A REPRODUCTIVE AND DEVELOPMENTAL TOXICITY STUDY IN CD RATS OF LY275585, [LYS(B28),PRO(B29)]-HUMAN INSULIN

LY275585, [Lys(B28),Pro(B29)]-human insulin, was administered daily by subcutaneous injection at doses of 0, 1, 5, or 20 U/kg. Male rats wer e treated with LY275585 beginning 2 weeks prior to cohabitation and th roughout the mating period. Females assigned to the teratology compone nt of the study were treated for 2 weeks prior to cohabitation with th e males and through gestation day (GD) 19. These darns were killed on GD 20 and uterine and fetal examinations were performed. Female rats a ssigned to the delivery component were treated for 2 weeks prior to co habitation through postpartum day (PD) 20. Dams were allowed to delive r and maintain their progeny through a 21-day lactation period. After weaning, 1 pup/sex/litter was assigned to the F-1 generation, and thes e animals received no treatment. Survival, growth, behavior, and repro ductive performance were evaluated, and reproductive organs were colle cted for histological evaluation. Treatment of F-0 male and female rat s with LY275585 resulted in isolated incidences of severe hypoglycemia at 5 and 20 U/kg/day and some modest changes in food consumption and body weight measures at all treatment levels. These changes were antic ipated and attributed to the pharmacology of this compound. Mating and fertility of the F-0 animals were unaffected by treatment. While slig ht decreases in fetal body weights and increased fetal runts/litter we re observed in the 20-U/kg/day group, PD 1 progeny weights were not af fected in the delivery component, and there was no indication of terat ogenicity in this study. There were no remarkable treatment-related ef fects on offspring growth patterns, survival, or reproductive performa nce, but the F-1 animals from the 20-U/kg/day treatment-derived group were more reactive than controls in the startle habituation test. Thus , F-0 parental toxicity, related to the hypoglycemic action of LY27558 5, was found at all doses. A dose of 5 U/kg/day was considered a no-ad verse-effect level for developmental toxicity. There were no remarkabl e effects of LY275585 treatment on F-0 or F-1 generation reproductive performance at 20 U/kg/day, the highest dose tested in this study.