[Federal Register Volume 62, Number 74 (Thursday, April 17, 1997)]
[Proposed Rules]
[Pages 18938-18964]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 97-9706]



[[Page 18937]]

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Part III





Department of Health and Human Services





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Food and Drug Administration



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21 CFR Parts 170, et al.



Substances Generally Recognized as Safe; Proposed Rule

Federal Register / Vol. 62, No. 74 / Thursday, April 17, 1997 / 
Proposed Rules

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 170, 184, 186, and 570

[Docket No. 97N-0103]


Substances Generally Recognized as Safe

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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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.

DATES: Written comments by July 16, 1997, except that comments 
regarding information collection should be submitted by May 19, 1997. 
The agency proposes that any final rule that may issue based on this 
proposal become effective 60 days after its date of publication.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, 
Rockville, MD 20857. Submit written comments on the information 
collection requirements to the Office of Information and Regulatory 
Affairs, Office of Management and Budget (OMB), New Executive Office 
Bldg., 725 17th St. NW., rm. 10235, Washington, DC 20503, ATTN: Desk 
Officer for FDA.

FOR FURTHER INFORMATION CONTACT:

Regarding Human Food Issues: Linda S. Kahl, Center for Food Safety and 
Applied Nutrition (HFS-206), Food and Drug Administration, 200 C St. 
SW., Washington, DC 20204, 202-418-3101.
Regarding Animal Feed Issues: George Graber, Center for Veterinary 
Medicine (HFV-220), Food and Drug Administration, 7500 Standish Pl., 
Rockville, MD 20855, 301-594-1731.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background
    A. The 1958 Amendment
    B. History of FDA's Approach to the GRAS Exemption
    1. The GRAS List
    2. Opinion Letters
    3. Agency-initiated GRAS Review
    4. GRAS Criteria and the GRAS Affirmation Process
    5. The Plant Policy Statement
    C. Elements of the GRAS Standard
    D. The GRAS Petition Process
II. Scope of the Proposed Regulations
III. Proposed Revisions to Sec. 170.30--Eligibility for 
Classification as GRAS
    A. General Criteria
    B. Scientific Procedures GRAS Determination
    1. Establishing General Recognition of Safety
    2. Corroboration of Safety
    C. Common Use GRAS Determination
    D. Other Provisions of Current Sec. 170.30
IV. The Technical Element of a GRAS Determination Through Scientific 
Procedures
    A. Consideration of Dietary Exposure
    B. Substantial Equivalence to a GRAS Substance
V. Proposed Revisions to Sec. 170.35--Affirmation of GRAS Status
VI. Proposed Establishment of a Notification Procedure
    A. General Requirements
    B. Specific Requirements
    1. GRAS Exemption Claim
    2. Identity and Specifications
    3. Self-limiting Levels of Use
    4. Scientific Procedures GRAS Determination
    5. Common Use GRAS Determination
    C. Agency Response
    1. Acknowledgment of Receipt
    2. 90-day Response Letter
    3. Subsequent Agency Action
    D. Appeals
    E. Public Disclosure and Accessibility
    1. Public Disclosure
    2. Public Accessibility
    F. Inventory
VII. Effect of the Proposed Notification Procedure on Existing GRAS 
Petitions
VIII. Interim Policy
IX. Conforming Amendments
X. International Harmonization
XI. Food Substances Used in Animal Feed
XII. Summary of the Proposal
XIII. Paperwork Reduction
XIV. Analysis of Impacts
    A. Regulatory Options
    B. Costs and Benefits
    1. Option One: Take No Action
    2. Option Two: Adopt Proposed GRAS Notification Procedure
    3. Option Three: Adopt a GRAS Notification Procedure Allowing 
FDA Feedback on Independent GRAS Determinations of Either a Higher 
or Lower Level of Authoritativeness than the Proposed Notification 
System
    4. Option Four: Eliminate Agency Participation in Independent 
GRAS Determinations
    C. Regulatory Flexibility Analysis
    D. Conclusions
XV. Environmental Impact
XVI. References

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'' (section 201(s) of the act (21 
U.S.C. 321(s))) and ``unsafe food additive'' (section 409(a) of the act 
(21 U.S.C. 348(a))), 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 (section 402(a)(2)(C) of the act (21 U.S.C. 
342(a)(2)(C))).
    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 (Ref. 1). FDA has 
incorporated this safety standard into its regulations (Sec. 170.3(i) 
(21 CFR 170.3(i))). 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

[[Page 18939]]

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'' (United States 
v. An Article of Food * * * Coco Rico, Inc., 752 F.2d 11, 15 n. 4 (1st 
Cir. 1985)). Instead, the substance must be shown to be ``generally 
recognized'' as safe under the conditions of its intended use (Id.; 
United States v. Articles of Food and Drug * * * Coli-Trol 80, 518 F.2d 
743, 745 (5th Cir. 1975)). 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 United States v. Western Serum 
Co., Inc., 666 F.2d 335, 338 (9th Cir. 1982); United States v. Articles 
of Drug * * * Promise Toothpaste, 624 F.Supp. 776, 778 (N.D. Ill. 
1985), aff'd 826 F.2d 564 (7th Cir. 1987); United States v. Articles of 
Drug * * * Hormonin, 498 F.Supp.2d 424, 435 (D.N.J. 1980).) Unanimity 
among experts regarding safety of a substance is not required. (See 
United States v. Articles of Drug * * * 5,906 boxes, 745 F.2d 105, 119 
n. 22 (1st Cir. 1984); United States v. An Article of Drug * * * 4,680 
Pails, 725 F.2d 976, 990 (5th Cir. 1984); Coli-Trol 80, supra, 518 F.2d 
at 746; Promise Toothpaste, supra, 624 F.Supp. at 782.) However, the 
existence of a severe conflict among experts regarding the safety of 
the use of a substance precludes a finding of general recognition 
(4,680 Pails, supra, 725 F.2d at 990; Premo Pharmaceutical Laboratories 
v. United States, 629 F.2d 795, 803 (2d Cir. 1980)) (Cf. Coli-Trol 80, 
supra, 518 F.2d at 746 (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 (Ref. 3), 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

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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.
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    \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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    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

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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 (5,906 boxes, supra, 745 
F.2d at 119 n. 22; United 4,680 Pails, supra, 725 F.2d at 990; Coli-
Trol 80, supra, 518 F.2d at 746; Promise Toothpaste, supra, 624 F.Supp. 
at 782). 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 (Cf. Coli-Trol 80, supra, 518 F.2d at 
746).

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.

