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`How U.S. FDA's GRAS Notification
`Program Works
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`December 2005/January 2006
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`Author
`Reprinted with permission of the publishers from Food Safety Magazine December 2005/January
`2006
`
`The U.S. Food and Drug Administration (FDA) regulates approximately 80% of the U.S. food
`supply and is involved with many facets of food safety. Within FDA, the Center for Food Safety and
`Applied Nutrition's (CFSAN) Office of Food Additive Safety is responsible for reviewing safety
`information for food ingredients and food packaging. This article provides an overview of a
`particular type of food ingredient regulatory classification: 'generally recognized as safe,' commonly
`referred to as GRAS. It describes the history of the GRAS program, how the Office of Food
`Additive Safety administers the program, and includes statistics about the program.
`
`In 1958, Congress enacted the Food Additives Amendment to the Federal Food, Drug, and
`Cosmetic Act (FD&C Act). The amendment and/or supporting legislative documents defined the
`term 'food additive'; required premarket approval for new uses of food additives; and established
`the standard of review ('fair evaluation of the data...'), the standard of safety, and formal
`rulemaking procedures for food additives. Congress broadly defined 'food additive' to include 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 component of food. Congress
`further stated that 'substances that are generally recognized, among experts qualified by scientific
`training and experience to evaluate their safety as having been adequately shown . . . to be safe
`under the conditions of their intended use,' are excluded from the definition. Put simply,
`substances that are GRAS under conditions of their intended use are not food additives and do not
`require premarket approval by FDA.
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`GRAS Determination vs. Food Additive Safety Determination
`Irrespective of whether a substance is deemed to be GRAS or if its safety is established through a
`premarket approval process, the safety determination is always limited to the substance's intended
`conditions of use. The difference between a GRAS determination and a premarket approval
`relates to who has access to the scientific data and information and who has reviewed the
`scientific data and information.
`
`[1]
`
`For a substance to be GRAS, the scientific data and information about the use of a substance
`must be widely known and there must be a consensus among qualified experts that those data and
`information establish that the substance is safe under the conditions of its intended use. GRAS
`determinations made in this manner are said to be made through scientific procedures. For a food
`additive, privately held data and information about the use of a substance are sent by the sponsor
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`to FDA, which evaluates those data and information to determine whether they establish that the
`substance is safe under the conditions of its intended use (21 CFR 171.1). Thus, for a food
`additive, FDA determines the safety of the ingredient; whereas a determination that an ingredient
`is GRAS can be made by qualified experts outside of government.
`
`There is, however, an additional way that a GRAS determination can be made. For a substance
`used in food before 1958, a GRAS determination can be made through experience based on
`common use in food. It should be noted that determinations based on common use in food require
`a substantial history of consumption in food by a significant number of consumers (21 CFR 170.30
`(c) and 170.3(f)), and that this basis for GRAS determination is seldom relied on today.
`
`GRAS Affirmation
`During the late 1960s new scientific information raised questions about the safety of cyclamate
`salts, substances previously considered GRAS. As a result, then-President Nixon directed FDA to
`re-examine the safety of substances considered to be GRAS. In response to this directive, FDA
`announced that the agency would evaluate, by contemporary standards of the time, the available
`safety information related to substances FDA considered GRAS. If the evaluation confirmed that
`the use of a particular substance was GRAS, FDA would issue a new GRAS regulation, affirming
`that finding. As part of the GRAS affirmation process, FDA also established procedures whereby
`individuals could petition FDA to review the GRAS status of substances not covered as part of the
`GRAS review that the agency undertook upon passage of the Food Additives Amendment in
`1958.
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`By 1997 FDA had tentatively concluded that it could no longer devote substantial resources to the
`GRAS affirmation petition process. The agency published a proposed rule outlining a GRAS
` As part
`notification process to replace the resource-intensive GRAS affirmation petition process.
`of the proposed rule the agency announced an interim policy, under which it would accept and in
`general administer GRAS notices as described in the proposed rule, until a final rule published.
`Under the interim policy, FDA indicated it would make a good faith effort to follow the timelines
`called for in the proposed rule; however, the agency would not be bound by them. In 1998 FDA
`received its first GRAS notice for a food ingredient.
`
`[2]
`
`The GRAS Notification Program
`The GRAS notification program provides a voluntary mechanism whereby a person may inform
`FDA of a determination that the use of a substance is GRAS, rather than petition FDA to affirm that
`the use of a substance is GRAS. Although operating under an interim procedure, pending the
`publication of a final rule, FDA has received and responded to nearly 200 GRAS notices for a
`variety of substances including carbohydrates, lipids, proteins, and chemicals such as gases,
`inorganics, organics (Figures 1 and 2).
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`Figure 1. Number of GRAS notices filed by year, from 1998 to November 2005.
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`Figure 2. Types of substances for which GRAS notices have been submitted.
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`Submitting a GRAS Notification
`FDA encourages individuals to thoroughly review its GRAS notification submission procedures
`prior to sending a notification to the Agency. Additionally, a notifier may request a pre-submission
`meeting with FDA to discuss issues that may be relevant to the submission of the notifier's GRAS
`notice.
