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Diss Factsheets

Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
31 August 2007 - 30 March 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: OECD Guideline study under GLP conditions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1,1,1,3,3,3-hexafluoropropan-2-ol
EC Number:
213-059-4
EC Name:
1,1,1,3,3,3-hexafluoropropan-2-ol
Cas Number:
920-66-1
Molecular formula:
C3H2F6O
IUPAC Name:
1,1,1,3,3,3-hexafluoropropan-2-ol
Details on test material:
- Physical state: Colorless clear liquid
- Purity: 99.9%
- Lot/batch No.: 3SMZD
- Stability under test conditions: Stable

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
- Source: Charles River Japan (Atsugi Farm)
- Age at study initiation: 9 weeks-old
- Weight at study initiation: Male: 317-361 g, Female: 199-251 g
- Fasting period before study: none
- Housing: Males and females were housed in stainless-steel wire-meshed cages except for gestation and lactation periods. During gestation and lactation periods, females were housed in polycarbonate cages.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: one week including quarantine period
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.8-23.6°C
- Humidity (%): 49.8-61.8%
- Air changes (per hr): 6-20 times per hour
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light

Administration / exposure

Route of administration:
oral: gavage
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Dosing solutions were prepared daily before administration Using purified water as a vehicle, solution with a concentration of 30 mg/mL was prepared first. Then, the solution was diluted with vehicle and prepared as solutions with concentrations of 1 and 6 mg/L.
Details on mating procedure:
M/F ratio per cage: 1:1
Length of cohabitation: up to 14 days
Proof of pregnancy: Vaginal plug or sperm in vaginal smear referred to day 0 of pregnancy.
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Because of high volatility of the test article, analytical verification of doses could not be performed.
Duration of treatment / exposure:
Male: 42 days including 14-days pre-mating period and mating period
Female: 42-52 days including 14 days pre-mating, mating and gestation periods, and days until lactation day 4.
Frequency of treatment:
once daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 10, 60, 300 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
Administration groups:
Control and high dose groups: 7 males and 12 females per dose
Low and mid dose groups: 12 per sex per dose

Recovery groups:
Control and high dose groups: 5 per sex per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: In 14-days preliminary study, a dose of 500 mg/kg/day tested was proved to be excess because of poor general conditions for the test animals. As a consequence, the top dose in the
main study was set down to 300 mg/kg/day. The mid and low doses were set as 60 and 10 mg/kg/day, respectively.
- Rationale for selecting satellite groups: Satellite groups for recovery study were set for control and high dose groups.
- Post-exposure recovery period in satellite groups: 14 days
Positive control:
none

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: 3 times (before and just after administration and about 3 hrs after administration) per day during administration period. Once daily during period other than administration.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: (Males) Day 1, 8, 15. 22, 29, 36, 42 and 43. (Females) Pre-mating Day 0, 7 and 17, once a week during mating period, gestation day (GD) 0, 7, 14 and 20, and lactation day 0
and 4. (Males and females, recovery groups) Day 50 and 56.

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/day: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OTHER:
HAEMATOLOGY: Yes
- Time schedule for collection of blood: (Males) Day 43; (Females) Lactation day 5; (Males and females, recovery) Day 57
- Anaesthetic used for blood collection: Yes (sodium pentobarbital)
- Animals fasted: Yes, 18-23 hrs from the day before.
- How many animals: 5 per sex per group
- Parameters checked in table 1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: the same schedule as haematology
- Animals fasted: Yes
- How many animals: 5 per sex per group
- Parameters checked in table 2 were examined.

URINALYSIS: Yes, but males only
- Time schedule for collection of urine: (Males) Day 40
- Metabolism cages used for collection of urine: No
- Animals fasted: Yes
- Parameters checked: pH, protein, glucose, keton body, birillubin, occult blood, urobilinogen

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: the day before start of administration, once a week during administration
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other: reactivity to stimuli
Oestrous cyclicity (parental animals):
Estrous cyclicity observation: performed daily from the imitation day of administration until confirmation of copulation.
Sperm parameters (parental animals):
Parameters examined in P male parental generations:
testis weight, epididymis weight
Litter observations:
The following parameters were examined in F1 offspring:
Number of pups delivered, Number of live pups on day 0, sex ratio, Number of live pups on day 4, body weight on day 0, body weight on day 4
Postmortem examinations (parental animals):
SACRIFICE:
Male animals: Rats were euthanized by exsanguination under anesthesia on the day after the last administration.
Maternal animals: Rats were euthanized by exsanguination under anesthesia on Day 4 of lactation.

