GRAS Flavoring Substances 26
The 26th publication by the Expert Panel of the Flavor and Extract Manufacturers Association provides an update on recent progress in the consideration of flavoring ingredients generally recognized as safe under the Food Additives Amendment.
[PLEASE DOWNLOAD THE ARTICLE PDF IN ORDER TO READ THE ACCOMPANYING GRAS TABLES.]
More than 50 years since the first FEMA Expert Panel began a program to assess the safety of flavor ingredients for their intended use in food, the program’s primary objective remains the evaluation of whether or not substances nominated by the flavor industry can be considered “generally recognized as safe” (GRAS) for their intended use as flavor ingredients. Operating since 1960 under the authority provided by the 1958 Food Additives Amendment to the Federal Food, Drug, and Cosmetic Act (Hallagan and Hall, 1995), the FEMA GRAS™ program continues as the longest-running and most widely recognized industry-sponsored GRAS assessment program.
The 1958 Food Additives Amendment defined 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.” With the Food Additives Amendment, Congress for the first time established a premarketing approval requirement for all substances meeting the definition of “food additive.”
Excluded from consideration as food additives are substances deemed to be “generally recognized as safe” (GRAS). Such substances are not subject to mandatory review by the Food and Drug Administration (FDA), but they are subject to the requirements established by the agency and the courts for GRAS assessments (Hallagan and Hall, 1995, 2009). Congress’ intent in excluding GRAS substances from the definition of “food additive” was to provide FDA with flexibility and discretion in allocating resources to food additive issues of greater safety concern.
This GRAS 26 publication includes the results of the Expert Panel’s review of 51 new GRAS flavoring substances (Tables 1 and 2). In addition, the Expert Panel determined that new use levels and/or use in new food categories for 18 flavoring substances are consistent with their current GRAS status (Table3). The Panel also describes its current operating principles regarding potential bias and conflict of interest issues. Also included are changes in the GRAS status of one substance recently re-evaluated by the Panel, and an update on the use of sensory evaluation data within FEMA GRAS evaluations conducted by the Panel.
Panel Statement on Conflict of Interest and Bias Protections
Addressing issues related to potential conflict of interest and bias has been an important part of the FEMA GRAS program. At the time the FEMA Expert Panel was established in 1960, there was little guidance on how to address potential bias and conflict of interest issues in the context of GRAS assessments. Subsequent years saw some clarification from the courts regarding GRAS assessments (Hallagan and Hall, 1995) but no specific guidance on conflicts of interest and bias protections from government agencies or nongovernmental organizations.
Initial conflict of interest and bias protections that were instituted by the Expert Panel at its origin included a prohibition on Expert Panel members serving as employees or consultants to FEMA member companies, conducting GRAS evaluations “blind” with the Panel not knowing the identity of the applicant, and a prohibition against applicants having contact with Expert Panel members regarding GRAS applications or activities.
The Expert Panel has continued to expand and refine its conflict of interest and bias protections over more than 50 years of operation. The following measures are currently in place to assure that Expert Panel decisions on GRAS status are fully objective and based solely on the merits of the available information.
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1) The Expert Panel is self-appointed—its members are not appointed by FEMA. When a member retires from the Panel, prospective Panel members’ qualifications and experience are reviewed by the Expert Panel and a new member is appointed to the Panel by the remaining Panel members.
2) FEMA Expert Panel members are not allowed to have consulting relationships with FEMA member companies regarding anything to do with flavors in the context of the FEMA GRAS™ program.
3) FEMA Expert Panel members do not prepare GRAS applications. Applications for FEMA GRAS™ assessments are prepared by the FEMA member seeking the GRAS assessment for the substance at issue.
4) Companies submitting GRAS applications are not allowed to contact Expert Panel members in any way nor are they allowed to attend meetings during which their applications are being considered.
5) When evaluating GRAS applications, Expert Panel members do not know the identity of the company responsible for the application. The identity of applicant companies is maintained as confidential information by the FEMA staff even after the substance is evaluated and granted GRAS status.
6) FEMA Expert Panel members conduct their reviews of GRAS applications during in-person meetings, usually three times per year and receive honoraria and reimbursement of expenses for their service whether or not they conclude that any substances are GRAS.
7) The identity of the members of the Expert Panel is known to the public through regular Panel publications in Food Technology, Food and Chemical Toxicology, and other publicly available journals or other media.
8) FEMA Expert Panel members provide a declaration of their consulting and business relationships prior to each Expert Panel meeting for review and action, if necessary, by the Panel’s Legal Advisor. Action may include mandated recusal at meetings during discussion of the relevant meeting agenda item.
