International Research and Development Corporation SPONSOR: 3M Company COMPOUND: Fluorad? Fluorochemical FC-143 SUBJECT: Ninety Day Subacute Rhesus Monkey Toxicity Study. Edwin I. ngaenchai, Vice Pres? at and Director of Research Collaborators: D. C. Jessup, Associate Director of Research R. G. Geil, D.V.M., Vice President and Director of Pathology J. S. Mehring, Director of Large Animal Toxicology Date: November 10, 1978 137?090 001723 International Research and Development Corporation A 0 (Continued) Late Table No. 5- 7. Individual Hematological Values . . . . . . . . . . . . . . 18-20 8. MEans and Significance of Biochemical Values . . . . . . . 21 9?11. Individual Biochemical Values . . . . . . . . . . . . . . . 22-2d 12. Means and Significance of Urinalysis Values . . . . . . . . 25 13-15. Individual Urinalysis Values . . . . . . . . . . . . . 26-28 16. Summary of Gross Necropsy Observations . . . . . . . . . . 29-30 17. Absolute and Relative Organ Weights . . . . . . . . . . . . 31?32 18. Microscopic Observations . . . . . . . . . . . . . . . . . 33-39 137?090 001724 International Research and Development Corporation Page 1 SYNOPSIS In a ninety day oral study in rhesus monkeys, Fluorad? Fluorochemical FCel43 was administered at dosage levels of 0 (control, treated only with 0.5% Methocel?), 3, 10, 30 and 100 mg/kg/day. Two male and two female monkeys were initiated at each dosage level and also in a control group. The monkeys were observed twice daily for general physical appearance and behavior and pharmacotoxic signs. Body weights were recorded weekly. Hematological, biochemical and urinalysis studies were conducted once in the control period, at the end of the first and third months of study. The monkeys treated with the higher dose, (100 mg/kg/day) all died during weeks 2 through 5 of the study. At the 30 mg/kg/day dosage level, three monkeys died during weeks 7-12. They all showed signs of toxicity in the gastrointestinal tract (anorexia, emesis, sometimes brown in color, black stools), pale face and gums, swollen face and eyes, slight to severe decreased activity and prostration. The monkeys of the 30 and 100 mg/kg/day dosage level showed body weight losses from the first week of the study. Because of the early deaths of the monkeys at the 100 mg/kg/day dosage level, the clinical laboratory tests were not conducted. The monkeys at the 30 mg/kg/day dosage level showed, in the first month of the study, slight increase in prothrombin time and in acti- vated partial thromboplastin time (A.P.T.T.) values, as well as decreased alkaline phosphatase activity in the serum (statistically significant). Only one monkey from this dosage level in this period showed a low albumin value. At the end of the study, the only remaining monkey from the 30 mg/kg/day dosage level showed apparent anemia, low blood glucose, alkaline phosphatase, total protein and albumin values. There was no mortality at the 10 mg/kg/day dosage level. One monkey had black stool on several days in week 12 and occasionally 137-090 0101725 International Research and Development Corporation Page 2 anorexia and one monkey exhibited pale face and gums. At this dosage level there was a very slight increase in the activated P.T.T. values in the female monkeys during the first month of the study (not sta- tistically significant). There were no changes in the other indices and no changes in the body weight. In single monkeys from the 3 and 10 mg/kg/day dosage levels, there were trends toward decreased alkaline phosphatase in the serum. In the control and the 3 mg/kg/day dosage level there was no mor- tality, no changes in the body weights and no signs of toxicity. Soft stool, diarrhea or emesis were observed occasionally. The mortality and the above mentioned signs of toxicity in the 30 and 100 mg/kg/day dosage levels were compound-related. There was a trend toward the same signs of toxicity in single monkeys at the 10 mg/kg/day dosage level. The 3 mg/kg/day dosage level seems to be free of signs of toxicity. There is an evident relationship between the administered doses and the degree of the toxicity. No gross or microscopic lesions which were considered compound- related were seen in tissues other than the adrenals, bone marrow, Spleen and nodes for male and female monkeys at the 30 and 100 mg/kg/day dosage levels. MicroscoPically, the adrenals from male and female monkeys at the 30 and 100 mg/kg/day dosage levels had compound- related marked diffuse lipid depletion; the bone marrow from male and female monkeys at the 30 and 100 mg/kg/day dosage levels had compound- related slight to moderate hypocellularity; the spleen and nodes from male and female monkeys at the 30 and 100 mg/kg/day dosage levels had compound related moderate atrophy of follicles. Statistically significant variations in sex group mean weights of a few organs occurred between the control and experimental groups. These variations were of unknown biological significance and were not accompanied by morphologic alterations. 137-090 001726 International Research and Development Corporation Page 3 II. COMPOUND The compound was received from 3M Company, on October 24, 1977 as shown below: Label Fluorad? Fluorochemical 3M Stock No. 98~0211-0008-0 Lot 340 Saint Paul, Minnesota Descrigtion white powder 137-090 001727 International Research and Development Corporation Page 4 CLINICAL STUDIES A. METHODS: 1. General Procedure: Ten male rhesus monkeys (weighing from 2.60 to 3.90 kilograms) and 10 females (weighing from 2.95 to 3.80 kilograms) were initiated on this study. The monkeys were purchased from Primate Imports Corporation, Port Washington, N. Y. 11050. The monkeys were housed individually in hanging wire mesh, "squeeze type" cages and maintained in a temperature, humidity and light controlled enviroment. Purina? Monkey Chow? was fed twice each day and fresh apples were fed 3 times a week. Water was available ?g_libitum. During the conditioning period, the monkeys were tattooed on the inner surface of the thigh and intrapalpebral tuberculin tests were conducted. Tuberculin tests were conducted at inter- vals during the treatment period. Also a complete physical examina? tion was conducted by the staff veterinarian prior to initiation of compound administration. Only monkeys in good health were selected for the study. This study was initiated on January 11, 1978. Terminal sacri- fices were conducted on April 12, 1978. 