Critical review and implications of the results of the National Toxicology Program’s carcinogenicity study of tris(chloropropyl)phosphate

The National Toxicology Program (NTP) conducted a 2-year carcinogenicity study on male and female Harlan Sprague-Dawley rats and B6C3F1 mice, which were given tris(2-chloroisopropyl)phosphate (TCPP) in their diet at concentrations up to 10,000-20,000<b> </b>ppm. The study found significant trends in the incidence of hepatocellular adenomas or carcinomas in male rats and uterine adenomas and carcinomas in female rats. Female mice showed a significant increase in hepatocellular carcinomas and adenomas at 10,000<b> </b>ppm, while male mice exhibited increased liver tumor incidences across all dosed groups (1250-5000<b> </b>ppm). NTP concluded that TCPP shows some evidence of carcinogenic activity in male and female rats and male mice, with clear evidence in female mice. Significant increases in tumor incidences were typically noted at higher concentrations, while no significant increases in the incidence of most tumors were reported at the lowest exposures that were higher than exposures expected in humans. Without specific data to develop a TCPP-specific carcinogenic mode of action (MOA) in rats or mice, the lack of genotoxicity suggests a nonlinear MOA or one with a threshold. This investigation applied the Environmental Protection Agency's (USEPA) benchmark dose (BMD) modeling and the European Union's (EU) PROAST modeling to predict acceptable exposure levels using both linear and nonlinear methods.