II. Scope of the Proposed Regulations

    Based on its experience applying the provisions of Sec. 170.30, FDA 
is proposing to clarify when use of a substance is exempt from the 
act's premarket approval requirements because such use is GRAS. In 
proposing these changes, FDA is: (1) Emphasizing that a GRAS substance 
is distinguished from a food additive by the common knowledge about the 
safety of the substance for its intended use rather than by what the 
substance is, or on the basis of the types of data and information that 
are necessary to establish its safety; (2) identifying the types of 
technical evidence of safety that could form the basis of a GRAS 
determination; and (3) clarifying the role of publication in satisfying 
the general recognition standard. For consistency with the proposed 
changes to Sec. 170.30, FDA is also proposing to amend the definition 
in Sec. 170.3(h) of ``scientific procedures.''
    In addition, in keeping with the Reinventing Food Regulations, FDA 
is proposing to replace the current GRAS affirmation petition process 
(Sec. 170.35(c)) with a notification procedure (proposed Sec. 170.36) 
whereby any person may notify FDA of a determination that a particular 
use of a substance is GRAS. The submitted notice would include a ``GRAS 
exemption claim'' that would provide specific information about a GRAS 
determination in a consistent format. This GRAS exemption claim would 
include a succinct description of the ``notified substance'' (i.e., the 
substance that is the subject of the notice), the applicable conditions 
of use, and the basis for the GRAS determination (i.e., through 
scientific procedures or through experience based on common use in 
food) and would be dated and signed by the notifier. The GRAS exemption 
claim also would include a statement that the information supporting 
the GRAS determination was available for FDA review and copying or 
would be sent to FDA upon request. In addition to the GRAS exemption 
claim, the notice would include detailed information about the identity 
and properties of the notified substance and a detailed discussion of 
the basis for the notifier's GRAS determination.
    Under the proposed notification procedure, the agency intends to 
evaluate whether the 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. Within 90 days of receipt of the notice, 
FDA would respond to the notifier in writing and could advise the 
notifier that the agency has identified a problem with the notice. 
Although information in a notice would be publicly available consistent 
with the Freedom of Information Act (FOIA), FDA would make readily 
accessible to the public the notice's GRAS exemption claim, as well as 
the agency's response to the notice. However, FDA does not intend to 
conduct its own detailed evaluation of the data that the notifier 
relies on to support a determination that a use of a substance is GRAS 
or to affirm that a substance is GRAS for its intended use.
    FDA has tentatively concluded that the proposed notification 
procedure has advantages over the current petition process because the 
resource-intensive rulemaking that is associated with a petition would 
be eliminated. This streamlining would allow FDA to redirect its 
resources to questions about GRAS status that are a priority with 
respect to public health protection. In addition, the proposed notice 
is simpler than a GRAS affirmation petition and therefore conceivably 
would provide an incentive for manufacturers to inform FDA of their 
GRAS determinations. This would result in increased agency awareness of 
the composition of the nation's food supply and the cumulative dietary 
exposure to GRAS substances. FDA has also tentatively concluded that 
the public health would be better served if some resources that are 
currently directed to the GRAS petition process were redirected to the 
preparation of documents that would provide the industry with guidance 
on certain food safety issues for complex substances (e.g., 
macroingredients or biological polymers, such as proteins, 
carbohydrates, and fats and oils). Finally, the reduction in resources 
devoted to the evaluation of GRAS substances would allow FDA to shift 
resources to its statutorily mandated task of reviewing food and color 
additive petitions.
    In light of its experience in reviewing GRAS petitions, FDA 
believes that the substitution of the proposed notification procedure 
for the current GRAS petition process would not adversely affect the 
public health because the agency would be replacing one voluntary 
administrative process with a different voluntary administrative 
procedure that would utilize FDA's resources more effectively and 
efficiently. Under both the current and the proposed procedures, a 
manufacturer may market a substance that the manufacturer determines is 
GRAS without informing the agency or, if the agency is so

[[Page 18942]]

informed, while the agency is reviewing that information. Thus, from a 
legal and regulatory perspective, this substitution is neutral.
    FDA is also proposing to remove Sec. 170.30(f), which expresses the 
agency's intent to review the GRAS status of certain food substances, 
because Sec. 170.30(f) is redundant with the provisions of Sec. 170.35 
(a) and (b) that the agency may, on its own initiative, affirm the GRAS 
status of substances that directly or indirectly become components of 
food (Sec. 170.35(a)) or publish a notice announcing its conclusion 
that there is a lack of convincing evidence that the substance is GRAS 
and that it should be considered a food additive (Sec. 170.35(b)).
    FDA's regulations regarding the eligibility of substances used in 
animal food or feeds for classification as GRAS, and the procedures for 
affirmation of GRAS status for such substances, are codified at 
Secs. 570.30 and 570.35 (21 CFR 570.30 and 570.35), respectively. FDA 
is proposing the following: (1) To amend the provisions of Sec. 570.30 
that are parallel to the provisions of current Sec. 170.30 (i.e., 
Sec. 570.30 (a) and (b)); (2) to eliminate the GRAS affirmation 
petition process provided for in Sec. 570.35 (a) and (c); and (3) to 
provide the option of a GRAS notification procedure for animal food or 
feeds that would be parallel to proposed Sec. 170.36. FDA is proposing 
these changes because the regulations in part 570 (21 CFR part 570) 
implement the same statutory provisions as the regulations in part 170 
(21 CFR part 170).
    Finally, FDA is proposing to make certain conforming amendments to 
Secs. 170.38, 184.1, 186.1, and 570.38.
    As FDA gains experience with the questions raised by industry in 
preparing notices, FDA expects, from time to time, to prepare guidance 
documents on issues of particular interest. However, such guidance 
documents are not a subject of this proposal.

III. Proposed Revisions to Sec. 170.30--Eligibility for 
Classification as GRAS

A. General Criteria

    FDA is proposing to expand the description of the general criteria 
provided in current Sec. 170.30(a) for a GRAS determination. FDA is not 
proposing any changes to the first two sentences of current 
Sec. 170.30(a), which reflect the language of the GRAS exemption as set 
out in section 201(s) of the act.
    The final sentence of current Sec. 170.30(a) provides that general 
recognition of safety requires that there be common knowledge about the 
substance throughout the scientific community knowledgeable about the 
safety of substances directly or indirectly added to food. FDA is 
proposing to amend this provision to define what that common knowledge 
is (i.e., that there is reasonable certainty that the substance is not 
harmful under the intended conditions of use). In other words, proposed 
Sec. 170.30(a) would clarify that the safety standard for a GRAS 
substance is identical to the safety standard in Sec. 170.3(i) and that 
a GRAS substance is neither more safe nor less safe than an approved 
food additive. Rather, the distinction between a GRAS substance and an 
approved food additive is that, for a GRAS substance, there is common 
knowledge of safety within the expert community.

