EDF Health

Broken GRAS: Companies ignore FDA draft guidance; Bias & conflicts of interest prevail in safety determinations

By Tom Neltner, Senior Director, Safer Chemicals, Klara Matouskova, PhD, Consultant, and Maricel Maffini, PhD, Consultant

What Happened?

In our new study, we evaluated Generally Recognized As Safe (GRAS) notices—a total of 403 between 2015-2020that food manufacturers voluntarily submitted to FDA for review. Our goal was to determine whether industry was adhering to FDA’s Guidance on Best Practices for Convening a GRAS Panel.

The guidance was designed to help companies comply with the law and avoid biases and conflicts of interest when determining whether substances added to food are safe and recognized as such by the scientific community. FDA published a draft of the guidance in 2017 and finalized it essentially unchanged in December 2022.Infographic showing that a small group of only 7 people takes up 46% of available positions on panels that determine whether food chemicals can be labeled Generally Recognized As Safe.

Our study found that no GRAS notices followed the draft guidance. Specifically, we also found there were high risks of bias and conflicts of interest because the companies:

  • Had a role—either directly or through a hired third party—in
    selecting panelists that likely resulted in bias and conflicts of interest.
  • Depended on a small pool of experts in which seven individuals occupied 46% of panel positions. The seven often served together, further enhancing risk of bias.
  • Relied on panels that did not realistically reflect the diverse scientific community that evaluates chemical risks to public health—which is needed to comply with the law’s requirement that there be a “general recognition” within that community that a substance is GRAS.

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Broken GRAS: FDA’s lack of post-market oversight continues to create health risks

What Happened?

In April, a company called Prime Research Reports issued a press release in which it claimed FDA had approved THP (tetrahydropiperine) as a Generally Recognized As Safe (GRAS) substance “for use in food products.” There is no record that FDA has either reviewed or approved THP for use in food.

The report describes Sabinsa as a manufacturer of THP and as “a major player” in that market.[1] The substance, commercially known as Cosmoperine, is derived from a highly purified extract from black pepper; the extract, which is more than 95% piperine, is also made by Sabinsa and is marketed as BioPerine. The company describes piperine as an alkaloid present in black and long pepper.

Why It Matters

First, the statement is at odds with the available evidence: there is no record of FDA reviewing the safety of THP as a GRAS substance. The only interaction we are aware of was in 2013, when Sabinsa voluntarily asked FDA to review its GRAS determination for BioPerine to be used as a flavoring agent. A few months later, Sabinsa sent a letter asking FDA to stop reviewing the safety assessment (also known as a “cease to evaluate” request). After that, there does not appear to have been any interactions between Sabinsa and FDA regarding either of its products.

Second, the statement mistakenly claims that FDA approves GRAS substances when in fact the agency issues an opinion when a manufacturer requests a review by FDA. In its opinion letters, the agency makes clear that it is not an approval.

Third, a decade ago, we identified significant safety concerns with BioPerine, the only product that FDA has had an opportunity to review although, as previously noted, that review was halted when Sabinsa withdrew its request for review. As a result, FDA did not issue an opinion. In 2013, the authors, on behalf of the Natural Resources Defense Council at the time, sent a letter to FDA listing many issues with the GRAS notice that Sabinsa had withdrawn, including:

  • Lack of toxicology testing for the extract, which is more than 95% piperine, the active ingredient.
  • Failure to correctly interpret toxicity data in the literature, which showed that piperine is toxic to the immune system and causes reproductive and developmental toxicity in animals and cell-based studies.
  • Dismissal of human studies showing that piperine affects the metabolism of other compounds including medications by increasing their bioavailability.

Piperine is “reported to enhance the bioavailability of drugs, nutrients, and herbal extracts,” and Cosmoperine is marketed as a “bioavailability enhancer.”

The presence of these substances in food could potentially increase the bioavailability of medications in ways that healthcare professionals prescribing the drug could not anticipate. As a result, the drug might have adverse health effects from the higher effective dose.

Our Take

It is clear that BioPerine and the related Cosmoperine are highly concentrated extracts from black pepper that have been neither adequately tested nor adequately evaluated to determine their uses are safe.

