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U.S. Department of Health and Human Services

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Guidance for Industry: Frequently Asked Questions About GRAS

Contains Nonbinding Recommendations

December 2004

Additional copies are available from:
Office of Food Additive Safety, HFS-200
Center for Food Safety and Applied Nutrition
Food and Drug Administration
5100 Paint Branch Parkway
College Park, MD 20740
(Tel) 301-436-1200
(Updated phone: 240-402-1200)
http://www.cfsan.fda.gov/guidance.html

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Food Safety and Applied Nutrition (CFSAN)
December 2004


Contains Nonbinding Recommendations

Guidance for Industry
Frequently Asked Questions About GRAS

This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach can be used if such approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, please contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, contact the appropriate number listed on the title page of this document.

 

Introduction

This list of frequently asked questions (FAQ) is intended to be a convenient place to find answers to common questions about the food ingredient classification known as "generally recognized as safe" or "GRAS." This FAQ addresses common questions about the regulatory process and regulatory considerations regarding whether the use of a food substance is GRAS. For more information about the GRAS program, please contact Dr. Paulette Gaynor (301-436-1192)(Updated phone: 240-402-1192) in the Office of Food Additive Safety, or email questions to premarkt@fda.hhs.gov. See additional contact information at the bottom of this page.

  1. What does "GRAS" mean?
  2. What are the criteria for GRAS status?
  3. In what way are the criteria for the use of a substance to be GRAS similar to that for the approved use of a food additive?
  4. In what way are the criteria for the use of a substance to be GRAS different from that for the approved use of a food additive?
  5. If an ingredient is GRAS for one use, is it GRAS for all uses?
  6. Is a substance that is used to impart color eligible for classification as GRAS?
  7. Is a substance that is used as a dietary ingredient of a dietary supplement eligible for classification as GRAS?
  8. Must FDA approve GRAS substances?
  9. What is GRAS affirmation?
  10. Does FDA currently have a program to affirm that one or more uses of a food substance are GRAS?
  11. What is the GRAS notification program?
  12. If I choose to notify FDA of my GRAS determination, how do I do so?
  13. Where do I send my GRAS notice?
  14. If I submit a GRAS notice, how long will it take for me to receive a response from FDA?
  15. If I submit a GRAS notice about a food substance, must I wait until I receive a response from FDA before I market that substance?
  16. Does FDA have a list of substances that are used in food on the basis of the GRAS provision?
  17. Can the use of a substance be GRAS even if it is not listed by FDA?

  1.  What does "GRAS" mean?

    "GRAS" is an acronym for the phrase Generally Recognized As Safe. Under sections 201(s) and 409 of the Federal Food, Drug, and Cosmetic Act (the Act), any substance that is intentionally added to food is a food additive, that is subject to premarket review and approval by FDA, unless the substance is generally recognized, among qualified experts, as having been adequately shown to be safe under the conditions of its intended use, or unless the use of the substance is otherwise excluded from the definition of a food additive. For example, substances whose use meets the definition of a pesticide, a dietary ingredient of a dietary supplement, a color additive, a new animal drug, or a substance approved for such use prior to September 6, 1958, are excluded from the definition of food additive. Sections 201(s) and 409 were enacted in 1958 as part of the Food Additives Amendment to the Act. While it is impracticable to list all ingredients whose use is generally recognized as safe, FDA published a partial list of food ingredients whose use is generally recognized as safe to aid the industry's understanding of what did not require approval.

  2.  What are the criteria for GRAS status?

    Under sections 201(s) and 409 of the Act, and FDA's implementing regulations in 21 CFR 170.3 and 21 CFR 170.30, the use of a food substance may be GRAS either through scientific procedures or, for a substance used in food before 1958, through experience based on common use in food.

    • Under 21 CFR 170.30(b), general recognition of safety through scientific procedures requires the same quantity and quality of scientific evidence as is required to obtain approval of the substance as a food additive and ordinarily is based upon published studies, which may be corroborated by unpublished studies and other data and information.
    • Under 21 CFR 170.30(c) and 170.3(f), general recognition of safety through experience based on common use in foods requires a substantial history of consumption for food use by a significant number of consumers.
  3.  In what way are the criteria for the use of a substance to be GRAS similar to that for the approved use of a food additive?

    Regardless of whether the use of a substance is a food additive use or is GRAS, there must be evidence that the substance is safe under the conditions of its intended use. FDA has defined "safe" (21 CFR 170.3(i)) as a reasonable certainty in the minds of competent scientists that the substance is not harmful under its intended conditions of use. The specific data and information that demonstrate safety depend on the characteristics of the substance, the estimated dietary intake, and the population that will consume the substance.

  4.  In what way are the criteria for the use of a substance to be GRAS different from that for the approved use of a food additive?

