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REPRODUCTION TOXICITY

Fertility and Reproduction Studies

Results :

Males :  Dose-related body weight gain suppressions of 17 and 25%, and food consumption suppressions of 7 and 16%, occurred during the 11-week premating treatment period at 100 and 175 mg/kg, respectively, compared with vehicle controls. There were no treatment-related effects on testes, epididymides or accessory organs weights, testicular or epididymal sperm counts, sperm motility, or sperm morphology during Week 15 of treatment. There were no effects on copulation or fertility indices, number of days to mating, or female reproductive parameters (number of implants, live fetuses, or pre- and postimplantation loss).⁽²³⁾

Females : The mean number of estrous cycles, copulation and fertility indices, number of days to mating, and number of viable litters were comparable between groups. In addition, term sacrifice parameters (number of corpora lutea, implants, live fetuses, pre- and postimplantation loss) were not significantly different between groups.⁽²³⁾

Teratogenic Effects

Results :

At 300 mg/kg in rats, 1 treatment-related death occurred on day 12 of gestation and maternal body weight gain and food consumption were decreased during treatment (43% and 23%, respectively). In addition, 1 animal at 300 mg/kg had total litter resorption. Increased postimplantation loss (not statistically significant) and slightly decreased fetal body weight (statistically significant only in males) were also observed at 300 mg/kg. There were no significant differences between treated and control groups in the incidence of fetal malformations or variations. No maternal or developmental toxicity was observed in rats at 10 or 100 mg/kg.⁽²⁴⁾

Results :

In rabbits, marked maternal toxicity (7 deaths, body weight loss during and after treatment, and decreased food consumption) and abortion occurred at 100 mg/kg. At 50 mg/kg, maternal toxicity (2 deaths and 72% body weight gain suppression) and abortion also occurred. There were no treatment-related effects on live litter size or sex ratio. At 50 and 100 mg/kg, nonstatistically significant increases in postimplantation loss and decreases in gravid uterine weight were observed, and at 100 mg/kg, decreases in fetal body weight were observed relative to controls.⁽²⁴⁾

Results :

Offspring survival at birth and during the neonatal period at 225 mg/kg was reduced relative to control by up to 45%, and 28% of litters had no viable offspring by 10 days postpartum. Additional effects on offspring included reduced body weight during the neonatal and maturation periods (100, 225 mg/kg), delayed appearance of pinnae detachment and incisor eruption (225 mg/kg), impaired rotorod performance (females only; 100, 225 mg/kg), reduced acoustic startle responding (males only; 20, 100, 225 mg/kg), and transient effects on shuttle avoidance (females only; 225 mg/kg). No treatment-related effects were observed on offspring reproduction.⁽²⁵⁾