`
`[3]
`
`Notifications should be sent to FDA's Office of Food Additive Safety and among many things
`include: a 'GRAS exemption claim' providing a succinct description of the substance, the
`applicable conditions of use, and the basis for the GRAS determination (scientific procedures or
`common use in food). The notice should also include information about the identity and properties
`of the substance and a discussion of the notifier's reasons for concluding that the substance is
`GRAS for its intended use. The information about the notified substance generally is chemical,
`toxicological, and, if applicable, microbiological in nature. The notifier should discuss information
`supporting the GRAS determination, as well as any information that would appear to be
`inconsistent with a GRAS determination, and explain why, in light of the totality of the information,
`the notifier concludes the substance is GRAS under the intended conditions of use.
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`FDA Response
`Within 30 days of receiving a notice FDA will inform the notifier in writing of the date on which the
`notice was received. FDA then evaluates whether the submitted notice provides a sufficient basis
`for a GRAS determination and whether information in the notice, or otherwise available to FDA,
`raises issues that lead the agency to question whether use of the substance is GRAS. On
`occasion, FDA will consult with other agencies; for example, when the notice includes use in meat
`and poultry products, FDA consults with the Food Safety and Inspection Service of the U.S.
`Department of Agriculture.
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`Following this evaluation FDA responds to the notifier with one of three types of letters. The first
`type of letter states that FDA does not question the basis for the notifier's GRAS determination.
`This type of letter may also note, among other things, potentially pertinent issues related to
`In the
`labeling, the substance's use in certain foods, and requirements for a color additive.
`second type of letter, the agency concludes that the notice does not provide a sufficient basis for a
`GRAS determination (e.g., because the notice does not include appropriate data and information,
`or because the available data and information raise questions about the safety of the notified
`substance). The third type of letter states that the agency has, at the notifier's request, ceased to
`evaluate the GRAS notice.
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`[4]
`
`[5]
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`As part of the 1997 GRAS proposal, FDA also announced its intention to maintain an inventory of
`GRAS notices and the agency's response to those notices. In accordance with this, the Office of
`Food Additive Safety has created and maintains a web page titled 'Summary of All GRAS
`Notices.' The page lists all GRAS notices that FDA has received, describes FDA's responses,
`and provides hyperlinks to FDA's response letters and additional correspondence. The page is
`organized by year, and within the summary table for each year, there is a link to a table that
`provides more details about the GRAS notices received in that year, including: the name of the
`person who made the GRAS determination (notifier); the substance that is the subject the notice; a
`description of the intended use of the substance; the basis for the GRAS determination; and FDA's
`response to the notice.
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`FDA encourages individuals contemplating filing a GRAS notice or who are just interested in
`knowing more about GRAS substances to review CFSAN's GRAS Notification Program web page
`at www.cfsan.fda.gov/~dms/opa-noti.html and the 'Frequently Asked Questions About GRAS'
`document on that page. Information on other programs under the purview of CFSAN's Office of
`Food Additive Safety can be found at www.cfsan.fda.gov/~lrd/foodadd.html.
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`Paulette Gaynor, Ph.D. is a consumer safety officer in CFSAN's Office of Food Additive Safety's
`Division of Biotechnology and GRAS Notice Review. She has worked for FDA for nine years and
`currently serves as a contact for the GRAS notification program.
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`Series editor Sebastian Cianci is a policy analyst and a member of CFSAN's Office of Food
`Safety, Defense, and Outreach. He has worked for FDA for 15 years and serves as the Center's
`trade press liaison.
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`Endnotes
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`1. FDA has defined 'safe' as 'a reasonable certainty in the minds of competent scientists that the
`substance is not harmful under the intended conditions of use' (21 CFR 170.3(i).
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`2. 62 FR 18938, April 17, 1997 (PDF - 272KB) (http://www.gpo.gov/fdsys/pkg/FR-1997-04-
`17/pdf/97-9706.pdf). Substances Generally Recognized as Safe.
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`3. How to Submit a GRAS Notice (ssLINK/ucm083062.htm).
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`4. Under section 201(s) of the FD&C Act, the GRAS substances are excluded from the definition of
`a food additive. There is no corresponding exclusion in the definition of a color additive (section
`201(t) of the FD&C Act). Given this difference, the use of a substance that is capable of imparting
`color may constitute use as both a color additive and as a food additive or GRAS substance.
`
`5. Summary of All GRAS Notices (/Food/IngredientsPackagingLabeling/GRAS/NoticeInven-
`tory/default.htm).
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`REPRODUCED FROM FOOD SAFETY MAGAZINE, DECEMBER 2005/JANUARY 2006, WITH PERMISSION OF THE
`PUBLISHERS. © 2002 BY THE TARGET GROUP.
`
`Note: Since the publication of this article, FDA's website has changed. Current versions of the links
`in the article are provided below
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`• GRAS Notification Program (/Food/IngredientsPackagingLabeling/GRAS/default.htm)
`• Other programs (/Food/IngredientsPackagingLabeling/default.htm) in CFSAN's Office of
`Food Additive Safety
`
`More in Generally Recognized as Safe (GRAS)
`(/Food/IngredientsPackagingLabeling/GRAS/default.htm)
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`GRAS Notice Inventory (/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/default.htm)
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`GRAS Substances (SCOGS) Database
`(/Food/IngredientsPackagingLabeling/GRAS/SCOGS/default.htm)
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`Enzyme Preparations Used in Food
`(/Food/IngredientsPackagingLabeling/GRAS/EnzymePreparations/default.htm)
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`Microorganisms & Microbial-Derived Ingredients Used in Food
`(/Food/IngredientsPackagingLabeling/GRAS/MicroorganismsMicrobialDerivedIngredients/default.htm)
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