Change in GRAS Status of 3-Acetyl-2,5-Dimethylthiophene
The FEMA GRAS status of 3-acetyl-2,5-dimethylthiophene (FEMA No. 3527) under conditions of intended use as a flavor ingredient was reviewed. The Panel concluded that additional data, including more detailed exposure information, comparative metabolism studies, and more comprehensive toxicity data including an in-depth evaluation of the mechanism of action for any potential adverse effects are required. Until such data are available for review, the flavor ingredient 3-acetyl-2,5-dimethylthiophene has been removed from the GRAS list. The Panel also reviewed data for related alkyl-substituted thiophene substances and confirmed that no change in the GRAS status of their uses was warranted.
Sensory Data Consideration in FEMA GRAS Evaluations
The Codex Alimentarius Guidelines for the Use of Flavourings (CAC/GL 66-2008) defines flavorings (or flavor ingredients) as products that are added to food to impart, modify, or enhance the flavor of food1. While not explicitly defined, flavors with modifying properties is a term that can be used to describe flavor ingredients that may not have nor impart a specific characteristic flavor of their own, but that modify or enhance the profile of a flavoring or food. Some of these flavor modifiers also display multiple characteristics, in that they have the ability to perform technical effects (e.g., as a sweetener) in food outside of their flavor modification properties. As the technical effect for all GRAS determinations made by the Panel is for flavoring, the Panel requires sensory testing to demonstrate the technical effect and functionality in food is limited to flavoring under conditions of intended use.
The format of these sensory data submissions to the Panel and the choice of tests that are conducted by applicants for such substances have varied widely. To ensure consistency between evaluations for substances with similar intended flavor modulation effects, the Panel has requested that sensory experts within the flavor industry develop best practices for conducting and reporting sensory evaluations that will be submitted as supporting evidence for FEMA GRAS™ status under conditions of intended use. The Panel has requested that this guidance include options for the choice of tests, analysis of data, and reporting of methodology and results to provide clear input to the Panel.
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FEMA GRAS Lists and updates/corrections to the lists published in Food Technology, in chronological order
Hall, R.L. 1960. Recent progress in the consideration of flavoring ingredients under the Food Additives Amendment. Food Technol. 14: 488-495.
Hall, L. and Oser, B.L. 1961. Recent progress in the consideration of flavoring ingredients under the Food Additives Amendment. II. Food Technol. 15(12): 20, 22-26.
Hall, R.L. and Oser, B.L. 1965. Recent progress in the consideration of flavoring ingredients under the Food Additives Amendment. 3. GRAS substances. Food Technol. 19(2, Part 2): 151-197.
Hall, R.L. and Oser, B.L. 1970. Recent progress in the consideration of flavoring ingredients under the Food Additives Amendment. 4. GRAS substances. Food Technol. 24(5): 25-34.
Oser, B.L. and Hall, R.L. 1972. Recent progress in the consideration of flavoring ingredients under the Food Additives Amendment. 5. GRAS substances. Food Technol. 26(5): 35-42.
Oser, B.L. and Ford, R.A. 1973a. Recent progress in the consideration of flavoring ingredients under the Food Additives Amendment. 6. GRAS substances. Food Technol. 27(1): 64-67.
Oser, B.L. and Ford, R.A. 1973b. Recent progress in the consideration of flavoring ingredients under the Food Additives Amendment. 7. GRAS substances. Food Technol. 27(11): 56-57.
Oser, B.L. and Ford, R.A. 1974. Recent progress in the consideration of flavoring ingredients under the Food Additives Amendment. 8. GRAS substances. Food Technol. 28(9): 76-80.
Oser, B.L. and Ford, R.A. 1975. Recent progress in the consideration of flavoring ingredients under the Food Additives Amendment. 9. GRAS substances. Food Technol. 29(8): 70-72.
Oser, B.L. and Ford, R.A. 1977. Recent progress in the consideration of flavoring ingredients under the Food Additives Amendment. 10. GRAS substances. Food Technol. 31(1): 65-74.
Oser, B.L. and Ford, R.A. 1978. Recent progress in the consideration of flavoring ingredients under the Food Additives Amendment. 11. GRAS substances. Food Technol. 32(2): 60-70.
Oser, B.L. and Ford, R.A. 1979. Recent progress in the consideration of flavoring ingredients under the Food Additives Amendment. 12. GRAS substances. Food Technol. 33(7): 65-73.
Oser, B.L., Ford, R.A., and Bernard, B.K. 1984. Recent progress in the consideration of flavoring ingredients under the Food Additives Amendment. 13. GRAS substances. Food Technol. 38(10): 66-89.
