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Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

2-Generation Rat Diet: Not a reproductive toxin. OECD 416; Reliability = 1

Link to relevant study records
Reference
Endpoint:
two-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPP 83-4 (Reproduction and Fertility Effects)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: EEC Directive 87/302/EEC: Two-Generation Reproduction Toxicity test
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: MAFF Toxicity Testing Guidelines for Reproduction Studies
Deviations:
no
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
Test substance name: XDE-795
Lot Number: TSN 100097
Purity: 97.4 ± 0.2%
Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
This strain of rat was selected because of its general acceptance and suitability for toxicity testing, and the availability of a reliable commercial source.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratory, Kingston, New York
- Age at study initiation: Approximately 6 weeks
- Weight at study initiation: P1: Males: 170.2 - 171.4 g, Females: 175.8 - 177.5 g
- Housing: Rats were housed singly in wire mesh, stainless steel cages in racks provided with deotized cage board to minimize odor and aid in maintaining a clean environment. During the gestation/lactation phases of the study, P1 females were housed in plastic cages provided with ground corn cob nesting material. The sperm-positive P2 adult females were transferred from the males breeding cage back to the wire mesh, stainless steel cages on gestation day 0. Sperm positive P2 females were then transferred to plastic nesting cages on or prior to gestation day 19. P2 females which failed to mate were transferred to nesting cages at the completion of the three week mating period.
- Diet: Purina Certified Rodent Chow No.5002, ad libitum
- Water: Municipal drinking water, ad libitum
- Acclimation period: Approximately 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature: Approximately 22°C
- Humidity: Approximately 40-60%
- Air changes (per hr):12-15
- Photoperiod (hrs dark / hrs light): 12
Route of administration:
oral: feed
Vehicle:
other: Feed
Details on exposure:
Diets were prepared by serially diluting a test material/ feed concentrate (premix). The premix was ball-milled for approximately 20 minutes in order to ensure a homogeneous mixture. Premixes were prepared as necessary based on available stability data. The homogeneity of the test diets was confirmed during the course of the study.
The target concentration of test substance in the diets fed during the first two weeks of study was calculated using body weight and feed consumption data collected approximately one week prior to the study start. Thereafter, the concentration of the test material in the diets was calculated using weekly body weights and feed consumption data in order to maintain the targeted dose levels on a mg/kg/day basis. Test animals were maintained on the appropriate test diets for approximately 10 and 12 weeks of treatment prior to breeding of the first parental (P1) and second parental (P2) generations, respectively.
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: 3 week period
- Proof of pregnancy: Vaginal plug referred to as Day 0 of gestation
- After successful mating each pregnant female was caged: During the gestation/lactation phases of the study, P1 females were housed in plastic cages provided with ground com cob nesting material. The sperm-positive P2 adult females were transferred from the males breeding cage back to the wire mesh, stainless steel cages on gestation day 0. Sperm positive P2 females were then transferred to plastic nesting cages on or prior to gestation Day 19. P2 females which failed to mate were transferred to nesting cages at the completion of the three week mating period.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analyses of the test diets to determine the concentration of the test substance were performed at least three times per generation. Analyses of the test diets showed that the average concentration of test substance present in the diets ranged from 98 to 101% of the targeted concentrations. Analysis of diet samples dispensed from the top and bottom of the storage packs confirmed that the diets were homogeneous.
Duration of treatment / exposure:
Approximately 6 weeks of age to scheduled necropsy
Frequency of treatment:
Daily
Details on study schedule:
Treatment of the P1 rats began at approximately 6 weeks of age. After approximately 10 weeks on test diets, P1 rats were mated (one male to one female of the respective treatment group) to produce the F1a litters. Following weaning (3 weeks of age) of the F1a litters, 30 males and 30 females (one/sex/litter whenever possible) from each treatment group were randomly selected to become the parents for the next generation (P2 adults). Approximately one week after weaning of the last F1a litter, the P1 adults were again mated, to produce the F1b litters. After approximately 12 weeks of treatment following weaning of the last F1a litter, the P2 adults were bred to produce the F2 litters.
Dose / conc.:
5 mg/kg bw/day
Dose / conc.:
20 mg/kg bw/day
Dose / conc.:
100 mg/kg bw/day
No. of animals per sex per dose:
30
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: These dose levels were selected based upon the results of the 4- and 13-week dietary toxicity studies. The high dose was expected to produce decreases in body weights and histopathologic alterations in the liver. Intermediate and low doses were chosen to provide dose-response data for any treatment-related effects observed in the high-dose group and to ensure definition of a NOEL for the test substance.
- Rationale for animal assignment: These rats were randomly assigned by weight to the treatment groups inorder to increase the probability of uniform group mean weights and standard deviations at the initiation of the study.
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Each rat on study was observed daily for changes in behavior or demeanor. An additional observation for moribundity, mortality and the availability of feed and water was made at least once daily throughout the duration of the study.

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights was recorded weekly for all P1 adults during the pre-breeding treatment period, beginning on or before the first day of
the study. Male body weights were recorded weekly throughout the course of the study. Sperm-positive females and females observed with in situ vaginal plugs were weighed on days 0, 7, 14 and 21 of presumed gestation. Females that delivered litters were weighed on days 1, 4, 7, 14, and 21 of lactation.

