Evaluation of chronic toxicity and carcinogenicity of HFPO-DA in mice

Ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate (HFPO-DA; CAS#: 62037-80-3) was tested for potential toxicity and carcinogenicity in CD-1 mice administered 0, 0.05, 0.1, 0.5, or 5 mg/kg-day HFPO-DA via oral gavage for 9 or 18 months. Histopathological examinations were conducted at each time point along with clinical chemistry measurements. Reduced survival was observed in male mice exposed to 5 mg/kg-day for 18 months but not 9 months. Hepatocellular hypertrophy was the most sensitive histopathological response to HFPO-DA and was significantly increased in both sexes at 9 and 18 months of exposure. At 18 months, hepatocellular hypertrophy was not observed below 0.1 mg/kg-day. Liver tumors were significantly increased at 5 mg/kg-day in males at both timepoints and in females at 18 months. No other treatment related tumors were observed. Consistent with previously published studies in mice, transcriptomic responses in the liver of both sexes showed enrichment of peroxisome proliferator-activated receptor alpha (PPARα) signaling pathways. These changes demonstrate that the tumor response in the liver is consistent with a PPARα mode of action. Other noncancer histopathological effects were limited to the adrenal gland (5 mg/kg-day at ≥9 months) and testes (≥0.5 mg/kg-day at 18 months) of male mice.