDNEYS LUNG NERVE, SCIATIC
OVARIES PARATHYROID PATCH RECTUM

SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR SPINAL CORD, THORACIC STOMACH

THYMUS THYROID TRACHEA URINARY BLADDER
VAGINA

End of Record? 17689

II-73

41830271PAGE 

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST

STUDY NUMBER T-7599

Appendix II
IndividuaI AnimaI Gross and HistomorphoIogy Data

 

 

ANIMAL NUMBER: 17691 DOSE GROUP: IV

SEX: DEATH TYPE: Sacrifice-ScheduTed
GROSS OBSERVATIONIS): HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabIe

HISTOMORPHOLOGIC OBSERVATIONS:

LIVER: infTammation, chronic, focal/muItifocaT (minimaI)
hypertrophy, hepatoceTIuTar, centriTobuTar (minimaT)

NODE, SUBMANDIBULAR: hyperpTasia, (minimaI)

MAMMARY GLAND: hyperpTasia, physioTogicaI

THYROID: uItimobranchiaT body/cyst

UTERUS: macrophages. pigmented (moderate)

THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM

COLON DUODENUM HEART ILEUM

JEJUNUM KIDNEYS LUNG NODE, MEDIASTINAL
NERVE, SCIATIC OVARIES PARATHYROID PATCH

RECTUM SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR SPINAL CORD, THORACIC
SPLEEN THYMUS TRACHEA

URINARY BLADDER VAGINA

End of Record? 17691

II-74

 1?105

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaI Animal Gross and HistomorphoIogy Data

 

 

ANIMAL NUMBER: 17692 DOSE GROUP: IV

SEX: DEATH TYPE: Sacrifice?ScheduIed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabIe



HISTOMORPHOLOGIC OBSERVATIONS:

KIDNEYS: mineralization, muItifocaI (minimaI)

LIVER: hypertrophy, hepatoceITuTar, centriIobuIar (minimaI)
NODE, MEDIASTINAL: (mild)

NODE, SUBMANDIBULAR: hyperplasia, (moderate)
MAMMARY GLAND: hyperpTasia, physioIogicaI

TWWB: aheMw(m1w

THE FOLLOWING WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM

COLON DUODENUM HEART ILEUM

JEJUNUM LUNG NERVE, SCIATIC OVARIES

PARATHYROID PATCH RECTUM SPINAL CORD, CERVICAL
SPINAL CORD, LUMBAR SPINAL CORD, THORACIC SPLEEN STOMACH

THYROID TRACHEA URINARY BLADDER UTERUS

VAGINA

End of Record- 17692

II-75

418-0271PAGE 

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418-027
STUDY NUMBER T-7599

Appendix II
IndividuaI AnimaT Gross and HistomorphoTogy Data

 

 

ANIMAL NUMBER: 17696 DOSE GROUP: IV

SEX: DEATH TYPE: Sacrifice-ScheduIed
GROSS HISTOMORPHOLOGIC OBSERVATIONYS):
THYMUS: Tissue not avaiTabTe

 

HISTOMORPHOLOGIC OBSERVATIONS:

HEART: ianammation, subacute, focal/muItifocaI (minimaT)
NODE, SUBMANDIBULAR: hyperpTasia, Iymphocytic/pTasmacytic (mde)
MAMMARY GLAND: hyperpIasia, physioTogicaT

THYROID: uTtimobranchiaI body/cyst

UTERUS: ianammation, endometrium, diffuse (mde)

macrophages, pigmented (moderate)
distention, Tumen (moderate)

THE FOLLOWING WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM

COLON DUODENUM ILEUM JEJUNUM

KIDNEYS LIVER LUNG NODE, MEDIASTINAL
NERVE, SCIATIC OVARIES PARATHYROID PATCH

RECTUM SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR SPINAL CORD, THORACIC
SPLEEN STOMACH TRACHEA URINARY BLADDER

VAGINA

NOT AVAILABLE FOR EVALUATION:
THYMUS

End of Record- 17696

II-76

 L107

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST

PROTOCOL 418~027
STUDY NUMBER T-7599

Appendix II

IndividuaT AnimaT Gross and HistomorphoTogy Data

ANIMAL NUMBER: 17699
SEX: 

DOSE GROUP: IV
DEATH TYPE: Sacrifice-ScheduTed

 

GROSS 

GENERAL: No gross changes.

HISTOMORPHOLDGIC OBSERVATIONS:

KIDNEYS:
LIVER:

SUBMANDIBULAR:
MAMMARY GLAND:

SPLEEN:

THYMUS:

THYROID:

UTERUS:

HISTOMORPHOLOGIC 

Not appTicabTe

mineraTization, muTtifocaT (minimal)

infTammation, chronic. focal/multifocal (minimaT)
hypertrophy, hepatoceTTuTar, centriTobuTar (minimaT)
hyperpTasia, (moderate)
hyperpTasia, physiologicaT

hematopoiesis, extrameduTTary, increased (minimaT)
ahe?w(Mnmd)

uTtimobranchiaT body/cyst

macrophages, pigmentedi(moderate)

THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM

DUODENUM HEART ILEUM

JEJUNUM LUNG NODE, MEDIASTINAL NERVE, SCIATIC
OVARIES PARATHYROID PATCH RECTUM

SPINAL CORD, CERVICAL SPINAL CORD. LUMBAR SPINAL CORD, THORACIC STOMACH
TRACHEA URINARY BLADDER VAGINA

End of Record? 17699

II-77

 I408

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST

STUDY NUMBER 

Appendix II
IndividuaI Animal Gross and HistomorphoIogy Data

ANIMAL NUMBER: 17711
SEX: 

DOSE GROUP: IV

DEATH TYPE: SacrificeeSchedUIed

 

GROSS 

GENERAL: No gross changes.

HISTOMORPHOLOGIC 

Not appIicabIe

HISTDMORPHOLDGIC OBSERVATIONS:

KIDNEYS: vacuoTation;
LIVER: hypertrophy,
vacuoTation,
MAMMARY GLAND: hyperpIasia, physioIogicaI
SPLEEN: atrophy (miId)
THYMUS: atrophy (moderate)
UTERUS: hemorrhage, endometrium (miId)
macrophages, pigmented (moderate)
VAGINA: ianammation, acute (moderate)

mucification (marked)



THE WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM)
COLON DUODENUM

JEJUNUM LUNG

NERVE, SCIATIC OVARIES

RECTUM SPINAL CORD. CERVICAL
STOMACH THYROID

BRAIN
HEART

NODE, MEDIASTINAL

PARATHYROID
SPINAL CORD. LUMBAR
TRACHEA

corticaI tubuIar epithelium (miId)
hepatooeITuIar, centriIobuIar (miId)
periporta) (minimaI)

CECUM

ILEUM

NODE, SUBMANDIBULAR
PATCH

SPINAL CORD, THORACIC
URINARY BLADDER

End of Recorde 17711

II-78

 1?109

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418*027
STUDY NUMBER 

Appendix II
Individua] AnimaT Gross and HistomorphoIOQy Data

 

 

ANIMAL NUMBER: 17712 DOSE GROUP: IV

SEX: DEATH TYPE: Sacrifice-ScheduIed
GROSS HISTOMORPHOLOGIC 
TAIL: Bent. No microscopic change to correlate

HISTOMORPHOLOGIC OBSERVATIONS:

LIVER: ianammation, chronic. focal/muItifocaT (minimaT)
hypertrophy, hepatoceTTuTar, centriIobuIar (minimaI)

NODE, SUBMANDIBULAR: hyperpTasia, (mde)

MAMMARY GLAND: hyperpIasia, physiologicaT

TAIL: No microscopic change to correIate

THYMUS: atrophy (minimal)

UTERUS: macrophages. pigmented (mde)

THE FOLLOWING WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM

COLON DUODENUM HEART ILEUM

JEJUNUM KIDNEYS LUNG NODE, MEDIASTINAL
NERVE, SCIATIC OVARIES PARATHYROID PATCH

RECTUM SPINAL CORD, CERVICAL SPINAL CORD. LUMBAR SPINAL CORD, THORACIC
SPLEEN STOMACH TAIL THYROID

TRACHEA URINARY BLADDER VAGINA

End of Record? 17712

II-79

 L110

ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 7599.7
WITH THE TOXICITY SCREENING TEST
PROTOCOL 418?027
STUDY NUMBER T-7599

Appendix II
IndividuaI AnimaI Gross and HistomorpHOTOQy Data

 

