FEMA has worked to protect the trade secrets of members, often explaining to government agencies the unique value of intellectual property of the flavor business.
FEMA Expert Panel (left to right): Dr. Steve Hecht, University of Minnesota (2010), Dr. Ivonne Rietjens, Wageningen University (2006) (Vice-Chair), Dr. Sam Cohen, University of Nebraska Medical Center (2002) (Chair), Dr. Larry Marnett, Vanderbilt University (Resigned), Dr. Nigel Gooderham, Imperial College London (2009), Dr. Shoji Fukushima, Japan Bioassay Research Center (2010), Dr. Robert Smith, Imperial College London (1981), Dr. F. Peter Guengerich, Vanderbilt University (2015) (not pictured).
In 1959, The Flavor and Extract Manufacturers Association of the United States (FEMA) took its initial actions to establish a novel program to assess the safety and “GRAS” (generally recognized as safe) status of flavor ingredients as described in the 1958 Food Additives Amendments to the Federal Food, Drug, and Cosmetic Act, the Federal law governing the regulation of flavors and other food ingredients. Since then, the FEMA GRAS™ program has become the longest-running and most widely recognized industry GRAS assessment program.
The FEMA GRAS™ program began in 1959 with a survey of the flavor industry to identify flavor ingredients then in use and to provide estimates of the amounts of these substances used to manufacture flavors. The initial FEMA Expert Panel was established in 1960 beginning the Expert Panel’s evaluation of the safety of flavor ingredients that continues today. Then and now, the Expert Panel usually consists of six to eight members and over the years has been comprised of top experts in toxicology, organic chemistry, biochemistry, metabolism, and pathology.
The FEMA Expert Panel’s GRAS assessments have from the beginning utilized a number of techniques now common in safety evaluations including the use of metabolic studies and structural relationships that had not previously been applied in a significant manner to food ingredients before the Panel did so in the 1960s in its evaluation of flavors. While the Expert Panel has been provided with financial support by FEMA it has always maintained its full independence in its operations and GRAS determinations and follows strict conflict of interest procedures.
The FEMA GRAS program is open to participation by Active Members of FEMA who may submit applications to the Expert Panel requesting consideration of flavor ingredients as generally recognized as safe.
Two publications by Hallagan and Hall (1995, 2009) provide a detailed review of the history of the FEMA GRAS™ Program, and its legal and scientific bases.
In the United States, the GRAS concept is one way in which the regulatory authority to use a food ingredient (other than color additives) can be determined with the other key path being through an application to the Food and Drug Administration for food additive status. GRAS status may be achieved either through the FDA’s voluntary GRAS notification program (FDA, 1997) or through a properly conducted GRAS determination made by a private party. Section 201(s) of the Federal Food, Drug, and Cosmetic Act provides:
The term food additive means any substance the intended use of which results or may reasonably be expected to result, directly or indirectly, in its becoming a component or otherwise affecting the characteristics of any food . . . if such substance is not generally recognized, among experts qualified by training and experience to evaluate its safety as having been adequately shown through scientific procedures (or in the case of a substance used in food prior to January 1, 1958, through either scientific procedures or experience based on common use in food) to be safe under the conditions of intended use . . .
The statutory definition of GRAS has four key criteria, all of which must be met for a food ingredient to be considered generally recognized as safe and exempt from the requirements for food additive approval:
A key part of the requirements for GRAS status is that there must be general recognition of safety and not just an assertion of safety per se. This means that there must be an opportunity for interested parties to review the basis for GRAS determinations not just the conclusions. Detailed discussions of the requirements for determining GRAS status are available in Hallagan and Hall (1995, 2009) and the many references cited in these two publications.
The mission of the FEMA Expert Panel is to protect the public health through the effective safety evaluation of flavor ingredients using the best available scientific procedures and information.
Over the years, members of the FEMA Expert Panel have included many prominent expert scientists. Most often, members of the FEMA Expert Panel are scientific experts from academia. Members of the Expert Panel have never been employees of FEMA member companies or employees of companies in the food industry. Current members of the FEMA Expert Panel are:
Samuel M. Cohen, M.D., Ph.D. – Chair
University of Nebraska
Shoji Fukushima, M.D., Ph.D.
Japan Bioassay Research Center
Nigel J. Gooderham, Ph.D.
Imperial College London
F. Peter Guengerich, Ph.D.
Stephen S. Hecht, Ph.D.
