Carcinogenesis studies of 4,4'‐methylenedianiline dihydrochloride given in drinking water to F344/N rats and B6C3F1mice

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Abstract
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. Croups 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 wk. Croups of 50 rats and 50 mice of each sex, given drinking water adjusted with 0.1 N HCI to the pH (3.7) of the 300‐ppm formulation, served as controls. Survival was comparable among groups except for male mice receiving the 300‐ppm dose of 4,4'‐methylenedianiline dihydrochloride; survival in that group was lower than that in controls. Mean body weight was reduced in 300‐ppm‐dose female rats and 300‐ppm‐dose male and female mice compared to controls. Water consumption was reduced in a dose‐related manner in both sexes of rats. No compound‐related clinical effects were observed. Under the conditions of these studies, there was clear evidence of carcinogenicity for F344IN rats and for B6C3F1, mice in that 4,4'‐methylenedianiline dihydrochloride caused increased incidences of (1) follicular‐cell carcinomas of the thyroid gland (controls, 0149; low dose, 0/47; high dose, 7/48, 15%; p ≤ 0.072; and neoplastic nodules of the liver (controls, 1/50, 2%; low dose, 12/50, 24%; high dose, 25/50, 50%; p ≤ 0.007; in male rats, (2) follicular‐cell adenomas (controls, 0/47; low dose, 2/47, 4%; high dose, 17/48, 35%; p ≤ 0.001) and C‐cell adenomas (controls, 0/47; low dose, 3/47, 6%; high dose, 6/48, 13% p ≤ 0.029) of the thyroid gland in female rats, (3) follicular‐cell adenomas of the thyroid gland (controls, 0/47; low dose, 3/49, 6%; high dose, 16/49, 33%; p ≤ 0.001), carcinomas of the liver (controls, 10/49, 20%; low dose, 33/50, 66%; high dose, 29/50, 58%; p ≤ 0.001), and pheochromocytomas of the adrenal gland in male mice (controls, 2/48, 4%; low dose, 12/49, 24%; high dose, 14/49, 29%; p ≤ 0.001), and (4) follicular‐cell adenomas of the thyroid gland (controls, 0/50; low dose, 1/47, 2%; high dose, 13/50, 26%; p ≤ 0.001), carcinomas (controls, 1/50, 2%; low dose, 6/50, 12%; high dose, 11/50, 22%; p ≤ 0.002) and adenomas (controls, 3/50, 6%; low dose, 9/50, 18%; high dose, 12/50, 24%; p ≤ 0.011) of the liver, malignant lymphomas (controls, 13/50, 26%; low dose, 28/50, 56%; high dose, 29/50, 58%; p ≤ 0.001), and alveolar/bronchiolar adenoma (controls, 1/50, 2%; low dose, 2150, 4%; high dose, 6/49, 12%; p ≤ 0.05) in female mice.