Developmental Toxicity of Pirmenol in Rats and Rabbits

Abstract

Pirmenol, a Class Ia antiarrhythmic agent, was evaluated for developmental toxicity in rats and rabbits. Suspensions of pirmenol in 0.5% methylcellulose were administered by gavage on gestation days (GD) 7 to 17 to groups of 40 rats (0, 75, 125 and 150 mg/kg) and on GD 6 to 18 to groups of 20 rabbits (0, 10, 25 and 50 mg/kg). 25 rats per group and all rabbits were euthan-atised near term (GD 21, rats; GD 30, rabbits) and fetuses were examined for external, visceral and skeletal variations and malformations. The remaining 15 rats per group were allowed to deliver and rear their offspring to postnatal (PN) day 21. Growth, survival, development, behaviour and reproductive performance were evaluated in the F1 group (offspring of the original animals). Maternal toxicity was observed during treatment at the 2 highest doses in rats (ataxia, hypoactivity, languid appearance, tremors, squinted eyes, and abnormal respiration) and in rabbits at the high (convulsion, mortality, bodyweight loss and significant suppression of food intake) and mid doses (suppression of bodyweight gain). Embryo/fetal or postnatal toxicity were not observed in rats. In rabbits, postimplantation loss was slightly increased at 25 and 50 mg/kg/day and the mean number of live fetuses was slightly decreased at 50 mg/kg/day. A statistically significant increase in the percentage of malformed fetuses per litter, observed at 50 mg/kg/day, was considered equivocal due to the limited number of surviving fetuses and litters (n = 5) at that dose. In conclusion, administration of pirmenol during organogenesis produced maternal, but not developmental, toxicity in rats at doses up to 150 mg/kg/day and maternal and developmental toxicity at doses less than 10 and 25 mg/kg/day or more, respectively, in rabbits.