8ehq_0109_16913E
DCN: 89090000106s

January 22,2009
Via Federal Express
Document Processing Center (Mail Code 7407M)
Room 6428
Attention: 8(e) Coordinator
Office of Pollution Prevention and Toxics
U.S. Environmental Protection Agency
1201 Constitution Ave., NW
Washington, DC 20004

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Dear 8(e) Coordinator:
8EHQ-07- 16913
Fluorinated Aliphatic Alcohol
This letter is to inform you of the results of a 90-day oril study in rats with the above referenced test
substance.

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Ninety-five male and ninety-five female Crl:CD(SD) dats were randomly assigned to five dosage groups
(Groups I through V), 10 rats per sex per groub, using a computer-generated (weight-ordered)
randomization procedure. An additional ten rats per s 'x in Groups I and V were assigned to the 1-month
7'
recovery phase of the study and an additional five rats er sex in Groups I through V were assigned to the
3-month recovery phase of the study. Rats assigned to the 10-day satellite portion of the study were
assigned to five dosage groups (Groups I through V , five rats per sex per group, using a computergenerated (weight-ordered) randomization
designated for possible future
biochemical analyses. Tissues fiom these rats were
for storage. If these tissues are
analyzed, the results ofthe analyses will be
the current report. Male and
female rats were administered formulations
in 0.5% (wlv) aqueous methylcellulose
administered the vehicle. All doses
prepared in reverse osmosis deionized water.
days via oral gavage
were administered once daily for 10
at dosages of 0 (Vehicle), 5,25,125,

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All rats were observed for viability at least twice
weekly during the acclimation period. At the
weekly thereafter, detailed clinical
Ophthalmological examinations were
main study prior to dosage and
daily before and one to two
postdosage period.

ay of the study and for general appearance at least
first week of dosage administration and once
conducted for all male and female rats.
ophthalmologist for all rats assigned to the
Clinical observations were recorded
animal), and once daily during the

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A functional observational battery (FOB) and motor activity assessment were conducted on all rats
designated for the main study and recovery evaluatio s prior to the initiation of test substance and/or
vehicle administration. During week 13 of test substa ce andlor vehicle administration, FOB and motor
activity evaluations were conducted on the rats designa ed for the main study evaluation and the 1-month
and 3-month recovery evaluations prior to the daily &age administration. Additional FOB and motor
activity evaluations were conducted on the rats dedipated for the 1-month and 3-month recovery
evaluations.
Body weights were recorded at least
during the dosage period and on the day before
the postdosage period (recovery rats
values were recorded weekly during the
on the day before sacrifice (feed left value).

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acclimation period (but not tabulated), weekly
Body weights were also recorded weekly during
sacrifice (terminal weight). Feed consumption
the postdosage period (recovery rats only) and

bmpany Sanitized

 14 (prior to necroiiy). Urine samples were collected during weeks 7, 9 and 14. On v;eek 14-of study and
after 1 and 3 months of recovery, whole blood was collected fiom main and recovery rats for plasma and
urine fluoride evaluation. Bone marrow smears were collected at the time of sacrifice. Blood, liver and fat
samples were also collected fiom all rats assigned to the main study and 1 and 3 month recovery periods for
possible analyses of test substance and/or metabolite. These blood, liver and fat samples were shipped to
the Sponsor for possible future analyses. If these anafyses are conducted in the future, the results of the
analyses will be reported in a supplement to the current report.
All rats were sacrificed by carbon dioxide asphyxiatiori on the day following the last administration of the
test substance andor vehicle and a gross necropsy was ierformed and organ weights recorded.
Rats assigned to the satellite groups were fasted after 3 PM (at least 15 hours) on the afternoon before their
scheduled sacrifice. Rats were sacrificed by carbon 'dioxide anesthesia and exsanguination on the day
following the last administration of the test substance andor vehicle, and a gross necropsy was performed.
At the time of sacrifice, liver samples were collected for possible future evaluation. Rats were discarded
without further evaluation.