We have published multiple articles describing the problems with the GRAS process. Among the most egregious of FDA’s failures are:

  • Allowing companies to withdraw a GRAS notice where the company realizes that FDA may not give it a favorable review;
  • Not proactively making the concerns publicly available[2] about the safe use of the substance;
  • Not conducting any apparent post-market oversight when FDA has concerns about the safety of a chemical.

In our Broken GRAS series we show many examples of chemicals of dubious safety that stealthily entered the food supply without any warnings.

In January, FDA Commissioner Califf announced a “new and transformative vision for the FDA Human Food Programs” These are important steps, but a real measure is ensuring that GRAS substances where FDA had safety concerns are subjected to strong oversight to protect American’s health by restricting the use of harmful chemicals such as THP.

Next Steps

We have alerted FDA to the claims and asked the agency to quickly investigate this product and its uses to protect consumers–especially those who might be using one of the medications that are affected by THP. FDA responded that it “will take a closer look and make sure this information is routed as appropriate.” We will continue to press FDA to act expeditiously to get products like this one off the market until the agency can verify its safety.

[1] We don’t know the relationship between Prime Research Reports and Sabinsa and have not heard back on a request for information.

[2] The information may be available through a Freedom of Information Act but that does not mean it is publicly available since only the requester gets the information.

Posted in Adverse health effects, Broken GRAS, FDA, Food, GRAS, Health hazards, Industry influence, Risk assessment, Risk evaluation / Tagged , , , , , , | Authors: , / Read 1 Response

Broken GRAS: FDA’s half-step to limit bias and conflicts of interest in GRAS determinations may backfire

Tom Neltner, Chemicals Policy Director and Maricel Maffini, consultant

What Happened? FDA finalized a long awaited guidance for industry in December to help reduce conflicts of interest and bias when a chemical manufacturer chooses to convene an expert panel to assess whether a new chemical additive is generally recognized as safe (GRAS).

Why It Matters: As written, FDA’s Best Practices for Convening a GRAS Panel guidance is excellent. If food companies convene GRAS panels consistent with the guidance, the panels’ evaluations will be more credible because they should have less of the pervasive bias and conflicts of interest that plague the current system and all too often result in unsafe chemicals being added to food. But that’s a big if.

Our Take: Unfortunately, we think the guidance is likely to backfire because of the limited scope — FDA explicitly makes GRAS panels optional – a choice the agency made when it finalized the GRAS rule in 2016. Chemical manufacturers will simply avoid convening GRAS panels, relying solely on their employees or a consulting firm they hire to conduct these safety evaluations. These employees and consultants typically have significant bias and conflicts of interest because positive opinions help their employer or client. We raised this issue in comments to FDA, calling for the best practices to apply to everyone involved in the safety evaluation process. FDA did not address our comments in their recommended best practices in the revised final guidance.

While making GRAS panels optional is a serious problem, a more fundamental concern is that FDA may not have an opportunity to review the GRAS safety evaluations made by employees or hire consultants because the company chooses not to notify the agency. FDA’s Office of Food Additive Safety fails to consider just how often companies choose not to tell the agency that a new chemical is being added to food. In our Broken GRAS series, we provided six examples of the serious risk posed by the GRAS system, the most public being hundreds of people sickened due to consumption of tara flour, an ingredient in a Daily Harvest frozen meal. Last November, using marketing materials we showed FDA that the number of new chemicals bypassing its review likely outnumber those voluntarily submitted to the agency.

We see no evidence that the agency systematically investigates or even audits the GRAS determinations that bypass their review despite promises made by the agency over the years and a scathing 2010 report by the U.S. Government Accountability Office calling for action.

Next Steps: In his effort to reform FDA’s dysfunctional food safety program, FDA Commissioner Califf told a reporter that “I want to throw in chemical safety as another really, really important area for the future – for humankind, really – and where science is evolving rapidly.”[1] If he follows through, fixing GRAS is an important step to rebuild consumer confidence and reduce the ongoing risk to public health. If he fails, the agency will continue to be hamstrung in preventing health risks posed by chemicals of unknown safety.

