A two-year study with cimetidine in the rat: Assessment for chronic toxicity and carcinogenicity

Abstract

Cimetidine [ N″-cyano- N-methyl- N′-{2-[(5-methylimidazol-4-yl)methylthio]ethyl}guanidine] was administered daily for 2 years by gavage to Wistar rats at dose levels of 950, 378, and 150 mg/kg/day. Two groups, one receiving distilled water daily and the other not treated, served as controls. Premature deaths occurred when cimetidine was accidentally introduced into the lungs or reached the lungs by seepage from the esophagus via the larynx during intragastric administration but cimetidine treatment did not otherwise affect survival, body weight gain, clinical condition, and hematological, or urinalysis parameters. Raised transaminase levels occurred occasionally during the second year of the study in top dose males and there was a significant increase in mean liver weight in top dose females killed terminally compared with controls. Histopathological observations of the livers of these animals indicated only nonspecific changes. Mean prostate and seminal vesicle weights were significantly lower in all groups receiving cimetidine than in controls and there was dose-related atrophy of the seminiferous tubules and atrophy of the male secondary sex organs. There were no other apprent effects of treatment on nontumor pathology. Overal tumor incidence, after the exclusion of Leydig-cell tumors, was not affected by cimetidine treatment. A significantly higher incidence of benign Leydig-cell tumors in the combined cimetidine-treated groups compared with the combined control groups was confined to rats killed during Weeks 105 and 106 and was not dose related. No meaningful treatment-related effects on incidence were observed for any other kind of neoplasm.