2. Compound Administration: At the end of the conditioning period the monkeys were divided into five groups on a random basis, so that the initial average body weights were similar: Number of Monkeys Male Female Dosage Level 2 2 Control 2 2 3 mg/kg/day 2 2 10 mg/kg/day 2 2 30 mg/kg/day 2 2 100 mg/kg/day 137-090 001728 International Research and Development Corporation Page 5 The test compound, suspended in 0.5% Methocel?, was admin- istered by gavage, 7 days each week. All doses were given in a constant volume. Also the same volume of 0.5% Methocel? was given to the vehicle control group. Individual daily doses were based upon the body weights obtained weekly. 3. Observations: The monkeys were observed twice daily for general physical appearance and behavior and pharmacotoxic signs. Individual body weights were recorded weekly. General physical examinations were con- ducted in the control period and during the study. 4. Clinical Laboratory Tests: Blood and urine samples were obtained for analysis from all monkeys once during the control period and at and 3 months of study. The monkeys were fasted overnight prior to the collection of blood and urine samples. a. Hematology: Hematological studies included: hemoglobinl, hematocritz, count3, total3 and differential leucocyte counts, reti- culocyte count4, platelet counts, prothrombin time6, activated partial thromboplastin time7 (A.P.T.T.). Mean corpuscular hemoglo- bin, mean corpuscular volume and mean corpuscular hemoglobin con- centration were calculated. b. Biochemistry: Biochemical studies included: fasting blood glucoses, blood urea nitrogens, serum alkaline phosphatases, serum glutamic oxalacetic and pyruvic transaminase activitiess, cholesterolg, total proteing, albumins, sodiumlo, potassiumlo, chlorideg, inorganic phosphate9, Y?glutamyl transpeptidase11 and creatinine phosphokinaseg. 137-090 001729 International Research and Development Corporation Page 6 c. Urinalysis: Urinalysis included: measurement of volume, pH12 and specific gravity; description of color and appearance; qualitative tests for proteinlz, glucoselz, ketoneslz, occult blood12 and microscopic examination of the sediment. d. Statistical Analysis: Analysis of body weights and clinical laboratory tests were performed. All statistical analyses compared the treatment groups with the control group, by sex. The tests were compared by analysis of variance (one-way classification) Bartlett's test for homogeneity and the appropriate t-test (for equal or unequal variances) as described by Steel and Torriel3 using Dunnett's14 multiple comparison tables to judge significance of differences. B. RESULTS: 1. General Behavior, Appearance and Survival: There was no mortality in monkeys at O, 3 and 10 mg/kg/day dosage levels. The monkeys from the control and 3 mg/kg/day dosage levels did not show any unusual behavior or signs of toxicity. Soft stool or moderate to marked diarrhea were noted occasionally. Frothy emesis was also noted occasionally. At the 10 mg/kg/day dosage level the monkeys did not show any unusual signs of toxicity, except Monkey 7363. In week 7 its face appeared swollen and pale. It had been occasionally anorexic in week 4 and black stools appeared for several days in week 12 of the study. At the 30 mg/kg/day dosage level, three monkeys died during weeks 7, 12 and 13 of the study. From week 4, the monkeys were anorexic. Slight to moderate and sometimes severe decreased activity was noted occasionally to frequently for the four monkeys. Emesis and ataxia were very rarely noted, for one monkey. 137-090 (301780 International Research and Development Corporation Page 7 Swollen face, eyes and vulva, as well as pallor of the face and gums were noted. From week 6, for two monkeys, black stools were noted. Monkey 7387 showed slight to moderate dehydration and ptosis of the eyelids. All monkeys from the 100 mg/kg/day dosage level died during weeks 2 through 5 of study. They showed the same of toxicity as the previous group, but they appeared sooner in the study (from week 1) and were more marked: anorexia, frothy emesis (sometimes brown in color) pale face and gums, swollen face and eyes, decreased activity from slight to severe, prostration and body trembling. 2. Body Weights (Tables 1-3): Changes in body weight were similar for monkeys from the control and the 3 and 10 mg/kg/day dosage levels. Monkeys at the 30 and 100 mg/kg/day dosage levels lost body weight after the first week of study. There was statistically significant decreases in the body weight for the male monkeys at the 30 mg/kg/day dosage level in week 13 of the study. The female monkeys of the same dosage level and the monkeys from the 100 mg/kg/day dosage level were dead in this period. 