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Subchronic Toxicity Studies Indicate that Tris(2-Chloroethyl)Phosphate Administration Results in Lesions in the Rat Hippocampus1

Tris(2-chloroethyl)phosphate (TRCP), a flame-retardant plasticizer used in plastics, polymeric foams and synthetic fibers, was studied as part of the National Toxicology Program's class study of phosphate flame-retardants. TRCP was administered at 0, 22, 44, 88, 175 and 350 mg/kg to both sexes of rats and 0, 44, 88, 175, 350 and 700 mg/kg to both sexes of mice in both fourteen day repeat dose and sixteen week subchronic studies. Results of these studies showed that TRCP toxicity in the 14-day studies was limited to modest increases in male rat kidney and female rat liver weights. Little evidence of toxicity was observed in mice in the 14 day studies. Toxicity observed in mice in the sixteen week studies was limited to increased liver weights in both sexes and decreased kidney weights in males. Administration of TRCP to rats for sixteen weeks resulted in increased mortality of both males and females, increased liver and kidney weights and a lesion in the hippocampal region of the brain. The lesion observed in rat brain appeared as loss of the pyramidal neurons of the CA1 region of the hippocampus and was both more common and more severe in female rats. This lesion, which was not observed in mice, is unusual for any chemical and is unique for a trialkyl phosphate such as TRCP. It is speculated that this highly directed toxicity of TRCP might be used as a chemical probe to investigate the role of the hippocampus in behavior and other functions.