Carcinogenesis in F344 Rats by N-Nitrosomethyl-n-propylamine Derivatives23

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Abstract
The carcinogenicity of N-nitrosomethyl-n-propylamine and five of its derivatives, including N-nitrosomethyl-n-butylamine, was compared by oral administration of the compounds to inbred F344 rats. N-Nitromethyl-n-propylamine and N-nitrosomethyl-n-butylamine given in drinking water induced tumors of the upper gastrointestinal tract, mainly carcinomas of the esophagus, and appeared to be of comparable potency. N-Nitrosomethyl(2-hydroxypropyl)amine also mainly induced esophageal carcinomas (100% incidence) and lung tumors, whereas N-nitrosomethyl(2,3-dihydroxypropyl)amine mainly induced nasal cavity tumors and gave rise to a high incidence of esophageal tumors; however, it appeared to be less potent than the monohydroxy compound. N-Nitrosomethyl(2-oxopropyl)amine, the ketone corresponding to N-nitrosomethyl(2-hydroxypropyl)amine, was a more potent carcinogen than the latter at comparable doses in drinking water and gave rise to a high incidence of esophageal tumors and tumors of the trachea; female rats had a high incidence (15/20) of angiosarcomas of the liver, but only 2 male rats died with this tumor. When N-nitrosomethyl(2-oxopropyl)amine was administered at a lower dose in drinking water or at the same dose given by gavage, the incidence of esophageal tumors was lower and there were fewer carcinomas. After administration of large doses in drinking water to male and female rats, N-nitrosomethyl(3-carboxypropyl)amine, a urinary metabolite of several N-nitrosomethyl-n-alkylamines that induce tumors of the urinary bladder in rats, gave rise to a high incidence of transitional cell carcinomas of the bladder. The time to death of animals with these tumors was long, and there were few other tumors.