3. Laboratory Test (Tables 4-15): a. Hematology: There were no noteworthy changes in monkeys from the 3 and 10 mg/kg/day dosage levels. In the first month of the study there was a slight increase (not statistically significant) of the A.P.T.T. values in the females at the 10 mg/kg/day dosage level and a statisti- cally significant increase of the A.P.T.T. and prothrombin time values in monkeys at the 30 mg/kg/day dosage level. In the third month of the study there was a high increase in the above mentioned indices for the one surviving monkey from the 30 mg/kg/day dosage level. The same monkey (#7455) had pronounced anemia as well. 137-090 0801731 I International Research and Development Corporation Page 8 The statistically significant increase in the hematocrit in monkeys at the 10 mg/kg/day dosage level and in the platelet count in monkeys at the 3 mg/kg/day dosage level at 3 months of study, were within the normal physiological limits. b. Biochemistry: There were no noteworthy changes in monkeys from the a control, 3 and 10 mg/kg/day dosage level. Only one monkey from the 3 mg/kg/day dosage level and one monkey from the 10 mg/kg/day dosage level showed trends toward decreases of alkaline phosphatase (432 and 474 units/l, respectively), without statistical significance. In the first month of the study, decrease in serum alka- line phosphatase was noted in monkeys at the 30 mg/kg/day dosage level (statistically significant) and in one monkey in the same dosage level, the albumin in the serum was lower (3.22 g/lOOml). The one surviving monkey (7455) from the 30 mg/kg/day dosage level showed decreasing of: blood sugar (66 mg/lOOml), total protein (5.52 g/lOOml) with albumin (2 g/lOOml) and alkaline phosphatase (360 units/1) and elevated cholesterol (240 mg/lOOml). c. Urinalysis: No changes considered to be related to compOund were seen in the urinalysis studies. 137~090 001732 IV. International Research and Development Corporation PATHOLOGICAL STUDIES A. METHODS: 1. Gross Pathology: Page 9 After completion of the compound administration period all surviving monkeys were anesthetized with Sernylan?*, exsanguinated and necropsied. At necropsy, the heart, liver, adrenals, spleen, pituitary, kidneys, testes/ovaries and brain were weighed and repre- sentative tissues were collected in buffered neutral 10% formalin. Eyes were fixed in Russell's fixative. weighed after fixation. The thyroid/parathyroid was Monkeys which died during the study were necr0psied as above. 2. Histopathologz: Microscopic examination of formalin fixed hematoxylin and eosin stained paraffin sections was performed for all monkeys in the control and treatment groups. The following tissues were examined: adrenals kidneys lumbar spinal cord aorta liver pituitary bone lung stomach brain skin testes/ovaries esophagus mesenteric node thyroid eyes retropharyngeal parathyroid gallbladder node thymus heart (with coronary mammary gland trachea vessels) nerve (with muscle) tonsil duodenum spleen tongue ileum pancreas urinary bladder jejunum prostate/uterus vagina cecum rib junction (bone tattoo colon marrow) rectum salivary gland and any other tissue(s) with lesions Bio-Cautic Laboratories, Inc., St. Joseph, Missouri. 137-090 001733 International Research and Development Corporation Page 10 B. RESULTS: 1. Gross Pathology (Table 16) and Organ Weights (Table 17): No gross lesions considered compound related were seen in male and female rhesus monkeys which died on study or were sacrificed after 90 days of study. Statistically significant variations in sex group mean weights of few organs occurred between the control and experimental groups. The following statistically significant organ weight variations occurred; Dosage Level Organ mg/kg/day 3 Weight Change Heart 10 absolute,relative decrease,decrease 0.05,0.01 Brain 10 absolute decrease 0.01 Pituitary 3 relative increase 0.05 The biological significance of these variations is unknown. These organ weight variations were not accompanied by morphologic changes which were considered compound related. 2. Histopathology (Table 18): One male and two female rhesus monkeys at the 30 mg/kg/day dosage level and all male and female rhesus monkeys at the 100 mg/kg/day dosage level had marked diffuse lipid depletion in the adrenals. All male and female rhesus monkeys at the 30 and 100 mg/kg/day dosage levels had slight to moderate hypocellularity of the bone marrow. All male and female rhesus monkeys at the 30 and 100 mg/kg/day dosage levels had moderate atrophy of follicles in the Spleen. One female at the 30 mg/kg/day dosage level and all male and female rhesus monkeys at the 100 mg/kg/day dosage level had moderate atrophy of the follicles in the nodes. No microscopic changes considered compound related were seen in the adrenals, bone marrow, Spleen and nodes of male and female rhesus monkeys at the 3 and 10 mg/kg/day dosage levels. NO microscopic 137-090 001734 I International Research and Development Corporation Page 11 lesions in tissues other than the adrenals, bone marrow, Spleen and nodes at the 30 and 100 mg/kg/day dosage levels were considered compound?related. 137?090 001735 10. 11. 12. 13. 14. International Research and Development Corporation Page 12 Reference Coulter Hemoglobinometer. Coulter Electronics, 590 W. 20th Street, Hialeah, Florida. Microhematocrit, John B. Miale, 3rd Ed., 1967, The C. V. Mosby Company, p. 1154. Coulter Particle Size Counter, Model 23, Coulter Electronics, 590 W. 20th Street, Hialeah, Florida. Gradwhol's Clinical Laboratory Methods and Diagnosis, Frankel and Reitman, Editors 6th Ed., 1963, The C. V. Mosby Company, p. 1132. Coulter Particle Size Counter, Model A, Coulter Electronics, 590 W. 20th Steet, Hialeah, Florida. General Diagnostics - Warner Chilcott Laboratories Revised April 1965. General Diagnostics - Warner Chilcott Laboratories Revised Janurary 1967. Technicon Auto Analyzer, 6/60 Micro Methodology. Micro Auto Analyzer II, 6/60 Micro Methodology. Atomic Absorption IL, MOdel 353 Sigma GGTP Procedure Bulletin #545. Sigma Chem. Co., St. Louis, Mo. Bililabstix (Ames Reagent Strips). Steel, R. G. D. and Torrie, J. H. (1960), Principles and Procedures of Statistics, McGraw-Hill, New York, N. Y. Dunnett, C. W., New Tables for Multiple Comparisons With a Control, Biometrics, McGraw~Hill, New York, N. Y. 137-090 001736 Ninety Day Subacute Rhesus Monkey Toxicity Study. TABLE 1. Mean Body Weights of Monkeys Week 13 of Study. Sex Grou I Grou II __?rou Grou IV Grou (Control) (3 mg/kg/day) (10 mg/kg/day) (30 mg/kg/day) (100 mg/kg/day) 3.78 3.50 3.68 2.30* dead 3.55 3.68 3.78 dead dead *Statistical significance. 