Evaluation of chronic toxicity and carcinogenicity of ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate in Sprague–Dawley rats

Abstract

Ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate, developed for use as a polymerization processing aid in the manufacture of fluoropolymers, was tested for its potential chronic toxicity and carcinogenicity in a 2-year oral dosing study in Sprague–Dawley rats. Male rats were given daily doses of either 0, 0.1, 1 or 50 mg/kg; females were given either 0, 1, 50 or 500 mg/kg. Body weights, food consumption and clinical signs were monitored daily; clinical pathology was conducted at designated intervals and animals were given a complete pathological evaluation after 12 months and 24 months of dosing. Normal survival was seen in all groups, no abnormal clinical signs were seen, and body weight gain was reduced only in female rats at 500 mg/kg. Both sexes at the high dose had mild decreases in red cell mass which were somewhat more pronounced in females. Clinical pathology indicative of liver injury was present in males that received 50 mg/kg and correlated with histomorphological liver changes that included both hypertrophic and degenerative/necrotic lesions. Similar histomorphological lesions were seen in the livers of females at 500 mg/kg. Previous shorter term toxicity studies have identified this chemical as a PPARα agonist and the finding of benign tumors of the liver, pancreas and/or testes in males at 50 mg/kg and females at 500 mg/kg is consistent with the rat response to peroxisome proliferators and is of questionable human relevance. Changes in the kidney, tongue, and stomach were observed only at the highest dose of 500 mg/kg in females. The no-observed-adverse-effect-level in this study lies between 1 and 50 mg/kg for males and between 50 and 500 mg/kg for females.

Development of an oral reference dose for the perfluorinated compound GenX

“…In 2016, RIVM (Beekman, Zweers, de Vries, Janssen, & Zeilmaker, ) derived a tolerable daily intake value for GenX based on changes in the albumin/globulin ratio (AGR) in male rats in the 2‐year bioassay (Caverly Rae et al, ; Craig, ). The rationale provided for selecting this endpoint was concern for immunotoxicity.…”

“…Overall, the change in male rats at 12 months (last time point measured) appeared minimal (0.88 in controls and 1.2 at 50 mg/kg). GenX is a PPARα activator (see above), and PPARα activators are known to affect expression of albumin and globulin with no known adverse sequelae (Caverly Rae et al, ). Indeed, RIVM noted that the change in AGR was consistent with other effects (e.g.…”

“…The database for GenX also includes a 2‐year combined chronic toxicity and carcinogenicity study, conducted in accordance with OECD 453 and performed under GLP conditions, in rats (Caverly Rae et al, ; Craig, ). Based on pharmacokinetic data and subchronic toxicity studies, male and female rats were administered different doses.…”

Perfluorinated Chemicals as Emerging Environmental Threats to Kidney Health

“…Although these replacement compounds were manufactured as ostensibly safer alternatives to PFASs, they have chemical properties (e.g., etherification, chlorination) that prompt serious concern, and studies such as the GenX Exposure Study are only just now beginning to investigate outcomes associated with exposure to these replacement compounds. Limited data demonstrate placental transfer (34), greater binding affinities to human liver fatty acid protein, extremely long t 1/2 in humans (37), and dose-dependent kidney tubular dilation and mineralization, papillary necrosis, and chronic progressive nephropathy in animal models (91). Further, many of the alternatives are themselves precursors to PFASs such as PFOA and PFOS, which through chemical breakdown or biotransformation can lead to persistent PFAS exposure despite phase-out efforts (92).…”

Detection of Poly- and Perfluoroalkyl Substances (PFASs) in U.S. Drinking Water Linked to Industrial Sites, Military Fire Training Areas, and Wastewater Treatment Plants

“…8 Limited available data suggest widespread exposure to replacement (short-chain) PFASs may also adversely affect human health. 11,12 …”