Sulfoxaflor, a novel active substance that targets sap-feeding insects, induced rodent hepatotoxicity when administered at high dietary doses. Specifically,
hepatocellular adenomas and
carcinomas increased after 18 months in male and female CD-1 mice at 750 and 1250 ppm, respectively, and
hepatocellular adenomas increased after 2 years in male F344 rats at 500 ppm. Studies to determine the mode of action (MoA) for these liver
tumors were performed in an integrated and prospective manner as part of the standard battery of toxicology studies such that the MoA data were available prior to, or by the time of, the completion of the carcinogenicity studies.
Sulfoxaflor is not genotoxic and the MoA data support the following key events in the etiology of the rodent liver
tumors: (1)
CAR nuclear receptor activation and (2) hepatocellular proliferation. The MoA data were evaluated in a weight of evidence approach using the Bradford Hill criteria for causation and were found to align with dose and temporal concordance,
biological plausibility, coherence, strength, consistency, and specificity for a CAR-mediated MoA while excluding other alternate MoAs. The available data include: activation of CAR, Cyp2b induction, hepatocellular
hypertrophy and
hyperplasia, absence of liver effects in KO mice, absence of proliferation in humanized mice, and exclusion of other possible mechanisms (e.g., genotoxicity, cytotoxicity, AhR, or
PPAR activation), and indicate that the identified rodent liver
tumor MoA for
sulfoxaflor would not occur in humans. In this case,
sulfoxaflor is considered not to be a potential human liver
carcinogen.