Initial Submission: A Range Finding Teratology Study in Rabbits with Tributyltin Oxide with Cover Letter dated 09/29/1992

摘要

Potential maternal and embryotoxic effects of TBTO were evaluated in this range-finding teratology study in rabbits. TBTO was administered orally by gavage, admixed in Mazola corn oil, to seven groups of five bred New Zealand White rabbits once daily from gestation days 6 through 18. Dosage levels of 0.2, 1.0, 5, 10, 20, 30 and 50 mg/kg/day were selected. A dosage volume of 0.5 ml/kg was used for all test groups. For comparative purposes, five control females were concurrently dosed with Mazola corn oil on a comparable regimen at 0.5 ml/kg. Throughout gestation all females were observed twice daily for appearance and behavior, and body weights were recorded at appropriate intervals. All surviving animals were sacrificed on gestation day 29 for a scheduled uterine examination. Seventeen compound-related deaths occurred in this study (2, 5, 5 and 5.in the 10, 20, 30 and 50 mg/kg/day groups, respectively). Although the direct cause of death for one female in the 20 mg/kg/day was intubation trauma, the macroscopic findings were similar to those of the animals found dead. Five females aborted (0, 1, 0, 3 and 1 in the control, 0.2, 1.0, 5 and 10 mg/kg/day groups, respectively). The abortions in the 5 and 10 mg/kg/day groups were considered a secondary effect of maternal toxicity. Treatment-related signs of toxicity including body weight losses, decreased defecation, soft stool, diarrhea, anogenital matting and wet red material on the cage paper were noted in the 5, 10, 20, 30 and 50 mg/kg/day TBTO treated groups. An increased mean postimplantation loss in the 5 mg/kg/day dose group may be a secondary effect of maternal toxicity; the two surviving females at the 10 mg/kg/day dose level had total litter resorption. Intrauterine survival in the 0.2 and 1.0 mg/kg/day dose groups were comparable to the control group. In conelusion, dose levels of 5, 10, 20, 30 and 50 mg/kg/day were clearly excessive for a teratology study in rabbits with TBTO. A dose level of 0.2 mg/kg/day was considered a 'no-effect' level. Based on the results of this study, dosage levels of 0, 0.2, 1 and 2.5 mg/kg/day were selected for the subsequent teratology study in rabbits with TBTO.