B. Scientific Procedures GRAS Determination

1. Establishing General Recognition of Safety
    Current Sec. 170.30(b) describes the technical element of a 
scientific procedures GRAS determination (i.e., that it requires the 
same quantity and quality of scientific evidence as is required to 
obtain approval of the substance as a food additive). Current 
Sec. 170.30(b) also describes the common knowledge element of a 
scientific procedures GRAS determination (i.e., that it ordinarily is 
based upon published studies, which may be corroborated by unpublished 
studies and other data and information).
    FDA is proposing two changes to the description of the common 
knowledge element in current Sec. 170.30(b). First, FDA is proposing to 
broaden this description to clarify the types of technical evidence of 
safety (currently described only as ``studies'') that could form the 
basis of a GRAS determination. FDA is proposing this change because the 
quantity and quality of scientific evidence required to obtain approval 
of a substance as a food additive vary considerably depending upon the 
estimated dietary exposure to the substance and the chemical, physical, 
and physiological properties of the substance; there can likewise be a 
comparable variation in the scientific evidence that forms the basis of 
a GRAS determination. Second, FDA is proposing to amend this 
description to clarify the role of publication in satisfying the common 
knowledge element. FDA is proposing this change because publication is 
ordinarily required, but may not always be sufficient, to satisfy the 
common knowledge element of the GRAS standard.
    Specifically, FDA is proposing to revise Sec. 170.30(b) to provide 
that general recognition of safety through scientific procedures be 
based upon generally available and accepted scientific data, 
information, methods, or principles, which ordinarily are published. 
Thus, under proposed Sec. 170.30(b), ``studies'' would be one of 
several types of scientific ``data and information'' that could support 
the technical element of a scientific procedures GRAS determination. 
However, depending on the circumstances, other scientific data and 
scientific information such as that relating to chemical identity or 
characteristic properties of a substance, as well as methods of 
manufacture, could support, and in some cases be sufficient to satisfy 
that element.
    In addition, under this proposed revision of Sec. 170.30(b), 
generally available and accepted scientific principles could be applied 
to, and relied on as part of, the technical element of a scientific 
procedures GRAS determination. Webster's New World Dictionary of the 
American Language defines a ``principle'' as ``a fundamental truth, 
law, doctrine or motivating force upon which others are based.'' For 
example, the common scientific principle ``the dose makes the poison,'' 
underlies a determination that a substance is safe for use in food at 
certain levels even if it exhibits toxicity when present at higher 
levels. A related scientific principle is that the toxicity of a 
substance may vary between animal species. FDA relies on both of these 
scientific principles when determining whether the proposed use of a 
substance added to food is safe within the meaning of section 409 of 
the act.
    For consistency with this proposed amendment, FDA is also proposing 
to amend the current definition of ``scientific procedures'' in 
Sec. 170.3(h). Under the current definition, scientific procedures 
include those human, animal, analytical, and other scientific studies, 
whether published or unpublished, appropriate to establish the safety 
of a substance. FDA is proposing to amend Sec. 170.3(h) by broadening 
it so that scientific procedures would include scientific data (such as 
human, animal, analytical, and other scientific studies), information, 
methods, or principles, whether published or unpublished, appropriate 
to establish the safety of a substance. In both this proposed 
definition and the proposed amendment to Sec. 170.30(b), the descriptor 
``scientific'' applies equally to ``data,''

[[Page 18943]]

``information,'' ``methods,'' and ``principles.''
    FDA is proposing to clarify the role of publication in satisfying 
the common knowledge element of the GRAS standard by adding the phrases 
``generally available and accepted'' and ``which ordinarily are 
published'' as descriptors of ``scientific data, information, methods, 
or principles'' in proposed Sec. 170.30(b). Thus, under proposed 
Sec. 170.30(b), publication of data and information about a GRAS 
substance is usually necessary, but may not always be sufficient, to 
satisfy the common knowledge element of the GRAS standard.
    The descriptor ``which ordinarily are published'' reflects that 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. This descriptor maintains the explicit 
emphasis of current Sec. 170.30(b) on the importance of publication in 
satisfying the common knowledge element. However, current 
Sec. 170.30(b) does not explicitly emphasize the second facet of the 
common knowledge element (i.e., that there is a basis to conclude that 
there is the requisite expert consensus that the generally available 
data and information establish the safety of the substance for its 
intended use). For example, there could be a basis to conclude that 
there is expert consensus that the published results of a particular 
safety study (i.e., the primary scientific literature) establish the 
safety of a substance for its intended use if the study raises no 
safety questions that experts would need to interpret and resolve. On 
the other hand, the published results of a particular safety study may 
not be sufficient to satisfy the common knowledge element if the study 
raises safety questions that require additional data to be resolved. In 
such cases, the general recognition standard usually requires more than 
a publication in the primary scientific literature. As mentioned, the 
basis for concluding that there is expert consensus historically has 
included publication in secondary sources, convening an expert panel, 
or relying on an opinion or recommendation of an authoritative body.
    The body of information published in secondary sources (such as 
review articles, articles describing scientific methods, general 
reference materials, and textbooks) can be more useful than the primary 
scientific literature for showing a basis for a conclusion that the 
necessary expert consensus exists because the existence of the 
secondary sources implies that the primary scientific literature has 
been evaluated after its publication. For example, FDA sometimes relies 
on generally available and accepted compendia such as Bergey's Manual 
of Systematic Bacteriology (Ref. 4) when evaluating the common 
knowledge element of the GRAS standard for food substances derived from 
a bacterial source.
    The opinion of a specially-convened expert panel can provide a 
basis for showing expert consensus when an individual published study 
raises safety questions. The opinion of an expert panel is also useful 
when multiple studies bearing on the safety of a substance are 
published but there are no secondary sources that evaluate these 
studies and draw general conclusions based on this comprehensive body 
of knowledge. For example, during the agency-initiated GRAS review, FDA 
commissioned, through the Life Sciences Research Office of the 
Federation of American Societies for Experimental Biology, the ``Select 
Committee on GRAS Substances'' (the Select Committee). The charge to 
the Select Committee was to summarize the available scientific 
literature and to provide a recommendation as to what restrictions, if 
any, on the use of the substance would be needed to ensure its safe use 
in food.
    In FDA's view, the common knowledge element of the GRAS standard 
precludes a GRAS determination if the data and information evaluated by 
such an expert panel are only available in files that are not publicly 
accessible, such as in confidential industry files. For example, in 
response to GRAS petitions requesting that FDA affirm the GRAS status 
of lactase from Kluyveromyces lactis entrapped in cellulose triacetate 
fibers for use in reducing the lactose content of milk, FDA affirmed 
that the lactase enzyme was GRAS (49 FR 47384, December 4, 1984) but 
issued a food additive regulation authorizing the secondary direct food 
additive use of cellulose triacetate as an immobilizing agent because 
the information that the petitioner relied on to establish the safety 
of the cellulose triacetate was not generally available (59 FR 36935, 
July 20, 1994).
    The opinions or recommendations of an authoritative body such as 
NAS or CON/AAP frequently bear on an issue that is related to a GRAS 
determination. For example, CON/AAP may recommend the use in infant 
formula of a food substance whose regulatory status is not explicitly 
identified in FDA's regulations. Similarly, NAS's Recommended Dietary 
Allowances (Ref. 5) are useful in establishing the safe level of an 
added nutrient source in foods, particularly when the safe level of 
intake is a narrow range because the difference between the recommended 
dietary intake and the intake at which the substance exhibits toxic 
properties is small. In cases such as these, the opinions or 
recommendations of the authoritative body may provide a basis for 
concluding that there is expert consensus regarding the safety of a 
substance for its intended use in food.
2. Corroboration of Safety
    FDA is proposing to retain the concept in current Sec. 170.30(b) 
that unpublished data and information that bear on safety may be used 
to corroborate published data and information that establish general 
recognition of safety. FDA is proposing to amend current Sec. 170.30(b) 
by removing the phrase ``unpublished studies and other data and 
information'' and substituting the phrase ``unpublished scientific 
data, information, or methods.'' This proposed revision is comparable 
to the proposed broadening of the description of the common knowledge 
element of the GRAS standard and likewise reflects the variation in the 
nature of the scientific evidence that would be required to obtain 
approval of the substance as a food additive.

