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GRAS Affirmation Process

Excerpt from [Federal Register Volume 62, Number 74 (Thursday, April 17, 1997)]



Food and Drug Administration

21 CFR Parts 170, 184, 186, and 570


Substances Generally Recognized as Safe


ACTION: Proposed rule.


SUMMARY: The Food and Drug Administration (FDA) is proposing to clarify the criteria for exempting the use of a substance in human food or in animal feed from the premarket approval requirements of the Federal Food, Drug, and Cosmetic Act (the act) because such use is generally recognized as safe (GRAS). FDA is also proposing to replace the current GRAS affirmation process with a notification procedure whereby any person may notify FDA of a determination that a particular use of a substance is GRAS. Under the proposed notification procedure, the agency intends to evaluate 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. This proposal reflects FDA's commitment to achieving the goals for the Reinventing Food Regulations part of the President's National Performance Review (hereinafter referred to as Reinventing Food Regulations). The proposed notification procedure would allow FDA to direct its resources to questions about GRAS status that are a priority with respect to public health protection.


I. Background


A. The 1958 Amendment


    In 1958, in response to public concern about the increased use of chemicals in foods and food processing and with the support of the food industry, Congress enacted the Food Additives Amendment (the 1958 amendment) to the act. The basic thrust of the 1958 amendment was to require that, before a new additive could be used in food, its producer demonstrate the safety of the additive to FDA. The 1958 amendment defined the terms “food additive'' (…) and “unsafe food additive'' (…), established a premarket approval process for food additives (section 409(b) through (h)), and amended the food adulteration provisions of the act to deem adulterated any food that is, or bears or contains, any food additive that is unsafe within the meaning of section 409 (…).


    Congress recognized that, under this scheme, the safety of an additive could not be established with absolute certainty, and thus provided for a science-based safety standard that requires producers of food additives to demonstrate to a reasonable certainty that no harm will result from the intended use of an additive (…). FDA has incorporated this safety standard into its regulations (…). If FDA finds an additive to be safe, based ordinarily on data submitted by the producer to the agency in a food additive petition (FAP), the agency issues a regulation specifying the conditions under which the additive may be safely used.


    In enacting the 1958 amendment, Congress recognized that many substances intentionally added to food would not require a formal premarket review by FDA to assure their safety, either because their safety had been established by a long history of use in food or by virtue of the nature of the substances, their customary or projected conditions of use, and the information generally available to scientists about the substances. Congress thus adopted, in section 201(s) of the act, a two-step definition of "food additive.'' The first step broadly includes 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 food. The second step, however, excludes from the definition of "food additive'' substances that are generally recognized, among experts qualified by scientific training and experience to evaluate their safety ("qualified experts''), 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 through experience based on common use in food) to be safe under the conditions of their intended use.


    Importantly, 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. In addition, it is well settled that a mere showing that use of a substance is "safe'' is not sufficient to exempt the substance from the act's definition of "food additive'' (...). Instead, the substance must be shown to be "generally recognized'' as safe under the conditions of its intended use (...). The proponent of the exemption has the burden of proving that the use of the substance is "generally recognized'' as safe (Id). To establish such recognition, the proponent must show that there is a consensus of expert opinion regarding the safety of the use of the substance. (See …) Unanimity among experts regarding safety of a substance is not required. (See … ) However, the existence of a severe conflict among experts regarding the safety of the use of a substance precludes a finding of general recognition (…(mere conflict among experts is not enough to preclude a finding of general recognition)).


    It is on the basis of the GRAS exemption to the food additive definition that many substances (such as vinegar, vegetable oil, baking powder, and many salts, spices, flavors, gums, and preservatives) are lawfully marketed today without a food additive regulation. Under the 1958 amendment, a substance that is GRAS for a particular use may be marketed for that use without agency review and approval. However, when a use of a substance does not qualify for the GRAS exemption or other exemptions provided under section 201(s) of the act, that use of the substance is a food additive use subject to the premarket approval mandated by the act. In such circumstances, the agency can take enforcement action to stop distribution of the food substance and foods containing it on the grounds that such foods are or contain an unlawful food additive.


    Importantly, under section 201(s) of the act, the GRAS exemption applies to the premarket approval requirements for food additives only. There is no corresponding exemption to the premarket approval requirements for color additives, which are defined in section 201(t) of the act.


B. History of FDA's Approach to the GRAS Exemption


1. The GRAS List

    Shortly after passage of the 1958 amendment, FDA clarified the regulatory status of a multitude of food substances that were used in food prior to 1958 and amended its regulations to include a list of food substances that, when used for the purposes indicated and in accordance with current good manufacturing practice, are GRAS. This list was incorporated into the agency's regulations as Sec. 121.101(d) (now parts 182 and 582 (21 CFR parts 182 and 582)) (24 FR 9368, November 20, 1959). As part of that rulemaking, however, FDA acknowledged that it would be impracticable to list all substances that are GRAS for their intended use (formerly Sec. 121.101(a); current Sec. 182.1(a)).


