GRAS 28 Flavoring Substances

The Flavor and Extract Manufacturers Association (FEMA) Expert Panel began a program in 1960 to assess the safety of flavor ingredients for their intended use in human food. The FEMA GRAS program continues through today as the longest-running and most widely recognized GRAS assessment program (Hallagan and Hall 1995, 2009).

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.” This amendment established a requirement for premarket approval and criteria for GRAS “generally recognized as safe” status, the rigor of which is no less than that established for a food additive. By excluding GRAS substances from the definition of “food additive,” Congress provided the Food and Drug Administration (FDA) flexibility and discretion in allocating resources to food additive issues of potentially greater safety concern. The FEMA GRAS program operates within the confines of the 1958 Food Additives Amendment.

This GRAS 28 publication includes the results of the Expert Panel’s review of 60 new FEMA GRAS flavorings (Tables 1 and 2). In addition, the Expert Panel determined that new use levels and/or use in new food categories for 18 flavorings are consistent with their current FEMA GRAS status (Table 3) and concluded that the FEMA GRAS status of one flavoring should be changed. The Panel also describes its progress evaluating natural flavor complexes for reaffirmation of GRAS status, and an update on the examination of sensory information on flavorings with modifying properties.

Progress in the Reevaluation of Natural Flavor Complexes
In 2005, the FEMA Expert Panel published an approach to the safety evaluation of natural flavor complexes, or naturally occurring mixtures derived from plants or other natural sources used for the flavoring of food (Smith et al. 2004; Smith et al. 2005a,b). The Panel’s approach included a rigorous assessment of the chemical and biological properties, including consideration of a complete chemical characterization of the natural flavor complex (NFC). The basis of the approach is grouping of the constituents into different congeneric groups exhibiting similar biological and toxicological properties, and a comparison of intake of each congeneric group to the threshold of toxicological concern (TTC) (Munro et al. 1996). Recently, the Panel updated the procedure from 2005 as described in Cohen et al. 2018. The update broadens the scope of the 2005 procedure to include complex mixtures obtained from nonbotanical sources, and refinements to the consideration of the unknown portion of a complex material and the genotoxicity evaluation, in addition to other minor changes.

As part of the reevaluation of citrus-derived natural flavor complexes, current practices of manufacture were reported, and it was revealed that orange essence oils are recovered through evaporation as part of the juicing process and that distillation is currently not used. The Panel has updated the description of FEMA 2821 to Orange Essence Oil (Citrus sinensis (L.) Osbeck). Additionally, FEMA 2822 is now described as Orange Oil Terpeneless (Citrus sinensis (L.) Osbeck). These changes are further discussed in the forthcoming publication on the FEMA GRAS assessment of natural flavor complexes: Citrus-derived flavoring ingredients.

Update on the Use of Sensory Data Within the Context of a FEMA GRAS Evaluation
Within the scope of the FEMA GRAS program, the FEMA Expert Panel reviews flavoring substances that impart or modify flavor and flavor adjuvants (“nonflavor ingredients”) that facilitate the function of compounded flavors in foods (Hallagan et al. 2018; Hallagan and Hall 2009). Included within the definition of flavoring substances are “flavorings with modifying properties” (FMPs), which may not have or impart a specific characteristic flavor of their own but can modify the flavor profile by altering the flavor attributes of the flavoring and the food to which it is added. To facilitate the review of FMPs, the Panel requires the submission of sensory testing to demonstrate that the technical effect and functionality in food is limited to flavoring under conditions of its intended use (Marnett et al. 2013). In 2013, the FEMA Science Committee Sensory Data Task Force, composed of sensory testing experts, published “Sensory Testing for Flavorings with Modifying Properties,” which outlined a set of tests designed to demonstrate if the technical function in food of the ingredient under conditions of intended use is that of a flavor (Harman et al. 2013). Since that publication, the Expert Panel has reviewed numerous flavoring substances with properties of flavor modification using the guidance outlined in Harman et al. 2013. Additionally, in Hallagan et al. 2018, an interpretation of the labeling implications for flavoring ingredients, including FMPs, is available to assist the flavor industry in understanding U.S. flavor labeling regulations and their applicability to these types of flavoring substances.

Change in GRAS Status of Methyl Eugenol
The FEMA GRAS status of methyl eugenol (CAS NO. 93-15-2; FEMA No. 2475) 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 methyl eugenol, including recent studies, the Expert Panel concluded that additional data are required to support the continuation of its GRAS status. Such data should clarify the relevance to humans of DNA adducts formed by methyl eugenol. Until such data are available for review by the Expert Panel, the flavor ingredient methyl eugenol has been removed from the FEMA GRAS list. The Expert Panel also considered the FEMA GRAS status of herbs, spices, and essential oils that contain naturally occurring methyl eugenol, including basil, pimento, allspice, etc., and their extractives. The Panel concluded that these flavorings continue to meet the criteria for FEMA GRAS under their conditions of intended use as flavorings.

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 from the University of Kaiserslautern, Dept. of Chemistry, Food Chemistry and Toxicology, Germany. Shoji Fukushima, MD, PhD, is Research Advisor of the Japan Bioassay Research Center, Japan. Nigel J. Gooderham, PhD, is Professor of Molecular Toxicology and the Assistant Provost in the Dept. of Surgery and Cancer, Imperial College London. F.P. Guengerich is Professor of Biochemistry and Director of Guengerich Research Laboratory, Vanderbilt University. 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. Christie L. Harman, is with the Flavor and Extract Manufacturers Association, Washington, D.C. Sean V. Taylor, PhD, is the Scientific Secretary to the FEMA Expert Panel, Washington, D.C.