2,4-Diaminotoluene is a widely used industrial intermediate. Most of this chemical produced in the United States is converted to toluene diisocyanate for use in the synthesis of polyurethanes. 2,4-Diaminotoluene is also an intermediate in the for the synthesis of dyes and used for textiles, fur, leather, biological stains and indicators, spirit varnishes and wood stains, and pigments. In addition, it has been used as a component of oxidation-type hair formulations. Two hundred and thirty-three million pounds of 2,4-diaminotoluene were produced in the United States in 1976. In addition, 356,000 pounds were imported in that year.
A bioassay of 2,4-diaminotoluene for possible carcinogenicity was conducted by administering the test chemical in feed to F344 rats and B6C3F1 mice.
Groups of 50 rats of each sex were administered 2,4-diaminotoluene at one of two doses, initially either 125 or 250 ppm, for 40 weeks. Because of excessive depression in the amount of mean body weight gained in both low- and high-dose groups, doses were then reduced to 50 and 100 ppm, respectively. Administration of 50 ppm to the low-dose groups was continued for 63 weeks, and surviving animals in these groups were then killed. Surviving animals in the high-dose males and females administered 100 ppm were killed at the end of 39 and 44 weeks, respectively, due to morbidity. The time-weighted average dose was 79 ppm for the low-dose male and females for 103 weeks, 176 ppm for the high-dose males for 79 weeks, and 171 ppm for the high-dose females for 84 weeks. Matched controls consisted of 20 untreated rats of each sex.
Groups of 50 mice of each sex were administered 2,4-diaminotoluene at one of two doses, either 100 or 200 ppm, for 101 weeks. Matched controls consisted of 20 untreated mice of each sex. Surviving mice were killed at the end of administration of the test chemical.
Mean body weights of dosed male and female rats and mice were lower than those of corresponding controls and were dose related except for the low-dose male mice, for which mean body weights were only slightly lower than those of controls. Mortality was not dose related in either the male or female mice, but was dose related in both the male and female rats. Survival was decreased and lesions of hepatonephrotoxicity were observed in the animals administered the 2,4-diaminotoluene.
In the rats, hepatocellular carcinomas or neoplastic nodules occurred at incidences that were dose related in both the males (P=0.014) and the females (P=0.008). In direct comparisons of incidences of the tumors in control and dosed groups, the incidence in the high-dose male group had a P value of 0.026 (males: controls 0/20, low-dose 5/49, high-dose 10/50; females: controls 0/20; low-dose 0/50, high-dose 6/49). The significance of the occurrence of these tumors in both the male and female rats was supported by the high incidences of associated nonneoplastic lesions of the liver in the dosed groups and by low incidences of liver tumors in historical-control male or female F344 rats at the same laboratory.
In addition, carcinomas or adenomas of the mammary gland occurred in the female rats at incidences that were dose related (P=0.002) and in direct comparisons were higher in the dosed groups (P<0.001) than in the control group (control 1/20; low-dose 38/50, high-dose 41/50).
In male rats, fibromas of the subcutaneous tissue occurred at incidences that were dose related (P=0.004) and in direct comparisons were higher in the dosed groups (P< 0.020) than in the control group (controls 0/20, low-dose 15/30, high-dose 19/50).
In the mice, hepatocellular carcinomas occurred in the females at incidences that were dose related (P=0.002) and in direct comparisons were higher in dosed groups (P< 0.007) than in the control group (controls 0/19, low-dose 13/47, high-dose 18/46). In addition, lymphomas occurred at a significant incidence (P<0.001) in the low-dose female mice (controls 2/19, low-dose 29/47, high-dose 11/46). No tumors occurred at significantly increased incidences in the dosed male mice.
Under the conditions of this bioassay, 2,4-diaminotoluene was carcinogenic for F344 rats, inducing hepatocellular carcinomas or neoplastic nodules in both males and females and carcinomas or adenomas of the mammary gland in females. The test chemical was also carcinogenic for female B6C3F1 mice, inducing hepatocellular carcinomas. The incidence of lymphomas in the female mice suggested that these tumors may also have been related to administration of the test chemical.