Studies of Carcinogenicity in the Rate of Derivatives of Aromatic Amines Related to N-2-fluorenylacetamide

Abstract

The carcinogenic activities have been investigated in a series of 18 compounds, derivatives, and isomers of the carcinogenic N-2-fluorenylacetamide, and 2 acetylated azo dyes. The chemicals were incorporated into diets by dissolving them in either propylene glycol, neutral fat, or acetone. The acetone solution was first mixed with a diet constituent and the solvent was evaporated before incorporation into the diet mixture; the levels of the chemicals in the diet varied from 0.025 to 0.05 percent. The diets containing the various chemicals were fed to female Buffalo-strain rats for periods varying from an average of 3.6 to 18.0 months. The average daily intake of the chemicals varied from 2.0 to 5.1 mg. and the average total intake per rat per experiment varied from 538 to 2,693 mg. Many of the animals were observed for several months after cessation of drug feeding. All the compounds studied except the noncarcinogenic compound, Pavatrine, a commercial product, were synthesized or purified specifically for these tests. Fluorene itself was slightly carcinogenic. When diets containing this chemical were fed, for an average of 7 to 19 months, respectively, in 2 separate experiments, a few tumors appeared at several sites. N-(7-iodo-2-fluorenyl)acetamide was noncarcinogenic. N-(3-iodo-2-fluorenyl)acetamide induced 2 leukemias, a large number of ear-duct tumors, a few lung tumors, and 1 mammary-gland tumor. A multiple hepatoma and a hemangioma of the liver, in 2 of 7 rats, occurred after ingestion of N-(7-chloro-2-fluorenyl)acetamide for 3 months. N-(2-fluorenyl)2,2,2-trifluoroacetamide was a highly active carcinogen for the liver, mammary gland, ear duct, and several other sites. Hepatoma was noted in the liver of 1 rat after ingestion of N-(2-fluorenyl)2-fluoroacetamide for a period of 6 months. The sulfur-containing 2-acetamido-4(2′-fluoryl)thiazole was noncarcinogenic. Five tumors of various sites including 1 mammary-gland tumor were observed, after 19 months, in rats that ingested the sulfur-containing 4,4′-sulfonylbisacetanilide for 10 months. One uterine tumor was noted in a group of rats fed a diet containing N-2-fluorenyl-p-toluenesulfonamide for approximately 6 months. Of 17 rats ingesting N-2-fluorenylsuccinamic acid, for an average of 17 months, 6 developed hepatomas. A few tumors of several other sites were also observed in this group. In 18 rats ingesting N-(9-oxo-2-fluorenyl)acetamide, there were a large number of mammary-gland tumors, 1 hepatoma, 4 ear-duct tumors, and several tumors of other types. Rats that ingested N-(7-methoxy-2-fluorenyl)acetamide for a year developed mammary-gland and ear-duct tumors, as well as a few tumors of several other sites. Rats fed diets containing m-tolylazoacetanilide or p-phenylazoacetanilide for a year developed no liver tumors, but a few tumors of other types were observed. Eighteen control animals, on the basal diet, which were autopsied at an average age of 18 months, developed 1 uterine adenocarcinoma, 1 pituitary adenoma, an inguinal region fibroma, and a polypoid hemangioma of the uterus. Some groups of rats ingesting the most active carcinogens lost weight during the first 2 weeks of the test period, while some other groups ingesting active carcinogens did not. Some groups ingesting compounds that were almost completely inactive as carcinogens also lost weight during the first 2 weeks of the test period. All groups except one rapidly regained this lost weight and continued to gain at a rate almost parallel to that of the control animals, for the remainder of the test periods. Thus, changes in body weight in this series of tests were not a reliable criterion of carcinogenic activity.