 

ANIMAL NUMBER: 17714 DOSE GROUP: IV

SEX: DEATH TYPE: Sacrifice?ScheduIed
GROSS HISTOMORPHOLOGIC 
GENERAL: No gross changes. Not appIicabIe



HISTOMORPHOLOGIC OBSERVATIONS:

LIVER: hypertrophy, hepatoceTTuTar, centriTobuTar (mde)
MAMMARY GLAND: hyperpTasia, physioIogjcaT

SPLEEN: hematopoiesis, extrameduIIary, increased (minimaT)
THYMUS: atrophy (miId)

THYROID: uTtimobranchiaI body/cyst

UTERUS: thrombus

macrophages, pigmented (moderate)

THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:

ADRENAL GLANDS BONE MARROW (STERNUM) BRAIN CECUM

COLON DUODENUM HEART ILEUM

JEJUNUM KIDNEYS LUNG NODE, SUBMANOIBULAR
NERVE, SCIATIC OVARIES PARATHYROID PATCH

RECTUM SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR SPINAL CORD, THORACIC
STOMACH TRACHEA URINARY BLADDER VAGINA

NOT AVAILABLE FOR EVALUATION:
NODE, MEDIASTINAL

End of Record- 17714

II-SO

APPENDIX 

HEMATOLOGY AND CLINICAL CHEMISTRY REPORTS

 K?l

Study Report for Hematology

 

INDIVIDUAL ANIMAL REPORT BY GROUP
PERIOD: TERMINAL

 

STUDY ID: ARGUS #418-027 SEX: MALE
STUDY NO: 060-063

 

 

 

 

Animal ID NBC RBC HGB HCT MCV MCH MCHC PLT
MM MM CU MICRONS PICO GRAMS MM
GROUP: 1-M
17608 13.5 7.61 15.7 43.5 57.1 20.6 36.1 1094
17618 10.9 8.24 16.3 46.8 56.8 19.8 34.8 1406
17630 12.6 7.67 15.7 43.3 56.5 20.5 36.3 1174
17631 16.6 7.34 15.8 42.4 57.7 21.5 37.3 1126
17639 20.0 6.89 15.7 42.4 61.6 22.8 37.0 1185
MEAN 14.7 7.55 15.8 43.7 57.9 21.0 36.3 1197
SD 3.61 0.493 0.26 1.82 2-09' 1.15 0.97 122GROUP: Z-M
17634 19.1 8.05 16.3 45.0 55.9 20.2 36.2 1174
17635 16.9 7.98 16.3 44.0 55.2 20.4 37.0 1237
17638 16.5 7.45 15.5 42.1 56.5 20.8 36.8 1096
17642 18-3 7.29 15.5 41.9 57.5 21.3 37.0 1204
17643 23.9 7.01 14.6 39.5 56.3 20.8 '37.0 1147
MEAN 18.9 7.56 15.6 42.5 56.3 20.7 36.8 1172
SD 2.96 0.448 0.71 2.12 0.84 0.42 0.35 54GROUP: 3-M
17620 13.6 7.17 15.6 40.5 56.5 21.8 38.5 1038
17623 20.7 7.74 15.6 43.3 55.9 20.2 36.0 1326
17627 13.1 7.21 14.9 41.6 57.7 20.7 35.8 1030
17628 16.5 6.95 14.9 41.6 59.8 21.4 35.8 1219
17633 12.7 7.30 14.8 39.9 54.7 20.3 37.1 1475
MEAN 15.3 7.27 15.2 41.4 56.9 20.9 36.6 1218
SD 3.36 0.291 0.40 1.30 1.94 0.70 1.17 190LABCAT HE4.43 

 
Study Report for Hematology

 

INDIVIDUAL ANIMAL REPORT BY GROUP
PERIOD: TERMINAL

 

STUDY ID: ARGUS #418-027 SEX: MALE
STUDY NO: 060?063

 

Animal ID NBC RBC HGB HCT MCV MCH MCHC PLT

 

MM MM 1 cu MICRONS P1c0 GRAMS MM

GROUP: 4-M
17621 17.2 7.54 16.1 43.5 57.7 21.4 37.0 1154
17622 11.0 6.87 14.7 38.6 56.2 21.4 38.1 1352
17625 14.5 7.24 14.5 41.0 56.6 20.0 35.4 1189
17629 22.3 7.25 14.9 39.4 54.3 20.6 37.8 1492
17636 31.3 6.94 15.5 40.2 57.9 22.3 38.6 1226
MEAN 19.3 7.17 15.1 40.5 56.5 21.1 37.4 1283
so 7.90 0.270 0.65 1.88 1.44 0.88 1.25 138LABCAT HE4.43 ZZ-MAY-ZOOZ

Study Report for Hematology

INDIVIDUAL ANIMAL REPORT BY GROUP
PERIOD: TERMINAL

418-0271PAGE 

 

STUDY ID: ARGUS #418-027

 

 

 

 

 

SEX: FEMALE
STUDY NO: 060-063
AnimaL ID NBC RBC HGB HCT MCV MCH MCHC PLT
MM MM CU MICRONS PICO GRAMS MM
GROUP: 
17694 16.8 5.72 14.2 37.7 65.9 24.8 37.7 1575
17703 23.3 5.54 13.1 35.3 63.7 23.6 37.1 1648
17681 19.8 6.55 14.5 38.6 59.0 22.1 37.6 1583
17690 20.9 5.63 13.8 35.6 63.2 24.5 38.8 1329
17695 MEAN 20.2 5.86 13.9 36.8 63.0 23.8 37.8 1534
SD 2.70 0.466 0.61 1.61 2.88 1.21 0.72 140GROUP: Z-F
17675 16.9 6.10 14.1 37.8 61.9 23.1 37.3 1381
17679 13.3 6.32 14.7 39.3 62.2 23.3 37.4 1259
17688 14.5 5.72 14.7 39.2 68.5 25.7 37.5 128
17698 16.8 6.09 14.2 37.9 62.3 23.3 37.5 1273
17684 12.8 5.79 13.6 36.7 63.3 23.5 37.1 692
MEAN 14.9 6.00 14.3 38.2 63.6 23.8 37.4 947
SD 1.92 0.246 0.46 1.08 2.77 1.08 0.17 531GROUP: 3-F
17693 24.0 5.26 13.4 34.1 64.8 25.5 39.3 2292
17697 16.3 5.71 13.2 35.3 61.8 23.1 37.4 1874
17700 18.0 6.80 14.9 41.1 60.4 21.9 36.3 1375
17701 21.2 5.81 13.6 36.0 62.0 23.4 37.8 1554
17687 21.2 5.19 12.7 33.2 64.0 24.5 38.3 1101
17709 20.6 5.85 14.2 38.0 65.0 24.3 37.4 1393
MEAN 20.2 5.77 13.7 36.3 63.0 23.8 37.8 1598
SD 2.71 0.578 0.78 2.88 1.87 1.26 1.01 423Clotted

LABCAT HE4.43

22-MAY-2002

 
Study Report for Hematology

 

INDIVIDUAL ANIMAL REPORT BY GROUP
PERIOD: TERMINAL

 

 

 

FEMALE
STUDY NO: 060-063
AnimaL ID NBC RBC HGB HCT MCV MCH MCHC PLT
MM MM 2 CU MICRONS PICO GRAMS MM
GROUP: 
17685 21.6 5.91 13.2 35.3 59.8 22.3 37.4 1570
17689 18.6 5.57? 12.9 33.8 60.6 23.2 38.2 1803
17692 25.4 5.37 12.5 30.8 57.4 23.3 40.6 1230
17691 20.8 6.21 14.1 36.5 58.8 22.7 38.6 1584
MEAN 21.6 5.76 13.2 34.1 59.2 22.9 38.7 1547
SD 2.83 0.371 0.68 2.46 1.38 0.46 1.36 236LABCAT HE4.43 - 22-MAY-2002

 
Study Report for Hematology

 

INDIVIDUAL ANIMAL. REPORT BY GROUP
PERIOD: TERMINAL

 

STUDY ID: ARGUS #418-027

 

 

 

 

