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EC number: 948-766-3 | CAS number: -
OBJECTIVE AND METHODS
The objective of this study was to characterize the effects of the test substance on the integrity and performance of the male and female reproductive systems, including gonadal function, the estrus cycle, mating behavior, conception, gestation, parturition, lactation, and weaning of the F1generation, as well as the neonatal survival, growth, and development of the F1and F2offspring. In addition, the systemic toxicity of the test substance was partially characterized in this study by evaluation of several nonreproductive tissues. Three groups of male and female Crl:CD(SD) rats (25 and 28/sex/group for the F0and F1generations, respectively) were administered the test item (CAS No. 848301-67-7), daily by oral gavage for at least 70 consecutive days prior to mating. Dosage levels were 50, 200, and 750 mg/kg/day for the F0and F1generations. A concurrent control group of 25 and 28/sex for the F0and F1generations, respectively, received the vehicle, corn oil (CAS No. 8001-30-7) on a comparable regimen. F0animals were approximately 6 to 7 weeks (42 to 46 days) of age at the initiation of test item administration. The test item was administered to offspring selected to become the F1parental generation following weaning, beginning on postnatal day (PND) 22. The F0and F1males continued to receive the test item throughout mating and through the day prior to euthanasia. The F0and F1females continued to receive the test item throughout mating, gestation, and lactation, and through the day prior to euthanasia. Animals were observed at least twice daily for mortality. Clinical observations, body weights, and food consumption were recorded at appropriate intervals for males throughout the study and for females prior to mating and during gestation and lactation. Vaginal smears were performed daily for determination of estrous cycles beginning 21 days prior to pairing. All F0and F1females were allowed to deliver and rear their pups until weaning on lactation day (LD≡PND) 21. Clinical observations, body weights, and sexes for F1and F2pups were recorded at appropriate intervals. For both generations (F1and F2), 10 pups per litter (5 per sex, when possible) were arbitrarily selected on PND 4 to reduce the variability among the litters. Offspring (28/sex/group) from the pairing of the F0animals were selected on PND 21 to constitute the F1generation. Developmental landmarks (balanopreputial separation and vaginal patency) were evaluated for the selected F1rats. Nonselected F1pups were necropsied on PND 21, and F2pups were necropsied on PND 21. Selected organs (brain, spleen, and thymus) were weighed from 1 pup/sex/litter (when possible) from both F1and F2pups that were necropsied on PND 21. Each F0and F1parental animal received a complete detailed gross necropsy (the surviving female parental animals were necropsied on LD 21), and selected organs were weighed. Spermatogenic endpoints [sperm motility (including progressive motility), morphology, and number] were recorded for F0and F1males as appropriate, and ovarian primordial follicle counts and the corpora lutea counts were recorded for all F1females in the control and high-dose groups. Designated tissues from all F0and F1parental animals were examined microscopically.
SUMMARY OF RESULTS AND CONCLUSION
Administration of the test substance to male and female rats at dosages up to 750 mg/kg/day had no effect on reproductive performance or gestation length and parturition of both the F0 and F1 parental generations. In addition, there were no test itemrelated effects on F1 and F2 litter parameters, postnatal survival, physical condition/mortality, anogenital distance, and pup body weights. Vaginal patency of F1 females was unaffected by test item administration. There was a statistically significant, test articlerelated increase in the mean age and adjusted age of attainment of balanopreputial separation in F1 males given 750 mg/kg/day. However, this change was not considered adverse, as the age and adjusted age of attainment fell within the historical control data range for this parameter. Reproductive performance parameters (mating and fertility indices) for F1 males given 750 mg/kg/day, although slightly lower than the control group, were not statistically significantly different from the control group and also fell within the historical control data range. In addition, andrology parameters and sperm morphology data for the individual F1 males in the high-dose group, with the longest delay in attainment of balanopreputial separation, were similar to the group mean data, further supporting the conclusion that the delay in preputial separation was non-adverse. Sperm morphology assessments of F1 males showed a statistically significant increase in the percent of abnormal sperm in those males given 750 mg/kg/day; however, this change was not observed in F0 males and resulted primarily from a single male, and was therefore considered equivocal and non adverse since the percent of abnormal sperm seen fell within the historical control data range for this parameter, reproductive performance parameters (mating and fertility indices) for F1 males given 750 mg/kg/day were unaffected, and there