Tom Neltner, J.D., is Chemicals Policy Director.
FDA’s decision to remove its approval of three long-chain perfluorinated compounds sets important precedents on the assessment of food ingredients, food contact substances, and chemicals used to make food.
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FDA concluded:
- Class: All long-chain chemicals with at least one linear, perfluorinated chain of eight or more carbon atoms should be considered a class.
- Data gaps: Where reproductive and developmental toxicity data are lacking for any chemical in this class, the data available for perfluorinated octanoic acid (PFOA) should be used to fill the gaps.
- Study methods: If a chemical is biopersistent in the body, standard toxicology methods used to evaluate food additives need to be upgraded.
[/pullquote]On Jan. 4, 2016, the Food and Drug Administration (FDA) announced that it changed its regulations to remove the agency’s approval of three specific long-chain perfluorinated compounds (PFCs) as food additives. The agency approved use of these chemicals between 1967 and 1997, allowing them to be added to paper and paperboard that comes in contact with aqueous and fatty foods. Until the late 2000s, they were commonly used in pizza boxes, sandwich wrappers, and paper in frozen food packaging – virtually anywhere a food manufacturer wanted to use paper packaging that would repel oil and water.
Domestic PFC manufacturers report that these food contact substance (FCS) uses have been abandoned, although others report trace levels still appearing in paper products used for food, most likely as a result of contamination. There are reports, however, that foreign companies have begun producing PFCs. As long as these additives are officially allowed by FDA, there is a possibility that food manufacturers who are not diligent could resume their use without knowing it. The agency’s decision makes it less likely that will happen.
FDA’s decision marks the first time it has used a food additive petition to remove an approval based on safety concerns; a few years ago, it removed approvals for use of bisphenol A in infant formula packaging and baby bottles and sippy cups – but those removals were based on market abandonment, not safety. This safety-driven decision sets a precedent and serves as a roadmap for how safety decisions should be made for all additives including those considered by industry to be ‘generally recognized as safe’ (GRAS).
No longer safe – unpacking the agency’s reasoning for a class of chemicals and safety concerns
In the Jan. 4, 2016 Federal Register notice, the agency stated that it removed the approval for the three FCSs “because new data are available as to the toxicity of substances structurally similar to these compounds that demonstrate there is no longer a reasonable certainty of no harm from the food-contact use of these FCSs.” In other words, without evidence establishing ‘a reasonable certainty of no harm’ – the agency’s safety standard for food additives – the use of these three FCSs is essentially considered unsafe. The agency’s safety assessment is described in detail in its July 27, 2015 Toxicology Memo referenced in the notice. Here’s a summary.
- Class: The agency designated as a class of long-chain PFCs any chemical with at least one linear, perfluorinated chain of eight or more carbon atoms. The class designation was based on published in vitro and animal studies demonstrating similar metabolic conversion of the chemicals to long-chain fluorotelomer alcohols (FTOH) and perfluorinated carboxylic acid (PFCA). The agency made this designation by applying the ‘Guidance for Grouping of Chemicals’ by the Organisation for Economic Co-operation and Development (OECD). The OECD guidance provides five criteria – referred to as rationales – for defining a group of chemicals as a category or class. FDA used a combination of two of the five:
• Common functional group(s) (e.g., aldehyde, epoxide, ester, specific metal ion); and
• The likelihood of common precursors and/or breakdown products via physical or biological processes that result in structurally similar chemicals (e.g., the “metabolic pathway approach” of examining related chemicals such as acid/ester/salt).
- Data gaps: FDA identified developmental and reproductive toxicity as the endpoints of concern in addition to cancer. It reached this conclusion when it found that a subset of chemicals in the class was associated with pre- and post-natal developmental toxicity and reproductive toxicity. The agency applied the Acceptable Daily Intake (ADI) for the most hazardous member of the class, perfluorooctanoic acid or PFOA, to all chemicals where the risks were not adequately studied. The agency calculated an ADI of 0.3 µg/kg-bw/day for the developmental toxicity endpoint of ‘increased percent litter loss’ corresponding to a dietary concentration of 6 parts per billion (ppb). This dietary concentration was in the same range as the 1 ppb FDA had calculated when it determined that PFOA was a carcinogen in 2002 and 2007.
- Study methods: The agency noted that biopersistence was a significant concern. Already in 2010, FDA had concluded that its recommended toxicity studies should be upgraded to better assess this issue. Animal studies showed that fluorotelomers (FTOH’s) have half-lives of up to 100 days and are persist in fat. Perfluorinated carboxylic acid metabolites accumulate in the liver and blood. Human data on long-chain PFCs show that the half-lives in humans is longer than in rodents. The agency used the International Agency for Research on Cancer’s (IARC) definition of biopersistence, and noted that this characteristic complicates risk assessment because
“there is not a simple correspondence between the daily dietary exposure to each compound and the systemic exposure to this compound and its metabolic byproducts. As such, the normal safety factors used in the risk assessment of this exposure would need to be adjusted to account for the systemic exposure produced by a given chronic dietary exposure. This would, in turn, require pharmacokinetic data for, at minimum, the FTOH components of the FCSs in both rodents and humans . . . .”
What does FDA’s decision mean for other long-chain PFCs?
The eight public interest organizations1 that submitted the petition to FDA selected the three long-chain PFCs for two reasons: 1) FDA had already documented the health risks they pose and effectively concluded they were unsafe and should not be used; and 2) a food additive petition was the best means to get the agency to act. In other words, the petitioners picked the most compelling case for FDA to make a precedential safety decision with an innovative use of an existing tool.
While FDA’s decision only directly affects the three long-chain perfluorinated compounds mentioned in the petition, it indirectly impacts two other groups of long-chain PFCs. These chemicals fit in the class.
- Seven long-chain perfluorinated compounds approved by FDA as food contact substances through its notification program between 2000 and 2006. For notifications, FDA’s approval consists of a letter stating it has no objections to the safety assessment made by the company and a posting of the decision on its website. The regulations don’t change. In 2011, at the agency’s urging, the manufacturers of these compounds voluntary suspended their use; an unenforceable option not described in FDA’s regulations. FDA should have notified each company that the use was no longer safe, given the companies an opportunity to respond. If the information submitted was not persuasive to change the agency’s opinion FDA would have published a notice in the Federal Register stating the notice(s) was no longer effective. A food additive petition is not necessary for FDA to act.
- Two sulfonated long-chain perfluorinated compounds approved by FDA that meet the agency’s definition of class of long-chain PFCs but were not mentioned in its evaluation of the petition. The industry maintains they have been abandoned. FDA can also act on its own without a food additive petition.
These nine chemicals lack the necessary safety data and should be considered unsafe. Presumably, FDA is preparing to take action.
With regard to short-chain PFCs – those with chains of six or fewer carbon atoms – they were not included in the petition. However, in the decision FDA indicated that these were not in the class because they were not biopersistent even though it lacks adequate studies on reproductive and developmental toxicity.
Overall, FDA’s action establishes important precedents that anyone must follow when evaluating the safety of chemically-related substances, especially those that lack relevant data and are biopersistent. It lays out a roadmap to the safety assessment that starts with defining a class of chemicals, addressing data gaps by assigning the ADI to the inadequately studied chemicals based on available information for a subset of chemicals in the class, and defining what toxicology studies would be needed to develop an ADI.
1 The eight petitioners were Natural Resources Defense Council, Center for Food Safety, Clean Water Action, Center for Science in the Public Interest, Children’s Environmental Health Network, Breast Cancer Fund, Center for Environmental Health, Environmental Working Group, and Improving Kids’ Environment.