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: During breeding, feed consumption of males and females was not measured due to cohousing. Following completion of the breeding periods, weekly feed consumption was again measured in males and dietary concentrations were adjusted accordingly. During gestation, feed consumption was measured at weekly intervals for presumed pregnant females. After parturition, feed consumption was measured twice a week through the first 2 weeks of lactation, and at 2 - 3 day intervals during the last week of lactation. A similar schedule was followed for the P2 generation.
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes


Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: No

PARAMETERS EXAMINED
The following parameters were examined in F1 / F2 offspring:
The parameters that were recorded on each litter includes, the date of parturition, litter size on the day of parturition (day 0), the number of live and dead pups on days 0, 1, 4, 7, 14, and 21 postpartum, and the sex and the weight of each pup on days 1, 4, 7, 14, and 21 of lactation. Any visible physical abnormalities or demeanor changes in the neonates were recorded during the lactation period.

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was/was not determined for pups born or found dead and discarded
Postmortem examinations (parental animals):
SACRIFICE
The scheduled necropsy was performed after the majority of the litters from the respective generation had been weaned.

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

HISTOPATHOLOGY
The tissues that were prepared for microscopic examination were cervix, coagulating glands, epididymides, kidneys, liver, mammary gland, ovaries, oviducts, pitutary glands, prostate gland, seminal vesicles, testes, uterus and vagina.
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring which were not selected as P2 adults and all F2 offspring were sacrificed at 21 days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows: At the time of weaning, 10 pups/sex/dose level from the F1a, F1b and F2 litters were randomly selected for a complete necropsy under the supervision of a veterinary pathologist. The pups were anesthetized with methoxyflurane and euthanized. Gross pathologic examination and preservation of tissue samples was performed for adults, except that testes and epididymides were preserved in neutral, phosphate-buffered 10% formalin. Histologic examination of tissues was not performed.