GROSS NECROPSY: Yes, Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

- Histopathological examined organ:
Control and 300 mg/kg/day groups: Brain, Heart, Kkidneys, Adrenal glands, Thymus, Spleen, Lymph node ( mandibular), Lymph node ( mesenteric), Bone marrow ( femur), Trachea, Lung(and bronchus), Stomach, Small intestine, Large intestine, Urinary bladder, Seminal vesicle, Prostate, Coagulating gland, Pituitary, Thyroid, Parathyroid, Spinal cord, Sciatic nerve, Ovary, Uterus, Vagina
All groups: Liver, Small intestine(duodenum), Testes, Epididymides,
- Weighted organ:
Brain, Heart, Liver, Kidneys, Adrenal glands, Thymus, Spleen, Testes, Epididymides,
Postmortem examinations (offspring):
SACRIFICE: The F1 offspring were sacrificed on PND 4.
GROSS NECROPSY: On PND 4, the pups were euthanized by exsanguination under anesthesia and gross internal examinations were performed.
Statistics:
For parametric data, homogeneity of variance was examined by Bartlett method. When the variance was equal, ANOVA was used. While variance was not equal or non-parametric data was applied, Kruskal-Wallis
method was used. When significant difference was recognized among the groups, either Dunnett method or Dunnett multiple comparison test was used. For qualitative data, Dunnett multiple comparison test,
Wilcoxon rank sum test, Fischer's exact probability, Student or Aspin-Welch's t-test were used as necessary.
Reproductive indices:
Mating index (%) = (Number of pairs with successful mating/number of pairs examined)×100
Fertility index (%) = (Number of pregnant animals/number of pairs with successful mating)×100
Gestation index (%) = (Number of females with live pups/number of pregnant females)×100
Implantation index (%) = (Number of implantation sites/number of corpora lutea)×100
Delivery index (%) = (Number of pups delivered/number of implantation sites)×100
Offspring viability indices:
Live birth index (%) = (Number of live pups on day 0/number of pups delivered)×100
Viability index (%) = (Number of live pups on day 4/number of live pups on day 0)×100

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
effects observed, treatment-related
Reproductive function: sperm measures:
not examined
Reproductive performance:
effects observed, treatment-related

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
-No abnormality was found at 10 and 60 mg/kg groups of both sexes. At 300mg/kg, prone position and a decrease in locomotor activity were observed in both sexes. These changes were seen throughout the administration period in one to almost all animals from immediately after dosing and disappeared by 3 to 6 hours after dosing. One of the females died during the delivery following administration on day 24 of gestation. In this animal, prone position and a decrease in locomotor activity were observed and did not disappear even after 6 hours after dosing on the day before death.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
-There were no changes in body weight and body weight gain in male and female groups of 10 and 60 mg/kg. In females at 300 mg/kg, body weight decreased or tended to decrease from the late gestation until day 4 of lactation. The body weight of males in this group tended to decrease late in the administration period, but recovered during the recovery period.

-There were no changes in food consumption in male and female groups of 10 and 60 mg/kg. At 300 mg/kg, food consumption in the females showed a decrease or a tendency to decrease in the latter gestation
and lactation period. Food consumption in males at 300 mg/kg was comparable to that of the control group during the administration period, but it decreased during the recovery period.

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
At 300 mg/kg, the mean estrous cycle was prolonged to 6 days in 4 dams and the mean estrous cycle in this group was significantly prolonged.

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
The copulation index was 83.3% (10/12 animals) at 300 mg/kg while other groups were all 100 % (12/12 animals).
During the gestation period, none of the dams completed the delivery on day 22 of gestation and one of them showed dystosia as it delivered on day 25 of gestation. The gestation length was prolonged in this group.
These changes were suspected to be caused by anesthetic action of the test substance.
In numbers of corpora lutea, implantations, and offspring, although they were comparable to the control values, number of live offspring and delivery index decreased.

