The GRAS Process Under the Final Rule (Part 2): Increased Emphasis on Exposure

October 1, 2016 - 9 minutes read

The finalized GRAS rule and associated Federal Register Notice1 emphasizes the FDA’s opinion that dietary exposure is a factor that must be considered in determining safety, regardless of whether the conclusion of GRAS status is through scientific procedures or experience based on common use in food, or even if a GRAS conclusion is notified or not.  While we agree with the assertion that exposure is integral to a safety determination, the new requirements for how exposure assessments are to be conducted and disclosed may have implications for several other aspects of the GRAS process, from specification development to publication of data.

In the GRAS rule comments, the FDA states that the rule requires a notifier to provide data and information about dietary exposure to the notified substance and any other substance that is present with the notified substance either naturally or due to its manufacture (e.g., contaminants or by-products). This requirement underscores the importance of developing specifications that include upper limits for contaminants or by-products that could be produced in manufacturing.  The permissible upper limit of a contaminant could be entered into a consumption program to determine the maximum estimated consumption of the contaminant by consumers of the foods containing the ingredient. A risk assessment could then be performed to determine if the level of the contaminant or by-product in the food would be toxicologically relevant. The requirement for an assessment of exposure to contaminants or by-products should prompt manufacturers to try to reduce concentrations of contaminants to a minimum (a requirement of current good manufacturing practice anyway) and only use food grade materials for manufacturing purposes.

When applicable, an estimate of dietary exposure to any other substance that is expected to be formed in or on food because of the use of the notified substance (e.g. hydrolytic products or reaction products) must also be provided. Thus, a manufacturer will have to disclose if the ingredient can react with any of the ingredients in the food product to produce other substance(s) and conduct an exposure assessment for the substance(s) that is formed. This mandate is a slippery slope to an infinite number of “what if” scenarios and will require notifiers to have manufacturing information about the foods to which the ingredient would be added to (e.g. pH, temperature, processing aids, other ingredients in the food, and substances used in packaging). The mandate potentially also requires the notifier to hypothesize what other substances might be used with the notified substance; that is, what possible recipes could be conjured up now or in the future. It is expected that this requirement will limit the use of GRAS ingredients to substances where the perceived benefit of the ingredient to the food manufacturer is worth full disclosure about what is in their food and how it is made.

The FDA is also requiring the safety assessment to include a discussion of why the data and information in the notice provides a basis that the notified substance is safe under the conditions of its intended use, considering all dietary sources (which includes exposure from the intended use and all other sources) and taking into account any chemically or pharmacologically related substances. Thus, an exposure assessment of the ingredient, plus other substances in the diet that are pharmacologically related needs to be conducted.  This is an onerous requirement, especially if the ingredient contains substances that are widely found in foods, such as polyphenols.

The FDA specifies for the source of food consumption data to be “described”, but does not mention the level of detail required for the description or acceptable sources of information for dietary exposure. It is unlikely that the FDA will accept outdated sources of consumption information; therefore, submitters of GRAS notices for new food uses of commonly used substances (e.g. DHA) must be aware of all approved uses of the substances to date and conduct their consumption assessments accordingly.  If a submitter inadvertently leaves out consumption of an ingredient from an approved use, the FDA may object to the notice.

If a notifier is attempting to notify a substance based on common use in food, they must provide evidence of substantial history of consumption of the substance for food use by a significant number of consumers prior to January 1, 1958. An estimate of dietary exposure prior to 1958 is not required.  The rule does not require for the consumers to be in the United States; however, use that “occurred outside of the United States shall be documented by published or other information and shall be corroborated by information from a second, independent source that confirms the history and circumstances of use of the substance.” The information used to document and to corroborate the history and circumstances of use of the substance outside of the U.S. must be widely available in the country in which the history of use has occurred and readily available to interested qualified experts in the United States.

The FDA also makes the point that dietary exposure may need to be reassessed when a key assumption in the methodology is changed; as dietary consumption patterns change; when there is an unresolved question about consumer intake; when there is a small margin of exposure; or when other new information becomes available. Any post-market exposure assessments should be made publicly available. Although the FDA does not define the term “publicly available” in the GRAS rule, they define “generally available” as publication in a peer-reviewed scientific journal, textbook or “other sources of technical literature”.  However, because the FDA also cautions the notifier about publication in sources that are not peer- reviewed, the best choice for publication of dietary exposure or any other data pertaining to a GRAS conclusion is a peer-reviewed journal.

As a final point, the FDA is mandating that all information relevant to the GRAS conclusion (including exposure information) should be publicly available. This means that exposure information, which has typically been left out of publications showing safety of new food ingredients, should now be included in the publications.  This requirement will increase the size and cost of publications and GRAS dossiers, and may slow down the reporting of data critical to GRAS conclusions due to page limitations in journals.

To conclude, the GRAS rule places a new emphasis on exposure because the FDA views exposure as a critical piece of a demonstration of “safety-in-use”, which is required for GRAS status. Exposure to the substance, toxic substances that may be formed from use of the material, and pharmacologically related substances must be made publicly available. Burdock Group has been performing dietary exposure assessments for decades, using the most modern survey data and can assist you with any dietary exposure assessment needed to satisfy the new GRAS rule, as well as other tasks required for a GRAS conclusion.


Substances Generally Recognized as Safe. Final Rule. Federal Register Volume 81, No. 159, August 17, 2016, pages 54709-55104.

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