C. Common Use GRAS Determination

    FDA is not proposing any changes to current Sec. 170.30(c)(1), 
which sets out criteria for a common use GRAS determination. However, 
FDA is proposing to amend current Sec. 170.30(c)(2), which sets out 
these criteria in the more narrow circumstance of that use occurring 
exclusively or primarily outside of the United States. FDA is proposing 
to revise the final sentence of current Sec. 170.30(c)(2) by replacing 
the recommendation that persons who claim GRAS status on such basis 
obtain FDA concurrence that the use of the substance is GRAS (i.e., 
through submission of a GRAS affirmation petition) with a 
recommendation that persons who assert such a claim for a substance 
notify FDA of that claim in accordance with proposed Sec. 170.36. This 
revision is a necessary conforming amendment because, as discussed in 
sections V and VI of this document, FDA is proposing to replace the 
current affirmation process in Sec. 170.35(c)(1) with a notification 
procedure (proposed Sec. 170.36). The recommendation in proposed 
Sec. 170.30(c)(2) is appropriate because notice will facilitate the 
lawful entry of GRAS substances into the United States. FDA will be 
aware that a

[[Page 18944]]

substance offered for import is the subject of a GRAS exemption claim 
and will also be aware of the basis for such claim. Absent notice, the 
substance may appear to be adulterated and thus, be detained under 
section 801(a) of the act (21 U.S.C. 381(a)). Therefore, it is prudent 
for an individual who claims that a substance is GRAS through 
experience based on its common use in food outside of the United States 
to notify FDA of that claim. The language of proposed Sec. 170.30(c)(2) 
is comparable to the language of current Sec. 170.30(c)(2) in that it 
is not a requirement.

D. Other Provisions of Current Sec. 170.30

    FDA is not proposing any changes to the remainder of current 
Sec. 170.30, except Sec. 170.30(f) as discussed below, because the 
changes that the agency is proposing in this document require no 
conforming amendments to those sections.
    Current Sec. 170.30(f) was issued under the auspices of the agency-
initiated GRAS review (36 FR 12093, June 25, 1971) and expresses the 
agency's intent to review the GRAS status of certain food substances. 
As discussed in section V of this document), FDA is proposing to remove 
the provision in Sec. 170.35(a) that the Commissioner of Food and Drugs 
(the Commissioner), on the petition of an interested person, may affirm 
the GRAS status of substances that directly or indirectly become 
components of food. The agency is proposing to retain, however, the 
provision in Sec. 170.35(a) that the Commissioner, on his/her own 
initiative, may affirm the GRAS status of such substances. In addition, 
the agency is proposing no changes to the provision in Sec. 170.35(b) 
that if the Commissioner concludes that there is a lack of convincing 
evidence that a substance is GRAS and that it should be considered a 
food additive, he/she shall publish a notice thereof in the Federal 
Register in accordance with Sec. 170.38. Therefore, Sec. 170.30(f) is 
redundant with Sec. 170.35 (a) and (b). Accordingly, in keeping with 
the agency's goals for the Reinventing Food Regulations, FDA is 
proposing to remove current Sec. 170.30(f).

IV. The Technical Element of a GRAS Determination Through Scientific 
Procedures

    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. Nonetheless, FDA is frequently asked about the types of data 
and information that are appropriate to establish the safety of a GRAS 
substance. Accordingly, FDA discusses below two topics that pertain to 
the technical element of a scientific procedures GRAS determination: 
(1) The importance of dietary exposure; and (2) the role of substantial 
equivalence.

A. Consideration of Dietary Exposure

    Section 409(c)(5) of the act requires that, in evaluating the 
proposed use of a food additive, FDA consider the probable consumption 
of the substance and of any substance formed in or on food because of 
its use, as well as the cumulative effect of the substance in the diet, 
taking into account any chemically or pharmacologically related 
substance or substances in such diet. FDA has incorporated this 
requirement into the definition of ``safe'' and ``safety'' with respect 
to substances added to food (Sec. 170.3(i)). Thus, the technical 
element of a scientific procedures GRAS determination must consider the 
probable consumption and cumulative effect of the substance in the diet 
because a scientific procedures GRAS determination requires the same 
quantity and quality of evidence as is required to obtain approval of 
the substance as a food additive. If the dietary exposure to the 
substance under the intended conditions of use presents a basis for 
concern about the safety of its use, data or information addressing 
those concerns are necessary to satisfy the technical element. As with 
other data and information that support a GRAS determination, data or 
information addressing a safety question raised by dietary exposure 
must also satisfy the common knowledge element by being generally 
available to, and accepted by, qualified experts.
    In some cases, dietary exposure is unlikely to present a basis for 
a safety concern. For example, dietary exposure to an enzyme 
preparation that is derived from a controlled fermentation of a 
nonpathogenic, nontoxigenic microorganism that does not produce 
antibiotics, and that is processed using substances that are acceptable 
for use in foods generally, would not ordinarily present a basis for a 
safety concern. On the other hand, consumption of a component of a 
commonly consumed food may present a basis for a safety concern if the 
dietary exposure to the isolated component under its intended 
conditions of use is many times greater than its dietary exposure when 
consumed as a component of food.
    For example, a fiber may be extracted from a vegetable that has a 
relatively low dietary exposure (such as beets) and added, at the same 
level, to other foods that have a relatively high dietary exposure. The 
probable cumulative intake of the fiber likely will be many times 
higher from the consumption of the foods to which it is added than from 
the consumption of beets. The probable intake of the fiber from 
consumption of foods to which it is added may present a basis for a 
safety concern, especially if the foods containing the added beet fiber 
will not replace beets in the diet. Likewise, in the case of a 
chemically synthesized substance that is structurally identical to a 
naturally occurring substance in commonly consumed food, technical 
evidence of safety would include consideration of whether the 
cumulative exposure to both the synthetic and the natural substance 
exceeds the exposure to the natural substance and whether the combined 
exposure presents a basis for a safety concern.

B. Substantial Equivalence to a GRAS Substance

    A report of a joint Food and Agriculture Organization (FAO) and 
World Health Organization (WHO) consultation (the 1996 FAO/WHO report) 
recommended that ``[s]afety assessment based on the concept of 
substantial equivalence * * * be applied in establishing the safety of 
foods and food components derived from genetically modified organisms'' 
(Ref. 6). The 1996 FAO/WHO report stated that:

[s]ubstantial equivalence embodies the concept that if a new food or 
food component is found to be substantially equivalent to an 
existing food or food component, it can be treated in the same 
manner with respect to safety (i.e. the food or food component can 
be concluded to be as safe as the conventional food or food 
component). Account should be taken of any processing that the food 
or food component may undergo as well as the intended use and the 
intake by the population.

The 1996 FAO/WHO report relied, in part, on previous expert reports 
that had discussed the concept of substantial equivalence, including 
the 1990 joint FAO/WHO consultation, ``[s]trategies for assessing the 
safety of foods produced by biotechnology'' (Ref. 7); a report prepared 
by an expert group of the Organization for Economic Co-operation and 
Development (OECD), ``[s]afety evaluation of foods produced by modern 
biotechnology: Concepts and principles'' (Ref. 8); and a report of a 
WHO workshop, ``[a]pplication of the principles of substantial 
equivalence to the safety evaluation of foods or food components from 
plants derived by modern biotechnology'' (Ref. 9).