Summary of Results

Male Rats
At 250 mgkglday, there was a significant increase in the number of male rats that were either found dead
or euthanized because of adverse clinical signs. Each df the deathslearly sacrifices at 250 mglkgtday were
attributed to the test substance and generally occurred after 56 to 8 1 dosages of the test substance had been
administered. Most of these deaths were attributed to( degeneration and necrosis in the kidneys. Three
male rats were also observed with moderate to marked Fmorrhage and acute inflammation in the nose.
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Dental effects were observed in male rats treated fith 250 mgkglday of the test substance during
the dosage period and were presumed related to the test substance. Relative to the vehicle control group
values, significantly more rats in the 250 mgkglday tiOsage group had excess salivation, urine-stained
abdominal fur, dehydration (based on skin turgor) and perioral substance. The dental effects noted during
the dosage period persisted into the recovery period, anh were noted in a significantly increased number of
male rats at 1. 125 mgkglday.
The adverse clinical signs observed during the detaileh clinical observations were consistent with those
mglkglday, significantly more male rats did not
observed during the standard clinical observations. At
appear normal during the detailed clinical observations
during the dosage period and weeks 14 to
occurred in significantly more male rats
18 of the recovery period. At 250 mglkgtday,
during weeks 19 to 24 of the study, in addition

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All ophthalmologic examinations appeared normal fort e male rats at the end of the dosage period. There
were no ophthalmological effects at any dose.
The average body weight gain at
vehicle control group value for
gains, mean body weights at the end of the
and remained reduced or
generally comparable
mglkglday or 25 mgkglday.

and 11% lower, respectively, than the
Interrelated with the reductions in body weight
were significantly reduced at 2 125 mgkglday,
period. Feed consumption values were
no effects on body weight gain at 5

With the exception of the reduction in the average body weight at 2 125 mgkglday, as previously
described, there were no effects on any parameters evaiuated in the functional observational battery, and
there were no changes in motor activity at any dose.

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There were no biologically important changes in the urin lysis parameters at any dose.

On day 43 of study, significant reductions in hernoglobid and hematocrit levels occurred at 250 mgkg/day.
At the end of the dosage period, red blood cell counts, hemoglobin and hematocrit levels were lower or

 activated partial thromboplastin time occurred in these :same dosage groups. These hematological changes
did not persist during the recovery period. There were no hematological effects at 5 mgkglday.
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There were no apparent treatment-related changes ini serum chemistry that occurred during the dosage
period. However, at the end of the dosage period, changes in serum chemistry that were presumed to be
test substance-related included an increase or significant increase in the albumin/globulin ratio at 2
25 mgkglday; and the inorganic phosphorus, proteid, albumin, total bilirubin and potassium at
Z 125 mgtkglday. There was also a reduction or significant reduction in blood urea nitrogen levels at 1
125 mgkglday. By the end of the recovery period, these changes in serum chemistry had resolved. There
were no serum chemistry effects at 5 mgkglday.
All necropsy observations for the male rats were considered unrelated to the test substance.
At the completion of the dosage period, a non-dosage-dependent reduction in terminal body weights
occurred at 2 125 mg/kg/day. Terminal body weights at 250 mgkglday remained reduced one month after
the completion of the dosage period. There were no terminal body weight effects at 5 mgkg/day or 25
mgkglday The absolute and relative (% brain weight) weight of'the liver and the paired kidneys was increased or
significantly increased at 2 125 mglkgtday at the end of the dosage period. Relative to body weight, these
organs were significantly increased at L 25 mg/kg/day at the end of the dosage period, and residual effects
were noted at 250 mgkglday one month after the completion of the dosage period. These observations
were not present three months after the completion of the dosage period. In addition, the relative weights
of the paired testes and paired epidydirnides was signifibantly increased at 2 25 mgkglday. There were no
absolute or relative weight effects on paired testes and pbired epidydimides at 5 mg/kg/day.
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In treated male rats, plasma fluoride levels were incdeased above control values and were statistically
significant in groups administered 25 mgkgiday and abbve. Mean plasma fluoride values at the end of the
dosing period were 0.1, 0.1, 0.2, 0.7 and 0.9 pdmL fo rats dosed with 0, 5, 25, 125, or 250 mgkglday.
Following approximately one month of recovery, plasma fluoride in the 250 mgkglday male group (the
only treated group evaluated at that time point) was still increased but had partial recovery. Plasma
fluoride levels were similar to control levels following approximately 3 months recovery. There was no
plasma fluoride level increase at 5 mgkglday.

