Collaborative work on evaluation of ovarian toxicity 16) Effects of 2 or 4 weeks repeated dose studies and fertility study of Chlorpromazine hydrochloride in rats

In order to examine potential ovarian toxicity in 2 weeks or 4 weeks repeated-dose studies and a fertility study, chlorpromazine hydrochloride (CPZ) was administered orally to Crl:CD(SD) female rats at dosage levels of 0, 3, 10 and 30 mg/kg/day. In the repeated-dose studies, ovarian weights were decreased at > or = 10 mg/kg in the 4 weeks study and an increase in large atretic follicles was observed histopathologically at > or = 3 mg/kg and > or = 10 mg/kg in the 2 and 4 weeks studies, respectively. In addition, decreased uterine weights and/or atrophic findings in the uterus and vagina at 30 mg/kg and > or = 10 mg/kg, mucification in the vaginal epithelium and alveolar hyperplasia in the mammary gland at > or = 3 mg/kg and > or = 10 mg/kg were seen in the 2 and 4 weeks studies, respectively. Irregular estrous cycles were seen at > or = 3 mg/kg and > or = 10 mg/kg in the 2 and 4 weeks studies. The no-observed-adverse-effect level (NOAEL) for the 2 and 4 weeks studies was considered to be less than 3 mg/kg and 3 mg/kg, respectively. The fertility study with dosing from 2 weeks before mating to day 6 of gestation showed irregular estrous cycles at > or = 10 mg/kg and prolonged copulatory intervals and a reduced fertility index at 30 mg/kg; the NOAEL was therefore considered to be 3 mg/kg, which was higher than that in the 2 weeks study. These results showed that oral CPZ treatment induced ovarian toxicity with 2 weeks or longer treatment and changed the fertility parameters and was therefore concluded that a 2 weeks administration period is adequate to detect the ovarian toxicity of CPZ.