Oser, B.L., Weil, C.L., Woods, L.A., and Bernard, B.K. 1985. Recent progress in the consideration of flavoring ingredients under the Food Additives Amendment. 14. GRAS substances. Food Technol. 39(11): 108-117.
Burdock, G.A., Wagner, B.M., Smith, R.L., Munro, I.C., and Newberne, P.M. 1990. Recent progress in the consideration of flavoring ingredients under the Food Additives Amendment. 15. GRAS substances. Food Technol. 44(2): 78, 80, 82, 84, 86.
Smith, R.L. and Ford, R.A. 1993. Recent progress in the consideration of flavoring ingredients under the Food Additives Amendment. 16. GRAS substances. Food Technol. 47(6): 104-117.
Smith, R.L., Newberne, P., Adams, T.B., Ford, R.A., Hallagan, J.B., and the FEMA Expert Panel. 1996a. GRAS flavoring substances 17. Food Technol. 50(10): 72-78, 80-81.
Smith, R.L., Newberne, P., Adams, T.B., Ford, R.A., Hallagan, J.B., and the FEMA Expert Panel. 1996b. Correction to GRAS flavoring substances 17. Food Technol. 51(2): 32.
Newberne, P., Smith, R.L., Doull, J., Goodman, J.I., Munro, I.C., Portoghese, P.S., Wagner, B.M., Weil, C.S., Woods, L.A., Adams, T.B., Hallagan, J.B., and Ford, R.A. 1998. GRAS flavoring substances 18. Food Technol. 52(9): 65-66, 68, 70, 72, 74, 76, 79- 92.
Newberne, P., Smith, R.L., Doull, J., Goodman, J.I., Munro, I.C., Portoghese, P.S., Wagner, B.M., Weil, C.S., Woods, L.A., Adams, T.B., Hallagan, J.B., and Ford, R.A. 1999. Correction to GRAS flavoring substances 18. Food Technol. 53(3): 104.
Newberne, P., Smith, R.L., Doull, J., Feron, V.J., Goodman, J.I., Munro, I.C., Portoghese, P.S., Waddell, W.J., Wagner, B.M., Weil, C.S., Adams, T.B., and Hallagan, J.B. 2000. GRAS flavoring substances 19. Food Technol. 54(6): 66, 68-69, 70, 72-74, 76-84.
Smith, R.L., Doull, J., Feron, V.J., Goodman, J.I., Munro, I.C., Newberne, P.M., Portoghese, P.S., Waddell, W.J., Wagner, B.M., Adams, T.B., and McGowen, M.M. 2001. GRAS flavoring substances 20. Food Technol. 55(12): 34-36, 38, 40, 42, 44-55.
Smith, R.L., Cohen, S.M., Doull, J., Feron, V.J., Goodman, J.I., Marnett, I.J., Portoghese, P.S., Waddell, W.J., Wagner, B.M., and Adams, T.B. 2003. GRAS flavoring substances 21. Food Technol. 57(5): 46-48, 50, 52-54, 56-59.
Smith, R.L., Cohen, S.M., Doull, J., Feron, V.J., Goodman, J.I., Marnett, I.J., Portoghese, P.S., Waddell, W.J., Wagner, B.M., and Adams, T.B. 2005. GRAS flavoring substances 22. Food Technol. 59(8): 24-28, 31-32, 34, 36-62.
Waddell, W.J., Cohen, S.M., Feron, V.J., Goodman, J.I., Marnett, L.J., Portoghese, P.S., Rietjens, I.M.C.M., Smith, R.L., Adams, T.B., Gavin, C. Lucas, McGowen, M.M., and Williams, M.C. 2007. GRAS flavoring substances 23. Food Technol. 61(8): 22-24, 26-28, 30-49.
Smith, R.L., Waddell, W.J., Cohen, S.M., Feron, V.J., Marnett, L.J., Portoghese, P.S., Rietjens, I.M.C.M., Adams, T.B., Lucas Gavin, C., McGowen, M.M., Taylor, S.V., and Williams, M.C. 2009. GRAS flavoring substances 24. Food Technol. 63(6): 46-48, 51-52, 55-56, 58, 60, 62, 64-66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98-105.
Smith, R.L., Waddell, W.J., Cohen, S.M., Fukushima, S., Gooderham, N.J., Hecht, S.S., Marnett, L.J., Portoghese, P.S., Rietjens, I.M.C.M., Adams, T.B., Lucas Gavin, C., McGowen, M.M., Taylor, S.V. 2011. GRAS flavoring substances 25. Food Technol. 65(7): 44-75.