SEX: MALE
STUDY NO: 060-063
Animal ID PT APTT MPV NRBC Segmented Bands Monocytes
seconds seconds CU MICRONS COUNT MM MM MM MM
GROUP: 1-M
17608 14.3 25.1 9.0 0 11.2 2.0 0.0 0.1
17618 14.3 26.6 9.0 0 8.8 1.9 0.0 0.1
17630 14.0 25.3 9.6 0 10.3 2.0 0.0 0.1
17631 15.5 27.5 9.5 0 14.9 1.5 0.0 0.2
17639 13.8 22.5 8.9 0 17.8 2.2 0.0 0.0
MEAN 14.4 25.4 9.2 0 12.6 1.9 0.0 0.1
so 0.66 1.89 0.32 0.0 3.67 0.26 0.00 0.GROUP: Z-M
17634 13.4 22.4 9.6 0 17.0 1.9 0.0 0.0
17635 14.3 27.9 9.5 0 12.7 4.1 0.0 0.2
17638 13.3 24.7 9.3 0 13.9 2.1 0.0 0.2
17642 13.7 27.0 9.1 0 14.6 2.9 0.0 0.5
17643 13.7 27.6 11.1 0 20.8 2.9 0.0 0.0
MEAN 13.7 25.9 9.7 0 15.8 2.8 0.0 0.2
so 0.39 2.33 0.79 0.0 3.21 0.87 0.00 0.GROUP: 3-M
17620 14.4 26.1 8.9 0 11.4 2.0 0.0 0.0
17623 14.1 27.9 11.0 0 18.2 2.3 0.0 0.0
17627 14.6 24.2 8.7 0 10.9 1.8 0.0 0.0
17628 14.4 28.8 8.7 0 15.0 1.2 0.0 0.2
17633 15.9 23.9 10.1 0 10.9 1.7 0.0 0.1
MEAN 14.7 26.2 9.5 0 13.3 1.8 0.0 0.1
SD 0.70 2.18 1.03 0.0 3.24 0.41 0.00 0.LABCAT HE4.43 ZZ-MAY-ZOOZ

 K56
Study Report for Hematology

 

 

INDIVIDUAL ANIMAL REPORT BY GROUP
PERIOD: TERMINAL

 

STUDY ID: ARGUS #418?027 SEX: MALE
STUDY NO: 060-063

 

AnimaL 1D . PT APTT MPV NRBC Segmented Bands Monocytes

 

seconds seconds CU MICRONS COUNT MM MM MM MM
GROUP: 
17621 16.0 30.7 9.5 0 15.8 1.0 0.0 0.3
17622 13.5 26.1 8.4 0 8.7 2.0 0.0 0.0
17625 14.9 27.3 9.5 0 13.1 1.5 0.0 o_o
17629 14.0 24.0 9.8 0 19.6 2.5 0.0 0.0
17636 14.4 25.6 8.4 13.1 18.2 0.0 0.0
MEAN 14.6 26.7 9.1 0 14.1 5.0 0.0 0.1
SD 0.96 2.51 0.67 0.0 4.01 7.38 0.00 0.LABCAT HE4.43 

 
Study Report for Hematology

 

INDIVIDUAL ANIMAL REPORT BY GROUP
PERIOD: TERMINAL

 

STUDY ID: ARGUS #418-027 SEX:

 

 

 

 

 

FEMALE
STUDY N0: 060'063
AnimaL ID PT APTT MPV NRBC Segmented Bands Monocytes
seconds seconds CU MICRONS COUNT MM MM MM MM
GROUP: 1-F
17694 12.8 18.2 7.0 13.6 2.7 0.0 0.3
17703 13.3 24.0 7.0 17.0 5.8 0.0 0.2
17681 13.9 22.2 7.9 0 15.2 3.8 0.0 0.8
17690 13.5 21.6 8.9 0 17.6 3.1 0.0 0.0
17695 13.2 19.3 CL CL -- 
MEAN 13.3 21.1 7.7 0 15.9 3.9 0.0 0.3
SD 0.40 2.32 0.91 0.0 1.81 1.38 0.00 0.GROUP: 2-F
17675 12.8 19.3 9.2 0 14.4 2.2 0.0 0.3
17679 13.6 ?15.5 7.8 0 10.6 2.7 0.0 0.0
17688 13.4 18.2 12.3 0 11.9 2.6 0.0 0.0
17698 13.2 19.9 7.5 0 15.6 0.8 0.0 0,3
17684 CL . CL 7.3 0 10.6 1.9 0.0 0.3
MEAN 13.3 18.2 8.8 0 12.6 2.0 0.0 0.2
SD 0.34 1.95 2.08 0.0 2.28 0.76 0.00 0.GROUP: 3-F
17693 13.3 21.5 6.8 0 17.8 5.5 0.0 0.7
17697 13.2 19.7 7.6 0 13.7 2.6 0.0 0.0
17700 13.2 23.6 8.4 0 12.2 5.4 0.0 0.0
17701 12.9 17.7 7.3 0 18.7 2.3 0.0 0.2
17687 13.3 27.3 8.2 0 16.1 5.1 0.0 0.0
17709 CL CL 0 14.6 5.6 0.0 0.2
MEAN 13.2 22.0 8.0 0 15.5 4.4 0.0 0.2
SD 0.16 3.70 1.02 0.0 2.48 1.54 0.00 0.Data Unavailable CL CLotted

LABCAT HE4.43 ZZ-MAY-ZOOZ

 
Study Report for Hematology

 

INDIVIDUAL ANIMAL REPORT BY GROUP
PERIOD: TERMINAL

 

STUDY ID: ARGUS #418?027 SEX:

 

 

FEMALE
STUDY NO: 060-063
Animal ID PT APTT MPV NRBC Segmented Bands Monocytes
seconds seconds CU MICRONS COUNT MM MM MM MM
GROUP: 
17685 13.0 25.3 9.0 0 13.0 6.9 0.2 1.3
17689 13.1 14.9 7.7 13.6 3.3 0.2 1.5
17692 13.5 20.8 7.9 0 22.1 2.5 0.0 0.5
17691 13.3 18.2 8-0 0 16.8 3.5 0.0 0.4
MEAN 13.2 19.8 8.2 0 16.4 4.1 0.1 0.9
SD 0.22 4.39- 0.58 0.0 4.17 1.95 0.12 0.LABCAT HE4.43 ZZFMAY-2002

 
Study Report for Hematology

INDIVIDUAL ANIMAL REPORT BY GROUP
PERIOD: TERMINAL

STUDY ID: ARGUS #418-027
STUDY NO: 060-063

SEX: MALE

 

AnimaL 1D Eos?inophiL Basophils AbnormaL Other
MM MM MM MM

 

 

 

GROUP: 1-M
17608 0.1 0.0 0.0 0.0
17618 0.1 0.0 0.0 0.0
17630 0.1 0.0 0.0 0.0
17631 0.0 0.0 0.0 0.0
17639 0.0 0.0 0.0 0.0
MEAN 0.1 0.0 0.0 0.0
so 0.05 0.00 0.00 0.00
5 5 5 5

GROUP: 2-M
17634 0.2 0.0 0.0 0.0
17635 0.0 0.0 0.0 0.0
17638 0.3 0.0 0.0 0.0
17642 0.2 0.0 0.0 0.0
17643 0.2 0.0 0.0 0.0
MEAN 0.2 0.0 0.0 0.0
so 0.11 0.00 0.00 0.00
5 5

GROUP: 3-M
17620 0.1 0.0 0.0 0.0
17623 0.2 0.0 0.0 0.0
17627 0.4 0.0 0.0 0.0
17628 0.2 0.0 0.0 0.0
17633 0.0 0.0 0.0 0.0
MEAN 0.2 0.0 0.0 0.0
50 0.15 0.00 0.00 0.00
5 5 5

 

LABCAT HE4.43 

 
Study Report for Hematology

 

ANIMAL REPORT BY GROUP
PERIOD: TERMINAL

 

STUDY ID: ARGUS #418?027
STUDY NO: 060-063

SEX: MALE

 

AnimaL ID Eosinophil Basophils Abnormal Other
MM MM MM MM

 

GROUP: 4-H
17621 0.0 0.0 0.0 0.0
17622 0.3 0.0 0.0 0.0
17625 0.0 0.0 0.0 0.0
17629 0.2 0.0 0.0 0.0
17636 0.0 0.0 0.0 0.0
MEAN 0.1 0.0 0.0 0.0
SD 0.14 0.00 0.00 0.00
5 5 5 

 

LABCAT HE4.43 

 K?ll

Study Report for Hematology

 

INDIVIDUAL ANIMAL REPORT BY GROUP
PERIOD: TERMINAL

 

STUDY ID: ARGUS #418-027
STUDY NO: 060-063

SEX: FEMALE

 

