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EC number: 239-370-5 | CAS number: 15337-18-5
The clinical condition of the offspring, litter size, offspring survival and sex ratio were unaffected by parental treatment. Ano-genital distance of both male and female offspring on Day 1 of age and male nipple counts on Day 13 of age showed no adverse effects of parental treatment. At 250 mg/kg/day, mean offspring body weight gain was marginally lower than in Controls with no statistical significance, so no effect of treatment was inferred. Macroscopic examination of offspring that died prior to the scheduled termination or were killed on Day 13 of age did not reveal any findings that were considered related to parental treatment at any dose level.
The purpose of this study was to assess the potential systemic toxicity in rats, including a screen for reproductive/developmental effects and assessment of endocrine disruptor relevant endpoints, with administration of the test item by oral administration for at least five weeks.
Three groups of ten male and ten female Crl:CD(SD) rats received the test item at doses of 28, 85 or 250 mg/kg/day by oral gavage administration. The dose levels were selected based on the results of a 14-day preliminary study in which 100, 250, 500 and 1000 mg/kg/day of the test item were administered to male and female Crl:CD(SD) rats and the dose levels of 500 or 1000 mg/kg/day were not tolerated and resulted in the early termination of these groups on Day 3 of study. Males were treated daily for two weeks before pairing, up to necropsy after a minimum of five consecutive weeks. Females were treated daily for two weeks before pairing, throughout pairing, gestation and until Day 13 of lactation. Females were allowed to litter, rear their offspring and were killed on Day 14 of lactation. The F1 generation received no direct administration of the test item; any exposure was in utero or via the milk. A similarly constituted Control group received the vehicle, arachis oil, at the same volume dose as treated groups.
During the study, clinical condition, detailed physical examination, body weight, food consumption, hematology (peripheral blood), blood chemistry, thyroid hormone (T4) analysis, estrous cycles, pre coital interval, mating performance, fertility, gestation length, organ weight and macroscopic pathology and histopathology investigations were undertaken.
The clinical condition, litter size and survival, sex ratio, body weight, ano-genital distance and macropathology for all offspring were also assessed. Thyroid hormone (T4) analysis was performed for the Day 13 offspring. Nipple counts were performed on male offspring on Day 13 of age.
There was no premature animal death related to the test item treatment. One female was sacrificed for reasons of animal welfare on Day 12 due to general poor clinical condition, however this death was considered not related to treatment.
Clinical condition, behavior in the arena, sensory reactivity, grip strength and motor activity were unaffected by treatment. There were no signs seen in association with dosing.
Slight variations of mean body weights and body weight gains were observed in females during the dosing period when compared with Controls. However, these variations were considered incidental because there were no statistical significance and no similar differences were observed in the male rats.
The food consumption of females received 250 mg/kg/day was slightly lower than that of the Control during Days 1-15 of treatment and throughout gestation and Days 1-7 of lactation, but it was considered non-adverse because there were no correlated body weight changes observed.
Haematological investigations of the plasma and biochemical examinations of the blood did not reveal any findings that could be attributed to treatment.
There was no effect of treatment on the circulating levels of thyroxine (T4) in adult males or in the Day 13 offspring.
The evaluation of organ weights of males after 5 weeks of treatment and of females on Day 14 of lactation revealed no significant differences when compared with the Controls.
The macroscopic and microscopic examination of adult males and females did not reveal any findings related to treatment. The clinical condition of the offspring, litter size, offspring survival and sex ratio were unaffected by parental treatment.
Ano-genital distance of both male and female offspring on Day 1 of age and male nipple counts on Day 13 of age showed no adverse effects of parental treatment.
At 250 mg/kg/day, mean offspring body weight gain was marginally lower than in Controls with no statistical significance, so no effect of treatment was inferred.
Macroscopic examination of offspring that died prior to the scheduled termination or were killed on Day 13 of age did not reveal any findings that were considered related to parental treatment at any dose level.
In conclusion, oral administration of the test item to parental Sprague Dawley (Crl:CD(SD)) rats at dose levels of 28, 85 or 250 mg/kg/day for five weeks to males and for two weeks before pairing, throughout gestation and up to Day 14 of lactation in females was well-tolerated in the adult animals with no treatment related adverse effects observed.
Reproductive performance, fertility and offspring survival were unaffected by parental treatment. There was no effect of treatment on the number of implantations, litter size or the growth of the offspring.
In the context of this study, the test item showed no evidence of being an endocrine disruptor.
The no-observed-adverse-effect-level (NOAEL) for systemic toxicity and for reproductive/developmental toxicity was considered to be 250 mg/kg/day, the highest tolerable dose tested.
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