4,4'-Methylenedianiline is used primarily as a chemical intermediate in the closed system production of
isocyanates and
polyisocyanates. These chemicals are used extensively in the manufacture of rigid
polyurethane foams for thermal insulation and in the production of semiflexible
polyurethane foams for automobile safety cushioning. The saturated isocyante of
4,4'-methylenedianiline [4,4'-methylene-bis(
cyclohexylisocyanate)] is an intermediate in the production of light-stable, high-performance
polyurethane coatings.
4,4'-Methylenedianiline is also a curing agent for
epoxy resins and
urethane elastomers, a
dye intermediate, and a corrosion inhibitor. NTP
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 (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. Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Positive Male Mice: Positive Female Mice: Positive