Animal ID Eosinophil Basophils Abnormal Other
MM MM MM MM

 

 

 

GROUP: 1-F
17694 0.0 0.0 0.2 0.0
17703 0.2 0.0 0.0 0.0
17681 0.0 0.0 0.0 0.0
17690 0.2 0.0 0.0 0.0
17695 
MEAN 0.1 0.0 0.1 0.0
so 0.12 0.00 0.10 0.00
4 4 4 A

GROUP: 2-F
17675 0.0 0.0 0.0 0.0
17679 0.0 0.0 0.0 0.0
17688 0.0 0.0 0.0 0.0
17698 0.0 0.0 0.0 0.0
17684 0.0 0.0 0.0 0.0
MEAN 0.0 0.0 0.0 0.0
so 0.00 0.00 0.00 0.00
5 

GROUP: 3-F
17693 0.0 0.0 0.0 0.0
17697 0.0 0.0 0.0 0.0
17700 0.4 0.0 0.0 0.0
17701 0.0 0.0 0.0 0.0
17687 0.0 0.0 0.0 0.0
17709 0.2 0.0 0.0 0.0
MEAN 0.1 0.0 0.0 0.0
so 0.17 0.00 0.00 0.00
6 6 6 6

 

- Data Unavailable

LABCAT HE4.43 22-MAY-2002

Study Report for Hematology



 

INDIVIDUAL ANIMAL REPORT BY GROUP
PERIOD: TERMINAL

 

STUDY ID: ARGUS #418-027
STUDY NO: 060-063

SEX: FEMALE

 

 

AnimaL ID EosinophiL BasophiLs AbnormaL Other
MM MM MM MM

GROUP: 
17685 0.0 0.0 0.2 0.0
17689 0.0 0.0 0.0 0.0
17692 0.0 0.0 0.3 0.0
17691 0.0 0.0 0.0 0.0
MEAN 0.0 0.0 0.1 0.0
SD 0.00 0.00 0.15 0.00
4 4 4 4

 

LABCAT HE4.43

22-MAY-2002

418?027 
Study Report for Hematology

SUMMARY REPORT
PERIOD: TERMINAL

 

STUDY ID: ARGUS #418-027

 

 

SEX: MALE
STUDY NO: 060?063

NBC RBC HGB HCT MCV MCH MCHC PLT PT

UNITS: MM MM CU MICRONS PICO GRAMS MM seconds

Group: 1-M

MEAN 14.7 7.55 15.8 43.7 57.9 21.0 36.3 1197 14.4
SD 3.61 0.493 0.26 1.82 2.09 1.15 0.97 122.5 0.Group: 2-M

MEAN 18.9 7.56 15.6 42.5 56.3 20.7 36.8 1172 13.7
SD 2.96 0.448 0.71 2.12 0.84 0.42 0.35 54.0 0.Group: 

MEAN 15.3 7.27 15.2 41.4 56.9 20.9 36.6 1218 14.7
SD 3.36 0.291 0.40 1.30 1.94 0.70 1.17 190.7 0.Group: 4-M

MEAN 19.3 7.17 15.1 40.5 56.5 21.1 37.4 1283 14.6
SD 7.90 0.270 0.65 1.88 1.44 0.88 1.25 138.9 0.LABCAT HE4.43 . 22-MAY-2002

 
Study Report for Hematology

 

SUMMARY REPORT
PERIOD: TERMINAL

 

STUDY ID: ARGUS #418-027 . SEX: MALE
STUDY NO: 060-063

 

 

APTT MPV NRBC Segmented Bands Monocytes EosinophiL BasophiLs

UNITS: seconds CU MICRONS COUNT MM MM MM MM MM MM

Group: 

MEAN . 25.4 9.2 0 121.89 0.32 0.0 3.67 0.26 0.00 0.07 0.05 0.Group: 

MEAN 25.9 9.7 0 152.33 0.79 0.0 3.21 0.87 0.00 0.20 0.11 0.Group: 3-M

MEAN 26.2 9.5 0 132.18 1.03 0.0 3.24 0.41 0.00 0.09 0.15 0.Group: 4-M

MEAN 26.7 9.1 0 142.51 0.67 0.0 4.01 7.38 0.00 0.13 0.14 0.LABCAT HE4.43 

Study Report for Hematology

K-15

 

SUMMARY REPORT
PERIOD: TERMINAL

 

STUDY ID: ARGUS #418-027
STUDY N0: 060?063

SEX: MALE

 

 

AbnormaL Other

UNITS: MM MM

Group: 

MEAN 0.0 0.0
SD 0.00 0.00
5 5

Group: 2-M

MEAN 0.0 0.0
SD 0.00 0.00
5 5

Group: 3-H

MEAN 0.0 ?0.0
SD 0.00 0.00
5 5

Group: 4-H

MEAN 0.0 0.0
SD 0.00 0.00
5 

 

LABCAT HE4.43

22-MAY-2002

 
Study Report for Hematology

 

SUMMARY REPORT
PERIOD: TERMINAL

 

STUDY ID: ARGUS #418-027

 

 

SEX: FEMALE
STUDY NO: 060-063

NBC RBC HGB HCT MCV MCH PLT PT

UNITS: MM MM CU MICRONS PICO GRAMS MM seconds

Group: 1-F

MEAN 20.2 5.86 13.9 36.8 63.0 23.8 37.8 1534 13.3
SD 2.70 0.466 0.61 1.61 2.88 1.21 0.72 140.4 0.Group: 

MEAN 14.9 6.00 14.3 38.2 63.6 23.8 37.4 947 13.3
SD 1.92 0.246 0.46 1.08 2.77 1.08 0.17 531.0 0.Group: 3-F

MEAN 20.2 5.77 13.7 36.3 63.0 23.8 37.8 1598 13.2
SD 2.71 0.578 0.78 2.88 1.87 1.26 1.01 423.9 0.Group: 4-F

MEAN 21.6 5.76 13.2 34.1 59.2 22.9 38.7 1547 ?13.2
SD 2.83 0.371 0.68 2.46 1.38 0.46 1.36 236.6 0.LABCAT HE4.43 ZZ-MAY-ZOOZ

 
Study Report for Hematology

 

SUMMARY REPORT
PERIOD: TERMINAL

 

STUDY ID: ARGUS #418-027

 

 

SEX: FEMALE
STUDY N0: 060-063

APTT MPV NRBC Segmented Bands Monocytes EosinophiL BasophiLs

UNITS: seconds CU MICRONS COUNT MM MM MM MM MM MM

Group: 1-F

MEAN 21.1 7.7 0 152.32 0.91 0.0 1.81 1.38 0.00 0.34 0.12 0.Group: 2-F

MEAN 18.2 8.8 0 12.6 2.0 0.0 0.2 -0.0 0.0
SD 1.95 2.08 0.0 2.28 0.76 0.00 0.16 0.00 0.Group: 3-F

MEAN 22.0 8.0 0 153.70 1.02 0.0 2.48 1.54 0.00 0.27 0.17 0.Group: 

MEAN 19.8 8.2 0 164.39 0.58 0.0 4.17 1.95 0.12 0.56 0.00 0.LABCAT HE4.43 ZZ-MAY-ZOOZ

Study Report for Hematology

418-0272PAGE 

 

SUMMARY REPORT
PERIOD: TERMINAL

 

STUDY ID: ARGUS #418?027
STUDY NO: 060-063

SEX: FEMALE

 

 

AbnormaL Other

UNITS: MM MM
Group: 1-F

MEAN 0.1 0.0

SD 0.10 0.00

4 4
Group: 2-F

MEAN 0.0 0.0

SD 0.00 0.00

5
Group: 3-F

MEAN 0.0 0.0

SD 0.00 0.00

6 6
Group: 

MEAN 0.1 0.0

SD 0.15 0.00

4 4

 

LABCAT HE4.43

22-MAY-2002

STUDY ID: ARGUS #418'027
STUDY NO: 060-063

GROUP: 1-M

Study Report for Hematology

WHITE DIFFERENTIAL DATA



 

 

