Integration of mechanistic and repeat dose toxicity data in the derivation of an oral reference dose for HFPO-DA

HFPO-DA (ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate) is a short-chain perfluoroether carboxylic acid used as a polymerization aid in the manufacture of some types of fluorinated polymers. Existing toxicity criteria for HFPO-DA include chronic and subchronic oral reference dose (RfD) values based on liver effects in mice. New mechanistic data demonstrate that these liver effects are incontrovertibly linked to rodent-specific peroxisome proliferator-activated receptor alpha (PPARα) signaling pathways that lack human relevance. Therefore, it was critical to reevaluate existing HFPO-DA RfD values. A literature review was conducted to identify human and animal studies that might serve as the basis of updated toxicity criteria. Relevant studies were considered along with a newly completed chronic bioassay in mice. No epidemiological studies were determined acceptable for use in toxicity value development. The only neoplasms in the chronic mouse bioassay were in the liver and were considered PPARα related. The most sensitive extrahepatic noncancer endpoints in rodents involved placental lesions in reproductive and developmental toxicity studies and reduced testicular cellularity in mice following chronic exposure. Both effects resulted in RfD values of 0.001 mg/kg-d. Also presented are probabilistic risk assessment methods that resulted in a similar probabilistic RfD. These results indicate the need to update existing toxicity criteria for HFPO-DA.