137-090 SI 982d Ninety Day Subacute Rhesus Monkey Toxicity Study. TABLE 2. Individual Body Weights, Kilograms. Group, Monkey Control Week of Study Number Sex Control: 7362 3.15 3.30 3.15 3.30 3.35 3.10 3.20 3.20 3.00 3.15 3.20 3.05 3.20 3.40 3.50 7365 3.50 3.50 3.50 3.50 3.50 3.40 3.55 3.60 3.60 3.80 3.75 3.75 3.80 4.00 4.05 7336 3.05 3.20 3.25 3.25 3.35 3.15 3.00 3.15 3.20 3.30 3.45 3.30 3.35 3.35 3.60 7386 3.90 3.70 3.70 3.65 3.55 3.45 3.40 3.55 3.40 3.40 3.55 3.40 3.50 3.50 3.50 Mean 3.40 3.43 3.40 3.43 3.44 3.28 3.29 3.38 3.30 3.41 3.49 3.38 3.46 3.56 3.66 3 mg/kg/dax: 7364 3.70 3.90 3.85 3.95 3.85 3.85 3.80 3.80 3.85 4.10 4.10 4.05 4.05 4.20 4.30 7366 2.60 2.60 2.70 2.60 2.65 2.65 2.70 2.70 2.50 2.70 2.70 2.45 2.55 2.50 2.70 7384 3.55 3.60 3.70 3.80 3.80 3.80 3.70 3.70 3.60 3.55 3.80 3.55 3.70 3.90 3.75 7385 3.50 3.55 3.45 3.45 3.45 3.45 3.40 3.40 3.50 3.55 3.60 3.40 3.30 3.40 3.60 Mean 3.34 3.41 3.43 3.45 3.44 3.44 3.40 3.40 3.36 3.48 3.55 3.36 3.40 3.50 3.59 10 mg/kg/dax: 7363 3.55 3.70 3.70 3.65 3.65 3.65 3.65 3.60 3.60 3.70 3.65 3.75 3.85 3.90 3.90 7458 3.10 3.10 3.25 3.20 3.10 3.05 2.95 3.20 3.00 3.15 3.10 3.10 3.25 3.25 3.45 7328 3.30 3.30 3.45 3.40 3.40 3.30 3.20 3.30 3.25 3.45 3.60 3.50 3.40 3.60 3.75 7383 3.60 3.60 3.50 3.80 3.60 3.55 3.50 3.60 3.60 3.65 3.80 3.65 3.75 3.75 3.80 Mean 3.39 3.43 3.48 3.51 3.44 3.39 3.33 3.43 3.36 3.49 3.54 3.50 3.56 3.63 3.73 55 9; -u ?1 .3 -090 Ninety Day Subacute Rhesus Monkey Toxicity Study. TABLE 2. Cont. Individual Body Weights, Kilograms. Group, Monkey Control Week of Study Number Sex mg/kg/dax: 7367 3.40 3.40 3.25 3.25 3.10 2.95 2.65 2.30 2.10* Died 7455 3.50 3.30 3.20 3.05 2.85 2.65 2.45 2.50 2.55 2.60 2.70 2.70 2.65 2.50 2.30 7382 3.25 3.30 3.20 3.20 3.05 3.00 2.85 2.80 2.80 2.80 2.80 2.80 2.80 2.60 2.25* Die. 7387 3.70 3.75 3.50 3.55 3.50 3.45 3.10 2.95 2.85 2.85 2.70 2.65 2.50 2.25* Died Mean 3.46 3.44 3.29 3.26 3.13 3.01 2.76 2.64 2.73 2.75 2.73 2.72 2.65 2.55 2.30 100 mg/kg/daxz 7361 3.50 3.85 3.50 3.30 3.00 2.55 2.40* Died 7456 3.10 3.10 2.60 2.70* Died 7335 2.80 2.95 2.70 2.45 2.05* Died 7381 3.85 3.80 3.55 3.20 2.80 2.60* Died Mean 3.31 3.43 3.09 2.98 2.90 2.55 CD 0 ?g *Terminal weight not included in mean. (3137-090 g1 339a Page 16 FC-143: Ninety Day Subacute Rhesus monkey Toxicity Study. TABLE 3. T-Test Comparison of Body Weights. Study Week Sex Control 3 mg/kg/day 10 mg/kg/day 30 mg/kg/day 100 mg/kg/day 13 3.78 3.50 3.68 2.303 3.55 3.68 3.78 - - *p<0.05 137-090 aNot included in statistical analysis due to only one surviving animal- - Line indicates animals had died prior to week 13. 091740 Page 17 FC-143: Ninety Day Subacute Rhesus Monkey Toxicity Study. TABLE 4. Means and Significance of Hematological Values. of Hematology Study Control 3 mg/kg/day 10 mg/kg/day 30 mg/kg/day 4.46 4.26 4.71 4.53 lo?/cmm 3 4-90 4.74 5.47 3.84a Hemoglobin, 1 11.7 11.4 12.1 11.7 g/100 ml 3 12.9 12.7 13.3 9.7a Hematocrit40** 30a Platelets, 253 233 210 219 103/cmm 3 210 285* 216 261a Reticulocytes, 0.2 0.5 0.5 0.2 3 0.3 0.2 0.2 0.2a Prothrombin 1 12 12 13 15** Time, sec 3 11 11 11 30a Activated 1 28 28 31 35** P.T.T9.49 9.78 9.93 8.44 10 /cmm 3 9.40 9 9.83 11.96 10.14a Neutrophils543 EosinophilsMbnocytesBasophilsMCV78a MCH25a MCHC, 1 31 31 32 32* 3/100 m1 3 36 35 34 32a *Significantly different from control group, p<0.05. 137_090_ **Significantly different from control group, p<0.01- aValue not used in statistical analysis due to only one animal surviving. 0491741 Flt- I I. ImIlequaI If?dI .. Squu-ulc- Rina-sun Tush- imm?u? In I.ympImv Grnup. vau? vanln- lru rlIl Iuryluu P.T.T. Numln-r Sex 1Irma? g] IIJII ml 7. [cum 2 sec 50c 20.0.92! 7362 II 5.0" 40 207 0.I I3 29 7355 4.72 II.9 3H 3I9 0.) I3 30 7336 5.27 I2.8 39 226 I6 29 7386 4.20 II.I 34 227 I4 2I Mann 4.82 I2.2 3? 245 D.4 14 27 1198/9215!de 7373?? 6.68 .0 37 297 I4 2 738a 4.55 38 I60 0.2 I3 30 7335 4.I9 35 I45 I3 2 Menu 4.43 II.7 37 232 0.6 I3 27 .10. Jug/.315! slay 7363 5.2h I3.7 42 264 I3 3 745? 5.29 I2.2 36 263 0.2 I3 29 7328 5.32 12.5 39 I92 I3 3 7333 5.04 I3.5 42 0.4 I3 28 "can 5.22 I3.0 4" 2I0 0.5 I3 30 30. 7367 ?.98 I2.h 38 0.2 I2 28 _7?55 5.I6 I3.6 40 333 I2 24 7382 38 I57 26 7387 ?.67 I2.2 35 II3 0.5 l& 27 Menu 4.9I I2.8 38 I37 I3 26 .105! geeks/51v 736I 5.75 3b 232 I2 27 745? 5.30 42 I96 II 28 7335 I2.8 4" [85 0.2 2H 738 4.82 Ii": 0.5 26 "P?ll I2.5 I95 II.3 I3 27 {74.1300 (0 137-1190 hp nun-ms Imm- In Ifmll I. It)! Slluly. I I 33" UN Inn Nun. Nunn?vu. rylon Irmm l0.90 3h I 62 I4.79 27 0 72 7.86 38 59 I2.09 59 0 39 ?.103 M) 0 58 8.98 42 0 57 7.39 hl 59 14.72 1 0 64 3.16 38 59 9.3I 3H 0 60 I2.Q7 d6 0 49 I7.34 0 78 7.89 35 65 8.22 47 48 II.6I 36 0 60 10.84 4 57 8.65 2! 76 5.83 26 73 5.I0 29 0 68 7.6] 29 0 68 In." 'In (I 67 3.84 II I2.8 18 5h 0 II.HH ?ll 57 Ilatllut- I'lewf phlis 85d. T00 m" INF143: Ninety 0:1v S?h?l?19 Rhnsus Nnukry Study. T681.F 6. 1nd!v1du.a1 Valuou I rhunlu. Brunp, "an? vantn- Roticu? 1MHH11- N1utrophilq _1.ymph07 Hunkvy lc.H gluhln Pla elets P.T.T. Sol Nnn- Sag. cylosd Numhvl Sex 10 g/100 ?32qu21 7362 4.80 11.9 38 224 0.2 12 30 6.91 28 0 69 7365 4.71 11.9 39 349 0.2 12 28 14.58 15 0 84 7336 4.20 11.2 37 246 0.2 13 28 7.46 11 0 89 7386 4.13 11.9 38 191 0.3 12 27 8.99 42 0 58 Menu 4.46 11.7 38 253 0.2 12 28 9.49 24 0 75 .1 walks/1'14: 7364 4.35 11.6 37 264 0.5 11 27 6.81 17 0 80 7366 3.96 10.7 35 188 0.4 12 28 5.83 16 0 78 7384 4.46 11.9 39 234 0.2 13 28 17.07 22 73 7385 4.25 119.41 18 0 73 Mean 4.26 11.4 37 233 0.5 12 28 9.78 19 0 76 ?ing/35311511: 7363 4.42 12.3 38 168 1.0 13 27 8.08 42 0 57 7458' 4.81 11.3 37 281 0.3 13 31 17.98 11 0 87 7328 4.70 12.0 39 181 0.5 13 33 7.01 35 0 63 7383 4.92 12.8 40 209 0.1 12 33 6.64 18 0 79 1knn 4.71 12.1 39 210 0t5 13 31 9.93 26 0 72 3.0. mum-u 7367 4.59 11.2 36 135 0.1 13 34 7.92 12 0 88 7455 4.44 11.8 37 237 0.2 14 33 11.11 27 0 73 7382 4.51 11.9 35 268 0.3 15 35 6.19 9 0 90 7387 4.56 12.0 37 237 0.2 16 38 8.54 13 0 87 Mean 4.53 11.7 36 219 0.2 15 35 8.44 15 0 85 199.231 4'1! 7361 8 ?led, week 5 7456 Died, week 2 7335 "led. week 3 7381 Died, week 4 ?180 11H1n1)l? means have hotn In (qu.1l 1007 137?090 Montr- I'yh?unsu? [1111 19117 11? 111811 111211 1111121'! 26 26 24 27 26 21) 21: 1112111? g/Inn '[mg 3131111111403 13.18 TABLE 7. liruup. Munkvv 1: ruI: l-Zryl hru? NmuIn-r ?l-x ml 7162 6.89 l2.? 7 I55 5.29 I 7TH) 738Ila-73h!) 7381! IL92 713"! 1I.M I2 . 