SEX: MALE
AnimaL ID TERMINAL
CNT ABS
17608 NucLeated Red Cells 0
83 11.2
Segmented NeutrophiLs 15 2.0
Bands 0 0.0
Monocytes 1 0.1
EosinophiLs 1 0.1
Basophils 0 0.0
AbnormaL 0 0.0
Other 0 0:0
NBC 13.5
17618 Nucleated Red 0
81 8.8
Segmented Neutrophils 17 1.9
Bands 0 0.0
Monocytes 1 0.1
Eosinophils 1 0.1
BasophiLs 0 0.0
Abnormal 0 0.0
Other 0 0.0
NBC 10.9
17630 NucLeated Red 0
82 10.3
Segmented NeutrophiLs 16 2.0
Bands 0 0.0
Monocytes 1 0.1
EosinophiLs 1 0.1
Basophils 0 0.0
AbnormaL 0 0.0
Other 0 0.0
NBC 12.6

 

LABCAT HE4.43

22-MAY-2002

 
Study Report for Hematology

WHITE DIFFERENTIAL DATA

STUDY ID: ARGUS #418-027

 

 

STUDY No: 060-063 GROUP: sex; MALE
AnimaL ID TERMINAL
CNT ABS
17631 NucLeated Red 0
90 14.9
Segmented NeutrophiLs 9 1.5
Bands 0 0.0
Monocytes 1 0.2
Eosinophils 0 0.0
BasophiLs 0 0.0
Abnormal 0 0.0
Other 0 0.0
NBC 16.6
17639 NucLeated Red 0
89 17.8
Segmented NeutrophiLs 11 2.2
Bands 0 0.0
Monocytes 0 0.0
EosinophiLs 0.0
BasophiLs 0 0.0
AbnormaL 0 0.0
Other 0 . 0.0
NBC 20.0

 

LABCAT HE4.43 22-MAY-2002

Study Report for Hematology

WHITE DIFFERENTIAL DATA

Ker

 

STUDY ID: ARGUS #418-027

 

 

STUDY NO: 060-063 GROUP: 2-H SEX: MALE
Animal ID TERMINAL
CNT ABS

17634 Nucleated Red Cells 0
89 17.0
Segmented Neutrophils 10 1.9
Bands 0 0.0
Monocytes 0 0.0
Eosinophils 1 0.2
Basophils 0 0.0
Abnormal 0 0.0
Other 0 0.0
NBC 19.1

17635 Nucleated Red Cells 0
75 12.7
Segmented Neutrophils 24 4.1
Bands 0 0.0
Monocytes 1 0.2
Eosinophils 0 0.0
Basophils 0 0.0
Abnormal 0 0.0
Other 0 0.0
NBC 16.9

17638 Nucleated Red Cells 0
84 13.9
Segmented Neutrophils 13 2.1
Bands 0 0.0
Monocytes 1 0.2
Eosinophils 2 0.3
Basophils 0 0.0
Abnormal 0 0.0
Other 0 0.0
NBC 16.5

 

LABCAT HE4.43

22-MAY-2002

STUDY ID: ARGUS #418?027

Study Report for Hematology

WHITE DIFFERENTIAL DATA



 

 

STUDY N0: 060-063 GROUP: 55x; MALE
AnimaL ID TERMINAL
CNT ABS
17642 Nucleated Red 
80 14.6
Segmented NeutrophiLs 16 2.9
Bands 0 0.0
Monocytes 3 0.5
Eosinophils 1 0.2
BasophiLs 0 0.0
AbnormaL 0 0.0
Other 0 0.0
NBC 18.3
17643 Nucleated Red 
87 20.8
Segmented Neutrophils 12 2.9
Bands 0 0.0
Monocytes 0 0.0
EosinophiLs 1 0.2
Basophils 0 0.0
Abnormal 0 0.0
Other 0 0.0
NBC 23.9

 

LABCAT HE4.43



STUDY ID: ARGUS #418?027
STUDY NO: 060-063

AnimaL ID

17620

17623

17627

GROUP: 3-H

NucLeated Red 


Segmented Neutrophils
Bands

Monocytes

Eosinophils

BasophiLs

Abnormal 
Other

NBC

Nucleated Red CelLs


Segmented NeutrophiLs
Bands

Monocytes

Eosinophils

Basophils

AbnormaL 
Other

NBC

Nucleated Red 


Segmented NeutrophiLs
Bands

Monocytes

Eosinophils

BasophiLs

Abnormal 
Other

NBC

Study Report for Hematology

WHITE DIFFERENTIAL DATA

TERMINAL

CNT

11



83
14

0000400

ABS

(18.



20.

10.

0000007ha.?

Ka23

SEX: MALE

 

LABCAT HE4.43

22-NAY-2002

STUDY ID: ARGUS #418-027

Study Report for Hematology

WHITE DIFFERENTIAL DATA



 

 

STUDY NO: 060-063 GROUP: 3-H SEX: MALE
Animal ID TERMINAL
CNT ABS
17628 Nucleated Red Cells 0
91 15.0
Segmented Neutrophils 7 1.2
Bands 0 0.0
Monocytes 1 0.2
Eosinophils 1 0.2
Basophils 0 0.0
Abnormal 0 0.0
Other 0 0.0
NBC 16.5
17633 Nucleated Red Cells 0
86 10.9
Segmented Neutrophils 13 1.7
Bands 0 0.0
Monocytes 1 0.1
Eosinophils 0 0.0
Basophils 0 0.0
Abnormal 0 0.0
Other 0 0.0
HBC 12.7

 

LABCAT HE4.43

22-MAY-2002

 
Study Report for Hematology

WHITE DIFFERENTIAL DATA

STUDY ID: ARGUS #418-027
STUDY N0: 060-063 GROUP: A-M

 

 

 

SEX: MALE
Animal ID TERMINAL
CNT ABS
17621 Nucleated Red Cells 0
92 15.8
Segmented Neutrophils 6 1.0
Bands 0 0.0
Monocytes 2 0.3
Eosinophils 0 0.0
Basophils 0 0.0
Abnormal 0 0.0
Other 0 0.0
NBC 17.2
17622 Nucleated Red Cells 0
79 8.7
Segmented Neutrophils 18 2.0
Bands 0 0.0
Monocytes 0 0.0
Eosinophils 3 0.3
Basophils 0 0.0
Abnormal 0 0.0
Other 0 0.0
HBC 11.0
17625 Nucleated Red Cells 0
90 13.1
Segmented Neutrophils 10 1.5
Bands 0 0.0
Monocytes 0 0.0
Eosinophils 0 0.0
Basophils 0 0.0
Abnormal 0 0.0
Other 0 0.0
NBC 14.5

 

LABCAT HE4.43 22-MAY-2002

STUDY ID: ARGUS #418-027

Study Report for Hematology

WHITE DIFFERENTIAL DATA



 

 

STUDY NO: 060-063 GROUP: SEX: MALE
AnimaL ID TERMINAL
CNT ABS
17629 Nucleated Red 0
88 19.6
Segmented Neutrophils 11 2.5
Bands 0 0.0
Monocytes 0 0.0
Eosinophils 1 0.2
Basophils 0 0.0
AbnormaL 0 0.0
Other 0 0.0
NBC 22.3
17636 Nucleated Red Cells 0
42 13.1
Segmented Neutrophils 58 18.2
Bands 0 0.0
Monocytes 0 0.0
Eosinophils 0 0.0
Basophils 0 0.0
Abnormal 0 0.0
Other 0 0.0
NBC 31.3

 

LABCAT HE4.43

22-MAY-2002

STUDY ID: ARGUS #418-027
STUDY N0: 060-063

GROUP: 1-F

Study Report for Hematology

WHITE DIFFERENTIAL DATA



 

 

SEX: FEMALE
Animal ID TERMINAL
CNT ABS
17694 NucLeated Red 0
81 13.6
Segmented NeutrophiLs 16 2.7
Bands 0 0.0
Monocytes 2 0.3
EosinophiLs 0 0.0
BasophiLs 0 0.0
Abnormal 1 0.2
Other 0 0.0
NBC 16.8
17703 NucLeated Red 0
73 17.0
Segmented Neutrophils 25 5.8
Bands 0 0.0
Monocytes 1 0.2
Eosinophils 1 0.2
BasophiLs 0 0.0
AbnormaL 0 0.0
Other 0 0.0
NBC 23.3
17681 NucLeated Red 0
77 15.2
Segmented Neutrophils 19 3.8
Bands 0 0.0
Monocytes A 0.8
Eosinophils 0 0.0
BasophiLs 0 0.0
Abnormal 0 0.0
Other 0 0.0
NBC 19.8

 

LABCAT HE4.43 

22-MAY-2002

STUDY ID: ARGUS #418?027

Study Report for Hematology

WHITE DIFFERENTIAL DATA



 

 