Go deeper: Broken GRAS series, Neltner et al (2013) Conflicts of Interest in Approvals of Additives to Food Determined to Be Generally Recognized as Safe: Out of Balance; Toxic Free Act; Food Chemical Reassessment Act.

[1] FoodFix, January 31, 2023 edition.

Updated April 9, 2023 to add link for Broken GRAS series.

Posted in Broken GRAS, Conflict of interest, FDA, GRAS / Tagged , , , | Authors: / Read 1 Response

Broken GRAS: FDA must declare abandoned uses of ortho-phthalates are not GRAS.

Maricel Maffini, EDF consultant and Tom Neltner, Chemicals Policy Director

This blog is the sixth in our Broken GRAS series where we explore the Food and Drug Administration’s (FDA) Generally Recognized as Safe (GRAS) voluntary notification system for novel chemicals added to food.

In May, FDA removed its approval for all uses of 19 ortho-phthalates (aka phthalates) and some uses for two more because it agreed with the industry petition claiming the uses had been abandoned. During the comment period when the petition was filed and again when the decision was published, Earthjustice, EDF, and others warned FDA that despite the removal of approvals, a company could still use any of the abandoned phthalates without the agency’s knowledge by determining on its own that the use was Generally Recognized as Safe (GRAS).

In its decision, FDA implicitly acknowledged that this could indeed happen. After explaining what a GRAS safety determination[1] entails and how its voluntary GRAS notification program[2] works, the agency said:

In the future, if a manufacturer wishes to establish safe conditions of use for one or more of these substances in food contact applications, we expect the manufacturer to submit either a food additive petition or a food contact substance notification prior to market entry because these intended uses were previously authorized under section 409 of the FD&C Act.[3]

Since the agency has no way of knowing that a company determined a substance’s use was GRAS or that it was actually in use, FDA’s expectation is little more than a hope. The agency’s own studies show that the abandoned phthalates show up in food and in food contact materials. Many other studies have shown the same thing, including one that found an unapproved phthalate in fast food.

Read More »

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Tara Flour: A Reminder of the Real-Life Consequences of Broken GRAS

Tom Neltner, Senior Director, Safer Chemicals and Maricel Maffini, EDF consultant

This blog is the fifth in our Broken GRAS series where we explore the Food and Drug Administration’s (FDA) Generally Recognized as Safe (GRAS) system for novel chemicals added to food.

In the spring, folks who ordered from a company that sells pre-assembled smoothies and other frozen foods for home delivery, started getting sick—really sick—after consuming an item called “French Lentil and Leek Crumbles” (Crumbles). Daily Harvest, the manufacturer, recalled the product on June 17. A month later, Daily Harvest said it had ruled out various food-borne pathogens, mycotoxins, heavy metals, and major allergens and had “identified tara flour as the cause of the issue.”

By the end of July, FDA reported the product had been linked to 329 illnesses and 113 hospitalizations in 36 states—a surprising number for a product that sold only 28,000 items. Consumer Reports described the health effects as fever, fatigue, vomiting, diarrhea, and liver problems. At least 25 people who consumed the Crumbles required surgery to remove their gallbladders. Read More »

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Broken GRAS: A scary maze of questions a corn oil producer couldn’t answer

Maricel Maffini, consultant and Tom Neltner, Chemicals Policy Director

This blog is the fourth in our Broken GRAS series where we explore the Food and Drug Administration’s (FDA) Generally Recognized as Safe (GRAS) voluntary notification system for novel chemicals added to food, how the process works in practice, and why it is broken. Companies voluntarily submit these notices seeking a “no questions” letter from FDA that makes it easier to market the chemical to food companies.

In our latest blog we address a chemical called “COZ corn oil” developed by the Iowa-based company, Corn Oil ONE. We obtained documents from FDA revealing that the agency twice raised significant concerns about the safety of COZ corn oil with the company, which withdrew its notification without addressing the agency’s questions. As with the other examples in the series, FDA did not make its concerns public or take steps to block the chemical’s use in food.  Read More »

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