7 .11! ml Raid-W 7363 I16 7458 II 5.70 7128 5.47 IJ.6 718! 5.65 I3.S Hun? 5.47 I3.) 19, 7367 Died, Hqu 7 7a55 1.saa.h 9.7 7332 Died, Huck 7387 Died. week I2 Hvun 3.84 9.7 II worth 5 7656 II IN MI mat-k 2 7335 Dled. week 1 718l Died, week bbpteo I 37?00? Ila-um lu- (?rll '"I'lw I 2 7 2 8 I70 27M 2H3 2?39 278 3 3 21:8 285 214 2I9 212 261 26I NIIu-l?y Ilnv Suhm'uto IIe-l Il?lI" vIels I0 [1:Ivmzm?ytos: wu'ucylu Imw- hum 'I'IlmUNIX. Iml I Itlun I I?ruihrmuhln AM Ivan-?l l.mu?u? (- Ive: 7.82 20 IZJM In If- 8.5 IH 9.40 lb 7.3.1 25 l8.2l lb 8.15 H) ?9.33 :9 20.18 I. 10.72 8.52 3n ?.96 25 I0.ll. 36 '16 Svg. [0 [rum 1 HunIu-y 'I'mrlulty Study. Vnimle~$ng".1th2?0 mrm?. 12/ um I?r I5 ?0 Page 21 Ninety Day Subacute Rhesus Monkey Toxicity Study. TABLE 8. Means and Significance of Biochemical Values. Month of Biochemistry Study Control 3 mg/kg/day 10 mg/kg/day 30 mg/kg/day Glucose, 1 89 117* 104 122 mg/100 ml 3 81 96 88 66a B.U.N., 1 23.0 21.2 22.5 26.1 mg/100 ml 3 27.6 20.2 22.0 22.6a Alk. Phos., 1 597 847 601 365* int'l 3 851 783 743 360a units/1 S.G.0.T., 1 29 35 34 59** int'l 3 45 41 35 88a units/1 S.G.P.T. 1: 15 21 34* 44 int'l 3 31 31 34 46a units/1 Cholesterol, 1 165 154 158 174 mg/100 ml 3 165 141 154 240a Total Protein, 1 7.94. 8.23 8.66 8.36 3/100 ml 3 8.21? 8.24 8.43 5.52a Albumin, 1 4.78 5.05 4.66 4.28 g/100 ml 3 4.82 5.12 5.17 2.00a Sodium, 1 153 152 155 152 meq/liter 3 151 154 159** 150a Potassium, 1 5.1 5.1 5.2 5.7 meq/liter 3 5.5 5.6 6.0 5.9a Chloride, 1 112 110 113 112 meq/liter 3 113 112 114 113a 61 49 47 33 Sigma 3 44 38 51 49a units/ml C.P.K., 1 9 14 16 19* Sigma 3 7 6 9 10a units/ml Inorganic 1 7.9 7.2 7.0 6.7 Phosphate, 3 6.9 6.3 7.3 5.0a mg/100 ml *Significantly different from control group, p<0.05. 137_090 **Significantly different from control group, p<0.01. aValue not used in statistical analysis due to only one animal surviving. (301745 cSigma units/ml Fit-143: Ninety llny Suhacute Rhesus Hunkey Study. ..- TABLE 9. Individual Values - Cont ml 1. Group, Alk. 91103. S.G.P.T. Cholcs- 'l'ot'ul Potas- Chlu? Inorganic Creatinlne Hunkey Glucose 8.0.11. Jnt'l lut'l int'l tern]. Pruteln Albumin Sodium slum ride Phosphate 143-159- Number Sex lug/100 m1 lug/100 ml unlts/l units/l units/l Hug/100 m1 ml g/100 ml meq/l meq/l meq/i lug/100 ml Slnmal u/ml Sigma (Jim I: :01 7362 94 41.0 780 40 99 21.9 8.68 5.7365 82 16.7 659 61 88 123 9.50 4.7336 79 24.0 915 30 80 185 9.52 5.7386 85 21.0 960 39 86 190 8.52 5.Mean 85 25.7 829 43 88 179 9.06 5.03 158 4.9 111. 6.6 47 34 3 mg/kg/daz: 7364 111 19.0 8m 42 94 197 9.08 5.7366 71 28.7 580 60 89 172 9.12 5.80 157 4.9 108 7.1 30 '26 7384 96 22.0 570 38 .106 133 10.12 5.7385 1? 107 22.0 1320 60 76 154 8.72 4.Mean 96 22.9 838 50 91 164 9.26 5.mg/kglg?x: 7363 89 27.2 1167 46 118 237 9.84 5.7458 180 24.2 806 63 136 107 10.08 3.7328 98 20.0 776 26 75 189 8.48 5.14 1.57 4.4 109 6.3 51 34 7383 98 27.3 581. 31 91 168 8.32 5.Heat) 116 24.7 833 42 105 175 9.18 4.7367 108 26.9 970 47 114 150 9.38 5.7455 110 24.0 687 37 86 205 9.50 5.7382 132 27.9 641 40 79 176 11.10 5.7387 117 23.8 978 45 138 194 9.44 5."can 117 25.7 819 42 104 181. 9.86 5.100 7361 93 29.0 598 43 80 155 8.60 5.7456 100 23.0 799 40 104 202 9.00 5.7335 75 28.0 570 40 96 151 8.98 5.7381 119 22.1 1233 40 103 124 9.60 4.Heal! 97 25.5 800 41 96 158 9.05 5.95LTGO 137-! I90 zz 989& FC-143: Nlnely Day Subacute Rhesus lhnkey Tnxlelty Study. TABLE 10. Individuui Bluchemical Values - 1 Month. Group. Alk. Fhoa. S.G.0.T. S.G.P.T. Choles- Total Potas? Chln? Inorganic Creatlnine Monkey Glucnse 8.0.8. Int'l int'l int'l ternl Protein Albumln Sodlum slum ride Phosphate Phosphoklnasc Number Sex m1 mgllUU ml units/l umlLs/l units/l mg/lUO ml 3/100 ml g/lUG nu nmq/l meq/l meq/l mgll?u ml Sigma u/ml Sigma u/m1 Egg rol: 7362 87 33.9 611 27 18 191 7.31 4.7365 84 14.2 626 33 17 121 8.40 4.7336 87 23.9 672 25 15 142 7.90 4.7386 96 14.9 480 3] 10 206 8.15 5.Mean 89 23.0 597 29 15 165 7.94 4.lea/13.11% 7364 112 18.0 970 30 36 173 8.15 5.7366 131 23.3 693 39 19 148 8.05 5.7384 105 24.2 539 30 15 141 8.70 4.7385 120 19.1 1185 40 13 153 8.00 4."can 117 21.2 847 35 21 154 8.23 5.walks/daz: I 7363 98 24.9 552 40 35 219 9.40 4.7458 97 22.5 732 40 43 134 9.05 4.7328 98 22.7 640 23 19 145 8.20 4.7383 124 20.0 480 31 37 132 8.00 5.?can 104 22.5 601 34 34 158 8.66 4.7367 112 35.2 376 48 11 180 8.20 4.7455 86 21.0 322 61 80 177 8.55 3.7382 104 25.2 400 83 43 161 8.15 4.7387 185 22.8 360 45 23 179 8.55 5.Menu 122 26.1 365 59 44 174 8.36 4.100 mg/kg/daz: 7361 Died. week 5 7456 Died, week 2 7335 ?led, week 3 7381 Died. week 4 \1 #5 \ernm) :3 3395 817L100 I'm Ninety Day Subncute Rhesus Mnnkey Study. TABLE II. Biochemical Values 3 Hunths. Group, Alk. Phoa. S.G.0.T. S.G.P.T. Chules? Tutal Potng? Chln- lunrganir Monkey Glucose H.U.N. lnt'l int'l Sigma terul Prnteln Albumln Sodium alum ride Phosphate Phosphoklnase . Number Sex mg/100 ml mg/100 ml unlta/l units/i unlts/ml mg7100 ml 37100 m1 37100 mi an/l nmq/l meq/i mg/lno m1 Sigma ulmi Sigma u/mi Cunt :01: 7362 95 41.9 804 55 44 197 7.59 4.7365 77 17.4 744 47 30 135 9.18 4.7336 67 33.1 786 39 24 150 8.31 4.7386 86 18.1 1068 39 27 I77 7.76 4.Mean 8 27.6 851 45 31 165 8.21 4.2331131561: 7364 106 17.1 1092 41 28 164 7.72 5.7366 111 18.1 594 39 33 126 8.09 5.7384 94 23.4 432 39 33 132 8.93 4.7385 74 22.0 1014 43 29 I42 8.21 4.Mean 96 20.2 783 41 31 141 8.24 5.mg/kg/dy: 7363 87 24.9 936 42 42 I94 8.44 5.7458 88 21.1 936 38 31 139 9.71 4.7328 75 21.8 624 30 25 155 7.93 5.7383 100 20.0 474 30 37 128 7.62 5.Mean 88 22.0 743 35 34 154 8.43 5.7367 Bled, week 7 7455 66 22.6 360 88 46 240 5.52 2.7382 Died, week 13 7387 Diedl week 12 Mean 66 22.6 360 88 46 240 5.52 2.100 7361 Died, week 5 7456 Died, week 2 7335 Died, week 3 7381 Died. week 4 137?090 72 3398 Page 25 Ninety Day Subacute Rhesus Monkey Toxicity Study. TABLE 12. Means and Significance of Urinalysis Values. Month of Urinalysis Study Control 3 mg/kg/day 10 mg/kg/day 30 mg/kg/day Volume8.3 7.6 8.2 6.6a Specific 1 1.028 1.026 1.026 1.026a Gravity 3 1.018 1.015 1.024 1.031 aValue not used in statistical analysis due to only 137_090 one animal surviving. 