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Urine fluoride (the product of urine
related manner in all treated dosage groups
during the dosing period at both the week 9
after I-month and 3-month recovery. There

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male rats at 125 (single cell
single cell necrosis, biliary
vacuolation). At 250 mgkglday, effects on the
of the ameloblastic epithelium) were also
in the 250 mgkglday treated male

hyperplasia, periportal inflammation and
teeth (ameloblastic dysplasia and
observed at terminal sacrifice.
rats. There were no

rats at 250 mgkg/day by the 1-month recovery
dysplasia and enamel dysplasia) and
There were no effects observed in

The liver findings were no longer apparent in the
sacrifice. Although decreased, effects on the
acinar cell apoptosis were apparent at the
the male rats at the 3-month recovery sacrifice.

Female Rats

urine .volume) was increased in a dosein the 1 25 mgkg/day dosage groups)
91 time points. Samples were not collected
increase at 5 mgkglday.

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At 125 mg/kglday, one female rat was sacrificed due to adverse clinical signs. There was also a significant
increase in the total number of female rats at 250 mg/k day that were either found dead or sacrificed due
to adverse clinical signs during the study. These dea hslearly sacrifices generally occurred after 19 to
73 dosages and were considered test substance-related! Most of these early deaths were attributed to
degeneration and necrosis in the kidneys. No mortality was observed at 5 mgkglday or 25 mgkg/day.

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 the dosage period and were presumed to be test substance-related. Significantly more female rats at 125
and 250 mg/kg/day had urine-stained abdominal fur, piloerection and scant feces, while excess salivation,
dehydration (based on skin turgor), hunched posture, ,coldness to the touch, ungroomed coat, decreased
motor activity and pale extremities were noted in sigriificantly more female rats at 250 mg/kg/day. The
dental effects noted during the dosage period persisted into the recovery period, and were noted in a
significantly increased number of female rats at 125 ahd 250 mg/kg/day. There were no adverse clinical
signs (including dental effects) observed at 5 mg/kg/day or 25 rngkglday.
The adverse clinical signs observed during the detailed clinical observations were consistent with those
observed during the standard clinical observations. At 125 mg/kg/day, there was a significant increase in
the number of female rats that did not appear normal: during the detailed clinical observations recorded
during the dosage period. These adverse observations included a significant increase in the number of
female rats observed with whitened teeth and urine-stabed abdominal fur in comparison with the vehicle
control group. At 250 mg/kg/day, there was an increase or significant increase in the number of female rats
that did not appear normal during the evaluation, which included dental effects; mild dehydration; urinestained abdominal fiw; coldness to the touch; ungroomed coat; decreased motor activity; ataxia; periorbital
swelling; brown fur on the lower midline; hunched posture; and slight excess salivation. There were no
adverse clinical signs observed during detailed clinical observations at 5 mg/kg/day or 25 mg/kg/day.
All eyes appeared normal for both sexes at the ophthalmologic examination prior to dosage administration.
There were no ophthalmological effects at any dose. i
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There were no test substance-related effects at any dosk on body weight or body weight gain observed in
the female rats during the dosage or recovery periods. I

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At 250 mg/kg/day, absolute and relative feed consumpt~onvalues were lower or significantly lower during
the entire dosage period. In general, female rats at 250 'mg/kg/day consumed less or significantly less feed
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on a g/day andlor a g/kg/day basis at each tabulated mterval
within the dosage period. There were no
effects on absolute and relative feed consumption valued at 5,25 or 125 mg/kg/day.

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With the exception of a single occurrence of unusual osture noted in the open field at 250 mg/kg/day,
there were no additional effects on any of the paramete s evaluated in the functional observational battery,
and there were no changes in motor activity at any dose.

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Significantly more female rats at 2 125 mg/kg/day had 'ace amounts of blood present in the urine at day 63
of study. In addition, a small amount of hemolyzed tra,e blood was present in the urine of five rats in the
25 mg/kg/day dosage group compared to one in the vehicle control group. A moderate amount of
hemolyzed trace blood was present in the urine o f t e rats in the 5 mg/kg/day dosage group; a large
amount of hemolyzed trace blood was present in the ine of one rat in the vehicle control group at this
same time point. These changes resulted in a statisticall, significant reduction in the number of female rats
at 2 25 mg/kg/day with blood absent in the urine. ~ h e r kwere no statistically significant changes observed
in trace amounts of blood present in urine at any dose t any other time point. At the end of the dosage
period, the specific gravity of the urine at 25 and 125 m g/day were significantly lower, and there were
trace amounts of protein present in the urine at 2 125 mg/kg/day. There were no biologically important
changes in the urinalysis parameters at the end of the recbvery period at any dose.