    Section 121.101(d) became commonly referred to as "the GRAS list.'' FDA added other categories of substances (e.g., spices, seasonings, and flavorings) to the GRAS list in subsequent rulemakings (25 FR 404, January 19, 1960; and 26 FR 3991, May 9, 1961).


2. Opinion Letters

    Many substances that were considered GRAS by the food industry were not included in the agency's GRAS list. Under the 1958 amendment, a substance that is GRAS for a particular use may be marketed for that use without agency review and approval. Nonetheless, as a practical matter, manufacturers who determined on their own initiative that use of a substance qualified for the GRAS exemption frequently decided to obtain the agency's opinion on whether their determination was justified. Many manufacturers wrote to FDA and requested an "opinion letter,'' in which agency officials would render an informal opinion on the GRAS status of use of a substance. Although convenient and expedient, these opinion letters were often available only to the requestor. Moreover, these opinion letters were not binding on the agency at the time they were issued and were in fact formally revoked in 1970 (21 CFR 170.6, 35 FR 5810, April 9, 1970).


3. Agency-Initiated GRAS Review

    In 1969 (34 FR 17063, October 21, 1969), FDA removed various cyclamate salts, a family of nonnutritive sweeteners, from the GRAS list because they were implicated in the formation of bladder tumors in rats (Ref. 2). In response to the concerns raised by the new information on cyclamates, then-President Nixon directed FDA to reexamine the safety of GRAS substances (...), and FDA announced that the agency was conducting a comprehensive study of substances presumed to be GRAS (35 FR 18623, December 8, 1970). The purpose of the study was to evaluate, by contemporary standards, the available safety information regarding substances presumed to be GRAS and to issue each item in a new (i.e., affirmed) GRAS list, a food additive regulation, or an interim food additive regulation pending completion of additional studies.


4. GRAS Criteria and the GRAS Affirmation Process

    In the notice announcing the comprehensive agency review of presumed GRAS substances, FDA proposed criteria that could be used to establish whether these substances should be listed as GRAS, become the subject of a food additive regulation, or be listed in an interim food additive regulation pending completion of additional studies (35 FR 18623). These criteria were incorporated into the agency's regulations as Sec. 121.3 (precursor of current Sec. 170.30 (21 CFR 170.30)) (36 FR 12093, June 25, 1971).


    FDA made a second announcement that it was conducting a study of presumed GRAS substances (36 FR 20546, October 23, 1971) and subsequently instituted a rulemaking to establish procedures that the agency could use, on its own initiative, to affirm the GRAS status of substances that were the subject of that review and were found to satisfy the criteria established in Sec. 121.3 (proposed rule, 37 FR 6207, March 25, 1972; final rule, 37 FR 25705, December 2, 1972). These procedures were subsequently codified at Sec. 170.35 (a) and (b) (21 CFR 170.35 (a) and (b)). Because the GRAS review did not cover all GRAS substances (e.g., it did not cover many substances that were marketed based on a manufacturer's independent GRAS determination), that rulemaking included a mechanism (the current GRAS petition process; Sec. 170.35(c)) whereby an individual could petition FDA to review the GRAS status of substances not being considered as part of the agency's GRAS review.


    In 1974, the agency proposed to clarify the criteria for GRAS status, the differences between GRAS status and food additive status, and the procedures being used to conduct the current review of food substances (39 FR 34194, September 23, 1974). The final regulations based on this proposal amended Sec. 121.3 (current Sec. 170.30) to distinguish a determination of GRAS status through scientific procedures (scientific procedures GRAS determination; current Sec. 170.30(b)) from a determination of GRAS status through experience based on common use in food (common use GRAS determination; current Sec. 170.30(c)) (41 FR 53600, December 7, 1976). Those final regulations also established definitions for "common use in food'' (current Sec. 170.3(f)) and "scientific procedures'' (current Sec. 170.3(h)). FDA subsequently added criteria (Sec. 170.30(c)(2)) for the determination of GRAS status through experience based on common use in food when that use occurred exclusively or primarily outside of the United States (53 FR 16544, May 10, 1988).


5. The Plant Policy Statement

    FDA's “Statement of Policy: Foods Derived From New Plant Varieties'' (the plant policy statement) (57 FR 22984, May 29, 1992) is an example of a recent agency policy announcement regarding agency priorities in reviewing the GRAS status of substances added to food. In the plant policy statement, FDA reviewed its position on the applicability of the food additive definition and section 409 of the act to foods derived from new plant varieties in light of the intended changes in the composition of foods that might result from the newer techniques of genetic modification such as recombinant deoxyribonucleic acid (rDNA) techniques:


    The statutory definition of “food additive'' makes clear that it is the intended or expected introduction of a substance into food that makes the substance potentially subject to food additive regulation. Thus, in the case of foods derived from new plant varieties, it is the transferred genetic material and the intended expression product or products that could be subject to food additive regulation, if such material or expression products are not GRAS. (57 FR 22984 at 22990)


    In the plant policy statement, FDA provided extensive guidance, including criteria and analytical steps that producers could follow, on situations in which producers should consult with FDA to determine whether an FAP is appropriate. FDA also stated its intent to use its food additive authority in regulating foods and their byproducts derived from new plant varieties to the extent necessary to protect public health.