001749 136-1103: Ninety Day Suhamlte lesus Htmkey Study. TABLE 13. Values - Guntrul l. ..111_ Ur?, Gruu I Color Nunkie; Volume and Spec. Urcult Leuun? Eryllirn? lipl . Triple (.le . Avid Number Sex ml Appear. Grav. Protein Glucose Blood Kelnnes cytes cytes Urates 'lms. ()xnl. Iinvu-rln 7362 100 1.5?c1 7.6 1.010 tr - occ ace out: 7365 28 LS-cl 7 2 1.037 - 1?3 7336 27 1.3-0 7.0 1.036 7386 70 1.5?cl 8 la 1.023 11+ - occ occ One Menu 56 7 6 1.027 9.231151%.2: 7360 25 13-111 7. 8 1.032 - - occ 1" - 7366 25 15?111 7 2 1.035 7384 215 8. 3 1.026 - - occ ucc occ 7385 35 LS-cl 8 3 1.020 - occ ucc - Mean 75 7 9 1.028 10 Inglis/dell: 7363 20 1.8-cl 7 7 1.020 tr - - 71-58 50 LS-cl 7 5 1.036 tr - - occ occ - 7338 35 LS?cl 7.8 1.036 tr - 1?3 one 11 - 138'! 35 L8-c1 8 2 1.020 1.028 29 m. 7367 20 LS-cl 7 1 1.050 tr 1-3 1?3 one occ occ 7455 35 LS?cl 6.8 1.030 7382 20 LS?cl 7.0 1.055 - - 1-3 occ - - 7387 1" ?58 l.S-c1 8. 2 1.030 - one (ICC Neal" 31 7 3 1.01.1 mall?s/dag: 7361 21 LS-cl 7 6 1.035 tr occ occ - 7656 25 1.S-cl 7.1 1 .042 tr - - net: 1? Dec - 7335 25 1.3-c1 7.2 1.041 tr 1+ - 1?3 - our: one 1' 7381 1" 1?0 LS-cl 8 1 1.042 14va 28 7. 5 .040 a ?2.15; tr Trace - Straw Negatlve QNS - Quantity not sufficient . 1+ .. Trace to 5113].: LS Light Straw Few norm - Nnrmal. 137-090 2+ .. tn moderate 08 - Dark Straw I. Landed None ?1 31? - Muck-rate Light Amlu-r - Many U1 Mr le - Dark Amhur Rare (Zlmuly m-s- {f (Elnnr 92 839a Ninety Day Suhacute Rhesus Monkey Study. 14. Urinalysis Valuer; Munth. Group. Cnlur Urlc Hunkcy Volume and Spec. (lacult Lumtn- Epl. Triple Cal. Acid Number Sux ml Appear. pi! (Jruv. l?rutuln Glucuse ulnud Kemucs cytu? (tells Uraces Phoa. leal. Bacteria Casts 9312111: 7362 55 1.37365 LS-C 8. 1.02 8 ucc ucc - 7336 20 8.5 1.033 1.5?0 8. 5 1.030 - - act: - - "can 35 8. 5 1.028 7361. 20 LS-C 8.8 1.019 - ucc occ - 7 20 1.57381: 40 8.0 1.021 4+ 2+ 8~12 - 1" ace 1" - 7385 50 LS?cl 8.5 1.027 - ace 1" ucc - Mean 33 8.5 1.026 [tiimh-Ikh-Iduy: 736 3 65 l.S-cl 7. 5 1.02 3 occ one - 7458 35 LS-C 8.0 1.028 - - - occ occ 7328 l?-cl 8.5 1.026 - - 1?3 occ one 7383 50 15?121 8. 5 1.028 ucc Dec .026 7387 30 7.5 1.021: - out: ucc occ 71455 30 LS?cl 8.0 1.026 - OLC - 7 '182 1.3-c1 8. 3 1.022 - nu. - - 7387 45 LS?cl 8.5 1.032 - - ucc 1? cu: ucc Hum; 111 8.1 1.026 Mluslkulilw 73111 Died, week 5 7456 11 ?led, week 2 7335 week 3 7381 Dlud. week 4 32min. tr - Trance 5 Straw - Negative QNS - Quantity not sufficient . 1+ Truce. [u LS Light Straw Few norm Normal 07137?0)? 2+ Slight tn moderate 05 - lhu?k Straw I. - Loaded seen 3+ - NndL-rulu Light Amber - Many 1 .. - . llAm Dark Amber Rare 4 "?de I11 - Cluudy our (2 - [z 339d 39.1.1300 Ninety Day Subncute Rhesus Monkey city Study. . .. TABLE 15. Individual Values - 3 Months. Group, Cnlor Monkey Volume and Spec. Occult Leuco? Epl. Triple Cal. Add - Number Sex ml Appear. p11 Grav. Pruteln (llucose Blood Ketmles cytes nytes Cells Ural?es Phos. 0m]. Bacteria Casts Control: 7362 ?0 LS7365 1.0 1.8?c1 8.1 1.029 1+ ucc 1?3 - - - 7336 85 8.2 1.015 7386 50 8. 8 1.016 3+ occ - ace 1" - Mean 71 8.3 1.018 3 mg/kg/day: 735/. 50 LS-C 5.0 1.020 tr - oec 0 7366 150 1.5-6 7.9 1.007 - nee ace - 738?. 125 1.5-0 8. 1 1.[.021 - out: 1? 3 ll - - Mean 94 7.6 1.015 11) mg/kg/djti: 7363 1.54: 8.0 1.027 - - occ occ occ - 7458 35 LS?cl 8. 7 1.022 - - - oec - - 7328 l" 50 LS-C 9.0 1.029 ace 0c: Gee - - 7383 813 15-131 7.0 1.019 ucc uec - Mean 51 8.2 1.024 30 7367 Died, week 7 7455 40 3?8 6.6 1.031 H- 1?3 out: OCC 7382 1" Med, week 13 7387 Died. week 12 "can ?40 6.6 1.031 7361 Died. week 5 7456 Died. week 2 7335 ?led, week 3 7381 Died, week 4 tr - Trance 8 Straw - Negative QNS - Quantity not suf?cient 137 1+ 'l'rare to slight LS - Light 8! raw - Few norm Nurmal 2+ - Slight tn nunlerate HS Dark Straw I. loaded - Nnm- m-un 3+ - Moderate Mm LIght Amber Many - Marked llAm - Dark Amber ll Rare rl - (llumly m?c - UccaHlonnl 1' 82 339d . awi BEST BBPY AVAIMILE Page 29 Tinety Day Subacute Rhesus Monkey Toxicity Study. TABLE 16. Summary of Gross Necropsy Observations. Terminal Sacrifice. mZ/ke/dav 100 I -2 nefk: dav 7 3 meszldav [ram l'n' Site Lesion 5 was: 7362 I 5(15 1156 7Jh? 73bb 7384 IJBS 7458 IIBJ [lb] 7455 ii?! Ilbl Vial So Gross Lesions A -u na :er swelling, area alopecia dehydrated emaciated red vaginal discharge scab. facial area N) Lung mite lesion adhesions dark red focifreddish purple area yellow, white foci nodules Heart nemo rhage, subendocardial gelatinized fat, endocardial atrophy Sodas enlarged reddish black in color Thymus atropny Abdominal Cavity depletion of fat 2? red foci a on. mucosa, pyloric portion hyperemia ge;atinous material, portion 3 ge, fundic mucosa Smal; Incastine greenisn-gray mucoid material dark red/brown mucoid material liquid, blood tinged fluid red'ish brown in color congestion, mucosa hemorrhage, mucosa a age, :ucosa a :disn black foci lid. blood stained contents 3 *Died on Study 001753 BEST WNW Mirage 3? FC-143: Ninety Day Subacute Rhesus Monkey Toxicity Study. TABLE 16. Cont. Summary of Gross Necropsy Observations. me/ke/dav 3 mg/kz/dav lO oR/kz/dav 30 agreefdav 100 nelke/dav 22's.; 22;: :z'aza E211 ?222: :93? Si-e sumac can-U? hm- Ti 25% ?522 ?225 .imzs sci; coin ?e50? 355] NIKE-- Ears-sh. Kin-E mix: 23:: Pancreas accessory spleen 3 Liver brownish color 3 accentuated looulations granular surface yellowish mottling reddish yellow color Kioneys brownish discoloration Skin subcutaneous edema, abdomen SuoCuraneOus hemorrhage, abdomen 1"Died on cud? 601754 SSLTOO 80?143: Nlnety Hay Suhacute Rhesus Monkey Study. TABLE I7. .-. .2 Ahsnlule and Relative (I Bndy Wright) 0rgan and Deaths. Group, limly 11 25 Number Sex kg 3 I 2x10 3 2x10' 14269111108155. Qmu??= 7362 1.25 2.35 0.07 70.73 2.18 0.65 0.20 11.82 0.16 0.85 0.03 7365 3.85 7.87 0.20 79.15 2.06 0.71 0.18 17.06 0.44 3.23 0.08 3.55 5.11 0.14 74.94 2.12 0.68 0.19 14.44 0.40 2.04 0.06 7316 3.40 5.03 0.15 84.79 2.49 - - 13.80 0.41 0.28 0.82 7386 3.50 3.87 0.11 77.77 2.22 0.62 0.18 19.58 0.56 0.27 0.77 Menu 3.45 4.45 0.13 81.28 2.36 0.628 0.18? 