Lack of Carcinogenic Activity and Metabolic Fate of Fluorenylacetamides in Monkeys23

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Abstract
During the past 4 years, N-2-fluorenylacetamide (2-FAA) and N,N'-2,7-fluorenylenebisacetamide (2,7-FAA) were administered orally to 16 macaque monkeys each, and the copper chelate of N-hydroxy-2-FAA(Cu-N-OH-2-FAA) was injected subcutaneously into 9 monkeys. With few exceptions, the animals were less than 24 hours old when initially exposed to the fluorenylacetamides. Histologic changes in the livers of monkeys fed 2-FAA and 2,7-FAA were relatively slight, and no tumors or hyperplastic nodules have been seen. Cysts and foreign-body granulomas formed at the site of repeated subcutaneous injections of Cu-N-OH-2-FAA. The metabolism of 2-FAA and 2,7-FAA was studied in 4 young male rhesus monkeys. Experiments with C14-labeled compounds showed that 2-FAA is excreted rapidly (72 hours) when given either orally or intra-peritoneally (97% in urine and 3% in feces). Eighty-seven percent of the urinary metabolites were identified by chromatography as 7-hydroxy-2-FAA (76-92% in conjugated form) and the rest as free amines (1.4%) and a mixture of N-OH-2-FAA and 2-FAA (3.7–6.4%). 2,7-FAA, when given orally, is excreted rapidly in the feces. Ninety-eight percent is recoverable, unmetabolized, from the feces within 1 week and 1.65 percent is present in the urine as metabolized material. When given intraperitoneally, however, the excretion is slower and is chiefly in the urine (65% the 1st week and 87% in 3 weeks). Only 13 percent of the compound was recovered from the feces in 22 days (1 O% in the 1st week). Potential metabolites of 2,7-FAA are not yet available for identification of the radioactive materials separated by chromatography. The possible relation of the metabolic behavior of these two fluorenyl compounds to their failure to show any carcinogenic effect after 1 to 3½ years of feeding is discussed.