Toxicity and Carcinogenicity of Chronic Exposure to Tris(2-chloroethyl)phosphate

Previous short-term studies of tris(2-chloroethyl)phosphate(TRCP), a flame retardant used in industrial and consumer products,demonstrated that repeated administration of 350 mg TRCP/kgbody wt by oral gavage resulted in necrosis of pyramidal neuronsin the CA1 region of the hippocampus of F344 rats, but not inB6C3F₁ mice. The 2-year studies reported here were designedto characterize the chronic toxicity and potential carcinogenicityof TRCP in each sex of F344 rats and B6C3F₁ mice. Groups of60 rats per sex received 0, 44, or 88 mg/kg by oral gavage,once per day, 5 days per week, for up to 103 weeks. Groups of60 mice per sex received 0, 175, or 350 mg/kg by oral gavageon the same dosing schedule. Each of these groups contained10 animals which were euthanized at 66 weeks. The principaltoxic effects of chronic exposure of rats to TRCP occurred inthe brain and kidney. In contrast to the findings in the 16-weekstudies, a hippocampal lesion was not observed in the brain,although degenerative lesions were widely distributed in thegray and white matter of the brain stem and cerebral cortexof high-dose female and, to a lesser extent, male rats. Thesefindings suggest that the hippocampal necrosis may be dependentupon the size of the individual doses or may have a pathogenesisdifferent from that of the lesions in the brain stem and cerebralcortex. The other primary effect of chronic exposure was a dose-dependentincreased incidence of renal tubule hyperplasia and adenoma.Renal tubule neoplasms, primarily adenomas, were observed in4% of control, 10% of low-dose, and 50% of high-dose male ratsand in 0% of control, 4% of low-dose, and 10% of high-dose femalerats. There were also marginal increases in mononuclear cellleukemia and in thyroid follicular neoplasms in dosed male andfemale rats that were not clearly related to TRCP administration.Mice were less sensitive to TRCP than rats and lesions attributableto chemical administration in mice were limited to a dose-dependentincreased incidence of karyomegaly (nuclear enlargement) inepithelial cells of proximal tubules in the inner cortex andouter stripe of the outer medulla of the kidneys both sexes.Marginal increases in the incidence of renal tubule neoplasmsin male mice and harderian gland neoplasms in female mice werenot considered clearly related to TRCP administration.