C. Elements of the GRAS Standard


    Under section 201(s) of the act, a substance is exempt from the definition of food additive and thus, from premarket approval requirements, if its safety is generally recognized by qualified experts. Accordingly, a determination that a particular use of a substance is GRAS requires both technical evidence of safety and a basis to conclude that this technical evidence of safety is generally known and accepted. In contrast, a determination that a food additive is safe requires only technical evidence of safety.1 Thus, 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 rather than on the basis of what the substance is or the types of data and information that are necessary to establish its safety. To emphasize this distinction between a GRAS substance and a food additive, and to simplify discussion about the standard for general recognition of safety, in this document, FDA uses the term "technical element'' when discussing technical evidence of safety and "common knowledge element'' when discussing general knowledge and acceptance of safety.


    The technical element of the GRAS standard requires that information about the substance establish that the intended use of the substance is safe. As discussed in section I.A of this document, FDA has defined "safe'' (Sec. 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. Current Sec. 170.30(b) provides that 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. Similarly, current Sec. 170.30(c)(1) provides that general recognition of safety through experience based on common use in food prior to January 1, 1958, may be determined without the quantity or quality of scientific procedures required for approval of a food additive regulation and must be based solely on food use of the substance prior to that date. Current Sec. 170.3(f) defines "common use in food'' as a substantial history of consumption for food use by a significant number of consumers.


    The common knowledge element of the GRAS standard includes two facets: (1) The data and information relied on to establish the technical element must be generally available; and (2) there must be a basis to conclude that there is consensus among qualified experts about the safety of the substance for its intended use. Neither facet is, by itself, sufficient to satisfy the common knowledge element of the GRAS standard.


    The usual mechanism to establish that scientific information is generally available is to show that the information is published in a peer-reviewed scientific journal. However, mechanisms to establish the basis for concluding that there is expert consensus about the safety of a substance are more varied. In some cases, publication in a peer-reviewed scientific journal of data (such as toxicity studies) on a test substance has been used to establish expert consensus in addition to general availability. In other cases, such publication of data and information in the primary scientific literature has been supplemented by: (1) Publication of data and information in the secondary scientific literature, such as scientific review articles, textbooks, and compendia; (2) documentation of the opinion of an "expert panel'' that is specifically convened for this purpose; or (3) the opinion or recommendation of an authoritative body such as the National Academy of Sciences (NAS) or the Committee on Nutrition of the American Academy of Pediatrics (CON/AAP) on a broad or specific issue that is related to a GRAS determination.


    In this document, FDA is using the term "consensus'' in discussing the common knowledge element of the GRAS standard. Such consensus does not require unanimity among qualified experts (…). For example, FDA would evaluate a single published report questioning the safety of use of a substance in food in the context of all the publicly available and corroborative information rather than conclude that such a report automatically disqualifies the substance from satisfying the GRAS standard (…).


D. The GRAS Petition Process


    The rulemaking process in Sec. 170.35(c) whereby manufacturers may petition FDA to affirm that a substance is GRAS under certain conditions of use was designed as a voluntary administrative process whose purpose was to provide a mechanism for official recognition of lawfully made GRAS determinations. To the extent that a person elected to submit a GRAS petition, the process could facilitate an awareness, by the agency as well as the domestic and international food industry, of independent GRAS determinations. However, GRAS affirmation involves the resource-intensive rulemaking process, including: (1) Publishing a filing notice in the Federal Register; (2) requesting comment on the petitioned request; (3) conducting a comprehensive review of the petition's data and information and comments received to the filing notice to determine whether the evidence establishes that the petitioned use of the substance is GRAS; (4) drafting a detailed explanation of why the use is GRAS (as opposed to simply being safe); and (5) publishing that explanation in the Federal Register. FDA believes that, in practice, this resource-intensive process deters many persons from petitioning the agency to affirm their independent GRAS determinations.



    1 In issuing a food additive regulation, the agency considers technical evidence of safety but does not address the GRAS standard of general recognition. Thus, in most cases, the agency's issuance of a food additive regulation means that FDA did not consider the possible GRAS status of that substance. In a few cases (e.g., 21 CFR 173.357, cellulose triacetate used as a fixing agent in the immobilization of lactase enzyme preparation), FDA concluded, in evaluating the GRAS status of a substance, that the safety of a use of a substance was not generally recognized and authorized its use as a food additive rather than affirm it as GRAS (59 FR 36935, July 20, 1994).




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