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
Statistics:
Descriptive statistics (means and standard deviations) were reported for feed consumption. Body weights and body weight gains were first evaluated by Bartlett's test for equality of variances. Based upon the outcome of Bartlett's test, either a parametric or nonparametric analysis of variance (ANOVA) was performed. If the ANOVA was significant, a Dunnett's test or the Wilcoxon Rank-Sum test with Bonferroni's correction was performed. Since litters were not culled, an analysis of covariance was used to test the effects of dose on pup weights with litter size as the covariate.
Gestation length, average time to mating and litter size were analyzed using a nonparametric ANOVA. If the ANOVA was significant, the Wilcoxon Rank-Sum test with Bonferroni's correction was performed. Statistical outliers were identified by the method of Grubbs (1969) and were routinely excluded from analysis for feed consumption only. Outliers for body weight, gestation length, litter size and average time to mating were only excluded from analysis for documented, scientifically sound reasons. The fertility indices were analyzed by the Fisher exact probability test and Bonferroni's correction was used for multiple testing of groups in comparison to a single control. Evaluation of the neonatal sex ratio was performed by the binomial distribution test. Survival indices and other incidence data among neonates was analyzed using the litter as the experimental unit by the Wilcoxon test as modified by Haseman and Hoel (1974).
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
- Excessive chromodacryorrhea of eyes was observed in one animal at all doses including control animals. Abrasion of skin, fur and mucous memebrane was observed at all doses in rats except in 20 mg/kg bw/d female. Perineal soiling was observed in one control female.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Two control male animals and one 5 mg/kg bw/d male died during study. one control animal which was found dead on Day 181, Upon histopathologic examination showed severe microscopic hemorrhages involving the skin/subcutis, esophageal wall, mesenteric, mandibular, and thoracic lymph nodes were noted. These observations were consistent with trauma, however, no clinical observations were made on this animal prior to its death. Another control male, and a 5 mg/kg/day male, died on test days 192 and 42, respectively. Histopathologically, each had spontaneous lymphosarcoma and died as a result of this neoplastic disease. The lymphosarcoma noted in each rat was accompanied by inflammation (very slight to severe) in one or more organs, probably the result of impairment or damage to the immune system caused by lymphosarcoma.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
No significant treatment-related effects on body weights were observed at any dose level in males throughout the entire test period or in females during the premating, gestation or lactation periods. Similarly, no treatment related effects were observed on the body weight gain of females during the F1a or F1b gestation or lactation periods. However, a statistically significant increase in body weight gain was noted in females given 100 mg/kg/day over the duration of the F1a lactation period when compared to control values. This increase in weight gain was not considered to be toxicologically significant as no dose response relationship was observed, test material effects would be expected to produce decreases in body weight gain rather than increases, and a similar increase was not observed during the F1b or F2 lactation periods.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
No significant effects were observed on feed consumption of males throughout the entire test period or females during pre-mating or gestation at any dose level. Slight decreases in feed consumption were noted during the final week of the F1a and F1b lactation periods, however, concomitant decreases in dam body weights were not observed. As rat pups begin consuming feed during the final week of lactation, this decrease may have been due to decreased feed consumption by the high-dose pups, rather than the maternal animals.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
A treatment-related increased incidence of slight or very slight hypertropy of the hepatocytes in the centrilobular region occurred in the livers of 24 male rats given 100 mg/kg/day test substance. The alteration was characterized by increased size of hepatocytes as a result of an apparent increase of agranular eosinophilic cytoplasm similar to that seen with agents that produce proliferation of smooth endoplasmic reticulum and metabolic enzyme induction. No treatment-related effects were observed on any reproductive parameter or histopathology of the reproductive organs for P1 adult animals at any dose level tested.
Reproductive performance:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related effects were observed on male or female reproductive indices, gestation survival index, gestation length or time to mating at any dose level for the F1a or F1b matings/litters.
Key result
Dose descriptor:
NOEL
Effect level:
20 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
histopathology: non-neoplastic
Key result
Dose descriptor:
NOEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: systemic toxicity
Remarks on result:
other: no systemic effects at highest dose tested
Key result
Dose descriptor:
NOEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Reproductive Toxicity
Remarks on result:
other: no repro effects at highest dose tested
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related effects on behavior or demeanor were observed in P2 adult males or females at any dose level during the pre-mating, gestation or lactation periods.
Mortality:
no mortality observed
Description (incidence):
All P2 adults survived the test period and were necropsied on the scheduled date of termination.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
No significant treatment-related effects on body weights were observed at any dose level in males throughout the entire test period or in females during the premating, gestation or lactation periods. However, statistically significant increases in body weight were noted sporadically in females given 5 and 20 mg/kg/day during the premating period. These increases were interpreted to be unrelated to treatment as there was no dose-response relationship observed. No treatment related effects were observed on the body weight gain of females during the gestation or lactation periods. A non-statistically identified decrease (~11 %) in body weight gain was, however, observed in females given 100 mg/kg/day over the entire gestation period. This decrease in weight gain was not considered to be toxicologically significant as no dose-response relationship was observed and similar decreases were not observed during the P1 female gestation periods.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
No significant effects were observed on feed consumption of males throughout the entire test period or females during pre-mating or gestation at any dose level. However, a decrease in feed consumption was noted during the final week of the F2 lactation period. This decrease was consistent with slight decreases observed during the final week of the P1 lactation periods. As in the F1a and F1b lactation periods, no correlate between decreased feed consumption and maternal weight gain was observed, suggesting decreases may have been due to decreased feed consumption by the high-dose pups.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related gross pathologic changes were observed in the P2 adults at any dose leveL The observations made for the P2 adults were similar to those of the P1 adults with no gross lesions attributed to test substance treatment. Generally, gross observations occured in only a single rat per dose level except for dilated renal pelvis, pale foci noted at the juncture of the right and left portions of the middle lobes of the liver, and the dark foci in the uterus associated with previous implantation sites.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Effects related to test substance treatment were similar to those in the first parental generation and involved the liver of male rats given 100 mg/kg/day. Slight or very slight hepatocellular hypertrophy was associated with treatment at 100 mg/kg/day in 28 of 30 males. The alteration was again characterized by increased size of hepatocytes as a result of an apparent increase of agranular eosinophilic cytoplasm. No treatment-related effects were observed on any reproductive parameter or histopathology of the reproductive organs for P2 adult animals at any dose level tested.
Reproductive performance:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related effects were observed on the male or female reproductive indices, gestation, gestation length or time to mating at any dose level for the F2 matings/litters. Statistically identified decreases in male and female conception and fertility indexes noted at 20 mg/kg/day were considered spurious and unrelated to treatment as no decreases were noted in these indexes at 100 mg/kg/day, no dose-response relationship was observed for the apparent change in these parameters, and similar effects were not noted for the F1a or F1b matings.
Key result
Dose descriptor:
NOEL
Effect level:
20 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
histopathology: non-neoplastic
Key result
Dose descriptor:
NOEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: systemic toxicity
Remarks on result:
other: no effects at highest dose tested
Key result
Dose descriptor:
NOEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Reproductive toxicity
Remarks on result:
other: Highest dose tested
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related clinical observations or physical alterations were observed in any F1a or F1b pups from any dose group during the lactation period. An increased incidence of F1b pups observed to have staining, lacerations or scaling in the perianal region was noted in all treatment groups. These observations were not attributed to treatment as these observations were noted in control as well as treated litters, no dose response relationship was observed and perianal staining/ scaling did not occur in any F1a pups from any dose group.
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
No effects on litter size were observed at 5 or 20 mg/kg/day at any time during the F1a or F1b lactation periods. The size of F1a litters from dams given 100 mg/kg/day was not significantly different from control litters, however, a statistically significant increase in litter size was noted in the 100 mg/kg/day F1b litters on lactation Days 1, 4 and 7. This increase was not considered to be treatment-related as this effect was not observed in the F1a or F2 litters. Neonatal survival was not adversely affected at any dose level in either generation.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Minimal neonatal effects were also observed at 100 mg/kg bw/d in F1a and F1b litters. Statistically decrease in mean body weights of both male and female pups on Day 21 of lactation period was observed. These transient decreases were attributed, in part, to the decreased feed consumption noted during the final week of the P1 and P2 lactation periods. No adverse effects were observed on pup body weights at doses of 5 or 20 mg/kg/day in either generation.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Minimal neonatal effects were also observed at 100 mg/kg bw/d in F1a and F1b litters. Although pup feed consumption was slightly decreased, the higher concentration of test material in the maternal diet they consumed would have resulted in a dose on a mg/kg/day basis greater than that targeted for the adults.
Sexual maturation:
effects observed, non-treatment-related
Description (incidence and severity):
The statistically significant deviation from a normal distribution in the sex ratio of F1b pups from dams given 100 mg/kg/day was not attributed to treatment as the sex ratio of pups in this dose group was similar to the control, and no significant effects were observed on the sex ratios of pups in the F1a litters at any dose level.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No treatment-related gross pathologic observations were observed at any dose level in the F1a or F1b weanlings.
Other effects:
no effects observed
Description (incidence and severity):
No treatment-related effects were observed on pup survival indices, pup sex ratios at any dose level for the F1a or F1b matings/litters.
Key result
Dose descriptor:
NOEL
Generation:
other: F1a & F1b
Effect level:
20 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Remarks on result:
other: The effect observed on pup body weight is transient
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related clinical observations or physical alterations were observed in any F2 pups from any dose group during the F2 lactation period. Three pups from a single 100 mg/kg/day litter were noted as having yellow skin as well as being cold to the touch. This skin discoloration was not felt to be treatment related as the observation did not occur in any other high-dose litters.
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
Neonatal survival was not adversely affected at any dose level in F2 generation.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Minimal neonatal effects were also observed at 100 mg/kg bw/d in F2 litters. Statistically decrease in mean body weights of both male and female pups on Day 21 of lactation period was observed. These transient decreases were attributed, in part, to the decreased feed consumption noted during the final week of the P1 and P2 lactation periods. No adverse effects were observed on pup body weights at doses of 5 or 20 mg/kg/day in either generation.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Minimal neonatal effects were also observed at 100 mg/kg bw/d in F2 litters. Although pup feed consumption was slightly decreased, the higher concentration of test material in the maternal diet they consumed would have resulted in a dose on a mg/kg/day basis greater than that targeted for the adults.
Sexual maturation:
no effects observed
Description (incidence and severity):
No significant effects were observed on the sex ratios of pups in the F2 litters at any dose level.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No treatment-related gross pathologic observations were observed at any dose level in the F2 weanlings.
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related effects were observed on pup survival indices, pup sex ratios at any dose level for the F2 matings/litters.
Key result
Dose descriptor:
NOEL
Generation:
F2
Effect level:
20 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Remarks on result:
other: The effect observed on pup body weight is transient
Key result
Reproductive effects observed:
no
Conclusions:
NOEL (Male) (Parental) (Systemic): 20 mg/kg bw/d
NOEL (Female) (Parental) (Systemic): 100 mg/kg bw/d (Highest dose tested)
NOEL (Male/Female) (Parental) (Reproductive): 100 mg/kg bw/d (Highest dose tested)
NOEL (Male/Female) (Neonatal): 20 mg/kg bw/d
Executive summary:

