Derivation of a chronic reference dose for perfluorohexane sulfonate (PFHxS) for reproductive toxicity in mice

By Jonathan M. Ali, Stephen M. Roberts, David S. Gordon, and Leah D. Stuchal
Reg. Tox. and Pharm.
October 21, 2019
DOI: 10.1016/j.yrtph.2019.104452


Perfluorohexane sulfonate (PFHxS) is a six-carbon perfluoroalkyl sulfonic acid that was used as an industrial surfactant, but is now found as an environmental contaminant worldwide. In addition to its use as an industrial surfactant, it is a legacy contaminant from the use of aqueous film-forming foams. Despite its widespread occurrence in the environment and evidence of biological activity associated with PFHxS and similar perfluoroalkyl sulfonic acids in rodents, there is no oral toxicity value currently available from the IRIS Database. To derive an oral reference dose (RfD) for PFHxS, available toxicity studies were reviewed using a weight-of-evidence approach. A 42-day mouse reproductive study was chosen as the critical study for the derivation of the oral RfD. Benchmark dose modeling was utilized to derive a point of departure (POD) for a reduction in litter size. A 95% lower confidence limit on the benchmark dose (BMDL) of 13,900 ng/mL (serum PFHxS) was modeled for a reduction in litter size. An oral RfD for PFHxS of 4.0 ng/kg/d was calculated by conversion of the BMDL to a human equivalent oral dose using a human half-life adjusted dosimetric conversion factor and the application of a total uncertainty factor of 300. Additional research is needed to better characterize the toxicity associated with oral exposure to PFHxS and refine the development of toxicity values.



• PFHxS has been detected in certain consumer products as well as drinking water, soil, agricultural products, and wildlife.

• Like other PFAS, PFHxS is highly bioaccumulative in humans with average half-lives ≥ 4.7 years.

• PFHxS is associated with a variety of human health outcomes, but more research is needed.

• Toxicity data from rodents indicate liver, thyroid and reproductive effects of PFHxS.

• Human and animal studies are sufficient to derive a chronic reference dose protective of human health of 4.0 ng/kg/day.

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