JV-Hydroxy Metabolites of 2-Acetylaminophenanthrene and 7-Fluoro-2-acetylaminofluorene as Proximate Carcinogens in the Rat1

N-Hydroxy-T-fluoro^-acetylaminofluorene (A^-hydroxy-7fluoro-AAF) and Ar-hydroxy-2-acetylaminophenanthrene (A7hydroxy-AAP) were identified as urinary metabolites of 7-fluoro2-acetylaminofluorene and 2-acetylaminophenanthrene, respectively, in the rat. When administered as 0.010-0.012% of the diet for 10-15 weeks AT-hydroxy-7-fluoro-AAF proved to be a much more potent carcinogen for the rat than 7-fluoro-AAF. The A^-hydroxy derivative produced high incidences of squamous cell carcinomas of the forestomach, adenocarcinomas of the small intestine, carcinomas of the liver, and carcinomas of the mam mary gland (females). In addition, this compound induced significant incidences of carcinomas of the ear duct gland and urinary bladder. On an average each rat had more than 2 primary tumors of different tissue origins. Under these conditions 7-fluoroAAF induced primarily liver and mammary carcinomas; even at these sites the amide was less active than the A^-hydroxy derivative. When administered by s.c. injection in young female rats Af-hydroxy-AAP induced sarcomas at the site of injection and a high incidence of mammary carcinomas. Under these conditions AAP induced only a few mammary carcinomas and no sarcomas. Repeated i.p. injections of the Ar-hydroxy derivatives of aniline and Af-ethylaniline (total doses of 58 and 72 mg) did not result in mammary tumor induction in female rats. These data, in addition to those reported earlier, indicate that N-hydroxylation is of general importance in the neoplastia processes induced by carcinogenic aromatic amides and amines. Syntheses are reported for the following new compounds: N-hydroxy^-fluoro^-acetylaminofluorene and Ar-hydroxj--2acetylaminophenanthrene.