The study was conducted according to OECD guideline 416 and EPA 83-4 to evaluate the effects of test substance on the reproductive capability and neonatal growth and survival of rats. Groups of 30 male and 30 female Sprague-Dawley rats, approximately 6 weeks of age, were fed diets that provided 0, 5, 20 or 100 mg/kg/day, 7 days/week, for two generations.

Dietary exposure of adult male and female rats to 100 mg/kg/day test substance resulted in parental and developmental effects. Parental effects consisted of centrilobular hepatocellular enlargement in high dose P1 and P2 male rats only. This effect was noted previously in a 13-week study with Fischer 344 rats. Slight decreases in female feed consumption were noted only during the final week of the P1 and P2 lactation periods, but were not associated with body weight effects in maternal animals. No significant effects were observed for P1 or P2 females given 100 mg/kg/day or male or female rats given 5 or 20 mg/kg/day in either parental generation. Additionally, no treatment-related effects were observed on any reproductive parameters or gross/histopathology of the reproductive organs for P1 or P2 adult animals at any dose level tested.

Minimal neonatal effects were also observed at 100 mg/kg/day test substance in the F1a, F1b, and F2 litters. Decreases, both statistically identified and otherwise, were noted on Day 21 of lactation in the mean body weights of male and female pups in this dose group. These transient decreases were attributed, in part, to the decreased feed consumption noted during the final week of the P1 and P2 lactation periods. Although pup feed consumption was slightly decreased, the higher concentration of test material in the maternal diet they consumed would have resulted in a dose on a mg/kg/day basis greater than that targeted for the adults. No adverse effects were observed on pup body weights at doses of 5 or 20 mg/kg/day in either generation. Neonatal survival was not adversely affected at any dose level in either generation.

