In studies on animals, toluene diisocyanate (TDI) was a contact and respiratory sensitizer, was not toxic by the oral or dermal routes, but was irritating, and toxic by inhalation. The respiratory tract was the target in acute, subchronic, and chronic exposure studies. Typically, at concentrations of above 0.1 ppm (parts per million), clinical signs of nasal irritation were evident, and histopathological investigations revealed rhinitis and epithelial hyperplasia of nasal passages. With increasing concentration, effects were more severe; affected the larynx, trachea, and lung; and, eventually, affected body weight and survival. The carcinogenicity of TDI to rats and mice was investigated. By inhalation, there was no treatment-related increase in tumor incidence in either species at the highest concentration tested (0.15 ppm). Effects of TDI were seen as rhinitis in nasal turbinates of both species, and as reduced body weight gain in mice. Through oral administration of TDI dissolved in corn oil to rats and mice (up to 120 mg/kg/day), increased incidence of a number of tumor types was seen. This route is of questionable relevance to occupational exposure. The dosing solutions were known to have degraded, and TDI would hydrolyze to diaminotoluene in the acidic stomach environment. Several in vitro tests for genotoxicity gave positive results, which can be ascribed to degradation of TDI by solvents. In properly conducted assays, in vivo TDI was negative for genotoxicity. In a two-generation reproduction study in rats, there were no effects on reproductive indices at the highest exposure concentration of 0.3 ppm TDI, which elicited toxicity in both generations. In a developmental toxicity study in rats, there was evidence of minimal fetotoxicity in the presence of maternal toxicity at 0.5 ppm, with no effects at 0.1 ppm. No treatment-related embryotoxicity or teratogenicity was observed.