Tetrachlorophthalic anhydride (TCPA) is primarily used as a flame retardant in plastics. Toxicology studies were conducted by administering TCPA by oral gavage to F344/N rats and B6C3F1 mice for 13 weeks. Evaluations included histopathology, clinical pathology, and analyses of reproductive system parameters. The genetic toxicity of TCPA was assessed with in vitro tests of mutagenicity in Salmonella typhimurium and induction of sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells; sister chromatid exchanges and chromosomal aberrations were also determined in mouse bone marrow cells following in vivo exposure. The ability of TCPA to induce sex-linked recessive lethal mutations was also studied in vivo in Drosophila melanogaster.
Groups of 10 rats and 10 mice of each sex received TCPA in corn oil vehicle by oral gavage (5 days/week) at doses of 0, 94, 187, 375, 750, and 1500 mg/kg. The deaths of 5 male rats and 1 female rat in the 1500 mg/kg dose group and 1 female rat in the 750 mg/kg dose group were considered due to chemical toxicity. Mean final body weights and body weight gains were depressed in male rats in the 375, 750, and 1500 mg/kg groups and in all groups of female rats receiving TCPA. Relative liver weights were slightly increased in males and females at doses of 187 mg/kg and higher, although a dose relationship was not apparent. Heart weights of surviving male rats in the high-dose group were also increased. Male and female rats exhibited dose-dependent increases in kidney weights and in the incidence and severity of renal tubule necrosis and/or dilation. No clinical pathology changes were clearly associated with chemical exposure.
There were no chemical-related effects on survival, body weights, or organ weights in dosed mice. No chemical-related lesions were identified in organs examined microscopically. Decreases in red blood cell parameters consistent with a mild, poorly regenerative anemia were the only evidence of possible compound toxicity in dosed mice. Sperm morphology and vaginal cytology evaluations in rats and mice revealed no adverse changes related to TCPA exposure. In genetic toxicology studies, TCPA, tested with and without exogenous metabolic activation (S9), was not mutagenic in Salmonella typhimurium and did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells. In the Drosophila melanogaster sex-linked recessive lethal test, TCPA gave equivocal results when administered by feeding and negative results when administered by injection. No induction of chromosomal aberrations was observed in bone marrow cells of mice 17 hours after intraperitoneal injection of TCPA, although an increase in sister chromatid exchanges was detected in these cells 23 hours after injection.
In summary, clear evidence of organ toxicity following administration of TCPA in corn oil by gavage for 13 weeks was limited to the kidney of rats. The no-observed-adverse-effect level for histopathologic lesions in this tissue was not achieved with doses as low as 94 mg/kg per day. No significant adverse effects were seen in mice given doses as high as 1500 mg/kg per day for 13 weeks.