The Carcinogenic Activity of Commercial Grade Toluene Diisocyanate in Rats and Mice in Relation to the Metabolism of the 2,4- and 2,6-Tdi Isomers

Abstract

Groups of 50 F344/N rats of each sex and 50 B6C3F1 mice of each sex were gavaged with corn oil or a mixture of toluene di- isocyanate (TDI) in corn oil for 5 days per week for 105 or 106 weeks. Female rats and mice were given doses of 60 or 120 mg/ kg body weight, while male rats received 30 or 60 mg/kg, and male mice received 120 or 240 mg/kg. The TDI reacted with the moisture in the corn oil vehicle resulting in doses that were 10% to 23% below the target dose concentrations.

The chemical product used was commercial grade TDI, which was an 80%-20% mixture of the 2,4- and 2,6-isomers. Chemical disposition and metabolism studies were conducted with each of the radiolabelled TDI isomers in male rats. Absorption of both of the TDI isomers occurred, with the highest concentrations found in the stomach, cecum, large intestine, and bladder. Ex- cretion occurred via the feces and urine. The major metabolic products from the metabolism of 2,4-TDI were shown to be identical with those from the metabolism of the carcinogen, 2,4- diaminotoluene, whereas the metabolism of the 2,6-TDI isomer yielded one major product, identified as 2,6- bis(acetylamino)toluene.

Greater than 10% depression in body weight gain occurred in all dosed groups of rats throughout most of the study. The major non-neoplastic lesions that were observed in both sexes of the TDI-exposed rats were dose-related increases in acute broncho- pneumonia, characterized as chemical pneumonitis, with inci- dences as high as 50%. In mice mean body weight gain was depressed in dosed male and in high dose females. The principle non-neoplastic lesion in mice that was attributed to chemical treatment was cytomegaly of the kidney tubular epithelium in males.

Survival in all groups of dosed rats was significantly lower than in controls. A dose-dependent pattern of mortality did not com- mence until 70 weeks of exposure, demonstrating that toluene di- isocyanate elicited a cumulative toxic response. There was also significantly lower survival in high dose male, but not female mice, by comparison to controls.

Despite the reduction of power and sensitivity in the rat studies caused by early mortality, statistically significant increases in tu- mor incidences were observed in many different target organs. TDI was carcinogenic in F344/N rats, causing subcutaneous fi- bromas and fibrosarcomas in males and females, pancreatic aci- nar cell adenomas in males, and pancreatic islet cell adenomas, neoplastic nodules of the liver, and mammary gland tumors in females. TDI was not carcinogenic in male mice, but caused he- mangiomas or hemangiosarcomas and hepatocellular adenomas in female B6C3F1 mice.

The pattern of multiple tumor induction caused by administra- tion of the commercial grade TDI was very similar to that found in previous studies of the carcinogen, 2,4-diaminotoluene. The specific target sites of carcinogenicity in the 2,4-diaminotoluene study were all seen in the 2,4-(80%) and 2,6-(20%) TDI study as well. Metabolic studies of these compounds showed that com- mon metabolites were produced from the 2,4-TDI isomer and from 2,4-diaminotoluene, indicating that the 2,4-isomer in the commercial grade TDI was probably responsible for the carcino- genic activity.