ORGAN WEIGHTS (PARENTAL ANIMALS) (See 7.5.1 Repeated dose toxicity (oral) : Table3)
-In males at 300 mg/kg, increase in relative liver weight, decrease in absolute and relative adrenal weight were observed. Decrease in adrenal weight was also observed in males at 10 and 60 mg/kg. When compared with the background data of the test facility, low values in groups of 10 and 60 mg/kg were within the range (mean±2S.D.). Therefore, these were considered not toxicologically significant.

GROSS PATHOLOGY (PARENTAL ANIMALS)
-In scheduled-necropsied animals, no treatment-related changes were observed.
-In one female dead animal, small size of spleen and thymus as well as dilatation of renal pelvis were observed. Moreover, black patch in mucosa of fundic gland or pylric region.

HISTOPATHOLOGY (PARENTAL ANIMALS)(See 7.5.1. Repeated dose toxicity (oral) : Table 4)
-Changes considered as treatment-related were limited to both sexes groups at 300 mg/kg.
-In scheduled-necropsied animals, centrilobular hypertrophy of hepatocytes were observed in 2 males and 3 females at this dose. In the same male group, erosion of duodenal mucosa was observed. In the recovery group, theses changes were not recognized.
-In dead female animal, the following changes were observed: erosion with hemorrhage in the fundic mucosa and erosion of the duodenal mucosa with hypertrophy of the duodenal glands, errosion of cecum, hypertrophy of the cortical cells in the fascicular zone, atrophy of the hematopoietic tissues, and necrosis of lymphocytes in thymus and mandibular lymph node.

OTHER FINDINGS (PARENTAL ANIMALS)
HAEMATOLOGY (See 7.5.1 Repeated dose toxicity (oral) : Table 1):
-No change was noted up to 60 mg/kg in both sexes. At 300 mg/kg, reticulocyte count decreased in males, however, there was no difference in red blood cell count as compared to the control group. Decreased platelet count in males and decreased white blood cell count in females were noted. Since there were no histological changes and they recovered at the end of the recovery period, the effects on the organism were considered to be slight.

CLINICAL CHEMISTRY (See 7.5.1 Repeated dose toxicity (oral) : Table 2):
-Increased triglyceride was noted in males and 1 female at 300 mg/kg. Although statistically not significant, a trend to increase in triglyceride was observed in male group at 60 mg/kg. Urea nitrogen increased in males at 300 mg/kg; however, creatinine did not differ from the control value without any effects on the renal function in other examinations. In female group at 300 mg/kg, decreases in calcium and potassium were observed. When compared with the background data of the test facility, potassium was within the range (mean±2S.D.) and calcium deviated from the range in 2 animals. Animal with the lowest value
demonstrated reduced food consumption, therefore it was suspected to be a nutritional change. These changes were not seen at the end of the recovery period.

NEUROBEHAVIOUR:
-In the detailed clinical observation, functional tests and motor activity measurement, the following changes were observed as the clinical sign at 300 mg/kg; prone/lateral position, crawling position, and abnormal gait in both sexes, slow reactivity to stimuli and disappearance of aerial lighting reaction in some males, decreased grip strength in both sexes, decreased motor activity in both sexes. PHF is the main metabolite of inhalative anesthetic, sevoflurane and reported to have central nervous system depression action. Moreover, PHF is a monohydric alcohol (C3) and C1 to C13 alcohol is known to have anesthetic potential. Therefore, these neurobehavioral signs were considered to relate to the central nervous system depression and anesthetic action of PHF.

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Effect level:
60 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: see 'Remark'
Dose descriptor:
NOEL
Effect level:
60 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: see 'Remark'

Results: F1 generation

General toxicity (F1)

Clinical signs:
not specified
Mortality / viability:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Histopathological findings:
not examined

Details on results (F1)

VIABILITY (OFFSPRING)
At 300 mg/kg, in addition to total litter loss in 3 dams including the above mentioned dystosia, the number of dead offsprings increased until 4 days after birth.
Consequently, the number of live offspring and viability index on day 4 decreased.
For these changes, the anesthetic action of the test substance was likely to work on the maternal behavior.

BODY WEIGHT (OFFSPRING)
Moreover, although the body weight at birth was comparable to that of the control group in both sexes, the variability index and body weight on day 4 decreased.

