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

Abstract

Toxicity and Carcinogenicity of Chronic Exposure to Tris(2-chloroethyl)phosphate. Matthews, H. B., Eustis, S. L., and Haseman, J. (1993). Fundam. Appl. Toxicol. 20, 477-485.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/kg body wt by oral gavage resulted in necrosis of pyramidal neurons in the CA1 region of the hippocampus of F344 rats, but not in B6C3F1 mice. The 2-year studies reported here were designed to characterize the chronic toxicity and potential carcinogenicity of TRCP in each sex of F344 rats and B6C3F1 mice. Groups of 60 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 of 60 mice per sex received 0, 175, or 350 mg/kg by oral gavage on the same dosing schedule. Each of these groups contained 10 animals which were euthanized at 66 weeks. The principal toxic effects of chronic exposure of rats to TRCP occurred in the brain and kidney. In contrast to the findings in the 16-week studies, a hippocampal lesion was not observed in the brain, although degenerative lesions were widely distributed in the gray and white matter of the brain stem and cerebral cortex of high-dose female and, to a lesser extent, male rats. These findings suggest that the hippocampal necrosis may be dependent upon the size of the individual doses or may have a pathogenesis different from that of the lesions in the brain stem and cerebral cortex. The other primary effect of chronic exposure was a dose-dependent increased incidence of renal tubule hyperplasia and adenoma. Renal tubule neoplasms, primarily adenomas, were observed in 4% of control, 10% of low-dose, and 50% of high-dose male rats and in 0% of control, 4% of low-dose, and 10% of high-dose female rats. There were also marginal increases in mononuclear cell leukemia and in thyroid follicular neoplasms in dosed male and female rats that were not clearly related to TRCP administration. Mice were less sensitive to TRCP than rats and lesions attributable to chemical administration in mice were limited to a dose-dependent increased incidence of karyomegaly (nuclear enlargement) in epithelial cells of proximal tubules in the inner cortex and outer stripe of the outer medulla of the kidneys both sexes. Marginal increases in the incidence of renal tubule neoplasms in male mice and harderian gland neoplasms in female mice were not considered clearly related to TRCP administration.