Under the conditions of this study, the parental no-observed-effect level (NOEL) for systemic effects was 20 mg/kg/day for males and 100 mg/kg/day for females. The NOEL for reproductive effects was 100 mg/kg/day, the highest dose level tested. Based upon the transient effects observed on pup body weights, the NOEL for neonatal effects was conservatively determined to be 20 mg/kg/day.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
20 mg/kg bw/day
Species:
rat
Quality of whole database:
Only one study was available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Groups of 30 male and 30 female Sprague-Dawley rats, approximately 6 weeks of age, were fed diets that provided 0, 5, 20 or 100 mg/kg/day, 7 days/week, for two generations. Dietary exposure of adult male and female rats to 100 mg/kg/day test substance resulted in parental and developmental effects. Parental effects consisted of centrilobular hepatocellular enlargement in high dose P1 and P2 male rats only. This effect was noted previously in a 13-week study with Fischer 344 rats. Slight decreases in female feed consumption were noted only during the final week of the P1 and P2 lactation periods, but were not associated with body weight effects in maternal animals. No significant effects were observed for P1 or P2 females given 100 mg/kg/day or male or female rats given 5 or 20 mg/kg/day in either parental generation. Additionally, no treatment-related effects were observed on any reproductive parameters or gross/histopathology of the reproductive organs for P1 or P2 adult animals at any dose level tested. Minimal neonatal effects were also observed at 100 mg/kg/day test substance in the F1a, F1b, and F2 litters. Decreases, both statistically identified and otherwise, were noted on Day 21 of lactation in the mean body weights of male and female pups in this dose group. These transient decreases were attributed, in part, to the decreased feed consumption noted during the final week of the P1 and P2 lactation periods. Although pup feed consumption was slightly decreased, the higher concentration of test material in the maternal diet they consumed would have resulted in a dose on a mg/kg/day basis greater than that targeted for the adults. No adverse effects were observed on pup body weights at doses of 5 or 20 mg/kg/day in either generation. Neonatal survival was not adversely affected at any dose level in either generation. Under the conditions of this study, the parental no-observed-effect level (NOEL) for systemic effects was 20 mg/kg/day for males and 100 mg/kg/day for females. The NOEL for reproductive effects was 100 mg/kg/day, the highest dose level tested. Based upon the transient effects observed on pup body weights, the NOEL for neonatal effects was conservatively determined to be 20 mg/kg/day.

Effects on developmental toxicity

Description of key information

Rat Developmental Oral gavage: Not a unique developmental toxin. OECD 414; Reliability = 1

Rabbit Developmental Oral gavage: Not a unique developmental toxin. OECD 414; Reliability = 1

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: 87/302/EEC Part B, Methods for the determination of toxicity, teratogenicity test - rodent and non-rodent.
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: JMAFF Notice 59, NohSan N4200
Deviations:
no
GLP compliance:
yes
Specific details on test material used for the study:
Substance ID: TSN 100097
Name of substance: XDE-795 (Technical grade)
Purity: 97.4%
Species:
rat
Strain:
other: Crl: CD(SD) BR VAF/Plus
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River, UK Limited, Manston Road, Margate, Kent, England.
- Age at study initiation: 8-10 weeks old
- Housing: The animals were housed individually in suspended stainless-steel cages equipped with solid sides and wire grid front, back, floor and top. The cages constituting each treatment group were dispersed within the batteries so that possible environmental influences arising from their spatial distribution were equilibrated as far as possible for all treatments.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: Not specified

ENVIRONMENTAL CONDITIONS
- Temperature: 18-23°C
- Humidity: 45-60%
- Photoperiod: 12 hrs dark /12 hrs light
Route of administration:
oral: gavage
Vehicle:
other: 1% methylcellulose
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Dose suspensions were prepared daily and used within 4 hours of preparation. The test substance was ground in a mortar with a small amount of the vehicle, 1% methylcellulose, until a smooth paste was formed. The formulation was then gradually made up to volume and mixed using a high shear homogeniser. A series of suspensions was made by serial dilution to achieve the required concentrations.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The achieved concentration of prepared formulations was assessed on the first day of treatment and results for all groups were within the range -1% to +5% of nominal.
Details on mating procedure:
- Impregnation procedure: Purchased timed pregnant
- Verification of same strain and source of both sexes: Yes
- Proof of pregnancy: Vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- Any other deviations from standard protocol: None
Duration of treatment / exposure:
GD6 to GD15
Frequency of treatment:
Daily
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
300 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
30 time mated females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dosages of 0, 100, 300 and 1000 mg/kg/day were selected on the basis of a preliminary study where no conclusive toxicity was apparent at dosages up to 750 mg/kg/day.
Maternal examinations:
CLINICAL OBSERVATIONS
- Time schedule: All animals were regularly handled and observed daily for obvious changes or signs of reaction to treatment.

BODY WEIGHT
- Time schedule for examinations: All animals were weighed by the supplier on the day of mating (Day 0 of pregnancy), on receipt at test facility (Day 1, batch A or Day 2, batch B of pregnancy) and on Days 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20.

