[PLEASE DOWNLOAD THE ARTICLE PDF IN ORDER TO READ THE ACCOMPANYING GRAS TABLES.]
For more than 60 years, the FEMA GRAS Program has operated to assess the safety of flavor ingredients for their intended use in human food. The GRAS provision of the 1958 Food Additives Amendment to the Federal Food, Drug, and Cosmetic Act defines a food additive as: “… any substance … which … may … [become] a component or… [affect] the characteristics of any food … if such substance is not generally recognized, among experts qualified by scientific training and experience to evaluate its safety, as having been adequately shown through scientific procedures … to be safe under the conditions of its intended use…” The FEMA GRAS program operates within the confines of the 1958 Food Additives Amendment using defined scientific procedures to assess the safety of flavoring ingredients under their conditions of intended use as published in Smith et al. 2005a and b, and Cohen et al. 2018a.
This publication includes the results of the Expert Panel’s review of 38 new flavorings under their conditions of intended use (Tables 1 and 2). In addition, the Expert Panel determined that new use levels and/or use in new food categories for 11 flavor ingredients are consistent with their current FEMA GRAS status (Table 3). The Expert Panel removed the FEMA GRAS status for the uses of one substance.
The Panel also describes recent progress evaluating natural flavor complexes for reaffirmation of GRAS status, releases its policy statement regarding cannabis-derived flavorings, addresses the consideration of new plant protein products within the food category classification system, and includes a discussion regarding the consideration of target tissue exposure in its review of in vivo genotoxicity study data.
In 2018, the FEMA Expert Panel published an updated safety procedure that it has used in its FEMA GRAS evaluation of natural flavoring complexes (NFCs), which are naturally occurring mixtures of chemicals that are produced using physical separation methods starting from botanical and other natural sources. The updated procedure has been applied to new potential NFCs as well as for NFCs that already have uses that are considered FEMA GRAS (Cohen et al. 2018). Utilizing the procedure, the Panel has completed comprehensive reassessments of over 200 NFCs to date, reported in seven publications. Many of these were in the first FEMA GRAS list that was published in 1965 (Hall and Oser 1965). These seven publications include the results of comprehensive, constituent-based safety evaluations of Citrus-derived NFCs (Cohen et al. 2019); mint, buchu, dill, and caraway-derived NFCs (Cohen et al. 2020); Cinnamomum and Myroxylon-derived NFCs (Rietjens et al. 2020); clove, cinnamon leaf, and West Indian bay leaf-derived NFCs (Gooderham et al. 2020a); lavender, guaiac, coriander-derived, and related NFCs (Fukushima et al. 2020); Eucalyptus-derived and other eucalyptol-containing NFCs (Eisenbrand et al. 2021); and origanum oil, thyme oils, and related phenol derivative-containing NFCs (Cohen et al. 2021). The Expert Panel continues preparing additional publications within the scope of this reevaluation program.
The FEMA Expert Panel has considered the U.S. Food and Drug Administration’s FDA Regulation of Dietary Supplement & Conventional Food Products Containing Cannabis and Cannabis-derived Compounds (FDA 2021) regarding the regulation of dietary supplements and conventional food products containing cannabis and cannabis-derived compounds. While FDA notes that “Ingredients derived from cannabis that do not contain CBD [cannabidiol] or THC [tetrahydrocannabinol] might be able to be used in foods and dietary supplements if all other FD&C requirements are met,” the FEMA Expert Panel has concluded that it will not review cannabis derivatives for FEMA GRAS status under conditions of intended use as flavorings, including derivatives with only trace amounts of THC and CBD. The FEMA Expert Panel may review this policy in the event of new actions from the FDA on regulatory considerations of cannabis-containing and cannabis-derived ingredients.
The FEMA Expert Panel uses a food category classification system that is derived from the U.S. Code of Federal Regulations’ (CFR) listing of food categories (21 CFR 170.3(n)) to establish conditions of intended use for FEMA GRAS determinations. Each main food category listed within 21 CFR 170.3(n) is accompanied by descriptions of the types of food products that would be included in that category, and these food products within each category typically have similar portion sizes. Recently, there has been increasing interest in the production and consumption of plant protein-derived food products that are used in substitution of some foods. These plant protein-derived food products are generally not included within the food category descriptions (of the foods for which they substitute) that are provided in the CFR. For the purposes of their safety assessments, the Expert Panel has determined that imitation or substitute products belong to the same food product categories as the products they imitate or for which they are intended to substitute, as it is expected that the portion sizes will be very similar.
