Developmental and reproduction toxicity studies of Biolimus A9 in SD rats

Biolimus A9 (BA9) is a novel rapamycin derivative. In this report we evaluated the potential toxicity of BA9 in a developmental and reproduction toxicity study (segment I, II, III). In segment I, body weight gains in F0 rats receiving 0.80 mg/kg/day were decreased. A lower fertility index of males was observed and females failed to become pregnant in the 0.80 mg/kg/day group. The number of live fetuses and implantations were decreased while the number of dead fetuses, resorptions, and implantation losses were increased in the 0.12 mg/kg/day group. In segment II, maternal toxicity: body weight gains in F0 females receiving 0.036 and 0.090 mg/kg/day group were decreased. Embryo toxicity: In the 0.090 mg/kg/day group, weights and body lengths of fetuses were decreased, the numbers of viable fetuses was decreased and resorbed fetuses increased. Teratogenic effects: The percent of visceral variations and skeletal variations were both increased in the 0.090 mg/kg/day group. In segment III, dosing F0 rats with BA9 at dose levels of 0.12 and 0.80 mg/kg/day resulted in reproductive and maternal toxicity, consisting of prolonged labor, dystocia, increased mortality, along with reductions in lactation food consumption. F1 rats in the 0.12 mg/kg/day group showed reproductive and developmental toxicity consisting of body weight decreases, decreased food consumption after weaning and a reduction in the gestation index of pregnant rats. Based on these findings, the no-observed-adverse-effect-level (NOAEL) of BA9 toxicity in segment I and III was 0.02 mg/kg/day. The NOAEL in segment II was 0.015 mg/kg/day.

Automated summary

In a developmental and reproduction toxicity study, BA9 showed potential toxicity. The experiment found that body weight gains decreased in F0 rats receiving a dosage of 0.80 mg/kg/day. In the 0.80 mg/kg/day group, a lower fertility index of males was observed and females failed to become pregnant. The number of live fetuses and implantations decreased, while the number of dead fetuses, resorptions, and implantation losses increased in the 0.12 mg/kg/day group.