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A Reproductive and Developmental Toxicity Study in CD Rats of LY275585, [Lys(B28),Pro(B29)]-Human Insulin

P.O. Box 708, Lilly Research Laboratories, Eli Lilly & Company, Greenfield, IN 46140, U.S.A.

R. A. Byrd

P.O. Box 708, Lilly Research Laboratories, Eli Lilly & Company, Greenfield, IN 46140, U.S.A.

J. A. Hoyt

P.O. Box 708, Lilly Research Laboratories, Eli Lilly & Company, Greenfield, IN 46140, U.S.A.

J. L. Zimmermann

P.O. Box 708, Lilly Research Laboratories, Eli Lilly & Company, Greenfield, IN 46140, U.S.A.

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 were treated with LY275585 beginning 2 weeks prior to cohabitation and throughout the mating period. Females assigned to the teratology component of the study were treated for 2 weeks prior to cohabitation with the males and through gestation day (GD) 19. These dams were killed on GD 20 and uterine and fetal examinations were performed. Female rats assigned to the delivery component were treated for 2 weeks prior to cohabitation through postpartum day (PD) 20. Dams were allowed to deliver and maintain their progeny through a 21-day lactation period. After weaning, 1 pup/sex/litter was assigned to the F₁ generation, and these animals received no treatment. Survival, growth, behavior, and reproductive performance were evaluated, and reproductive organs were collected for histological evaluation. Treatment of F₀ male and female rats 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 anticipated and attributed to the pharmacology of this compound. Mating and fertility of the F₀ animals were unaffected by treatment. While slight decreases in fetal body weights and increased fetal runts/litter were observed in the 20-U/kg/day group, PD 1 progeny weights were not affected in the delivery component, and there was no indication of teratogenicity in this study. There were no remarkable treatment-related effects on offspring growth patterns, survival, or reproductive performance, but the F₁ animals from the 20-U/kg/day treatment-derived group were more reactive than controls in the startle habituation test. Thus, F₀ parental toxicity, related to the hypoglycemic action of LY275585, was found at all doses. A dose of 5 U/kg/day was considered a no-adverse-effect level for developmental toxicity. There were no remarkable effects of LY275585 treatment on F₀ or F₁ generation reproductive performance at 20 U/kg/day, the highest dose tested in this study.

Key Words: LY275585 • [Lys(B28),Pro(B29)]-Human insulin • Toxicity study.

International Journal of Toxicology, Vol. 13, No. 4, 247-260 (1994)
DOI: 10.3109/10915819409140597


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