    A GRAS substance is distinguished from a food additive on the basis of the common knowledge about the safety of the substance for its intended use. As FDA discussed in a proposed rule to establish a voluntary notification program for GRAS substances (62 Fed. Reg. 18938; April 17, 1997), the data and information relied on to establish the safety of the use of a GRAS substance must be generally available (e.g., through publication in the scientific literature) and there must be a basis to conclude that there is consensus among qualified experts about the safety of the substance for its intended use. Thus, the difference between use of a food additive and use of a GRAS substance relates to the widespread awareness of the data and information about the substance, i.e., who has access to the data and information and who has reviewed those data and information.

    • For a food additive, privately held data and information about the use of the substance are sent by the sponsor to FDA and FDA 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).
    • For a GRAS substance, generally available data and information about the use of the substance are known and accepted widely by qualified experts, and there is a basis to conclude that there is consensus among qualified experts that those data and information establish that the substance is safe under the conditions of its intended use. (proposed 170.36 (c)(4)(i)(C))
  5.  If an ingredient is GRAS for one use, is it GRAS for all uses?

    Not necessarily. Under section 201(s) of the Act, it is the use of a substance, rather than the substance itself, that is eligible for the GRAS exemption (62 Fed. Reg. 18939; April 17, 1997). A determination of the safety of the use of an ingredient includes information about the characteristics of the substance, the estimated dietary intake under the intended conditions of use, and the population that will consume the substance (proposed 21 CFR 170.36 (c)(1)(iii)). Dietary intake of a substance depends on the food categories in which it will be used and the level of use in each of those food categories. For information about how FDA estimates dietary intake of a food substance, see FDA's document entitled "Estimating Exposure to Direct Food Additives And Chemical Contaminants in the Diet" [August 2006: See updated information "Guidance for Industry - Estimating Dietary Intake of Substances in Food"]. Some uses of a food substance are intended for a narrowly defined population, such as newborn infants who consume infant formula as the sole item of the diet; in such a circumstance, there may be special considerations associated with that population but not with general use of the food substance.

  6.  Is a substance that is used to impart color eligible for classification as GRAS?

    The short answer is "No." Under section 201(s) of the Act, the GRAS provision applies to the definition of a food additive. There is no corresponding provision in the definition (in section 201(t) of the Act) of a color additive.

    However, under section 201(t)(1) and 21 CFR 70.3(f), the term color additive means a material that is a dye, pigment, or other substance made by a process of synthesis or similar artifice, or extracted, isolated, or otherwise derived from a vegetable, animal, mineral, or other source, and that is capable (alone or through reaction with another substance) of imparting color when added or applied to a food; except that such term does not include any material which FDA, by regulation, determines is used (or intended to be used) solely for a purpose or purposes other than coloring. Under 21 CFR 70.3(g), a material that otherwise meets the definition of color additive can be exempt from that definition on the basis that it is used or intended to be used solely for a purpose or purposes other than coloring, as long as the material is used in a way that any color imparted is clearly unimportant insofar as the appearance, value, marketability, or consumer acceptability is concerned. Given the construct of section 201(t)(1) of the Act and 21 CFR 70.3(f) and (g), 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. For example, beta-carotene is both approved for use as a color additive (21 CFR 73.95) and affirmed as GRAS for use as a nutrient (21 CFR 184.1245); in some food products, beta-carotene may be used for both purposes.

  7.  Is a substance that is used as a dietary ingredient of a dietary supplement eligible for classification as GRAS?

    Under section 201(s) of the Act, the ingredients whose use is GRAS are excluded from the definition of a food additive. That definition of food additive also specifies that the term "food additive" does not include a dietary ingredient of a dietary supplement described in section 201(ff) of the Act or intended for use in a dietary supplement. Thus, it is meaningless to refer to a GRAS exclusion from the food additive definition for dietary ingredients that are already excluded from that definition. However, some dietary ingredients that may be used in a dietary supplement may also be GRAS for use in a conventional food (e.g., vitamin C; calcium carbonate).

  8.  Must FDA approve GRAS substances?

    No. If the use of a food substance is GRAS, it is not subject to the premarket review and approval requirement by FDA.

  9.  What is GRAS affirmation?

    GRAS affirmation is a process that FDA developed in the 1970s. In response to concerns raised by new information on cyclamate salts, then-President Nixon directed FDA to re-examine the safety of substances considered to be GRAS. FDA announced that the agency would evaluate, by contemporary standards of the time, the available safety information regarding substances considered to be GRAS. If the revaluation of current data confirmed that use was GRAS, FDA would promulgate a new GRAS regulation, affirming that finding. FDA also established procedures whereby an individual could petition FDA to review the GRAS status of substances that would not have been considered as part of the agency's GRAS review.

