Nitrapyrin has been registered as a
nitrogen stabilizer in the United States for many years based on a robust set of regulatory data. These data demonstrated that
nitrapyrin was not genotoxic and that there were no
tumors elicited in rats or mice that were relevant for human risk assessment. A repeat carcinogenicity study in B6C3F1 mice, conducted at two substantially higher-dose levels (0, 125 or 250 mg/kg/day) than the original study (0, 5, 25 or 75 mg/kg/day) identified liver, stomach, epididymal and Harderian gland
tumors. In order to assess the relevance of these findings for human risk assessment, a Scientific Advisory Group (SAG) examined relevant microscopic changes in these tissues and also evaluated genotoxicity and mechanistic data. The SAG determined that the maximum tolerated dose had been exceeded in mice given 125 or 250 mg/kg/day, based on 26-33% decreased
body weight gains (males-250 mg/kg/day), hepatocellular
necrosis and compensatory hepatocellular proliferation (males and females-125 and 250 mg/kg/day). The SAG believed that the increased incidences of hepatocellular foci of alteration and hepatocellular
neoplasms represented an epigenetic response to hepatocellular
necrosis and increased mitogenesis. Increased incidences of proliferative lesions in the forestomach mucosa were likely secondary to the
irritant effects of
nitrapyrin. Neither the liver nor forestomach effects were interpreted to be a direct carcinogenic effect. Higher incidences of Harderian gland
adenomas (females) and undifferentiated
sarcomas in the epididymis represented normal
biological variations in incidence and were unrelated to
nitrapyrin. Therefore, it was the SAG's opinion that
nitrapyrin exposure that does not produce target organ toxicity in exposed individuals would not be expected to increase the risk of
cancer.