STUDY N0: 060-063 GROUP: 1-F SEX: FEMALE
AnimaL ID TERMINAL
CNT ABS
17690 NucLeated Red 0
84 17.6
Segmented NeutrophiLs 15 3.1
Bands 0 0.0
Monocytes 0 0.0
EosinophiLs 1 0.2
BasophiLs 0 0.0
Abnormal 0 0.0
Other 0 0.0
NBC 20.9
17695 NucLeated Red 0
0 
Segmented NeutrophiLs 0 
Bands 0 
Monocytes 0 
EosinophiLs 0 
BasophiLs 0 
Abnormal 0 
Other 0 

NBC

 

(--) - Data Unavailabte

LABCAT HE4.43

22-MAY-2002

STUDY ID: ARGUS #418-027
STUDY NO: 060-063

Animal ID

17675

17679

17688

GROUP: Z-F

Nucleated Red Cells


Segmented Neutrophils
Bands

Monocytes

Eosinophils

Basophils

Abnormal 
Other

WBC

Nucleated Red Cells


Segmented Neutrophils
Bands

Monocytes

Eosinophils

Basophils

Abnormal 
Other

NBC

Nucleated Red Cells


Segmented Neutrophils
Bands

Monocytes

Eosinophils

Basophils

Abnormal 
Other

NBC

WHITE DIFFERENTIAL DATA

Study Report for Hematology

TERMINAL

CNT

85
13



80
20

000000

82
18

000000

ABS

10.

00.0.0999SEX: FEMALE

 

LABCAT HE4.43



STUDY ID: ARGUS #418-027

Study Report for Hematology

WHITE DIFFERENTIAL DATA



 

 

STUDY N0: 060-063 GROUP: Z-F SEX: FEMALE
Animal 1D TERMINAL
CNT ABS
17698 NucLeated Red Cells 0
93 15.6
Segmented NeutrophiLs 5 0.8
Bands 0 0.0
Monocytes 2 0.3
Eosinophils 0 0.0
BasophiLs 0 0.0
Abnormal 0 0.0
Other 0 0.0
NBC 16.8
17684 NucLeated Red 0
83 10.6
Segmented NeutrophiLs 15 1.9
Bands 0 0.0
Monocytes 2 0.3
EosinophiLs 0 0.0
Basophils 0.0
AbnormaL 0 0.0
Other 0 0.0
NBC 12.8

 

LABCAT HE4.43

22-MAY-2002

STUDY ID: ARGUS #418?027

Study Report for Hematology

WHITE DIFFERENTIAL DATA



 

 

STUDY NO: 060-063 GROUP: sex; FEMALE
Animal ID TERMINAL
CNT ABS

17693 Nucleated Red Cells 0
74 17.8
Segmented NeutrophiLs 23 5.5
Bands 0 0.0
Monocytes 3 0.7
Eosinophils 0 0.0
BasophiLs 0 0.0
Abnormal 0.0
Other 0 0.0
NBC 24.0

17697 NucLeated Red 0
84 13.7
Segmented NeutrophiLs 16 2.6
Bands 0 0.0
Monocytes 0 0.0
Eosinophils 0 0.0
BasophiLs 0 0.0
Abnormal 0 0.0
Other 0 0.0
NBC 16.3

17700 Nucleated Red 0
68 12.2
Segmented NeutrophiLs 30 5.4
Bands 0 0.0
Monocytes 0 0.0
EosinophiLs 2 0.4
Basophils 0 0.0
AbnormaL 0 0.0
Other 0 0.0
NBC 18.0

 

LABCAT HE4.43



STUDY ID: ARGUS #418-027
STUDY N0: 060-063

Animal ID

17701

17687

17709

GROUP: 3-F

Nucleated Red Cells


Segmented Neutrophils
Bands

Monocytes

Eosinophils

Basophils

Abnormal 
Other

NBC

Nucleated Red Cells


Segmented Neutrophils
Bands

Monocytes

Eosinophils

Basophils

Abnormal 
Other

NBC

Nucleated Red Cells


Segmented Neutrophils
Bands

Monocytes

Eosinophils

Basophils

Abnormal 
Other

NBC

WHITE DIFFERENTIAL DATA

Study Report for Hematology

TERMINAL

CNT

24

000000

COCO



SEX: FEMALE

 

LABCAT HE4.43



STUDY ID: ARGUS #418?027

Study Report for Hematology

WHITE DIFFERENTIAL DATA

4189027IPAGE 

 

 

STUDY N0: 060?063 GROUP: SEX: FEMALE
Animal ID TERMINAL
CNT ABS

17685 Nucleated Red Cells 0
60 13.0
Segmented NeutrophiLs 32 6.9
Bands 1 0.2
Monocytes 6 1.3
Eosinophils 0 0.0
BasophiLs 0 0.0
Abnormal 1 0.2
Other 0 0.0
NBC 21.6

17689 NucLeated Red 
73 13.6
Segmented Neutrophils 18 3.3
Bands 1 0.2
Monocytes 8 1.5
EosinophiLs 0 0.0
Basophils 0 0.0
AbnormaL 0 0.0
Other 0 0.0
NBC 18.6

17692 Nucleated Red 0
87 22.1
Segmented Neutrophils 10 2.5
Bands 0 0.0
Monocytes 2 0.5
Eosinophils 0 0.0
BasophiLs 0 0.0
AbnormaL 1 0.3
Other 0 0.0
NBC 25.4

 

LABCAT HE4.43

22-MAY-2002

 
Study Report for Hematology

WHITE DIFFERENTIAL DATA

STUDY ID: ARGUS #418?027
STUDY N0: 060-063 GROUP: A-F

 

 

SEX: FEMALE
AnimaL ID TERMINAL
CNT ABS
17691 NucLeated Red 0
81 16.8
Segmented NeutrophiLs 17 3.5
Bands 0 0.0
Monocytes 2 0.4
Eosinophils 0 0.0
BasophiLs 0 0.0
AbnormaL 0.0
Other 0 0.0
HBC 20.8

 

LABCAT HE4.43 22-MAY-2002

418-0272PAGE 
Study Report for Clinical Chemistry

INDIVIDUAL ANIMAL REPORT BY GROUP
PERIOD: TERMINAL

STUDY ID: ARGUS #418-027

 

 

 

 

SEX: MALE
STUDY NO: 060-063
AnimaL 10 TP ALB GLU CHOL T-BIL BUN CREAT ALT
g/dL g/dL mg/dL mg/dL mg/dL mg/dL mg/dL 
GROUP: 1-M
17608 617618 517630 617631 617639 6MEAN 60.29 0.16 11.0 11.9 0.00 1.6 0.GROUP: 
17634 617635 617638 617642 617643 6MEAN 60.34 0.15 23.9 5.3 0.00 2.3 0.04 1.6
5 5 5 5
GROUP: 3-M
17620 617623 617627 517628 617633 MEAN 60.29 0.21 12.7 5.5 0.00 1.3 0.LABCAT CC4.43 

418-0271PAGE 
Study Report for Clinical Chemistry

 

INDIVIDUAL ANIMAL REPORT BY GROUP
PERIOD: TERMINAL

 

STUDY ID: ARGUS #418-027

 

 

SEX: MALE
STUDY NO: 060?063
Animal ID TP ALB GLU CHOL T-BIL BUN CREAT ALT
g/dL g/dL mg/dL mg/dL mg/dL mg/dL mg/dL 
GROUP: 
17621 617622 617625 617629 617636 6MEAN 60.16 0.43 11.5 8.2 0.00 5.9 0.LABCAT cc4.43 

 
Study Report for Clinical Chemistry

INDIVIDUAL ANIMAL REPORT BY GROUP
PERIOD: TERMINAL

 

STUDY ID: ARGUS #418-027

 

 

 

 

SEX: FEMALE
STUDY NO: 060-063
Animal ID TP ALB GLU CHOL T-BIL BUN CREAT ALT
g/dL g/dL mg/dL mg/dL mg/dL mg/dL mg/dL 
GROUP: 1-F
17694 517695 617703 617681 717690 6MEAN 60.45 0.30 26.9 11.8 0.05 3.6 0.GROUP: Z-F
17675 717679 617684 517688 617698 6MEAN 60.61 0.25 6.6 7.5 0.04 3.3 0.09 13GROUP: 3-F
17693 617687 617697 617700 617701 617709 5MEAN 60.44 0.33 27.4 14.5 0.00 3.3 0.04 13LABCAT CC4.43 22-MAY-2002

41 8-0271PAGE 
Study Report for Clinical Chemistry

 