  10.  Does FDA currently have a program to affirm that one or more uses of a food substance are GRAS?

    In a proposed rule that FDA published in 1997 (62 Fed. Reg. 18938; April 17, 1997), FDA explained why the agency could no longer devote resources to the voluntary GRAS affirmation petition process that is described in 21 CFR 170.35(c) and proposed to abolish that process and replace it with a notification procedure. The agency has not yet issued a final rule however, and the petition procedure remains in the agency's regulations. However, at this time FDA is not committing resources to the review of GRAS affirmation petitions.

  11.  What is the GRAS notification program?

    The GRAS notification program is a voluntary procedure that is operating under a proposed rule issued in 1997 (62 Fed. Reg. 18938; April 17, 1997). The notification program is intended to replace the GRAS affirmation process by providing a 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. The submitted notice includes a "GRAS exemption claim" that includes a succinct description of the substance, the applicable conditions of use, and the statutory basis for the GRAS determination (i.e., through scientific procedures or through experience based on common use in food). A GRAS notice also includes information about the identity and properties of the notified substance and a discussion of the notifier's reasons for concluding that the substance is GRAS for its intended use.

  12.  If I choose to notify FDA of my GRAS determination, how do I do so?

    FDA described the procedure for submitting a GRAS notice in the proposed rule to establish the notification procedure (62 Fed. Reg. 18938; April 17, 1997). Because the proposed rule is a lengthy document, our Internet site has a specific link to the part of the proposed rule that describes the procedure. You can find both the complete proposed rule and the link to the procedure on the main page of the GRAS notification program.

  13.  Where do I send my GRAS notice?

    You should send your GRAS notice to the Office of Food Additive Safety (HFS-255), Center for Food Safety and Applied Nutrition, Food and Drug Administration, 5100 Paint Branch Parkway, College Park, MD 20740. [Note that our office moved since we issued the proposed rule to establish a GRAS notification procedure and, thus, the address where you should send your GRAS notice is different from the address that we published in the proposed rule that describes the procedure].

  14.  If I submit a GRAS notice, how long will it take for me to receive a response from FDA?

    Our goal is to respond to most GRAS notices within 180 days.

  15.  If I submit a GRAS notice about a food substance, must I wait until I receive a response from FDA before I market that substance?

    No. If one is correct in determining that the intended use of an ingredient is GRAS, use of the ingredient is not subject to any legal requirement for FDA review and approval. Your decision to submit a GRAS notice is voluntary, and FDA's response to a GRAS notice is not an approval. You may market a substance that you determine to be GRAS for a particular use without informing FDA or, if FDA is so informed, while FDA is reviewing that information (62 Fed. Reg. 18951; April 17, 1997). We recognize, however, that some firms prefer to know that FDA has reviewed its notice of a GRAS determination, without raising safety or legal issues, before marketing.

  16.  Does FDA have a list of substances that are used in food on the basis of the GRAS provision?

    FDA has several lists of GRAS substances. Importantly, these lists are not all-inclusive. Because the use of a GRAS substance is not subject to premarket review and approval by FDA, it is impracticable to list all substances that are used in food on the basis of the GRAS provision.

    • 21 CFR Part 182 contains the remnants of a list, which FDA established in its regulations shortly after passage of the 1958 Food Additives Amendment. The list is organized according to the intended use of these substances. As part of the agency's comprehensive review of GRAS substances in the 1970s, FDA affirmed that the use of some of the ingredients on this original GRAS list is GRAS, and moved the affirmed uses of the substance to 21 CFR Part 184.
    • 21 CFR Part 184 contains a list of substances that FDA affirmed as GRAS as direct food ingredients for general or specific uses. This list derives from the agency's 1970s comprehensive review of GRAS substances and from petitions that FDA received to affirm the GRAS status of particular uses of some food ingredients.
    • 21 CFR Part 186 contains a list of substances that FDA affirmed as GRAS for certain indirect food uses.
    • FDA's Internet site also contains a list of substances that have been the subject of a notice to FDA - i.e., when a firm has notified FDA about its view that a particular use of a substance is GRAS. You can access this summary of GRAS notices, along with FDA's response, from the GRAS Notification Program page.
  17.  Can the use of a substance be GRAS even if it is not listed by FDA?

    Yes. Because the use of a GRAS substance is not subject to premarket review and approval by FDA, it is impracticable to list all substances that are used in food on the basis of the GRAS provision (21 CFR 182.1). The use of a substance is GRAS because of widespread knowledge among the community of qualified experts, not because of a listing or other administrative activity.

 

Contact FDA

(240)-402-1192
GRAS Notification Program

Additional Contact Information

Office of Food Additive Safety

5100 Paint Branch Parkway

College Park, MD 20740