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

POST-MORTEM EXAMINATIONS
- Sacrifice on gestation day # 20
- Organs examined: Liver, ovaries, uteri
Ovaries and uterine content:
The ovaries and uterine content was examined after termination include:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: number and distribution of live young, individual foetal weight (from which the litter weight was calculated) and foetal abnormalities
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [half per litter]
- Skeletal examinations: Yes: [half per litter]
Statistics:
Significance tests, employing analysis of variance or covariance followed by an intergroup comparison with the control, were performed on the following parameters and results are presented in relevant tables of this report:
bodyweight change, food consumption, liver weight, litter data, sex ratios, foetal anomalies and variants.
For maternal parameters the tests employed were dependent on the heterogeneity of variance between treatment groups. Parametric tests (analysis of variance or covariance (Snedecor and Cochran, 1967) followed by Williams' test (Williams, 1971/2) or non-parametric tests (Kruskal-Wallis (Hollander and Wolfe, 1971) followed by Shirley's test (Shirley, 1977) were used to analyse these data, as appropriate. For litter data and foetal changes, the basic sample unit was the litter and, due to the preponderance of non-normal distributions the above mentioned non-parametric analyses were used. Analysis of malformations and anomalies was performed using a trend test on the number of litters affected followed by a 2 sample permutation test (Edgington, 1980; Franck, 1986).
All significant (i.e., P ≤0.05) intergroup differences from the control were reported and are supported by a significant analysis of variance (p ≤0.05.
Where a non-parametric test was usually employed but 75% or more of the values for a given variable were the same (i.e., late embryonic deaths), a Fisher's exact test (Fisher, 1950) was used.
Clinical signs:
effects observed, non-treatment-related
Mortality:
mortality observed, non-treatment-related
Description (incidence):
There was a single mortality at 1000 mg/kg/day, one female died prior to dosing on Day 12 post coitum during weighing. Clinical findings noted immediately prior to death were pallor, lethargy and respiratory distress. Post mortem examination indicated this death was due to an intubation error, probably on Day 11 post coitum and not, therefore, related to treatment.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Liver weight, as assessed at Day 20 of pregnancy (5 days after the end of the dosing period), showed no notable or significant (P>0.05) intergroup differences.
Gross pathological findings:
no effects observed
Pre- and post-implantation loss:
effects observed, non-treatment-related
Description (incidence and severity):
There was one notable litter with a single viable implantation. Preimplantation loss, which is considered to occur prior to the start of treatment, was very high for this litter and influenced other values, especially size and weight of the litter.
Total litter losses by resorption:
no effects observed
Key result
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Remarks on result:
other: Highest dose tested
Fetal body weight changes:
no effects observed
Changes in litter size and weights:
no effects observed
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
At 100 mg/kg/day (the low dosage), the 6 malformed foetuses came from one litter. Findings in these foetuses included translucent or mottled white appearance to skin, brachygnathia, cleft palate, mal rotated hindlimbs, apparent ring of constriction around lower thorax and symphalangy, oligodactyly or syndactyly. Microscopic examination of abdominal skin from one of these foetuses with mottled appearance, revealed marked dermal oedema with absent hair follicles/adnexa. In view of the absence of similar effects at this or higher dosages and considering this event as an isolated cluster of foetuses in a single litter showing the same syndrome of defects, no association with treatment was indicated.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
At 1000 mg/kg/day, there was a slightly higher number of foetuses with extra (14) ribs but differences did not attain statistical significance, were well inside the historical control range and were considered not to be treatment-related.
Key result
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: Highest dose tested
Key result
Developmental effects observed:
no
Conclusions:
NOEL (Rat, maternal and developmental toxicity): 1000 mg/kg/day (highest dose tested)
Executive summary:

This study was conducted to assess the effect of the test substance on pregnancy of the rat according to the guidelines OECD 414 and EPA OPP 83-3. Dosages of 0 (Control), 100, 300 or 1000 mg/kg/day were administered by gavage to groups of 30 time-mated CD rats from Day 6 to 15 of pregnancy, inclusive. The animals were killed on Day 20 of pregnancy and in utero development was assessed by determination of litter values and subsequent examination of foetuses for visceral or skeletal abnormalities.

No effects of treatment on maternal clinical signs, bodyweight gain, food intake, liver weight or macroscopic abnormalities at autopsy were observed.

No effects of treatment on in utero development were observed. Litter size, pre- and post-implantation losses, litter and mean foetal weight, sex ratio and the distribution of foetuses with abnormalities were considered unaffected by treatment.