There were no significant differences between the test substance-treated groups and control group in number of days until copulation, incidence of females without the estrous cycle, fertility index, implantation index, numbers of corpora lutea and implantation, gestation index, and number of offspring.
SEXUAL MATURATION (OFFSPRING)

ORGAN WEIGHTS (OFFSPRING)

GROSS PATHOLOGY (OFFSPRING)
In offspring at 300 mg/kg, among fetuses or dead offsprings of 3 dams including the dead dam during the gestation period, generalized edema and protruding tongue were observed in 20 fetuses/offsprings and in 22 fetuses/offsprings, respectively.
In this group, increased pleural fluid was observed in 3 offsprings.
Blackish and/or dark reddish abnormal contents in the intestine were observed in 6 offsprings.
Since it is reported that ethanol similar to a monohydric alcohol (C3) of PHF affected the offspring’s intestines by embryonic exposure, this change was suspected to be test substance effects.

HISTOPATHOLOGY (OFFSPRING)

OTHER FINDINGS (OFFSPRING)

Effect levels (F1)

open allclose all
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
60 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Dose descriptor:
NOEL
Generation:
F1
Effect level:
60 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Table 1 Fertility and pregnancy data in rats treated orally with 2-Propanol, 1,1,1,3,3,3-hexafluoro- in the combined repeated dose and reproductive/developmental toxicity screening test

Dose level (mg/kg) Administration period
0 10 60 300

Number of pairs examined

12 12 12 12
Estrous cycle  4.25 ± 0.40  4.09 ± 0.30 4.22 ± 0.44 5.23 ± 0.68**
Irregular estrous cycle 0/12 1/12 3/12 1/12
Number of pairs with successful mating 12 12 12 10
Mating index (%) a) 100.0 100.0 100.0 83.3
Number of pregnant females 12 12 11 10
Fertility index (%) b) 100.0 100.0 91.7 100.0
Pairing days until mating 2.7 ± 1.2 3.3 ± 2.5 1.9 ± 1.4 3.2 ± 2.1
Number of estrous stages without mating 0.0 ± 0.0  0.0 ± 0.0  0.0 ± 0.0  0.1 ± 0.3

a) Mating index (%) = (Number of pairs with successful mating/number of pairs examined)×100

b) Fertility index (%) = (Number of pregnant animals/number of pairs with successful mating)×100

Values are expressed as Mean ± S.D.

Significantly different from 0 mg/kg group; * p<0.05, ** p<0.01

Table2 Delivery and litter data in rats treated orally with 2-Propanol, 1,1,1,3,3,3-hexafluoro- the combined repeated dose and reproductive/developmental toxicity screening test

Dose level (mg/kg) Administration period
0 10 60 300
Number of females examined 12 12 11 10
Number of females with live pups 12 12 11 9
Gestation index (%) a) 100.0 100.0 100.0 90.0
Gestation length (days)   22.3 ± 0.5  22.6 ± 0.5  22.7 ± 0.5  23.4 ± 0.7**
Number of corpora lutea 16.3 ± 2.3  17.5 ± 1.8  16.9 ± 2.8  17.7 ± 2.5
Number of implantation sites 15.2 ± 2.0  16.4 ± 1.8  15.3 ± 3.4  16.2 ± 2.4
Implantation index (%) b) 93.03 ± 4.60  93.93 ± 5.44  89.18 ± 9.10  91.78 ± 4.35
Delivery index (%) c) 95.68 ± 4.75  92.38 ± 4.38  95.40 ± 6.44  80.64 ± 18.94
Number of pups delivered 14.5 ± 2.0  15.2 ± 1.9  14.5 ± 3.4  13.3 ± 4.5
Number of live pups on day 0 14.5 ± 2.0  15.1 ± 1.9  14.3 ± 3.4  10.4 ± 4.9
Number of live pups on day 4 14.3 ± 2.1  14.9 ± 1.6  14.2 ± 3.4  5.2 ± 5.3**
Live birth index (%) d) 100.00 ± 0.00  99.44 ± 1.93  98.10 ± 3.30  70.20 ± 33.60**
Viability index on day 4 (%) e) 98.23 ± 3.28  99.07 ± 2.18  99.44 ± 1.87  39.71 ± 40.52**
Sex ratio of total number of offspring at birth (M/Total) 0.53 (92/174)  0.51 (92/182)  0.46 (73/160)  0.53 (62/117)
Sex ratio of total number of live offspring at birth (M/Total) 0.53 (92/174)  0.51 (92/181)  0.45 (71/157)  0.57 (54/94)
Sex ratio of total number of live offspring on day 4 (M/Total) 0.53 (91/171)  0.51 (91/179)  0.45 (70/156)  0.55 (26/47)
Sex ratio of total number of offspring at birth (M/Total, litter) 0.531 ± 0.098  0.497 ± 0.124  0.464 ± 0.110  0.497 ± 0.208
Sex ratio of total number of live offspring at birth (M/Total, litter ) 0.531 ± 0.098  0.499 ± 0.122  0.458 ± 0.105  0.577 ± 0.145
Sex ratio of total number of live offspring on day 4 (M/Total, litter ) 0.533 ± 0.097  0.501 ± 0.123  0.455 ± 0.103  0.650 ± 0.208
Body weight of pups (g)
on day 0 male 6.7 ± 0.4  6.9 ± 0.6  7.1 ± 0.7  6.3 ± 0.4
on day 0 female 6.3 ± 0.4  6.5 ± 0.6  6.7 ± 0.9  5.8 ± 0.3