The FEMA Expert Panel recently published on the use of genotoxicity information within the context of flavor safety evaluations (Gooderham et al. 2020b). During the development of that publication, the Panel considered the role that target tissue exposure would play in drawing conclusions about the validity of in vivo genotoxicity studies for which negative results are reported.
Standard guidelines, such as those developed by the Organization for Economic Cooperation and Development (OECD), provide recommendations for the criteria for determining that a study has produced a clear negative result. As an example, for in vivo micronucleus studies, the four criteria are that:
“a) None of the treatment groups exhibits a statistically significant increase in the frequency of micronucleated immature erythrocytes compared with the concurrent negative control,
b) There is no dose-related increase at any sampling time when evaluated by an appropriate trend test,
c) All results are inside the distribution of the historical negative control data (e.g., Poisson-based 95% control limits), and
d) Bone marrow exposure to the test substance(s) occurred” (OECD 474 2016).
Additionally, the OECD in vivo micronucleus study guideline states that, “In cases where the response is not clearly negative or positive and in order to assist in establishing the biological relevance of a result (e.g., a weak or borderline increase), the data should be evaluated by expert judgement and/or further investigations of the existing experiments completed” (OECD 474 2016).
The Panel notes that while it is desirable to obtain clear positive or clear negative outcomes from in vivo genotoxicity studies, in many cases evidence of target tissue exposure is not available. On that basis, the Panel relies upon its use of expert judgment in concluding whether the data from an in vivo genotoxicity study, even in the absence of direct evidence of target tissue exposure, do not indicate a concern for genotoxicity.
The FEMA GRAS status of mintlactone (5,6,7,7a-tetrahydro-3,6-dimethyl-2(4H)-benzofuranone, CAS No. 13341-72-5; formerly FEMA No. 3764) under its conditions of intended use as a flavor ingredient was reviewed by the FEMA Expert Panel. After reviewing the available information relevant to the FEMA GRAS status of mintlactone, including recent studies kindly provided to the FEMA Expert Panel by the Research Institute for Fragrance Materials (RIFM), the Expert Panel concluded that additional data are required to support the continuation of its GRAS status. Such data should include OECD- and GLP-compliant in vitro and in vivo genotoxicity testing, and confirmation from the industry that the commercial substance will not degrade to mutagenic impurities. Until such data are available for review by the Expert Panel, the flavor ingredient mintlactone has been removed from the FEMA GRAS list.
About the Authors
Samuel M. Cohen, MD, PhD, is Havlik-Wall Professor of Oncology in the Dept. of Pathology and Microbiology, University of Nebraska Medical Center.
Gerhard Eisenbrand, PhD, is retired Professor from the University of Kaiserslautern, Dept. of Chemistry, Division of Food Chemistry and Toxicology, Germany.
Shoji Fukushima, MD, PhD, is Research Advisor of the Japan Bioassay Research Center, Japan.
Nigel J. Gooderham, PhD, is Emeritus Professor of Molecular Toxicology in the Dept. of Metabolism, Digestion and Reproduction and the Former Assistant Provost of Imperial College London.
F. Peter Guengerich, PhD, is Professor and Tadashi Inagami Chair in Biochemistry, Vanderbilt University School of Medicine.
Stephen S. Hecht, PhD, is the Wallin Land Grant Professor of Cancer Prevention, Masonic Cancer Center, and Dept. of Laboratory Medicine and Pathology, University of Minnesota.
Ivonne M. C. M. Rietjens, PhD, is Full Professor in Toxicology at the Division of Toxicology, Wageningen University, Wageningen, The Netherlands.
Thomas J. Rosol, DVM, PhD, MBA, is a Professor of Veterinary and Toxicological Pathology and Chair of the Dept. of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio.
Christie L. Harman, is Senior Science and Policy Advisor to the FEMA Expert Panel, Washington, D.C.
Jeanne M. Davidsen, PhD, is with FEMA, Washington, D.C.
Danarubini Ramanan, is with FEMA, Washington, D.C.
Sean V. Taylor, PhD, is the Scientific Secretary to the FEMA Expert Panel, Washington, D.C.