[[Page 18945]]

    FDA believes that in certain instances the concept of substantial 
equivalence may have applicability to the technical element of a GRAS 
determination, and the agency has already applied this concept when 
evaluating the safety of new or modified food substances. For example, 
the agency's approach (57 FR 22984 and Ref. 10) to assessing the safety 
of foods derived from new plant varieties, including the safety of 
newly introduced substances in the food (primarily proteins, 
carbohydrates, and fatty acids) and unintended changes in the food's 
composition, is similar to the concept of substantial equivalence 
posited by FAO, WHO, and OECD. 2 As another example, FDA has 
applied this concept in affirming the GRAS status of several 
microbially-derived chymosin (i.e., rennet) enzyme preparations (55 FR 
10932 at 10935, March 23, 1990; 57 FR 6476 at 6479, February 25, 1992; 
58 FR 27197 at 27202, May 7, 1993) and several animal-and plant-derived 
enzyme preparations (60 FR 32904 at 32911, June 26, 1995).
---------------------------------------------------------------------------

    \2\ In the plant policy statement, FDA used the term 
``substantial similarity,'' rather than ``substantial equivalence,'' 
to avoid possible confusion with the agency's use of the concept of 
``substantial equivalence'' with respect to the premarket 
notification process for medical devices. For consistency with 
current thinking from international expert groups such as the FAO/
WHO and OECD consultation groups, FDA is now using the term 
``substantial equivalence'' with respect to food products.
---------------------------------------------------------------------------

    However, the concept of substantial equivalence may be of minimal 
relevance in circumstances where the differences between two substances 
outweigh the similarities. Thus, a critical factor that must be 
considered when applying the concept of substantial equivalence is any 
difference in composition or characteristic properties between the 
substances being compared. In the example of a microbially-derived 
enzyme preparation, its principal enzyme component may show substantial 
equivalence in structure and function to that of a GRAS enzyme 
preparation derived from an animal source but exhibit different 
properties such as specific activity (i.e., the rate at which the 
enzyme catalyzes a reaction) or optimum reaction conditions of pH and 
temperature because of changes, either through natural selection or 
through selective chemical modification, in the particular amino acid 
sequence of the enzyme's active site. Such differences, which are 
common when comparing enzyme preparations derived from different 
sources, generally do not outweigh the similarities between the enzyme 
preparations.
    On the other hand, the product resulting from the chemical reaction 
of two or more GRAS substances is a discrete new substance that may 
have properties that are distinctly different from the individual GRAS 
substances from which it is synthesized or from a simple mixture of 
those GRAS substances. The concept of substantial equivalence may not 
be relevant here unless the reaction product is widely recognized to be 
metabolized in the same way as the individual components from which it 
is synthesized. Likewise, in the case of a chemically synthesized 
substance that is structurally identical to a naturally occurring 
substance in commonly consumed food, compositional differences between 
the synthesized and naturally occurring substance may include the 
presence of any residues of potentially harmful chemicals carried over 
to the synthetic substance from the manufacturing process.
    FDA invites comment on the applicability of the concept of 
substantial equivalence to the technical element of a GRAS 
determination.

V. Proposed Revisions to Sec. 170.35--Affirmation of GRAS Status

    As a result of the agency's experience in processing FAP's and GRAS 
affirmation petitions, FDA has tentatively concluded that the petition 
process, which is the statutorily mandated process for food additives, 
should no longer be applied to GRAS substances, where the conditions of 
safe use of a substance have already been recognized by qualified 
experts. FDA believes that the lengthy rulemaking associated with the 
GRAS petition process deters many persons who independently determine 
that use of a substance is GRAS from informing the agency of such 
determinations. Moreover, FDA believes that the current commitment of 
its resources to the GRAS petition process provides limited public 
health benefit because manufacturers who submit an affirmation petition 
frequently market the substance at issue before FDA reaches a decision 
on the GRAS status of its intended use.
    Accordingly, FDA is proposing to amend current Sec. 170.35(a) to 
remove the provision that FDA may review the GRAS status of a substance 
added to food in response to a petition from an interested party. FDA 
has tentatively concluded that the elimination of the GRAS petition 
process would not adversely affect public health because the agency is 
simultaneously proposing to establish a notification procedure for GRAS 
substances. FDA has also tentatively concluded that the proposed 
notification procedure, discussed more fully in section VI of this 
document, would allow the agency to direct its resources to the more 
significant questions about GRAS status.
    Proposed Sec. 170.35(a) would continue to provide a mechanism 
whereby FDA, on its own initiative, may affirm the GRAS status of the 
use of a substance that directly or indirectly becomes a component of 
food. FDA proposes to retain the option of agency-initiated 
affirmations for those circumstances where such action is necessary or 
useful. For example, FDA may propose to revise an existing regulation 
affirming the GRAS status of a use of a substance if the agency 
determines that the current regulation is confusing or unnecessarily 
restrictive. In addition, the agency may choose to complete a 
rulemaking already begun as part of the agency-initiated GRAS review.
    Proposed Sec. 170.35(a) includes a technical revision that amends 
current Sec. 170.35(a) to place it in the singular. For consistency 
with the language of the statute, proposed Sec. 170.35(a) also has been 
revised to clarify that the Commissioner might affirm the GRAS status 
of a use of a substance, rather than the substance itself.
    In light of the increasing complexity of the food supply, FDA 
recognizes that members of the food industry may wish to engage in 
discussions with the agency concerning novel issues that accompany the 
technical element of some GRAS determinations. FDA believes that the 
elimination of the GRAS petition process will not constrain industry 
from consulting with the agency about such novel issues. Rather, FDA 
believes that the substitution of the proposed notification procedure 
for the current petition process will encourage industry to consult 
with FDA early in development of food substances to identify the 
critical aspects of the safety determination that would need general 
recognition to qualify for a GRAS exemption.
    FDA is also proposing to remove current Sec. 170.35(c), which 
prescribes the procedure for the submission of a GRAS affirmation 
petition. Under proposed Sec. 170.35(a), FDA will no longer be bound to 
review such a petition. Therefore, if proposed Sec. 170.35(a) becomes 
final, current Sec. 170.35(c) will become obsolete.