Treatment of parent females with the test substance at dosages up to 1000 mg/kg/day was determined as being without adverse effect on the mother or developing conceptus in this study.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Directive 87/302/EEC: Teratogenicity Test - Rodent and Non-Rodent Species
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: MAFF Toxicity Testing Guidelines for Teratogenicity Studies
Deviations:
no
GLP compliance:
yes
Specific details on test material used for the study:
Substance ID: TSN 100097
XR-795, XDE-795
Purity: 96.2%
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: HRP, Inc., Kalamazoo, Michigan
- Age at study initiation: Approximately 5.0 to 6.0 months
- Weight at study initiation: 2.44-3.52 kg
- Housing: Animals were housed individually in suspended cages with flattened tube-grid floors
- Diet: Animals received 2 oz of Certified Laboratory Rabbit Chow No. 5322 (Purina Mills, Inc., St. Louis, Missouri) upon receipt, with the amount of feed being increased incrementally by 2 oz/day up to a total of 8 oz.
- Water: ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature: ~20°C
- Humidity: 40-60%
- Air changes: 12 per hr
- Photoperiod: 12 hrs dark /12 hrs light
Route of administration:
oral: gavage
Vehicle:
other: aqueous solution of 0.5% METHOCEL A4M
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The test substance was administered as a suspension in an aqueous solution of 0.5% METHOCEL A4M such that a dose volume of 4 ml/kg body weight yielded the appropriate dose.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analyses of all dose suspensions initially revealed mean concentrations of the test substance ranging from 91% to 105% of targeted concentrations and the suspensions were homogeneous. Following dosing, the concentrations of all dose suspensions were found to be higher than the targeted concentrations. The reason for the increases was likely due to evaporation of the vehicle (water) as the suspensions were kept constantly stirring at room temperature during the study. The change in the dose suspension concentrations did not adversely impact the outcome of the study and the animals received equal to or greater than the targeted doses throughout the duration of the study.
Details on mating procedure:
- Impregnation procedure: Purchased timed pregnant
- Verification of same strain and source of both sexes: Yes
- Observed day of breeding referred to as day 0 of pregnancy
Duration of treatment / exposure:
GD7 to GD19
Frequency of treatment:
Daily
Dose / conc.:
20 mg/kg bw/day
Dose / conc.:
80 mg/kg bw/day
Dose / conc.:
200 mg/kg bw/day
No. of animals per sex per dose:
18 time mated females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dose levels were selected based on the results of the previously conducted probe studies:
Probe study 1: Five mated female CD rats were administered the test substance via oral gavage in a 10% acacia solution at targeted dose levels of 0, 25, 100 or 600 mg/kg/day on Days 6-15 of gestation. Maternal weight loss and decreased feed consumption were observed at 600 mg/kg/day. No significant maternal effects were observed at 25 or 100 mg/kg/day nor were there any adverse embryonal/fetal or teratogenic effects observed at any dose level tested
Probe study 2: Groups of seven time-mated adult female New Zealand White rabbits were orally administered as a suspension in an aqueous solution of 0.5% METHOCEL A4M on Days 7-19 of gestation at dose levels of 0, 100, 300, 600 or 1000 mg/kg/day. Treatment-related maternal in life effects at 300, 600 and 1000 mg/kg/day included decreases in fecal output, body weight, body weight gains and feed consumption. Due to the severity of the maternal toxicity, as evidenced by marked inanition and weight loss, all rabbits from the 600 and 1000 mg/kg/day dose group were euthanatized on Day 15 of gestation with no further data collected on these animals. Of the rabbits given 300 mg/kg/day, one rabbit was found dead on Day 16 of gestation and two additional rabbits exhibiting weight loss and marked inanition were euthanatized and necropsied on Days 15 and 17 of gestation. All other rabbits survived to the scheduled necropsy. Rabbits given 100 or 300 mg/kg/day had increased relative liver weights. No evidence of maternal toxicity was observed at 100 mg/kg/day nor were there any adverse embryonal/fetal effects observed at 100 or 300 mg/kg/day.

Maternal examinations:
CAGE SIDE OBSERVATIONS: All animals were observed daily during the study for alterations in behavior or demeanor.

BODY WEIGHT: Body weights were recorded on Day 0 (at supplier facility), daily during the dosing period, and on Day 20 and 28 of gestation.

FOOD CONSUMPTION: Feed consumption was recorded daily during the test period beginning on Day 4 of gestation.

POST-MORTEM EXAMINATIONS
- Sacrifice on gestation day # 28
- Organs examined: Any obvious gross pathologic alterations were recorded, and the weight of the liver, kidneys and gravid uteri were recorded. Representative sections of liver with gallbladder, kidneys, and gross lesions were preserved in neutral, phosphate-buffered 10% formalin.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination include:
- number and position of the fetuses in utero
- number of live and dead fetuses
- number and position of resorption sites
- number of corpora lutea
- sex and body weight of each fetus
- any gross external alterations
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [all per litter]
- Skeletal examinations: Yes: [all per litter]
- Head examinations: Yes: [all per litter]
Statistics:
Descriptive statistics (means and standard deviations) were calculated for feed consumption. Statistical analyses of body weights and body weight gains were performed using data collected on Days 0, 7, 10, 13, 16, 20 and 28 of gestation. Maternal body weights, body weight gains, organ weights (absolute and relative) and fetal body weights were evaluated by Bartlett's test for equality of variances. Based on the outcome of Bartlett's test, a parametric or nonparametric analysis of variance (ANOVA) was performed.
If the ANOVA was significant, analysis by Dunnett's test or the Wilcoxon Rank-Sum test with Bonferroni's correction was performed, respectively. Statistical evaluation of the frequency of pre-implantation loss and resorptions among litters and the fetal population was performed using a censored Wilcoxon test with Bonferroni's correction. The number of corpora lutea and implantations, and litter size were evaluated using a nonparametric ANOVA followed by the Wilcoxon Rank-Sum test with Bonferroni's correction. Pregnancy rates were analyzed using the Fisher exact probability test. Fetal sex ratios were analyzed using a binomial distribution test. Nonpregnant females, females detected as pregnant following staining of the uterus or females having totally resorbed litters were excluded from the appropriate analyses.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Clinical alterations observed at an increased incidence in dams given 200 mg/kg/day included decreased fecal output, soft feces, perineal soiling, blood or urine containing blood in the cage pan, and abortion. There were no observations made on the surviving animals at the time of necropsy that were attributed to treatment in any dose level tested.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One high-dose rabbit died due to gavage error
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The mean body weight gain of rabbits given 200 mg/kg/day was decreased relative to the controls throughout the exposure period, with a statistically identified decrease occurring on Days 16-20 of gestation. In addition, the decreased weight gains resulted in statistically significant lower body weights on Day 20 of gestation at 200 mg/kg/day. The lower body weight gain in the high dose rabbits was mostly due to individual animals that aborted their litters. An apparent compensatory weight gain occurred in the surviving rabbits given 200 mg/kg/day during Days 20-28 of gestation, so that body weight gains over the entire pregnancy were virtually identical to the controls. There were no statistically significant effects on body weights or body weight gains in rabbits given 20 or 80 mg/kg/day.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Marked decreases in feed consumption were observed on Days 13-22 of gestation in rabbits given 200 mg/kg/day. In general, the decreased feed consumption corresponded with the decreased fecal output and decreased body weight gain observed during the dosing interval. This conclusion is further supported by the observation that the high-dose rabbits appeared to increase their feed consumption post dosing and regained weight. There were no effects on feed consumption observed in rabbits given 20 or 80 mg/kg/day.
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
In the 200 mg/kg/day dose group, five rabbits aborted and are interpreted to be treatment-related. Few observations at necropsy were early and late resorptions (2 dams), nonspecific lesions (1 dam) (which included gas and watery cecal contents, decreased ingesta and a gastric hairball), fetal membranes present in the vagina, perineal soiling and slight liver necrosis with fibrous adhesions (1 dam), consolidation of the intermediate lobe of lung (1 dam) and pale liver foci (1 dam).
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Changes in number of pregnant:
no effects observed
Key result
Dose descriptor:
NOEL
Effect level:
80 mg/kg bw/day (nominal)
Basis for effect level:
body weight and weight gain
clinical signs
food consumption and compound intake
gross pathology
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There were no statistically or biologically significant treatment-related differences in the incidence of any fetal alteration in any of the dose groups. All variations observed in fetuses from dams occurred at low frequencies, were not dose-related or within the range of New Zealand White rabbit historical control data.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There were no statistically or biologically significant treatment-related differences in the incidence of any fetal alteration in any of the dose groups. All variations observed in fetuses from dams occurred at low frequencies, were not dose-related or within the range of New Zealand White rabbit historical control data.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There were no statistically or biologically significant treatment-related differences in the incidence of any fetal alteration in any of the dose groups. All variations observed in fetuses from dams occurred at low frequencies, were not dose-related or within the range of New Zealand White rabbit historical control data.
Key result
Dose descriptor:
NOEL
Effect level:
200 mg/kg bw/day (nominal)
Sex:
male/female
Remarks on result:
other: highest dose tested
Key result
Developmental effects observed:
no
Conclusions:
NOEL (maternal toxicity): 80 mg/kg/day
NOEL (embryonal/ fetal): 200 mg/kg/day (highest dose tested)
Executive summary:

