Comparison of nitrosocimetidine with nitrosomethylnitroguanidine in chronic feeding tests in rats.

N-Nitrosocimetidine, a nitroso derivative of the drug cimetidine, was given to groups of 20 male and 20 female rats in drinking water at a concentration of 0.5 mM for more than 2 years. The life span of the rats was not decreased compared with untreated control animals, and there was no significant increase in incidence of any tumor that could be attributed to the treatment. In comparison, 45% or more of 20 male rats treated with the analogous nitrosoguanidine, N-nitroso-N-methyl-N'-nitroguanidine, at an equimolar concentration in drinking water developed neoplasms of the glandular stomach. There was some shortening of life span in these animals. An additional group of 20 male rats was given an identical treatment with N-nitroso-N-methyl-N'-nitroguanidine in water, but prepared fresh on alternate days, rather than once a week, to minimize decomposition. These animals died more rapidly than did the previous group and had a higher incidence of neoplasms of the glandular stomach. The neoplasms seen in this organ were usually adenomas or adenocarcinomas, but there were a few hemangiosarcomas and neurosarcomas. There is a possibility that nitrosocimetidine could be formed by interaction of cimetidine with nitrite in the stomach, but the carcinogenic risk arising would be very small based on the negative result of this study.