Studies in detoxication. 84. The metabolism of [14C]aniline in the rabbit and other animals

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Abstract
The fate of [C14]aniline has been studied in the rabbit, dog and other animals. With the rabbit, an average of 70% of the aniline is eliminated in the urine in 3 days as p-aminophenol (51%), o-aminophenol (9%), m-amino-phenol (0.1%), phenylsulfamic acid (5.5%), aniline-N-glucuronide (3.5%) and acetanilide (0.2%). The isomeric dihydroxyanilines and the free o- and p-acetamidophenol do not occur in the urine. In 3-4 days the expired air contains no detectable aniline and up to 0.4% of the dose as CO2- The elimination of CO2 begins on the 2d day and continues beyond the 4th day. The total excretion of radioactivity in 3 days in the urine, expired air (up to 1%) and feces (1%) amounts to about 75-90% of the dose. The remainder is present in the tissues and is slowly eliminated as CO2 and as metabolites in the urine. Rabbits killed 5-8 days after dosing contained about 6% of the dose in their tissues. These experiments account for 80-100% of the dose. Free glucuronic acid is excreted in the urine of rabbits after oral administration of aniline, particularly at high doses (500 mg/kg). With the dog, about 20% of the aniline is eliminated in the urine in 16 hr. and about 50% in 2 days. The principal metabolites are o-aminophenol (25%), p-aminophenol (11%) and conjugates of aniline (5%). In both rabbit and dog there was no evidence for the N-methylation or deamination of aniline, nor for mercapturic acid formation. Nitrosobenzene, azoxybenzene, azobenzene and benzidine, the presence of which would have confirmed the oxidation of aniline to nitrosobenzene, did not occur in the urine. However, 2 unidentified metabolites, which have also been found in the urines of rabbits dosed with nitrosobenzene or azoxybenzene, were detected in trace amounts by paper chromatography. The ratio of p- to o-aminophenol excreted in the urines of various animal species dosed with aniline was: gerbil, 15; guinea pig, 11; golden hamster, 10; rabbit, 6; rat, 6 (male) and 2.5 (female); chicken, 4; mouse, 3; ferret, 1; dog, 0.5; cat, 0.4. With the dog, the para/ortho ratio changes with time and it is suggested that at least 2 different enzyme systems are involved in the hydroxylation of aniline.