VI. Proposed Establishment of a Notification Procedure

A. General Requirements

    Proposed Sec. 170.36(a)(1) provides that any person may notify FDA 
of a claim

[[Page 18946]]

that a particular use of a substance is exempt from the statutory 
premarket approval requirements based on the notifier's determination 
that such use is GRAS. The agency encourages manufacturers and 
developers of food substances and of new processes for producing food 
substances to use this notification procedure to inform FDA if such 
manufacturers or developers conclude that there is general recognition 
that use of a substance is safe.\3\
---------------------------------------------------------------------------

    \3\ FDA considers that the current voluntary procedure whereby 
developers of new plant varieties modified through the use of rDNA 
techniques notify the agency about food derived from the plant is 
parallel to, and has some overlapping provisions with, the proposed 
GRAS notification procedure but is nonetheless distinct from this 
proposed procedure. For example, current notices to the agency 
concerning new plant varieties generally are broader in scope than 
the regulatory status of substances introduced into the new plant 
variety and usually include a safety and nutritional assessment of 
food derived from the new plant variety in addition to a basis for 
the notifier's determination that an FAP is not required for any of 
the substances introduced into that food.
---------------------------------------------------------------------------

    Current agency regulations concerning the eligibility of a 
substance for a health claim (Sec. 101.14(b)(3)(ii)) (21 CFR 
101.14(b)(3)(ii)) require that a substance that is to be consumed as a 
component of conventional food at other than decreased dietary levels 
be a food, food ingredient, or a component of a food ingredient, whose 
use, at the levels necessary to justify a claim, be demonstrated by the 
proponent of the claim, to FDA's satisfaction, to be safe and lawful 
under the applicable food safety provisions of the act. In the final 
rule establishing Sec. 101.14(b)(3)(ii) (58 FR 2478 at 2502, January 6, 
1993), FDA explained that the preliminary requirement that a substance 
be safe and lawful was necessary in the health claim regulation because 
FDA's authorization of a health claim places the agency's imprimatur on 
the claim. FDA further stated that it would be a violation of the 
agency's responsibility under the act to authorize a health claim for a 
substance without the agency being satisfied that the particular use of 
the substance is safe. As discussed in detail in section VI.D of this 
document, an agency response to a GRAS notice would not be equivalent 
to an agency affirmation of GRAS status. Therefore, if adopted, the 
GRAS notification procedure proposed in this notice will not satisfy a 
health claim petitioner's responsibilities under Sec. 101.14(b)(3)(ii).
    In addition, FDA recently proposed that good manufacturing practice 
for infant formula requires that only substances whose use in infant 
formula is safe and suitable under the applicable food safety 
provisions of the act be used to make this product; that is, that the 
substance be GRAS for such use, used in accordance with the agency's 
food additive regulations, or authorized for such use by a prior 
sanction (proposed Sec. 106.40(a); 61 FR 36154 at 36212, July 9, 1996). 
FDA also proposed that a ``new infant formula'' submission required 
under section 412 (c) and (d) of the act (21 U.S.C. 350a (c) and (d)) 
include the basis on which each ingredient meets the requirements of 
proposed Sec. 106.40(a), and that any claim that an ingredient is GRAS 
be supported by a citation to the agency's regulations or by an 
explanation as to why there is general recognition of the safety of the 
use of the ingredient in infant formula (proposed 
Sec. 106.120(b)(6)(ii); 61 FR 36154 at 36217). Again, as discussed in 
detail in section VI.D of this document, an agency response to a GRAS 
notice would not be equivalent to an agency affirmation of GRAS status 
or place an agency imprimatur on the substance that is the subject of 
the notice. Therefore, if adopted, this proposed GRAS notification 
program will not substitute for the requirements proposed for new 
infant formula submissions.
    The fact that the proposed GRAS notification program will not 
satisfy the requirements of either Sec. 101.14(b)(3)(ii) or proposed 
Sec. 106.120(b)(6)(ii) is reflected in proposed Sec. 170.36(a)(2). 
Under proposed Sec. 170.36(a)(2)(i), any person who submits a health 
claim petition under Sec. 101.14 must comply in full with 
Sec. 101.14(b)(3)(ii), regardless of whether the agency has been 
notified under proposed Sec. 170.36 about a relevant GRAS determination 
and regardless of the nature of the agency's response to that notice. 
Similarly, proposed Sec. 170.36(a)(2)(ii) provides that any person who 
makes a new infant formula submission under Sec. 106.120 must comply in 
full with Sec. 106.120(b)(6)(ii), regardless of whether the agency has 
been notified under proposed Sec. 170.36 about a relevant GRAS 
determination and regardless of the nature of the agency's response to 
that notice.
    Proposed Sec. 170.36(b) requires that notice of a GRAS exemption 
claim be submitted in triplicate and provides the address for such a 
submission. FDA plans to use one copy of the notice for the agency's 
administrative record. FDA anticipates that at least two agency 
scientists, with food safety expertise relating to identity, dietary 
exposure and health effects, will evaluate most notices. Thus, for 
efficient administration of the notification procedure, FDA is 
stipulating that three copies of a notice be submitted.
    FDA is aware that there is increasing interest in submitting an 
electronic copy of information prepared for regulatory purposes. FDA 
requests comment on whether it would be appropriate to require or 
recommend that the submission include an electronic copy in addition to 
the three paper copies required under proposed Sec. 170.36(b).

B. Specific Requirements

    Proposed Sec. 170.36(c) provides details on information that must 
be included in a notice. FDA recognizes that a decision to submit a 
notice is voluntary. However, as discussed (see discussion of proposed 
Sec. 170.36(e)), under the proposed notification procedure, FDA would 
respond to a notice within 90 days. In order for the agency to meet 
this timeframe, the information in the notice needs to be presented in 
an orderly and consistent fashion. Moreover, FDA believes that a 
prescribed format and a description of information that the agency 
considers important in supporting a GRAS determination would simplify 
the notifier's task of preparing the notice.
1. GRAS Exemption Claim
    A GRAS determination must comply with the provisions of Sec. 170.30 
and the person making such determination is responsible for ensuring 
such compliance, regardless of whether that person notifies the agency 
about the determination. Accordingly, proposed Sec. 170.36(c)(1) 
requires that the notice include a claim (hereinafter referred to as 
the ``GRAS exemption claim''), dated and signed by the notifier, that a 
particular use of a substance is exempt from the premarket approval 
requirements of the act because the notifier has determined that such 
use is GRAS. Proposed Sec. 170.36(c)(1) would distinguish the 
notification procedure, in which the notifier explicitly accepts 
responsibility for the GRAS determination, from the GRAS petition 
process, in which the notifier is requesting that the agency affirm the 
GRAS status of use of a substance.
    Proposed Sec. 170.36 (c)(1)(i) through (c)(1)(iv) identify specific 
information required in a GRAS exemption claim in a prescribed format. 
This requirement will simplify the notifier's task of preparing this 
section of a notice and will enable the agency to use this section of a 
notice to effectively and efficiently inform the public about received 
notices (see discussion of proposed Sec. 170.36(f)(2)).
    FDA has requested comment on whether proposed Sec. 170.36(b) should 
require or recommend that an electronic copy of the entire notice be 
submitted