INDIVIDUAL ANIMAL REPORT BY GROUP
PERIOD: TERMINAL

 

 

 

STUDY ID: ARGUS #418-027 SEX: FEMALE

STUDY N0: 060-063

AnimaL ID TP ALB GLU CHOL T-BIL BUN CREAT ALT

g/dL g/dL mg/dL mg/dL mg/dL mg/dL mg/dL 

GROUP: 4-F

17685 617689 617692 5.4 3.9 96 41 0.1 22 0.3 102

17691 6MEAN 60.59 0.14 28.1 12.9 0.05 2.5 0.LABCAT CC4.43 22-MAY-2002

418-0271PAGE 
Study Report for Clinical Chemistry

 

INDIVIDUAL ANIMAL REPORT BY GROUP
PERIOD: TERMINAL

 

STUDY ID: ARGUS #418-027 SEX: MALE
STUDY NO: 060?063

 

 

 

 

Animal ID AST ALP CA PHOS TRIG NA CL
mg/dL mg/dL mg/dL mmoL/L mmoL/L mmoL/L
GROUP: 
17608 90 106 11.6 8.3 66 147 5.5 94
17618 92 63 10.6 7.7 45 150 6.0 98
17630 89 131 11.2 8.6 76 147 4.9 94
17631 83 129 11.2 9.9 106 148 5.9 96
17639 88 106 10.9 7.9 66 146 6.2 97
MEAN 88 107 113.4 27.4 0.37 0.87 22.2 1.5 0.GROUP: 
17634 101 74 11.5 9.8 39 144 6.2 95
17635 86 88 11.0 8.2 69 147 5.0 96
17638 80 118 11.9 8.3 69 151 6.3 102
17642 89 113 11.0 8.2 66 148 5.9 100
17643 74 148 11.4 13.9 53 144 7.8 97
MEAN 86 108 1110.2 28.6 0.38 2.45 13.1 2.9 1.GROUP: 3-H
17620 102 149 11-3 9.2 48 147 5.8 97
17623 88 96 11.8 8.0 68 147 6.7 100
17627 92 91 11.0 9.8 52 148 7.0 103
17628 100 122 11.4 10.3 56 149 6.9 101
17633 96 122 11.4 9.9 105 148 6.3 99
MEAN 96 116 115.7 23.4 0.29 0.90 23.2 0.8 0.LABCAT cc4.43 . 22-MAY-2002

41 
Study Report for Clinical Chemistry

 

INDIVIDUAL ANIMAL REPORT BY GROUP
PERIOD: TERMINAL

 

STUDY ID: ARGUS #418?027 SEX: MALE
STUDY NO: 060-063

 

 

AnimaL ID AST ALP CA PHOS TRIG NA CL
mg/dL mg/dL mg/dL mmoL/L mmoL/L mmoL/L
GROUP: 4-H
17621 89 117 11.5 9.3 24 151 5.9 100
17622 105 109 11.1 8.9 30 147 6.3 100
17625 109 104 11.3 9.8 47 150 6.3 103
17629 108 133 11.3 12.6 24 144 7.9 95
17636 98 153 11.3 9.2 28 147 6.1 98
MEAN 102 123 11.3 10.0 31 148 6.5 99
SD 8.3 20.0 0.14 1.51 9.5 2.8 0.LABCAT CC4.43 22-MAY-2002

 
Study Report for Clinical Chemistry

INDIVIDUAL ANIMAL REPORT BY GROUP
PERIOD: TERMINAL

STUDY ID: ARGUS #418?027

 

 

 

 

sax: FEMALE
STUDY No: 060?063
Animal ID AST ALP CA PHOS TRIG NA CL
mg/dL mg/dL mg/dL mmoL/L mmoL/L mmoL/L
GROUP: 
17694 102 49 11.5 9.5 44 140 7.0 96
17695 92 59 11.5 9.4 51 141 7.0 101
17703 99 59 11.8 9.2 46 143 6.1 99
17681 114 51 12.4 9.2 66 145 6.8 93
17690 92 97 11.8 9.3 72 144 6.7 98
MEAN 100 63 119.1 19.5 0.3? 0.13 12.5 2.1 0.GROUP: Z-F
17675 107 39 12.4 8.0 84 141 6.0 96
17679 82 43 11.8 9.3 27 141 7.4 98
17684 120 56 10.9 7.0 47 141 6.1 99
17688 75 61 11.6 8.5 72 143 5.5 95
17698 86 56 11.7 7.8 53 143 6.8 99
MEAN 94 51 1118.8 9.5 0.54 0.85 22.2 1.1 0.GROUP: 3-F
17693 95 91 11.6 10.5 36 141 6.9 102
17687 107 48 11.4 9.1 91 143 6.2 100
17697 104 24 11.2 6.7 37 143 7.1 102
17700 114 68 12.1 10.6 36 143 6.7 98
17701 129 43 11.4 8.1 34 142 7.3 103
17709 150 49 11.5 7.9 52 144 6.0 100
MEAN 117 54 1120.0 23.0 0.31 1.54 22.2 1.0 0.LABCAT CC4.43 ZZ-MAY-ZOOZ

 
Study Report for Clinical Chemistry

INDIVIDUAL ANIMAL REPORT BY GROUP
PERIOD: TERMINAL

STUDY ID: ARGUS #418-027

 

 

SEX: FEMALE
STUDY N02 060*063
AnimaL ID AST ALP CA PHOS TRIG NA CL
mg/dL mg/dL mg/dL mmoL/L mmoL/L mmoL/L
GROUP: 4-F
17685 93 76 11.6 9.5 54 140 6.7 98
17689 147 68 12.2 10.0 69 140 6.8 98
17692 109 ?129 11.1 8.8 62 138 6.4 102
17691 131 73 12.6 9.6 79 143 6.9 95
MEAN 120 87 1123.8 28.5 0.66 0.50 10.6 2.1 0.LABCAT cc4.43 

 
Study Report for Clinical Chemistry

 

INDIVIDUAL ANIMAL REPORT BY GROUP
PERIOD: TERMINAL

 

STUDY ID: ARGUS #418-027
STUDY NO: 060-063

SEX: MALE

 

 

 

 

AnimaL ID GLOB 
g/dL none
GROUP: 1-M
17608 2.4 1.8
17618 2.0 2.0
17630 2.4 1.7
17631 2.3 1.7
17639 2.1 2.0
MEAN 2.2 1.8
SD 0.18 0.15

GROUP: 
17634 2.3 1.7
17635 2.6 1.6
17638 2.4 1.8
17642 2.0 2.0
17643 2.0 2.1
MEAN 2-3 1.8
SD 0.26 0.21
5 
GROUP: 3-H
17620 1.9 2.2
17623 2.3 1.8
17627 2.1 1.8
17628 2.3 1.8
17633 1.9 2.2
MEAN 2.1 2.0
SD 0.20 0.22


 

LABCAT CC4.43 22-MAY-2002

418-0271PAGE K344
Study Report for Clinical Chemistry

 

INDIVIDUAL ANIMAL REPORT BY GROUP
PERIOD: TERMINAL

 

STUDY ID: ARGUS #418?027 SEX: MALE
STUDY N0: 060-063

 

 

AnimaL ID GLOB 
g/dL none
GROUP: 4-H
17621 2.1 2.1
17622 1.8 2.4
17625 1.8 2.4
17629 2.1 2.0
17636 2.8 1.2
MEAN 2.1 2.0
SD 0.41 0.49
5

 

LABCAT CC4.43 

 
Study Report for Clinical Chemistry

 

INDIVIDUAL ANIMAL REPORT BY GROUP
PERIOD: TERMINAL

 

STUDY ID: ARGUS #418?027 sex:
STUDY NO: 060?063

FEMALE

 

 

 

 

AnimaL ID GLOB 
g/dL none
GROUP: 
17694 2.1 1.8
17695 2.2 2.0
17703 2.5 1.7
17681 2.5 1.8
17690 2.2 1.9
MEAN 2.3 1.8
SD 0.19 0.11
5 5
GROUP: 2-F
17675 2.8 1.6
17679 2.1 2.0
17684 1.9 2.0
17688 2.3 1.8
17698 2.7 1.6
MEAN 2.4 1.8
SD 0.38 0.20
5 5
GROUP: 3-F
17693 2.2 1.8
17687 2.2 2.0
17697 2.2 1.7
17700 2.4 1.9
17701 2.1 2.0
17709 2.0 1.8
MEAN 2.2 1.9
SD 0.13 0.12
6 6