16.69 0.48 0.28 0.80 2.531k6/qny= 7364 4.10 4.67 0.11 91.40 2.23 0.77 0.19 19.76 0.48 3.66 0.09 7366 2.65 1.87 0.07 63.17 2.38 0.82 0.31 12.40 0.47 0.85 0.03 Mean 3.38 3.27 0.09 77.29 2.31. 0.80 0.25 16.08 0.47 2.26 0.06 7384 3.70 6.82 0.18 102.64 2.77 0.78 0.2] 17.60 0.48 0.18 0.49 7385 3.45 2.94 0.09 67.25 1.95 0.55 0.16 14.44 0.42 0.16 0.46 1km": 3.58 4.88 0.13 84.95 2.36 0.67 0.19 16.02 0.45 0.17 0.48 1.0. 136.1111; {(181 7363 3.80 2.39 0.06 87.25 2.30 0.74 0.19 16.84 0.44 1.75 0.05 7458 3.25 4.91 0.15 82.30 2.53 0.67 0.21 16.54 0.51 1.99 0.06 Mean 3.53 3.65 0.11 84.78 2.41 0.71 0.20 16.69 0.48 1.87 0.05 7328 3.55 4.06 0.11 83.00 2.34 0.66 0.19 15.32 0.43 0.29 0.02 7383 3.70 3.99 0.11 85.35 2.31 0.86 0.23 13.56 0.37 0.39 1.05 Mean 3.63 4.03 0.11 84.18 2.12 0.76 0.21 14.44 0.40 0.34 0.94 :12 396112616111 7455 2.40 1.50 0.15 70.76 2.95 0.84 0.15 16.85 0.70 1 16 0.05 Deaghg: 30 92 ?g [111! 7367 2.10 1.45 0.07 75.33 3.59 1.63 0.78 16.34 0.78 1.94 0.09 7382 2.35 3.01 0.13 112.87 5.02 1.74 0.77 19.03 0.85 0.21 0.93 7387 2.25 1.97 0.09 85.17 3.79 1.20 0.53 15.96 0.71 0.32 1.42 100 7361 2.40 1.65 0.07 79.02 3.29 1.59 0.66 21.88 0.91 1.37 0.06 7456 2.70 1.76 0.07 85.08 3.15 1.45 0.54 14.77 0.55 0.71 0.03 7335 2.05 2.49 0.12 74.28 3.62 1.03 0.50 15.40 0.75 0.!0 0.51 7381 2.60 3.05 0.12 82.58 3.18 1.16 0.45 18.28 0.70 0.13 0.50 ?rnup relative organ vsighls ?hnun In this table were hy averaging 100 individually 137-090 weighty. *Slgniflnantlv group mun". p<0.05. {rum krnup mun". In analysis. -- lint ,J?iu?l 1g 339d 9341300 l-?li? I 1'1 I I (20111. linmp NunkL-y Number $11ch [100: 11503303 7362 7365 "mm 7336 73110 Menu 736-51 7 1671 Menu 738/1 7 385 Moan 19.004404907: 736] 71158 Mean 7 328 7 38'! Menu 21101111013120 7?155 22.9.1110 30 7367 7382 7387 100 Ig?/kg/dux: 7361 71156 7335 738] I 37-090 Ninety Day Sulmcute thm?k?ey Toxicity Study. -1-.- . Absolute (Grams) and Relatlve (2 Body Weight) Urgau Heights, 'l'erlnlual Sacrifice and Deaths. -7- . - 4 - 2.- Body Ht. -. _q 7 . llul_111ry . Sex kg 2 p, 71d? 0 3.25 11.09 0.30 1.050 0.32 87.04 2.00 0.051 0.10 0 3.05 10.17 0.47 0.290 0.00 90.39 2.35 0.003 0.10 3.55 14.93 0.42 0.073 0.20 08.72 2.51 0.050 0.10 3.40 15.30 0.45 - 02.04 2.43 0.050 11.15 7 3.50 14.75 0.42 0.039 0.24 01.55 2.33 0.073 0.21 3.45 15.03 0.44 0.0398 0.248 02.10 2.30 0.003 0.10 0 4.10 10.90 0.40 0.093 0.22 90.01 2.34 0.000 0.20 11 2.05 12.70 0.40 0.370 0.14 03.50 3.15 0.051 0.19 3.30 15.00 0.47 0.030 0.18 09.70 2.75 0.000 0.104 0 3.70 10.07 0.40 01094 0.19 70.00 2.13 0.000 0.23 3.45 15.19 0.44 0.543 0.10 00.21 2.32 0.053 0.15 3.50 10.03 0.45 0.019 0.17 79.44 2.23 0.070 0.19 11 3.00 15.10 0.40 1.211 0.32 77.73 2.05 0.003 0.17 3.25 14.14 0.44 0.400 0.15 83.30 2.57 0.047 0.14 3.53 14.02 0.42 0.050 0.23 00.50 2.31 0.055 0.10 3.55 11.05 0.33 0.401 0.13 77.19 2.17 - 3.70 11.09 0.32 0.537 0.15 75.00 2.05 0.071 0.10 3.03 11.77* 0.32** 0.499 0.14 70.54** 2.11 0.071.1 0.10n 2.40 10.50 0.44 0.292 0.12 75.01 3.13 0.049 0.20 0 2.10 10.39 0.49 0.532 0.25 02.27 3.92 0.008 0.32 2.25 11.93 0.53 0.543 0.24 03.22 3.70 0.070 0.31 2.25 10.21 1L45 0.045 0.30 91.45 4.00 0.057 1025 0 2.40 14.54 0.01 0.791 0.33 92.43 3.05 0.072 0.30 0 2.70 15.55 0.50 0.710 0.27 95.42 3.53 0.040 0.17 2.05 11.44 0.50 0.479 0.23 74.20 3.02 0.050 0.27 2.00 12.95 0.50 0.417 0.10 80.20 3.32 0.002 0.32 l?ronp mean relative organ welghm shown l_n li1l0 [:1I1lo wert- calculated luy nveraglnp individually 1:1l1ulnlul 1111? 7111170 organ group 1110111. 11 0. US. (Ilffment 111111111 7111-7111, Nut ?1011111911 in 1111:1Iysi11. -Nul zg 989a Page 33 pc-143: Ninety Day Subacute Rhesus Monkey Toxicity Study. TABLE 18. Microscopic observations. Control 3 mg/kg/dav 10 mg/kg/dav 30 mg/ka/day 100 mg/kg/day 35:; Lesion Brain 1 1 focal perivascular infiltrates 3 Spinal cord r?I pa 0" Peripheral nerve 1 1 1 1 Sarcocystis 3p. in ocular muscle focal infiltrates in sclera 3 focal infiltrates in lacrimal gland 3 3 focal infiltrate in palpebral conjunctiva 3 cystic tarsal gland MU Pituitary 1 diffuse congestion 3 small ls) b) h! Thyroid 1 1 1 1 1 foci of interstitial infiltrates focal interscitial fibrosis diffuse congestion um Parathyroid - - - - - - - - - - - I diffuse congestion Tongue foci of inflammatory cell infil- trates in lamina propria and mucosal epithelium 3 3 foci of inflammatory cell infil- trates in muscle sarcocystis 313. la) hi IO Code: - condition present A moderate a - autolyzed 5 - marked 1 - not remarkable 6 - extreme 2 - very slight - not available 3 - slight *Died or sacrificed 137-090 001757 TABLE 15. Cont. Tissue Lesion Group, 5 Monkey 6 Numbe Tonsil foci of inflammatory cell infil- trates in mucosal epithelium and tonsillar Sarcocystis sp. in muscle Gongylonema sp. in mucosal epithelium atrophy of follicles 7362 Control 3 7365 Ninety Day Subacute Rhesus Monkey Toxicity Study. Microscopic Observations. 7336 7336 7366 7366 mg/kg/dav El- 7384 10 30 mg/kg/day k: be 7385 7363 7658 7328 7383 7455 I 7367* 7382* 7387* Page 34 100 mg/kg/day 7456* 7361* 7335* 7381* Adrenal foci of mineralizao tion diffuse congestion diffuse lipid depletion Eoci of infiltrates in sinusoids acidophilic degeneration of individual to small groups of cells Ulb Unu UnmN trachea foci of inflammatory cell infil- trates in lamina propria Salivary gland focal interstitial infiltrates diffuse congestion decreased cell size, loss of cytoplasmic granules ?c Lung acarian pigment (peribronchial, peribronchiolar, perivas- cular) focal perivascular infiltrates focal perihronchial/peribron- chiolar aggregates lung mite in bronchiolar lumen interstitial pneumonia diffuse congestion foreign body pneumonia focal hemorrhage acute focal broncnopneumonia numerous aggregates of pigment laden alveolar macrophages Code: 137-090 onH?K e~x condition present autolyzed not remarkable very slight slight [ll 4 - moderate 5 - marked 6 - extreme - - not available *Died or sacrificed in extremis (601758 Page 35 pc~1a3; Ninety Day Subacute Rhesus Monkey Toxicity Study. 