The purpose of this study was to evaluate the maternal toxicity, embryonal/fetal toxicity and teratogenic potential of the test substance in rabbits following repeated oral gavage according to the guidelines OECD 414. Groups of 18 adult female time-mated New Zealand White rabbits were administered the test substance via gavage on Days 7 through 19 of gestation at targeted dose levels of 0 (control), 20, 80 or 200 mg/kg/day. In-life parameters evaluated included clinical observations, body weight, body weight gain and feed consumption. On Day 28 of gestation, all surviving rabbits were euthanatized. Liver, kidneys and gravid uterine weights, and the number of corpora lutea, implantations, resorptions and live/ dead fetuses were recorded. All fetuses were weighed, sexed and examined for external, visceral and skeletal alterations.

Oral administration of the test substance to time-mated female rabbits resulted in maternal toxicity in dams given 200 mg/kg/day as evidenced by decreased feed consumption, fecal output, body weight and body weight gain. In addition, the abortion of five dams at the high dose was also interpreted to represent maternal toxicity. No significant maternal effects were observed in rabbits given 20 or 80 mg/kg/day, and no adverse embryonal/fetal effects were observed at any dose level tested. Therefore, the no-observed-effect-level (NOEL) for maternal toxicity was 80 mg/kg/day; the embryonal/ fetal NOEL was 200 mg/kg/day.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
Data were available in both rats and rabbits.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Dosages of 0 (Control), 100, 300 or 1000 mg/kg/day were administered by gavage to groups of 30 time-mated CD rats from Day 6 to 15 of pregnancy, inclusive. The animals were killed on Day 20 of pregnancy and in utero development was assessed by determination of litter values and subsequent examination of fetuses for visceral or skeletal abnormalities. No effects of treatment on maternal clinical signs, bodyweight gain, food intake, liver weight or macroscopic abnormalities at autopsy were observed. No effects of treatment on in utero development were observed. Litter size, pre- and post-implantation losses, litter and mean fetal weight, sex ratio and the distribution of fetuses with abnormalities were considered unaffected by treatment. Treatment of parent females with the test substance at dosages up to 1000 mg/kg/day was determined as being without adverse effect on the mother or developing conceptus in this study.

Oral administration of the test substance to time-mated female rabbits resulted in maternal toxicity in dams given 200 mg/kg/day as evidenced by decreased feed consumption, fecal output, body weight and body weight gain. In addition, the abortion of five dams at the high dose was also interpreted to represent maternal toxicity. No significant maternal effects were observed in rabbits given 20 or 80 mg/kg/day, and no adverse embryonal/fetal effects were observed at any dose level tested. Therefore, the no-observed-effect-level (NOEL) for maternal toxicity was 80 mg/kg/day; the embryonal/ fetal NOEL was 200 mg/kg/day.

Justification for classification or non-classification

There is no evidence to suggest that the test substance causes adverse effects on reproduction or development of the offspring. Therefore, the test substance is not classified for reproductive or developmental toxicity according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.

Additional information