Abstract for TR-248

Carcinogenesis studies of 4,4'-methylenedianiline dihydrochloride (98.6% pure) were conducted by administering this chemical in the drinking water of F344/N rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex received drinking water containing 150 or 300 ppm 4,4'-methylenedianiline dihydrochloride (dosage expressed as the free base) for 103 weeks. Groups of 50 rats and 50 mice of each sex, given drinking water adjusted with 0.1N HCl to the pH (3.7) of the 300-ppm formulation, served as controls.

Survival was comparable among groups except for male mice receiving the high dose of 4,4'-methylenedianiline dihydrochloride; survival in that group was lower (P=0.006) than that in controls. Mean body weight was reduced in high dose female rats and in high dose male and female mice. Water consumption was reduced in a dose-related manner in both sexes of rats. No compound-related clinical effects were observed.

Compound-related nonneoplastic lesions of the thyroid in female rats included follicular cysts and hyperplasia. The incidence of thyroid follicular cell hyperplasia was elevated in high dose male and female mice. The incidences of thyroid neoplasms in the high dose groups were elevated compared with those of the control groups for both sexes of both species. Thyroid follicular cell carcinoma was increased in male rats (controls, 0/49; low dose, 0/47; high dose, 7/48, 15%: P<0.012). Follicular cell adenoma was increased in high dose female rats (0/47; 2/47, 4%; 17/48, 35%: P<0.001), in high dose male mice (0/47; 3/49, 6%; 16/49, 33%: P<0.001), and in high dose female mice (0/50; 1/47, 2%; 13/50, 26%: P<0.001) as compared with controls. In female rats, thyroid C-cell adenoma was also elevated in a dose-related manner (0/47; 3/47, 6%; 6/48, 13%, P<0.029).

Dose-related increases in nonneoplastic lesions were observed for male rats (nonspecific liver dilatation) and for male and female rats (fatty metamorphosis and focal cellular change). Liver degeneration was present in 80% of the low dose and 60% of the high dose male mice but was not found in the controls. Neoplastic nodules of the liver were observed at greater incidences (P<0.002) for low and high dose male rats as compared with controls (control, 1/50, 2%; low dose, 12/50, 24%, P<0.002; high dose 25/50, 50%, P<0.001). Hepatocellular adenoma was increased in a dose-related manner in dosed female mice (3/50, 6%; 9/50, 18%; 12/50, 24%, P<0.011). Hepatocellular carcinoma was observed in greater incidence in dosed male mice (10/49, 20%; 33/50, 66%, P<0.001; 29/50, 58%, P<0.001) and in high dose female mice (1/50, 2%; 6/50, 12%; 11/50, 22%, P=0.002).

Male rats had a dose related increase in kidney mineralization. Nephropathy was increased in dosed mice of both sexes; renal papillary mineralization was greater in high dose male mice and female mice than in the controls.

Other tumors that were elevated in dosed animals included adrenal pheochromocytomas in male mice (control, 2/48, 4%; low dose, 12/49, 24%, P<0.006; high dose, 14/49, 29%; P<0.001), alveolar/bronchiolar adenoma in female mice (1/50, 2%; 2/50, 4%; 6/49, 12%, P<0.05) and malignant lymphomas in female mice (13/50,26%; 28/50, 56%, P=0.002; 29/50, 58%; P=0.001).

Uncommon tumors were observed in dosed animals at low incidences but may be important because the historical control incidences are very low; bile duct adenoma in 1/50 high dose male rats (historical control 3/3,663), transitional-cell papillomas of the urinary bladder in female rats (historical control, 3/3,664, 0.08%; low dose, 2/50, 4%; high dose, 1/50, 2%) and granulosa cell tumors of the ovary in female rats (historical control, 11/3,642, 0.3%; low dose, 3/50, 6%; high dose, 2/50, 4%).

Decreases in tumor incidences were observed for leukemia in male rats (control, 12/50, 24%; low dose, 6/50, 12%; high dose, 5/50, 10%, P=0.048) and alveolar or bronchiolar adenomas (combined) in male mice (12/49, 24%; 9/49, 18%; 3/49, 6%, P<0.011).

Under the conditions of these studies, 4,4'-methylenedianiline dihydrochloride was carcinogenic for F344/N rats and B6C3F1 mice of each sex, causing significantly increased incidences of thyroid follicular cell carcinomas in male rats, thyroid follicular cell adenomas in female rats and in mice of each sex, C-cell adenomas of the thyroid gland in female rats, neoplastic nodules in the liver of male rats, hepatocellular carcinomas in mice of each sex, adenomas of the liver and malignant lymphomas in female mice, and adrenal pheochromocytomas in male mice.