[[Page 18947]]

in addition to three paper copies. In particular, receiving electronic 
copies of the GRAS exemption claim may make FDA's administration of the 
GRAS notification procedure more efficient, especially if the agency 
uses an electronic means to make those claims readily accessible to the 
public. Accordingly, FDA specifically requests comment on whether the 
regulation should include a recommendation or requirement that the 
notice include an electronic copy of the GRAS exemption claim required 
by proposed Sec. 170.36(c)(1).
    a. Notifier. Proposed Sec. 170.36(c)(1)(i) requires that the GRAS 
exemption claim include the name and address of the notifier. This is 
necessary for full identification of the person who accepts 
responsibility for the claim. This is also necessary so that the agency 
can both acknowledge receipt of the notice (proposed Sec. 170.36(d)) 
and inform the notifier of the agency's response to the notice 
(proposed Sec. 170.36(e)).
    b. Name of notified substance. Proposed Sec. 170.36(c)(1)(ii) 
requires that the GRAS exemption claim include the common or usual name 
of the notified substance. This is necessary to identify the notified 
substance as well as to identify whether there are any labeling issues 
that need to be addressed. The notifier may include in the GRAS 
exemption claim additional information, such as that described in 
proposed Sec. 170.36(c)(2), concerning the identity of the substance if 
such information is appropriate or necessary to fully and unambiguously 
describe it.
    The agency recognizes that notifiers may have questions concerning 
the common or usual name for a notified substance. FDA advises that in 
such circumstances, a notifier should consult with the Office of Food 
Labeling in FDA's Center for Food Safety and Applied Nutrition (CFSAN).
    c. Conditions of use. Proposed Sec. 170.36(c)(1)(iii) requires that 
the GRAS exemption claim identify the applicable conditions of use of 
the notified substance, including the foods in which the substance is 
to be used, levels of use in such foods, and the purposes for which the 
substance is used, including, when appropriate, a description of the 
population expected to consume the substance (e.g., if the substance is 
intended for use in a limited population, such as ingredients used 
mainly in infant formula, medical foods, or in specially designed food 
products typically consumed as a sole source of the diet by persons who 
are unable to consume food in conventional form). Information 
describing the conditions of use is necessary to delineate the 
boundaries of the GRAS exemption claim consistent with section 201(s) 
of the act, which states that a GRAS substance must be generally 
recognized as safe ``under the conditions of its intended use.'' This 
information is also necessary to determine whether dietary exposure to 
the substance presents a basis for concern about the safety of its use.
    d. Basis for the GRAS determination. Proposed Sec. 170.36(c)(1)(iv) 
requires that the GRAS exemption claim identify the basis for the GRAS 
determination as either scientific procedures or experience based on 
common use in food. The act differentiates between these two bases for 
GRAS determination and, under Sec. 170.30, the requirements for a 
scientific procedures GRAS determination are different from the 
requirements for a common use GRAS determination. The basis for a GRAS 
determination is thus fundamental to the GRAS exemption claim.
    e. Availability of information. A GRAS determination must comply 
with the provisions of Sec. 170.30 and the person making such 
determination is responsible for ensuring such compliance, regardless 
of whether that person notifies the agency about the determination. As 
discussed more fully below (see discussion of proposed 
Sec. 170.36(c)(4)), and in keeping with the agency's commitment to 
achieving the goals for Reinventing Food Regulations, FDA is proposing 
to require that a notifier supply a detailed summary of the information 
that is the basis for a GRAS determination rather than the information 
itself. Proposed Sec. 170.36(c)(1)(v) provides a mechanism for FDA to 
verify the information that supports a GRAS determination by requiring 
that the GRAS exemption claim include a statement that the data and 
information that are the basis for the determination are available for 
review and copying by FDA or will be sent to FDA upon request. 
Notifiers who voluntarily choose to notify FDA of a GRAS determination 
receive as a benefit a response that documents the agency's awareness 
of the determination. As a condition of that benefit, the notifier must 
consent to grant FDA access to the data and information that are the 
basis of the GRAS determination.
    There is no burden on the notifier for developing the data and 
information that are the basis for the GRAS determination because such 
data and information must already be generally available in order to 
satisfy the common knowledge element of a GRAS determination. 
Additionally, any person who determines that a substance is GRAS should 
have assembled and evaluated the evidence that forms the basis of such 
a determination, regardless of whether the person subsequently notifies 
the agency about the claim. Therefore, FDA believes that the burden to 
the notifier of the proposed rule is the minimal burden of maintaining 
the information. Such preservation of the data and information that are 
the basis for the GRAS determination also represents prudent practice 
for those who claim an exemption from a statutory requirement.
    The new procedure that FDA is proposing to establish will involve 
the submission of a detailed summary of the information that forms the 
basis for an exemption from a statutory requirement rather than the 
submission of the information itself. It therefore is prudent that FDA 
monitor compliance with the essence of the statutory requirement (i.e., 
that there is common knowledge among qualified experts that there is 
reasonable certainty that the substance is not harmful under the 
intended conditions of use). Accordingly, FDA intends to conduct random 
audits of data and information maintained by the notifier. Moreover, 
because the proposed substitution of a notification procedure for the 
current petition process would allow FDA to direct its resources to 
priority questions about GRAS status, FDA might conduct an audit on a 
broad issue or class of products if the issue or use of a class of 
products raises important public health issues.
2. Identity and Specifications
    Proposed Sec. 170.36(c)(2) requires that the notice include 
detailed information about the identity of the notified substance, 
including, as applicable, the chemical name, Chemical Abstracts Service 
(CAS) registry number, Enzyme Commission (EC) number, empirical 
formula, structural formula, quantitative composition, method of 
manufacture (excluding any trade secret information), characteristic 
properties, any potential human toxicants, and specifications for food-
grade material. This detailed information, which would be in addition 
to the substance's common or usual name that would be included under 
proposed Sec. 170.36(c)(1)(ii), is necessary to describe accurately the 
notified substance using commonly accepted scientific nomenclature and 
practice.
    For some substances, such as calcium acetate (21 CFR 184.1185), the 
most relevant information concerning identity may be chemical 
information such as its CAS registry number and empirical formula. For 
other substances, such as whey (21 CFR 184.1979), a

[[Page 18948]]

