Environmental Toxicity of Hexafluoropropylene Oxide

Hexafluoropropylene oxide (HFPO) is a versatile fluorointermediate that can be used in the synthesis of fluoromonomers and fluoropolymers and to add fluorine functionality to a variety of organic precursors. Perfluorinated vinyl ethers utilized in the production of commercial fluoropolymers are produced using HFPO as the key intermediate. In addition, the commercial perfluorinated Krytox™ lubricant has HFPO as the monomer unit. Hexafluoropropylene oxide is a key intermediate in the synthesis of organofluorine compounds. Many commercial fluoropolymers use HFPO, either as a monomer or a monomer precursor. The epoxide ring is opened by nucleophiles to give a variety of derivatives. Hexafluoropropylene oxide may be isomerized to either pentafluoropropionyl fluoride (PPF) or HFA. The thermolysis of HFPO can also serve as a source of difluorocarbene. A few examples of HFPO chemistry are given below; the chemistry of HFPO has been reviewed.

Bioaccumulation and toxicity of hexafluoropropylene oxide homologs

Hexafluoropropylene oxide (HFPO) and its homologs are emerging per-and polyfluoroalkyl substances (PFAS), gaining attention as potential alternatives to perfluorooctanoic acid (PFOA) for industrial applications (Wang et al., 2019). Their molecular backbone comprises one or more oxygen atoms alternately inserted into fluorinated carbon chains, forming a polyether structure (Sunderland et al., 2019). This endows HFPO homologs with unique chemical inertness and low surface energy, resulting in excellent water and oil resistance (Strynar et al., 2015; Wang et al., 2015). The main Hexafluoropropylene oxide homologs are HFPO dimer acid (HFPO-DA), HFPO trimer acid (HFPO-TA), and HFPO tetramer acid (HFPO-TeA); however, their widespread use in industrial manufacturing processes, such as fluoropolymer production, has raised increasing concerns about their environmental distribution and potential ecological risks. Given the widespread distribution and bioaccumulation potential of Hexafluoropropylene oxide homologs, their potential toxicity to aquatic ecosystems cannot be overlooked. Both in vitro and in vivo studies have shown that HFPO-DA and HFPO-TA induce cytotoxicity, hepatotoxicity, endocrine disruption, and reproductive toxicity. For example, exposure to HFPO-DA and HFPO-TA in zebrafish embryos has been linked to delayed development, cardiac malformations, and liver damage, highlighting their acute toxic effects.[1]

Thus, this study investigated the bioaccumulation and toxicological differences of PFOA and HFPO homologs in Manila clams (Ruditapes philippinarum), and explored how these relate to their molecular structures. The results of this study provide critical insights into the bioaccumulation potential and toxicity of Hexafluoropropylene oxide homologs, laying a foundation for the rational selection of safer PFOA alternatives and contributing to a more comprehensive understanding of their ecological and environmental risks. The bioaccumulation potential of PFAS is critically influenced by their chemical structure, molecular dimensions, and physicochemical properties. Although Hexafluoropropylene oxide homologs share fundamental features with PFOA, such as perfluorinated carbon chains and terminal carboxyl groups, the insertion of ether oxygen atoms introduces distinct conformational and electronic alterations. These modifications significantly modulate their accumulation behavior in aquatic organisms. Our experimental data revealed that both the BCF values and protein-binding rates of PFOA and HFPO homologs increased with the extension of the backbone length, specifically showing an order of HFPO-DA<PFOA<HFPO-TA<HFPO-TeA. The BCF of PFOA observed in this study was comparable to that reported in European mussels (Mytilus galloprovincialis).

In conclusion, the results of this study indicated that the bioaccumulation of PFOA and Hexafluoropropylene oxide homologs in Manila clams increased with the length of the backbone in the order HFPO-DA<PFOA<HFPO-TA<HFPO-TeA. Histopathological analysis showed that these compounds caused varying degrees of damage to the visceral mass of the clams, with HFPO-DA, PFOA, and HFPO-TA causing minor damage, mainly characterized by enlarged digestive tube lumen, whereas Hexafluoropropylene oxide-TeA caused more severe damage, primarily in the form of cell detachment and necrosis of the digestive tubes. IBR and RDA identified oxidative stress effects as the most significant among the observed toxic responses. Moreover, as the backbone length increased, these targets positively affected MDA levels and SOD and CAT activity, while inhibiting CYP450 levels and POD, GSH, and GST activity, resulting in levels of oxidative stress damage ranging from mild to severe. Transcriptomic and metabolomic analyses further elucidated the similarities and differences in amino acid metabolism, energy metabolism, and antioxidant capacity of clams in response to PFOA and Hexafluoropropylene oxide homologs, revealing how clams gradually lose control over their cellular fate as a result of inflammatory injuries and depletion of compensatory energy sources.

References

[1]Qin, Hanlin et al. “Bioaccumulation and toxicity of hexafluoropropylene oxide homologs in Manila clams (Ruditapes philippinarum) compared with PFOA: Correlations with molecular backbone length.” Aquatic toxicology (Amsterdam, Netherlands), vol. 291 107660. 29 Nov. 2025, doi:10.1016/j.aquatox.2025.10766

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