University of Minnesota
Ivonne M.C.M. Rietjens, Ph.D.– Vice Chair
Wageningen University, Netherlands
Robert L. Smith, Ph.D.
Imperial College London
Scientific Procedures to Determine Safety
As part of the FEMA GRAS™ program’s policy of transparency, the scientific criteria employed by the FEMA Expert Panel for its GRAS assessments are published in the peer-reviewed scientific literature so that they may be reviewed and understood by regulators, business, and the public. The current criteria for the GRAS assessment of single, chemically defined flavoring substances are described by Smith et al. (2005a). The current criteria for natural flavor complexes are described in Smith et al. (2004) and Smith et al. (2005b). The safety standard applied by the FEMA Expert Panel is the same standard required by FDA, a “reasonable certainty of no harm.”
Safety Under Conditions of Intended Use
The FEMA Expert Panel only evaluates substances for GRAS status that are used to formulate flavors to be added to human foods. The Expert Panel does not evaluate food ingredients with functions other than flavoring nor does it evaluate flavorings for use in products other than human food. For example, the Expert Panel does not evaluate flavor ingredients for use in tobacco products, e-cigarettes, or other products that involve routes of exposure other than ingestion.
General Recognition of Safety
The general recognition requirement for GRAS status is perhaps the most important factor. The Expert Panel and the FEMA GRAS™ program meet this requirement in a number of ways:
In addition to the multiple sources of published information listed above, FEMA’s policy is to share information on all FEMA GRAS™ substances with anyone upon request. For example, if a person wants to question or challenge the status of a FEMA GRAS™ substance the person may obtain from FEMA all of the available information used to determine that the substance is GRAS under its conditions of intended use as a flavor ingredient.
Additional support to meet the general recognition requirement is FDA’s acknowledgment in Federal Register notices that FEMA GRAS™ substances were “approved for inclusion in the FDA GRAS review process” and therefore were eligible for the application of its bulk flavor labeling policy. (41 Fed. Reg. 4954. 3 February 1976). FDA’s 1976 notice explicitly accounted for “FEMA GRAS lists 3 through 9.” (41 Fed. Reg. 4954. 3 February 1976). Subsequent notices accounted for new FEMA GRAS substances as follows:
“GRAS 10” – 42 Fed. Reg. 55643. 18 October 1977
“GRAS 11” – 43 Fed. Reg. 22784. 26 May 1978
“GRAS 12” – 44 Fed. Reg. 71460. 11 December 1979
FDA published its last notice in 1979 due to a change in agency priorities.
A number of measures are in place to assure that Expert Panel decisions on GRAS status are fully objective and based solely on the merits of the available information and are not subject to bias.
The FEMA GRAS™ program meets the highest standards for transparency. All GRAS determinations made by the FEMA Expert Panel are provided to FDA along with the scientific information supporting the determinations. It is important to note that the receipt by FDA of the information provided by FEMA does not constitute FDA’s “approval” of the GRAS determinations made by the FEMA Expert Panel. The identities of all flavor ingredients determined to be GRAS are published regularly in the widely read journal Food Technology. The scientific basis for the Expert Panel’s GRAS determinations including detailed summaries of the supporting scientific information are published in widely read scientific journals including Food and Chemical Toxicology. Extensive summaries of the information supporting the safety of FEMA GRAS™ substances are also published by the Joint FAO/WHO Expert Committee on Food Additives (JECFA), an independent international scientific advisory body managed through the United Nations (See http://apps.who.int/food-additives-contaminants-jecfa-database/search.aspx).
A significant additional transparency measure is that anyone wishing to review the scientific information supporting the GRAS status of any FEMA GRAS™ flavor ingredient may request the information from FEMA and receive it for only the cost of duplication.
Evidence of the high degree of transparency of the FEMA GRAS™ program can be found in a list of more than two hundred individual publications describing the FEMA GRAS™ program and the safety of flavor ingredients. This list is available upon request from FEMA.
In conclusion, the FEMA GRAS™ program meets the highest standards for transparency and in doing so provides a high level of assurance in its GRAS determinations for flavor ingredients.
For more information on the FEMA GRAS™ program please contact John Hallagan – FEMA Senior Advisor and General Counsel ([email protected]) or Sean Taylor – Scientific Secretary to the FEMA Expert Panel ([email protected]).
References available from FEMA upon request.