Toxicity and Carcinogenicity Studies of Chlorpromazine Hydrochloride and p-Cresidine in the p53 Heterozygous Mouse Model

Abstract

The carcinogenic potential of chlorpromazine hydrochloride, a psychotropic agent, was assessed in the p53 heterozygou s mouse assay. In a 4-week dose range fi nding study in p53 wild-type mice, doses of 20, 40, 60, and 80 mg/kg were poorly tolerated becaus e of mortality secondary to the severe sedative and hypotensive effects of chlorpromazine. Based on 40% mortality at a dose of 20 mg/kg in the dose-range fi nding study, a high dose of 10 mg/kg was chosen for the 26-week carcinogenicity study in p53 heterozygous mice. Doses of 2.5, 5, and 10 mg/kg chlorpromazin e hydrochloride were well tolerated in the 26-week study. The administration of chlorpromazine hydrochloride at dose levels up to and including 10 mg/kg to p53 heterozygous and wild-type mice did not result in a dose-related increase in tumor incidence or in the type of tumors seen in comparison to controls. Findings related to the administration of chlorpromazine in the 26-week study were limited to minimal uterine and ovarian atrophy in p53 wild-type mice dosed with 10 mg/kg chlorpromazine hydrochloride. However, p53 heterozygous mice administered 400 mg/kg p-cresidine, a genotoxic carcinogen commonly used as a positive control for this model, developed urinary bladder tumors. Administration of p-cresidine also resulted in a regenerative anemia, splenic and hepatic hemosiderosis, renal findings, and ovarian and uterine atrophy. This study demonstrated that chlorpromazine hydrochloride, at the doses tolerated, was not carcinogenic in the p53 heterozygou s mouse assay.