Tom Neltner, J.D., Chemicals Policy Director and Maricel Maffini, Ph.D., Consultant
Note to readers: As we all grapple with the grave global health challenge from COVID19, we want to acknowledge the essential services that professionals at the Food and Drug Administration (FDA) and in the food production, processing and retail industries provide in continuing to deliver food. In the meantime, we are continuing to work towards improved health protections – including reducing chemicals in food. We’ll plan to keep sharing developments that may be useful to you. In the meantime, please stay safe and healthy.
Last year, we reported on a sophisticated analysis performed by FDA’s scientists showing that 5:3 acid, a breakdown product of a short-chain PFAS known as 6:2 fluorotelomer (6:2 FTOH) was slow to be eliminated by the body. The authors concluded that the metabolite was an important biomarker for assessment of long-term exposure to 6:2 FTOH and showed potential bioaccumulative (aka biopersistence[1]) properties. The chemical 6:2 FTOH is a common starting substance in the manufacture of many PFAS polymers, including those used to greaseproof paper and paperboard. As a result, it is a major impurity in, and degradation product of, these polymers.
We are now reporting on two recent publications by the same group of FDA scientists (Kabadi et al.[2] and Rice et al.)[3] in which they not only confirmed their initial findings but also produced new evidence on the behavior of short-chain PFAS when they enter the body. The new evidence highlights:
- Bioaccumulation: 6:2 FTOH is transformed by the body into several metabolites; one of them, called 5:3 acid, bioaccumulates, and the bioaccumulation is greater with lower exposure to 6:2 FTOH.
- Toxicity: The toxicity of 6:2 FTOH is concerning and its risk to human health may have been significantly underestimated previously. Data on perfluorohexanoic acid (PFHxA), the industry’s proposed reference chemical for the short-chain PFAS class are not appropriate for assessing the potential health effects of 6:2 FTOH.
The FDA’s scientists reached these important conclusions after reviewing “recently received additional data on 6:2 FTOH and 5:3 acid” and more than a dozen reports on oral toxicity studies that “had been conducted and submitted by industry in support for food contact uses” of short-chain PFAS in addition to a study by the National Toxicology Program. They also called out flaws in industry-funded analyses that reached different conclusions.
FDA’s commitment to review its authorized PFAS uses in food packaging is showing results
The latest publications are likely the result of the agency’s ongoing review of the authorized uses of short-chain PFAS in food contact applications. The thorough analysis by FDA’s scientists comparing the toxicology databases for 6:2 FTOH and PFHxA “directly contradicts” conclusions published by consultants paid by industry that “PFHxA may also represent a suitable marker for safety of fluorotelomer replacement chemistry.”
In a previous blog and a Letter to the Editor, we called out the FluoroCouncil-funded publications for making overreaching statements unsubstantiated by the evidence while ignoring an earlier publication by FDA’s scientists describing, for the first time, the “high biopersistence potential of 6:2 FTOH.” Now, in their January 7, 2020 publication, Kabadi et al. have not only confirmed their initial analysis, but produced significant new information on how the body responds to consumption of 6:2 FTOH.
The authors performed a detailed review of a 90-day repeated-dosing oral 6:2 FTOH pharmacokinetic study performed by DuPont.[4] In the DuPont study, rats were administered 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctan-1-ol, the 6:2 FTOH used to make the food contact substance authorized under food contact notification (FCN) 940.[5] The DuPont study is dated 2012, two years after FDA authorized its use. Even though the study is more than seven years old, Kabadi et al. describe the study as “recently received,” suggesting that DuPont did not proactively share it with the agency.
In addition to characterizing the bioaccumulation of short-chain FTOH metabolite, Rice et al. performed a comparative analysis of toxicology data for 6:2 FTOH and perfluorohexanoic acid (PFHxA), a breakdown product of 6:2 FTOH touted by industry as “less hazardous to human health than PFOA” and a suitable marker for the “safety of fluorotelomer replacement chemistry.” The findings by FDA’s scientists could not be more different than industry’s. Compared to PFHxA[6], 6:2 FTOH:
- Has higher mortality rates;
- Is more toxic to the liver and kidney;
- Causes developmental, reproductive and immune toxicity; and
- Is more toxic during the postnatal period, with increased mortality in pups and decreased growth during lactation.
This critical comparative work demonstrates that “the dataset for PFHxA is not appropriate for assessing the potential human health effects associated with 6:2 FTOH exposure,” since the toxicological profile of 6:2 FTOH is much more concerning. FDA scientists concluded that applying safe exposure levels from toxicity studies conducted for PFHxA when performing “the human health risk assessment of 6:2 FTOH exposure may significantly underestimate the risk to human health.”
