Absorption, distribution, metabolism, excretion, and kinetics of 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)propanoic acid ammonium salt following a single dose in rat, mouse, and cynomolgus monkey

Gannon, Shawn A.; Fasano, William J.; Mawn, Michael P.; Nabb, Diane L.; Buck, Robert C.; Buxton, L. William; Jepson, Gary W.; Frame, Steven R.

doi:10.1016/j.tox.2015.12.006

Cited by 85 publications

(53 citation statements)

References 17 publications

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“…Pharmacokinetic studies on GenX have been conducted in rats, mice and monkeys (Gannon et al, ). Female rats demonstrate clearances rates for GenX that are approximately 10‐fold higher than male rats.…”

Section: Resultsmentioning

confidence: 99%

“…Unlike rats, mice do not demonstrate large sex differences in GenX clearance. Comparing male rats and mice, the latter have slightly longer half‐lives for GenX (Gannon et al, ). The clearance rates in male and female monkeys were both similar to male rats.…”

Section: Resultsmentioning

confidence: 99%

“…The clearance rates in male and female monkeys were both similar to male rats. Broadly, Gannon et al () concluded that the pharmacokinetics in monkeys were more similar to rats than mice.…”

Section: Resultsmentioning

confidence: 99%

“…In 2002, the major manufacturer (3M) phased out production of PFOS; in 2006, the US EPA initiated the PFOA Stewardship Program, which was aimed at eliminating emissions and product content of PFOA by 2015; in 2006, the European Union issued a directive restricting the use of perfluorooctane sulfonates; in 2009, the Stockholm Convention included PFOS on the list of persistent organic pollutants and identified it as an Annex B substance; in 2010, the Canadian environmental and health agencies reached an agreement with manufacturers to restrict long‐chain PFAS in products (Buck et al, ; Lau et al, ). However, because of the usefulness of these compounds across a broad array of consumer and industrial applications, efforts were undertaken to find replacements with more favorable environmental and biological properties (Gannon et al, ). Scientific evidence at that time suggested that short‐chain PFAS, such as GenX, were a less toxic, less bioaccumulative alternative to PFOA (Goecke‐Flora & Reo, ; Kudo et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…Scientific evidence at that time suggested that short‐chain PFAS, such as GenX, were a less toxic, less bioaccumulative alternative to PFOA (Goecke‐Flora & Reo, ; Kudo et al, ). As a result, GenX replaced PFOA as a processing aid in the production of fluoropolymers (Gannon et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Development of an oral reference dose for the perfluorinated compound GenX

Thompson

Fitch

Ring

et al. 2019

J of Applied Toxicology

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Ammonium 2,3,3,3‐tetrafluoro‐2‐(heptafluoropropoxy)‐propanoate, also known as GenX, is a processing aid used in the manufacture of fluoropolymers. GenX is one of several chemistries developed as an alternative to long‐chain poly‐fluoroalkyl substances, which tend to have long clearance half‐lives and are environmentally persistent. Unlike poly‐fluoroalkyl substances, GenX has more rapid clearance, but has been detected in US and international water sources. There are currently no federal drinking water standards for GenX in the USA; therefore, we developed a non‐cancer oral reference dose (RfD) for GenX based on available repeated dose studies. The review of the available data indicate that GenX is unlikely to be genotoxic. A combination of traditional frequentist benchmark dose models and Bayesian benchmark dose models were used derive relevant points of departure from mammalian toxicity studies. In addition, deterministic and probabilistic RfD values were developed using available tools and regulatory guidance. The two approaches resulted in a narrow range of RfD values for liver lesions observed in a 2‐year bioassay in rats (0.01–0.02 mg/kg/day). The probabilistic approach resulted in the lower, i.e., more conservative RfD. The probabilistic RfD of 0.01 mg/kg/day results in a maximum contaminant level goal of 70 ppb. It is anticipated that these values, along with the hazard identification and dose‐response modeling described herein, should be informative for risk assessors and regulators interested in setting health‐protective drinking water guideline values for GenX.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…The clearance rates in male and female monkeys were both similar to male rats. Broadly, Gannon et al () concluded that the pharmacokinetics in monkeys were more similar to rats than mice.…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Development of an oral reference dose for the perfluorinated compound GenX