13313 18. Cont. Microscopic Observations. Control 3 mg/kg/dav 10 mg/kg/dsy 3D me/kg/dav 100 mg/kg/dav 1m? 2352 a: as as as tzs? if Lesion Heart 1 I 1 focal interstitial infiltrates focus of infiltrate in endocardium 3 focal subendocardial hemorrhage 3 atrophy of epicardial fat 4 a 4 Aorta Spleen 1 1 atrophy of follicles diffuse congestion focal amyloidosis in follicles 3 increased amount of hemosiderin pigment 3 node 1 '1 1 1 1 1 atrophy of follicles a a a a a increased amount of hemosiderin pigment 3 3 neutrophil infiltrate in sinuses 3 3 5 diffuse congestion 3 3 hyperplasia 3 Esophagus 1 foci of inflammatory cell infil- trates in lamina propria ice: of interstitial infiltrates in muscularis 2 2 2 2 2 Gongylonema sp. in mucosal epithelium Stomach foci of inflammatory cell infil- trate in lamina propria diffuse congestion 2 3 3 3 foci of inflammatory cell infil- trates in submucosa 4 4 3 foci of inflammatory cell infil- trates in muscularis 3 3 foci of inflammatory cell infil- trates in serosa 3 parasitic granuloma in omentum focal mucosal hemorrhage 2 2 2 focal coagulation necrosis in mucosa 3 Code: - condition present 4 - moderate a - autolyzed 5 - marked 1 - not remarkable 6 extreme 2 - very slight - I not available 3 - slight *Died or sacrificed extremis 137-090 001759 Page 36 pc-143; Ninety Day Subacute Rhesus Monkey Toxicity Study. TABLE 18. Cont. Microscopic Observations. Control 3 mg/kg/dav 10 mg/kg/dav 30 mg/kg/day 100 ng/kg/dav Tissue 8Lesion ?71?. 2 2 flSmall intestine diffuse villous atrophy 5 5 focal hemorrhage 3 3 3 diffuse congestion 3 3 3 3 3 focal aggregate of brown pigment- laden foamy macrophages in mesentery inflammatory cell infiltrates in serosa a atrophy of nodule A a 4 Cecum - 1 1 transmural inflammatory cell infiltrates A diffuse congestion 3 3 3 3 3 focal mucosal hemorrhage 2 2 a inflammatory cell infiltrates in serosa 2 parasitic granuloma in muscularis atrophy of nodule 4 A Colon 1 1 diffuse congestion 3 3 3 3 3 parasitic granuloma in suhmucosa transmural inflammatory cell infiltrates 4 focal mucosal hemorrhage 3 atrophy of nodule a A Rectum 1 1 1 - 1 diffuse congestion 3 3 3 3 inflammatory cell infiltrates in muscularis 3 atrophy of nodule a a Pancreas 1 1 a a focal periductal infiltrates 3 2 3 3 3 2 focal interstitial infiltrates 3 2 diffuse congestion 3 3 3 Thymus Code: - conditiOn present a - moderate a - autolyzed 5 - marked 1 - not remarkable 6 - extreme 2 - very slight - not available 3 - slight *Died or sacrificed ?g?g?gzgg$? 137-090 001760 Page 37 pc.143; Ninety Day Subacute Rhesus Monkey Toxicity Study. TABLE 15. Cong. Microscopic Observations. Control 3 mg/kz/dav 10 mg/kg/day 3O mz/kg/day 100 mg/kg/dav a a a Tissue Lesion Group, 8 Monkey 3 Number 7362 7365 7336 7386 736% 7366 7384 7385 7363 7458 7328 7383 7455 7367* 7382* 7387* 7&56* 7361* 7335* 7381* Liver portal inflammatory cell infil- traces inflammatory cell infiltrates diffuse congestion . a 3 3 3 3 3 acidophilic degeneration of individual to small groups of hepatocytes 3 3 diffuse hepatocellular hyper~ trophy with cytoplasmic vacuolation 3 3 neutrophil infiltrates in sinusoids 3 Ln) to La Li} L.) L.) La) Gallbladder a a a a a a foci of inflammatory cell infil- trates in lamina propria Kidney focal interstitial infiltrates 2 2 2 3 3 multinucleated lining epithelium in papillary ducts in medulla chronic interstitial nephritis 3 diffuse congestion microlith in renal tubules small foci of miner- alization Urinary bladder foci of inflammatory cell infil- trates in lamina propria diffuse congestion 3 3 3 3 Testes prepuheral development chronic focal vasculitis focal perivaacular infiltrate 2 l-?K Ovaries 1 1 1 1 small foci of mineral- ization 2 diffuse congestion UN Code: - condition present a - moderate a - autolyzed 5 - marked 1 - not remarkable 6 - extreme 2 - very slight - I not available 3 - slight *Died or sacrificed in ex2remis 7-090 001761 FC-th: TABLE 18. Cont. Tissue Lesion Group, 8 Monkey Prostate focal interstitial infiltrates focal infiltrate in corpus cavernosum Uterus diffuse congestion blood in uterine glands small foci of hemorrhage in endometrium brown pigment-laden macrophages in endometrium inflammatory cell infiltrates in endometrium proteinaceous fluid and inflam- matory cells in uterine lumen Vagina foci of infiltrates in lamina propria and mucosal epithelium foci of infiltrates in muscularis Sarcocystis sp. focal infiltrate in tunica adventitia diffuse congestion focal neutrophil infiltrate in mucosa Skeletal muscle Sarcoeystis sp. focal interstitial inflammatory cell infiltrates interstitial fibrosis iotal/multifocal atrophy of muscle increased sarcolemmal nuclei Skin brown/black pigment in dermis dermal inflammatory cell infil- trates diffuse acanthosis iffuse congestion hyperkeratosis few large areas of hemorrhage in subcutis Code: 137-090 M. Number I 7362 Control I 7365 Microscopic Observations. II: 7336 3: 7386 7364 7366 ha {in 7384 - condition present autolyzed not remarkable very slight slight 3 mg/kR/dav 7385 at China? Died or sacrificed Ea extremis Ninety Day Subacute Rhesus Monkey Toxicity Study. 10 mg/kg/dav 30 7363 7458 7328 7383 7455 moderate marked extreme not available mg/kz/dav 7367* 7382* Nb) OJ 7387* Page 38 100 mg/ke/day 3: 7456* 7361* 7335* 7381* I U1 P- 001762 IABLE 18. Cont. Ninety Day Subecute Rhesus Monkey Toxicity Study. Microscopic observations. Page 39 Control 3 mg/kg/day 10 mg/kg/dev 3O mg/kg/dev 100 mg/kg/dav a a 2 Tissue 3333383333222333332; Lesion 22222222232232222222 Mammary gland 1 brown pigment in dermis hyperkeretosis detail inflammatory cell infil- trates inflammatory exudate in eciner lumen/ducts 2 2 2 inflammatory cell infiltrates in intrelobuler connective tissue 3 2 diffuse congestion 3 intrnepidermal microebscese Femur - - - - - - - - - - - - - 1 - 1 1 1 Bone marrow (Rib junction) 1 1 hypocelluler marrow 3 A 3 a 4 4 congestion Miscellaneous acute focal cheilitis, lip 4 Code: - condition present 4 - moderate a - autolyzed 5 - marked 1 not remarkable 6 - extreme 2 - very slight I not available 3 - slight *Died or sacrificed 137-090 001??6??