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In female rats, red blood cell counts, hemoglobin
d hematocrit levels were significantly lower at 2
125 mg/kg/day relative to vehicle control
43 of study. In addition, the percent red cell
distribution width, percent
were increased in these same dosage
groups. These findings, with the
reticulocytes, were consistent with
observations noted at the end of the
at 250 mg/kg/day reflected the only
surviving female in this dosage
of female rats to the test substance at
dosages of 125 or 250 mg/kg/day resulted in mild, but statistically significant reductions in the activated
partial thromboplastin time at the end of the dosage perrod. There were no effects observed on red blood
cell counts, hemoglobin levels, hematocrit levels, percent reticulocytes and absolute reticulocytes at 5
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mglkglday or 25 mglkdday.

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included a significant increase in cholesterol at 2 25'n&kg/day; albumin, total bilirubin and triglyceride
levels at P 125 mg/kg/day; and creatinine levels, blood/urea nitrogen levels, calcium levels and inorganic
phosphorus levels at 250 mg/kg/day. By the end of the dosage period, most of the changes in clinical
chemistry had resolved with the exception of the changes in total bilirubin levels. Additional findings that
occurred at the end of the dosage period included an increase or significant increase in cholesterol levels at
L 125 mg/kg/day, and elevations in aspartate aminotrandferase and alkaline phosphatase at 2 25 mg/kg/day.
The elevations in aspartate aminotransferase and alkaline phosphatase were consistent with changes in liver
weights that occurred in these same dosage groups. There were no residual effects of the test substance
noted on serum chemistry parameters evaluated at the end of the recovery period. There were no serum
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chemistry effects at 5 mg/kg/day.
All necropsy observations in the female rats were considered unrelated to the test substance.
Terminal body weights were unaffected by dosages of the test substance as high as 250 mg/kg/day at the
end of the dosage period and during the recovery period.'
The absolute and relative (% body weight and % brain ,weight) weight of the liver and the paired kidneys
was increased or significantly increased at L 25 mg/kg(day at the end of the dosage period. One month
after the completion of dosage administration, the wkights of the liver and paired kidneys remained
significantly increased at 250 mg/kg/day. In general, /residual effects were noted in these organs three
months after the completion of the dosage period at P 25, mg/kg/day; however, these increases did not reach
statistical significance when compared to the vehicle bontrol group values. There were no absolute or
relative organ weight effects at 5 mg/kg/day.
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In treated female rats, plasma fluoride levels were incfeased above control values and were statistically
significant in groups administered 1 125 mg/kg/day. M an plasma fluoride values at the end of the dosing
period were 0.1,0.1, 0.1, 0.6 and 1.1 pg/mL for rats dos ; d with 0, 5,25, 125, or 250 mg/kg/day. Following
approximately one month of recovery, plasma fluoride in the 250 mg/kg/day female group was still
increased but had partial recovery. Plasma fluoride levels were similar to controls following approximately
3 months of recovery. There were no plasma fluoride inLreases at 5 rng/kg/day or 25 m a d d a y .

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Urine fluoride (the product of urine fluoride
related manner in all treated female dosage groups
25 mg/kg/day) during the dosing period at both the
not collected after 1-month and 3-month recovery.

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urine volume) was increased in a dosesignificant in the female rats dosed with 3
day of study 91 time points. Samples were
urine fluoride increase at 5 mgkglday.

Histopathological effects in the liver were observed at tkrminal sacrifice in the female rats at 25 (oval cell
hyperplasia) and 125 rnglkgiday (single cell necrosis land oval cell hyperplasia). There was only one
0 mg/kg/day dosage group and there were no
female rat remaining at terminal sacrifice in the
histopathological effects observed in this female.
were no histopathological effects in the liver at 5
mg/kg/day.
At 250 mg/kg/day, the liver findings (oval cell
teeth (loss of ameloblastic epithelium and
at the 1-month recovery sacrifice. The
female rats in the 125 and 250

and periportal pigmentation), effects on the
and acinar cell apoptosis were all apparent
the 3-month recovery sacrifice was a few
residual biliary hyperplasia.
Sincerely,