were no microscopic findings in the testes. Overall, there were 19 unscheduled deaths of parental animals (4 F0 males, 6 F0 females, 5 F1 males, and 4 F1 females). None of the deaths were directly attributed to the test item. Based on macroscopic (and in some cases microscopic) findings, 11 of the deaths were likely due to gavage error and/or aspiration of the dose formulation into the lungs. With the low viscosity nature of the test item and the use of corn oil as the vehicle, aspiration events were not unexpected. Two F0 females were injured by their mating partner and euthanized for humane reasons, and 1 F0 male was euthanized for humane reasons due to lesions on the neck, likely caused by scratching at the ear tag. One F0 female given 750 mg/kg/day was euthanized due to dystocia, and 1 F1 female given 750 mg/kg/day was found dead the day after dystocia was observed. The cause of death for 3 animals (1 F1 male given 50 mg/kg/day, 1 F1 male given 750 mg/kg/day, and 1 F1 female given 750 mg/kg/day) could not be definitively determined at necropsy. There were no adverse test item-related effects on F0 and F1 parental body weights, body weight changes, feed consumption, and food efficiency. Test item-related histopathological lesions were identified in the lungs of both males and females of the F0 and F1 generations and the kidneys (males only) of the F1 generation. There was an increased incidence and severity of chronic interstitial/alveolus inflammation in the F0 and F1 males and females given 750 mg/kg/day; this microscopic finding correlated with macroscopic observations in F0 and F1 males and F1 females, as well as increased absolute and relative lung weights in F0 and F1 males and females. As these lung lesions were considered to be secondary to aspiration of the dose formulation, and the chronic interstitial/alveolus inflammation finding was not unanticipated based on a previous 90-day, repeat-dose study with a similar test item, the lungs from the lowand mid-dose animals were not evaluated. In the F1 males, test item-related slight increases in renal tubule degeneration/necrosis and renal tubule hyaline droplets, suggestive of hydrocarboninduced α2μ-globulin male rat nephropathy, were seen in the males given 750 mg/kg/day. Special staining of kidneys from males in the control and high-dose group confirmed this lesion to be hydrocarbon-induced α2μ-globulin male rat nephropathy, an anticipated outcome of this study; therefore, the kidneys of the low- and mid-dose animals were not evaluated. In the F0 males, renal tubule mineralization was noted. Since this finding may be an artifactual change resulting from tissue fixation and/or processing, and since mineralized tubules were only observed in the F0 males given 750 mg/kg/day, with no similar mineralized tubules seen in the F0 control males, F0 females given 750 mg/kg/day, and F1 males and females given vehicle or 750 mg/kg/day, this finding was considered equivocal and non-adverse. There were no test item-related effects on F1 and F2 litter parameters, postnatal survival, physical condition, mortality, pup body weights and anogenital distance. Equivocal, non-adverse decreases (not statistically significant) in absolute and relative spleen weights were observed in the F1 and F2 male and female PND 21 pups in the group given 750 mg/kg/day, compared with the control group. Macroscopic and microscopic findings in PND 21 pups were not test item related.
CONCLUSIONS The test substance [0 (vehicle), 50, 200, or 750 mg/kg/day)] was given orally to F0 and F1 parental male and female rats for at least 70 days prior to mating and throughout the 14-day mating, post mating holding (for males), and gestation and lactation (for females) periods. For F1 males given 750 mg/kg/day, there was a test item-related, non-adverse effect on preputial separation (slight delay) and an equivocal, non-adverse effect on sperm morphology (slight increase in percent abnormal sperm); the slight changes in these parameters fell within the historical control data range. Test item-related histopathological lesions were identified in the lungs (chronic interstitial/alveolus inflammation) of both males and females of the F0 and F1 generations with corresponding macroscopic findings and increased lung weights and the kidneys (renal tubule degeneration/necrosis and renal tubule hyaline droplets confirmed to be α2μ-globulin) of F1 males only. The lung lesions were most likely secondary to aspiration of the test material and therefore not relevant for human risk assessment. The renal effects are a well known male rat specific effect which is induced by hydrocarbons and has no relevance for humans. Additional equivocal, non-adverse findings included renal tubule mineralization in the kidneys of F0 males given 750 mg/kg/day and slightly decreased spleen weights in F1 and F2 pups. Based on the absence of adverse, test item-related findings on the integrity and performance of the male and female reproductive systems, and the absence of adverse findings directly attributable to the test item in non reproductive tissues, a dosage level of 750 mg/kg/day was considered to be the no-observed-adverse-effect level (NOAEL) for reproductive and systemic toxicity.
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