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Animal Studies
The National Toxicology Program (NTP) (1986) exposed male and female Fischer 344 344/N rats and
B6C3F 1 mice (50/sex/exposure group) to commercial grade TDI (86% 2,4 isomer; 14% 2,6 isomer) in
corn oil by gavage 5 days/week for 106 and 105 weeks, respectively. Rat exposure groups were 30 or
60 mg/kg for males and 60 or 120 mg/kg for females. Mouse exposure groups were 120 or 240 mg/kg
body weight for males and 60 or 120 mg/kg for females. Vehicle control groups (50/sex/species) were
included.
A dose-dependent reduction in survival occurred in treated rats; 36/50 (72%) controls, 14/50 (28%)
low-dose and 8/50 (16%) high-dose males, and 36/50 (72%) controls, 19/50 (38%) low-dose and
6/50 (12%) high-dose females survived to study termination (108 weeks). A treatment-related
induction of subcutaneous fibromas and fibrosarcomas was noted in males and females. The combined
fibroma/fibrosarcoma incidence was 3/50 (6%) in controls, 6/50 (12%) in low-dose and 12/50 (24%)
in high-dose males, and 2/50 (4%) in controls, 1/50 (2%) in low-dose and 5/50 (10%) in high-dose
females. Fibromas and fibromasarcomas occurred in male and female rats with a statistically positive
trend, and the incidence in both high-dose males and females was significantly greater than controls.
Increased mammary gland tumor incidence in female rats was found to be significant in both the lowand
high-dose groups by life table and incidental tumor analysis. The first mammary tumor was seen in
an animal dying at week 84; the survival-adjusted mammary tumor incidences were 17/45 (38%) for
controls, 25/36 (69%) for low-dose and 21/28 (75%) for high-dose animals. Increased incidences of
pancreatic acinar cell adenomas with a statistically significant trend were observed in male rats; the
incidence in the high-dose group was significantly greater than that in the controls. Pancreatic acinar
nodular hyperplasia incidence was also increased in male rats in a dose-dependent manner (control,
0%; low-dose, 4%; high-dose, 8%). A statistically significant trend was noted for pancreatic islet cell
adenoma incidence in both male and female rats; the incidences were significantly greater than those in
the controls in both dose groups for females, and in the high-dose group for males. A significant doserelated
increase in hepatic neoplastic nodule incidence in high-dose female rats was also noted.
Survival of high-dose male mice was reduced; 26/50 (52%) animals in this group were still alive at study
termination (week 107) compared to 46/50 (92%) controls and 40/50 (80%) in the low-dose group.
No statistically significant increase in tumor incidence was noted in treated male mice. A statistically
significant positive trend was observed in the incidence of hemangiomas and hemangiosarcomas (in liver,
ovaries or peritoneum), lymphomas, and hepatocellular adenomas and carcinomas in female mice.
Overall hemangioma and hemangiosarcoma incidence was 0/50 in controls, 1/50 (2%) in the low-dose
group and 5/50 (10%) in the high-dose group. Pairwise comparisons between the control and highdose
groups also indicated a significantly increased tumor incidence in the high-dose group. Combined
hepatocellular adenoma and carcinoma incidence was 4/50 (8%) in controls, 5/50 (10%) in the lowdose
group and 15/50 (30%) in the high-dose group. Tumor incidence in the high-dose group was
significantly greater than in the controls. Overall lymphoma incidence was 10/50 (20%) in controls,
17/50 (34%) in the low-dose group, and 16/50 (32%) in the high-dose group; high-dose group tumor
incidence was significantly greater than controls.
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