FDA’s studies highlight weaknesses in the current chemical safety assessment program
In addition to the important and relevant scientific data generated and made public by the agency’s scientists, the studies also highlight the weakness of the current chemical safety assessment program at FDA, namely:
- Companies are not required to submit new information to FDA that raises questions about health risks of food contact substances as well as their components, impurities and degradation products.
- There is no systematic post-market reassessment of safety decisions. Once chemical uses are approved, there is no look-back.
If either of these measures were in place, the agency could have acted more promptly to restrict uses of PFAS in contact with food.
It’s time for FDA to translate the science into action
The new evidence from FDA’s scientists indicates that 6:2 FTOH and similar short-chain PFAS no longer meet the safety standard of reasonable certainty of no harm. Therefore, it makes sense that, in June 2019, FDA said it was “reviewing the limited authorized uses of PFAS in food contact applications.” We are hopeful the agency would exercise its authority to protect the public from these PFAS exposures.
As we explained in an August 2019 blog, FDA’s regulations lay out the procedure for the agency to reassess the safety of an FCN like those for short-chain PFAS. The agency notifies the company that it has determined that the intended use is no longer safe and gives the company an opportunity to respond. If, based on the response, FDA affirms its conclusion, it will post a notice in the Federal Register.
In 2010, FDA concluded some long-chain PFAS were carcinogens, bioaccumulate and posed risks to fetal development and reproduction. But the agency did not follow through, instead allowing the companies to “voluntarily suspend” the authorizations – an option that is not part of the regulations.
The work by FDA’s scientists makes it clear that all toxicity studies conducted on 6:2 FTOH to date are woefully inadequate because of the bioaccumulation of its metabolite 5:3 acid. Specifically, “the time taken for the 5:3 acid to reach steady state in plasma and assessed tissues is approximately close to 1 year, which is significantly longer than the 90-day toxicity studies currently available.” This bioaccumulation leads to long-term exposure that contributes to toxicity.
As we reported previously, companies submitting FCNs to FDA have assumed short-chain PFAS do not bioaccumulate and we found no evidence that FDA has asked about data supporting that assumption. They appear to have drawn an artificial bright line between short-chain and long-chain PFAS when it comes to bioaccumulation. However, we are now learning that evidence and unbiased data analysis trump assumptions.
We have been assuming that FDA has initiated the reassessment of short-chain PFAS as part of its review announced nine months ago. Despite our requests for updates, the only evidence we have seen of the review are scientific articles by its scientists. Therefore, on March 19, we submitted a Freedom of Information Act (FOIA) request seeking communications between FDA and six companies with effective FCNs authorizing uses of PFAS in contact with food. We also requested the unpublished studies conducted by the companies that were referenced in the two articles by FDA’s scientists.
Conclusion
When we evaluate new studies on chemical safety or FDA’s policies, we compare them to how they advance our three priorities for chemicals in food: 1) ending secrecy in decision-making; 2) using modern science in assessing safety; and 3) ensuring existing chemicals are safe. We call out shortcomings (see per- and polyfluorinated alkyl substances (PFAS)) and have gone to court when the Food and Drug Administration (FDA) makes seriously flawed decisions (see GRAS rule and perchlorate) that undermine public health. We also applaud positive outcomes (see bans on carcinogenic flavors and long-chain PFAS as well as creation of toxic elements work group).
Today, we applaud the agency. In the two articles, FDA’s scientists critically reevaluated the assumption used by industry as the linchpin of the safety claims for short-chain PFAS: there is no bioaccumulation. They used modern scientific methods and identified significant issues that to us, appear to indicate there is no longer a reasonable certainty of no harm – the safety standard for chemical additives – for these chemicals. Importantly, FDA’s lack of conflict of interest highlights the shortcomings of the industry-funded analysis that underestimated the risk. We look forward to FDA wrapping up its reassessment of the safety of these substance in a transparent manner consistent with its responsibilities.
[1] FDA uses both “biopersistence” and “bioaccumulation.” We prefer “bioaccumulation” because biopersistence can be confused with persistence in the environment rather than the accumulation in the body because it is not being fully and quickly excreted.
[2] Kabadi et al. Characterizing biopersistence potential of the metabolite 5:3 fluorotelomer carboxylic acid after repeated oral exposure to the 6:2 fluorotelomer alcohol. Toxicology and Applied Pharmacology 388 (2020) 114878
[3] Rice et al. Comparative analysis of the toxicological databases for 6:2 fluorotelomer alcohol (6:2 FTOH) and perfluorohexanoic acid (PFHxA). Food and Chemical Toxicology 138 (2020) 111210
[4] In 2015, DuPont spun-off its fluoroproducts and other businesses to form Chemours.
[5] In April 2019, Chemours notified the FDA that by June 2019 it will have voluntarily ceased introduction and delivery for introduction into interstate commerce products authorized by FCNs 885, 940 and 1027.
[6] See Tables 5 and 6 of Rice et al.