Thompson

Fitch

Ring

et al. 2019

J of Applied Toxicology

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Dietary Uptake and Depuration Kinetics of Perfluorooctane Sulfonate, Perfluorooctanoic Acid, and Hexafluoropropylene Oxide Dimer Acid (GenX) in a Benthic Fish

Hassell

Coggan

Cresswell

et al. 2020

Enviro Toxic and Chemistry

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Per‐ and poly‐fluoroalkyl substances (PFAS) are ubiquitously distributed throughout aquatic environments and can bioaccumulate in organisms. We examined dietary uptake and depuration of a mixture of 3 PFAS: perfluorooctanoic acid (PFOA; C8HF15O2), perfluorooctane sulfonate (PFOS; C8HF17SO3), and hexafluoropropylene oxide dimer acid (HPFO‐DA; C6HF11O3; trade name GenX). Benthic fish (blue spot gobies, Pseudogobius sp.) were fed contaminated food (nominal dose 500 ng g–1) daily for a 21‐d uptake period, followed by a 42‐d depuration period. The compounds PFOA, linear‐PFOS (linear PFOS), and total PFOS (sum of linear and branched PFOS) were detected in freeze‐dried fish, whereas GenX was not, indicating either a lack of uptake or rapid elimination (<24 h). Depuration rates (d–1) were 0.150 (PFOA), 0.045 (linear‐PFOS), and 0.042 (linear+branched‐PFOS) with corresponding biological half‐lives of 5.9, 15, and 16 d, respectively. The PFOS isomers were eliminated differently, resulting in enrichment of linear‐PFOS (70–90%) throughout the depuration period. The present study is the first reported study of GenX dietary bioaccumulation potential in fish, and the first dietary study to investigate uptake and depuration of multiple PFASs simultaneously, allowing us to determine that whereas PFOA and PFOS accumulated as expected, GenX, administered in the same way, did not appear to bioaccumulate. Environ Toxicol Chem 2020;39:595–603. © 2019 SETAC

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Toxicity assessment of hexafluoropropylene oxide-dimer acid on morphology, heart physiology, and gene expression during zebrafish (Danio rerio) development

Gong

McLamb

Shea³

et al. 2022

Environ Sci Pollut Res

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Hexafluoropropylene oxide-dimer acid (HFPO-DA) is one of the emerging replacements for the “forever” carcinogenic and toxic long-chain PFAS. HFPO-DA is a polymerization aid used for manufacturing fluoropolymers, whose global distribution and undetermined toxic properties are a concern regarding human and ecological health. To assess embryotoxic potential, zebrafish embryos were exposed to HFPO-DA at concentrations of 0.5–20,000 mg/L at 24-, 48-, and 72-h post-fertilization (hpf). Heart rate increased significantly in embryos exposed to 2 mg/L and 10 mg/L HFPO-DA across all time points. Spinal deformities and edema phenotypes were evident among embryos exposed to 1000–16,000 mg/L HFPO-DA at 72 hpf. A median lethal concentration (LC50) was derived as 7651 mg/L at 72 hpf. Shallow RNA sequencing analysis of 9465 transcripts identified 38 consistently differentially expressed genes at 0.5 mg/L, 1 mg/L, 2 mg/L, and 10 mg/L HFPO-DA exposures. Notably, seven downregulated genes were associated with visual response, and seven upregulated genes were expressed in or regulated the cardiovascular system. This study identifies biological targets and molecular pathways affected during animal development by an emerging, potentially problematic, and ubiquitous industrial chemical.

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Absorption, distribution, metabolism, excretion, and kinetics of 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)propanoic acid ammonium salt following a single dose in rat, mouse, and cynomolgus monkey

Cited by 85 publications

References 17 publications

Development of an oral reference dose for the perfluorinated compound GenX

Development of an oral reference dose for the perfluorinated compound GenX

Dietary Uptake and Depuration Kinetics of Perfluorooctane Sulfonate, Perfluorooctanoic Acid, and Hexafluoropropylene Oxide Dimer Acid (GenX) in a Benthic Fish

Toxicity assessment of hexafluoropropylene oxide-dimer acid on morphology, heart physiology, and gene expression during zebrafish (Danio rerio) development

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