The carcinogenic potential of
chlorpromazine hydrochloride, a psychotropic agent, was assessed in the p53 heterozygous mouse assay. In a 4-week dose range finding study in p53 wild-type mice, doses of 20,40, 60, and 80 mg/kg were poorly tolerated because 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 finding 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
chlorpromazine 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 heterozygous mouse assay.