on day 4 male

10.4 ± 0.9  10.7 ± 1.0  11.1 ± 2.2  7.1 ± 2.3*
on day 4 female 9.9 ± 1.0  10.2 ± 1.0  10.5 ± 2.2  7.4 ± 1.5*

a) Gestation index (%) = (Number of females with live pups/number of pregnant females)×100

b) Implantation index (%) = (Number of implantation sites/number of corpora lutea)×100

c) Delivery index (%) = (Number of pups delivered/number of implantation sites)×100

d) Live birth index (%) = (Number of live pups on day 0/number of pups delivered)×100

e) Viability index (%) = (Number of live pups on day 4/number of live pups on day 0)×100

Values are expressed as Mean±S.D.

Significantly different from 0 mg/kg group; * p<0.05, ** p<0.01

Applicant's summary and conclusion

Conclusions:
As for the reproductive and developmental toxicity, the NOEL and NOAEL for parental animals and offspring were judged to be 60 mg/kg/day, since prolonged estrous cycle and gestation length, decreased copulation index and delivery index in dams as well as generalized edema and protruding tongue, a change in the color of the gastrointestinal contents, decreased number of live offspring, body weight, and viability index in offspring were noted in the 300 mg/kg group.
Executive summary:

In accordance with the OECD guideline on combined repeated dose and reproductive/developmental toxicity screening test, 2-propanol, 1,1,1,3,3,3-hexafluoro- (PHF) was studied for oral toxicity in rats at doses of 0, 10, 60, and 300 mg/kg/day.

At 300 mg/kg, the mean estrous cycle was prolonged to 6 days in 4 dams and the mean estrous cycle in this group was significantly prolonged. The copulation index was 83.3% (10/12 animals) at 300 mg/kg while other groups were all 100 % (12/12 animals). During the gestation period, none of the dams completed the delivery on day 22 of gestation and one of them showed dystosia as it delivered on day 25 of gestation. The gestation length was prolonged in this group. These changes were suspected to be caused by anesthetic action of the test substance. In numbers of corpora lutea, implantations, and offspring, although they were comparable to the control values, number of live offspring and delivery index decreased.

In offspring at 300 mg/kg, among fetuses or dead offsprings of 3 dams including the dead dam during the gestation period, generalized edema and protruding tongue were observed in 20 fetuses/offsprings and in 22 fetuses/offsprings, respectively. In this group, increased pleural fluid was observed in 3 offsprings. Blackish and/or dark reddish abnormal contents in the intestine were observed in 6 offsprings. Since it is reported that ethanol similar to a monohydric alcohol (C3) of PHF affected the offspring’s intestines by embryonic exposure, this change was suspected to be test substance effects. At 300 mg/kg, in addition to total litter loss in 3 dams including the above mentioned dystosia, the number of dead offsprings increased until 4 days after birth. Consequently, the number of live offspring and viability index on day 4 decreased. For these changes, the anesthetic action of the test substance was likely to work on the maternal behavior. Moreover, although the body weight at birth was comparable to that of the control group in both sexes, the variability index and body weight on day 4 decreased.

There were no significant differences between the test substance-treated groups and control group in number of days until copulation, incidence of females without the estrous cycle, fertility index, implantation index, numbers of corpora lutea and implantation, gestation index, and number of offspring.