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Corrections and Errata to Previous GRAS Publications • Intake of Isoeugenol. In the Safety Assessment of Isoeugenol (FEMA No. 2468) described in “GRAS Flavoring Substances 24” (Smith et al., 2009), the estimated daily per capita intake of isoeugenol as a flavoring agent in the United States was reported as 0.00002 mg/kg bw/day. The correct corresponding estimated daily per capita intake of isoeugenol as a flavoring agent in the U.S. is 0.4 mg/kg bw/day.
• Magnolol Synonym. In Table 1 of “GRAS Flavoring Substances 24” (Smith et al., 2009), magnolia bark extract was incorrectly included as a synonym for the chemically defined substance magnolol (FEMA 4559). Magnolia bark extract is not a synonym for FEMA 4559.
• Isomeric Clarification of FEMA 4680. In Table 1 of “GRAS Flavoring Substances 25” (Smith et al., 2011), the primary name of FEMA 4680 was incorrectly listed as 5-isopropyl-2,6-diethyl-2-methyltetrahydro-2H-pyran. The correct name of FEMA 4680 is (±)-5-isopropyl-2,6-diethyl-2-methyltetrahydro-2H-pyran, as the substance is a mixture of the (+) and (-) isomers.
• Use Levels in Tables 4 and 5. In “GRAS Flavoring Substances 25” (Smith et al., 2011), the new use levels listed in Table 3 for FEMA 3455 contained errors in two food categories and the new use levels for FEMA 4309 were omitted from Table 3. The correct and the previously omitted new use levels for both substances, respectively, are listed in Table 4 of this current publication. The updated average usual use levels in chewing gum listed in Table 5 of “GRAS Flavoring Substances 25” (Smith et al., 2011) for several substances are corrected in Table 5 of this current publication.
A Note of Thanks
In January 2012, Dr. Timothy B. Adams retired from his role as the Scientific Secretary to the FEMA Expert Panel. The Panel deeply appreciates the dedication and support that Dr. Adams provided over many years of service to the Panel.
Lawrence J. Marnett, Ph.D., Chairman of the FEMA Expert Panel, is Mary Geddes Stahlman Professor of Cancer Research and Professor of Biochemistry, Chemistry, and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN. Other members of the FEMA Expert Panel are Samuel M. Cohen, Ph.D, M.D., Professor, Dept. of Pathology and Microbiology, and Havlik-Wall Professor of Oncology, University of Nebraska Medical Center,Omaha, NE; Shoji Fukushima, M.D., Director, Japan Bioassay Research Center, Japan Industrial Safety and Health Association, Kanagawa, Japan; Nigel J. Gooderham, Ph.D., Professor of Molecular Toxicology and Senior College Consul, Dept. of Surgery and Cancer, Imperial College London, England; Stephen S. Hecht, Ph.D., Wallin Professor of Cancer Prevention, Masonic Cancer Center and Dept. of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN; Ivonne M.C.M. Rietjens, Ph.D., Professor of Toxicology and Chair, Dept. of Toxicology, Wageningen University, Wageningen, The Netherlands; and Robert L. Smith, Ph.D., Emeritus and Senior Research Fellow, Molecular Toxicology, Dept. of Surgery and Cancer, Imperial College London, London, England.
Sean V. Taylor is the Scientific Secretary to the FEMA Expert Panel. Christie Harman, Margaret M. McGowen, and Timothy B. Adams, are associated with the Flavor and Extract Manufacturers Association, 1620 I Street, NW, Suite 925, Washington, DC 20006. John B. Hallagan is Legal Advisor to the FEMA Expert Panel. Send reprint requests to author Taylor ([email protected]).
NOTE
1 From Codex Guidelines for the Use of Flavourings (CAC/GL 66-2008): “Flavourings means products that are added to food to impart, modify, or enhance the flavour of food with the exception of flavour enhancers considered as food additives under the Codex Class Names and the International Numbering System for Food Additives—CAC/GL 36-1989. Flavourings do not include substances that have an exclusively sweet, sour, or salty taste (e.g. sugar, vinegar, and table salt). Flavourings may consist of flavouring substances, natural flavouring complexes, thermal process flavourings or smoke flavourings and mixtures of them and may contain non-flavouring food ingredients within defined conditions such as carriers, solvents, etc. Flavourings are not intended to be consumed as such.”
References
Hallagan, J.B. and Hall, R.L. 1995. FEMA GRAS—A GRAS assessment program for flavor ingredients. Regul. Toxicol. Pharmacol. 21, 422.
Hallagan, J.B. and Hall, R.L. 2009. Under conditions of intended use—New developments in the FEMA GRAS program and the safety assessment of flavor ingredients. Food Chem. Toxicol. 47, 267.