 

LABCAT CC4.43 22-MAY-2002

418-0272PAGE 
Study Report for Clinical Chemistry

INDIVIDUAL ANIMAL REPORT BY GROUP
PERIOD: TERMINAL

 

STUDY ID: ARGUS #418-027 SEX:
STUDY No: 060-063

FEMALE

 

 

AnimaL ID GLOB 
g/dL none

GROUP: 4-F
17685 2.3 1.8
17689 2.5 1.7
17692 1.5 2.6
17691 2.4 1.7
MEAN 2.2 2.0
SD 0.46 0.44
4 4

 

LABCAT cc4.43 - 22-MAY-2002

 
Study Report for Clinical Chemistry

SUMMARY REPORT
PERIOD TERMINAL

 

STUDY ID: ARGUS #418?027

 

 

SEX: MALE
STUDY N0: 060-063

TP ALB GLU CHOL T-BIL BUN CREAT ALT AST

UNITS: g/dL g/dL mg/dL mg/dL mg/dL mg/dL mg/dL 

Group: 

MEAN 60.29 0.16 11.0 11.9 0.00 1.6 0.Group: 2-H

MEAN 60.34 0.15 23.9 5.3 0.00 2.3 0.04 1.6 10Group: 3-H

MEAN 60.29 0.21 12.7 5.5 0.00 1.3 0.Group: 

MEAN 60.16 0.43 11.5 8.2 0.00 5.9 0.LABCAT CC4.43 22-MAY-2002

 
Study Report for Clinical Chemistry

 

SUMARY REPORT
PERIOD: TERMINAL

 

STUDY ID: ARGUS #418-027

 

 

SEX: MALE
STUDY N0: 060-063

ALP CA PHOS TRIG NA CL GLOB 

UNITS: mg/dL mg/dL mg/dL mmoL/L mmoL/L mmoL/L g/dL none

Group: 

MEAN 107 1127.4 0.37 0.87 22.2 1.5 0.51 1.8 0.18 0.Group: Z-M

MEAN 108 1128.6 0.38 2.45 13.1 2.9 1.01 2.9 0.26 0.Group: 

MEAN 116 1123.4 0.29 0.90 23.2 0.8 0.49 2.2 0.20 0.Group: 

MEAN 123 11.3 1020.0 0.14 1.51 9.5 2.8 0.80 2.9 . 0.41 0.LABCAT cc4.43 I ZZ-MAY-ZOOZ

418-0272PAGE Ku49
Study Report for Clinical Chemistry

SUMMARY REPORT
PERIOD: TERMINAL

STUDY ID: ARGUS #418-027

 

 

SEX: FEMALE
STUDY N0: 060-063

TP ALB GLU CHOL T-BIL BUN CREAT ALT AST

UNITS: g/dL g/dL mg/dL mg/dL mg/dL mg/dL mg/dL 

Group: 1-F

MEAN 60.45 0.30 26.9 11.8 0.05 3.6 0.Group: 2-F

MEAN 60.61 0.25 6.6 7.5 0.04 3.3 0.09 13.0 18Group: 

MEAN 60.44 0.33 27.4 14.5 0.00 3.3 0.04 13.3 20Group: 4-F

MEAN 60.59 0.14 28.1 12.9 0.05 2.5 0.08 7.4 23LABCAT CC4.43 

. 
Study Report for Clinical Chemistry

 

SUMMARY REPORT
PERIOD: TERMINAL

 

STUDY ID: ARGUS #418-027 SEX: FEMALE
STUDY N0: 060-063

 

 

ALP CA PHOS TRIG NA CL GLOB 

UNITS: mg/dL mg/dL mg/dL mmoL/L mmol/L mmoL/L g/dL none

Group: 

MEAN 63 1119.5 0.37 0.13 12.5 2.1 0.37 3.0 0-19 0.Group: 

MEAN 51 119.5 0.54 0.85 22.2 1.1 0.74 1.2 0.38 0.Group: 

MEAN 54 1123.0 0.31 1.54 22.2 1.0 0.51 1.8 0.13 0.Group: 4-F

MEAN 87 1128.5 0.66 0.50 10.6 2.1 0.22 2.9 0.46 0.LABCAT CC4.43 ZZ-MAY-ZOOZ

Study Number: 418027

418-0272PAGE 

QUALITY ASSURANCE STATEMENT

Redfield Study Number: 060-063

This study has been inspected and audited by the Quality Assurance Unit (QAU) as required by the
Good Laboratory Practice (GLP) regulations promulgated by the US. Food and Drug Administration
or US. Environmental Protection Agency or other international regulations, as required. The
following is a record of the dates that audits/inspections were performed and reported by the QAU.

 

 

 

 

DATE OF TYPE OF DATES REPORTED TO STUDY
DIRECTOR AND MANAGEMENT
05/1 7/02, 05/20/02 Clinical Pathology 05/20/02

 

 

 

APPROVED BY:



gm?

Jill er ch, B.S.
Qua' Assurance Auditor

Redfield Laboratories

Date 

APPENDIX 

STATEMENT OF THE STUDY DIRECTOR

 L?l



V: 4 ARGUS RESEARCH

1  ?5 '3 glad? RiVe? Laboratories
Tdetbx: (215)443-8581 5- - . DiScovery and DevelopmentServices

PROTOCOL 418?027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY
STUDY OF 7599.7 WITH THE 
DEVELOPMENTAL TOXICITY SCREENING TEST

STUDY NUMBER: T-7599

STATEMENT OF THE STUDY DIRECTOR

This final report accurately re?ects the raw data obtained during the performance of the
study. No deviations from the US. Food and Drug Administration (FDA) Good Laboratory
Practice Regulations; Final Rulea, the Japanese Ministry of Health and Welfare (MHW) Good
Laboratory Practice Standard for Safety Studies on Drugsb, the Organisation for Economic
Co?operation and Development (OECD), the Revised OECD Principles of Good Laboratory
Practicesc and the Organisation for Economic Co?operation and Development (OECD), The
OECD Guideline for Testing of Chemicalsd occurred that affected the quality or integrity of the
study.

    

 

W?Q?gf? LA .. Mae 2&6

4rond G. York, Date
Associate Director 0 earch
Study Director

Argus Research

 

a. US. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule.
21 CFR Part 58.

b. Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice Standard for
Safety Studies on Drugs, MHW Ordinance No. 21, March 26, 1997.

c. Organisation for Economic Co?operation and Development (1998). The Revised OECD
Principles of Good Laboratory Practices 
d. Organisation for Economic Co?operation and Development (1996). OECD Guideline for

Testing of Chemicals. Section 4, No. 422: Combined Repeated Dose Toxicity Study
with the Reproductior?Developmental Toxicity Screening Test, adopted 22 March 1996.

APPENDIX 

QUALITY ASSURANCE STATEMENT

418-0271PAGE M-l

IARGUSRESEARCH

i i . Chad? RiVBrLaboratories
Tdcfax: (215)443-8587 Discovery and Development'Services

QUALITY ASSURANCE STATEMENT

Argus Protocol: 418-027

Sponsor?s Study Number: T-7599

Study Director: Raymond G. York, DABT

The protocol, critical phases, raw data and final report were inspected by the Quality
Assurance Unit (QAU), to assure conformance with:

Organisation for Economic Co-operation and Development (1998). The Revised OECD
Principles of Good Laboratory Practices 

US. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule.
21 CFR Part 58.

Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice Standard
for Safety Studies on Drugs, MHW Ordinance Number 21, March 26, 1997.

The undersigned indicate that the report is an accurate representation of the raw data.
Data provided by the Sponsor or a subcontractor were not audited by the Argus Research
Quality Assurance Unit.

 

The QAU inspection and report audit dates are listed below:

 

Date(s) Findings Date(s) Findings
Submitted to Study Submitted to

Inspection Phase Inspection Date(s) Director Management
Protocol Administration Preparation Motor Activity FOB1 Natural Delivery/
Litter Observations Blood Collection Dam/Litter Sacrifice Male Sacrifice?
Raw Data Check In-Life Data 17-19,

22-Necropsy Data 18Formulations Data 03Report Tables 26?Report Text 25?1Functional Observational Battery

WK 
0??:th (:69 33W {3 am as was

Maureen O?Brien, B.S. Date

Matthew J. Vaneman, B.S. Date
Manager of Regulatory Compliance Quality Assurance Associate and
Principal Auditor