chemical formula cannot be used for identification; instead, source and 
quantitative composition (e.g., percent of protein, fat, ash, lactose, 
and moisture) appropriately describe the substance.
    In many cases, the method of manufacture provides important 
identity information. For example, an enzyme preparation that is 
derived from an animal source and contains the enzyme chymosin as its 
principal enzyme component (Sec. 184.1685(a)(1) (21 CFR 
184.1685(a)(1))) is chemically different from an enzyme preparation 
that is derived from a microbial source and contains the enzyme 
chymosin as its principal enzyme component (Sec. 184.1685(a)(2)) 
because the components and contaminants derived from the source 
material are distinctly different.
    In some cases, the characteristic properties of a substance may be 
important when defining the conditions under which the substance may 
safely be used. For example, if an isolated or chemically processed 
fiber is intended for use as a replacement for part of the flour used 
in baked goods, information about its physicochemical properties, such 
as its ability to swell due to high water absorption or to bind 
physiologically important ions, may be important in establishing a safe 
level of the fiber in baked goods.
    The proposed requirement that information relating to identity 
include any potential human toxicants in the notified substance derives 
from the known presence of such toxicants in substances of natural 
biological origin. For example, it is well known that potatoes contain 
the naturally occurring toxicant, solanine. In the plant policy 
statement (57 FR 22984 at 22987), FDA discussed the importance of 
ensuring that new plant varieties do not contain significantly higher 
levels of toxicants than are present in other edible varieties of the 
same species. This consideration applies to all food products that 
derive from a source known to contain naturally occurring toxicants.
    Specifications are an important factor in establishing food-grade 
quality for any substance intended for use in food. Substances that do 
not meet the specifications may not be suitable for use in food. 
Specifications may be general or particular and may relate to identity, 
purity, or both.
    General specifications governing both identity and purity are 
common for GRAS substances. For example, the regulations for 
microbially-derived GRAS substances usually stipulate, as a general 
identity specification, that the source microorganism be a 
nontoxigenic, nonpathogenic strain. Similarly, the regulations for many 
GRAS substances stipulate, as a general purity specification, the 
maximum permissible level of a heavy metal toxicant such as lead.
    In addition, GRAS substances frequently require a particular 
identity specification to adequately define the substance whose safety 
is generally recognized. For example, in affirming that canola oil 
(i.e., low erucic acid rapeseed oil) is GRAS for use as an edible fat 
and oil, FDA only considered the GRAS status of oil that contains 
levels of a specific fatty acid (erucic acid) that are no more than 2 
percent of the component fatty acids. Therefore, the identity 
specification for low erucic acid rapeseed oil (21 CFR 184.1555(c)(1)) 
stipulates that, chemically, the oil is a mixture of triglycerides, 
composed of both saturated and unsaturated fatty acids, with an erucic 
acid content of no more than 2 percent of the component fatty acids.
    In some cases, FDA expects that the specifications for a notified 
substance may be generally available in a standard reference such as 
the Food Chemicals Codex (FCC), which contains general and specific 
requirements for more than 900 substances used in food. In other cases, 
the specifications for the notified substance may be the same as, or 
similar to, specifications in the agency's GRAS regulations but not 
available in any other standard reference. For example, the 
specifications for an oil that is substantially similar to hydrogenated 
and partially hydrogenated menhaden oil, which FDA has affirmed as GRAS 
for use as an edible fat or oil, could be based on the specifications 
in 21 CFR 184.1472.
3. Self-limiting Levels of Use
    Proposed Sec. 170.36(c)(3) requires that the notice include any 
self-limiting levels of use of the substance. If a substance is added 
to food above its technologically self-limiting level, the food becomes 
unpalatable, unappealing or otherwise unfit for consumption. 
Information on a technologically self-limiting level of use of a 
substance would be important in addressing concerns about the level of 
use of the substance as a food component. For example, it is generally 
known that the taste associated with many GRAS synthetic flavoring 
substances limits the levels at which the flavoring substances can be 
used to levels below those known to exhibit toxic properties.
4. Scientific Procedures GRAS Determination
    The technical element of a scientific procedures GRAS determination 
requires that information about the substance show that there is 
reasonable certainty in the minds of competent scientists that the 
substance is not harmful under the intended conditions of use. The 
nature of the information that the notifier relies on to establish the 
technical element of the GRAS standard may vary from substance to 
substance. Such information may include, but is not limited to, the 
identity, characteristic properties, and methods of manufacture of the 
notified substance, applicable toxicological studies, and information 
relating to dietary exposure.
    The common knowledge element requires both that the information 
relied on be generally available and that there be a basis to conclude 
that there is expert consensus about the safety of the substance for 
its intended use. A notice summary that fully describes the technical 
evidence of safety, but does not provide a basis to conclude that the 
technical evidence is generally available and accepted, would be 
incomplete. The common knowledge element applies to all of the evidence 
that is the basis for the safety determination.
    a. Technical evidence of safety. Proposed Sec. 170.36(c)(4)(i)(A) 
requires that the notice include a detailed summary of the basis for 
the notifier's determination that a particular use of the substance is 
GRAS through scientific procedures. This summary would include a 
comprehensive discussion of, and citations to, generally available and 
accepted scientific data, information, methods, or principles that the 
notifier relies on to establish safety.
    Proposed Sec. 170.36 (c)(2) and (c)(3) of the notice would require 
that information relating to the identity, characteristic properties, 
and methods of manufacture of the notified substance be described in 
detail; therefore, the comprehensive discussion in the notice summary 
should focus on how that information is relevant to the GRAS 
determination. Under proposed Sec. 170.36(c)(4), the comprehensive 
discussion in the notice summary of any applicable toxicological 
studies should fully describe such studies, identify the conclusions 
drawn from such studies, and explain how these conclusions are relevant 
to the GRAS determination. FDA is not proposing to require that the 
notice include the raw data supporting the conclusions of applicable 
toxicological studies because the agency does not intend, in most 
cases, to conduct its own detailed evaluation of those data.

[[Page 18949]]

    Proposed Sec. 170.36(c)(4)(i)(A) specifies that the discussion in 
the notice summary include a consideration of the probable consumption 
of the substance and the cumulative effect of the substance in the 
diet, taking into account any chemically or pharmacologically related 
substances in such diet. This consideration of dietary exposure is 
mandated for food additives by section 409(c)(5) of the act; 
Sec. 170.30(b) further provides that a scientific procedures GRAS 
determination requires the same quantity and quality of scientific 
evidence as would be required to approve a food additive. Thus, such 
information should be included in the notice summary. Several technical 
documents that discuss the practical details of estimating consumer 
exposure to a food substance are available from the agency.4
---------------------------------------------------------------------------

    \4\ For example, ``Recommendations for Submission of Chemical 
and Technological Data for Direct Food Additive and GRAS Food 
Ingredient Petitions'' (1993); ``Estimating Exposure to Direct Food 
Additives and Chemical Contaminants in the Diet'' (1995); and 
``Recommendations for Chemistry Data for Indirect Food Additive 
Petitions'' (1995).
---------------------------------------------------------------------------

    The notice summary may also include a comprehensive discussion of 
scientific data, information, and methods that, in the notifier's view, 
corroborate the GRAS determination. For example, for a substance whose 
safety is established based on its identity, method of manufacture, and 
characteristic properties, a notifier may describe a toxicological 
study and rely on these data as corroborative. However, as with studies 
that are relied on to support a GRAS determination, the comprehensive 
discussion should fully describe such studies, identify the conclusions 
drawn from such studies, and explain how these conclusions are relevant 
to the GRAS determination.
    b. General availability of information supporting safety. The 
inclusion of citations to published articles is customary scientific 
practice and is the simplest way to demonstrate the general 
availability of the information on which the notifier relies. Proposed 
Sec. 170.36(c)(4)(i)(A) does not require that a notifier submit copies 
of published information identified in the notice summary because, in 
most cases, the agency does not intend to conduct its own detailed 
evaluation of the data that the notifier relies on to support a 
determination that a use of a substance is GRAS. Rather, the agency 
intends to evaluate whether the notice summary establishes a basis to 
conclude that there is expert consensus regarding the safety of use of 
the substance.
    Under proposed Sec. 170.36(c)(4)(i)(A), notifiers should limit 
published information citations to those that the notifier discusses 
and relies on to support a GRAS determination or that are appropriately 
discussed and explained because they may appear to be inconsistent with 
a GRAS determination (see discussion of proposed 
Sec. 170.36(c)(4)(i)(B)). Accordingly, the notifier should not cite 
published information unless the cited information bears directly on 
the GRAS determination. For example, a bibliography describing an 
exhaustive literature search about a notified substance is of limited 
or no value in supporting the common knowledge element of a GRAS 
determination if the relevance of the cited literature is not readily 
apparent or fully discussed. Moreover, such a bibliography would not, 
absent a discussion of the relevance of the material cited to the GRAS 
determination in question, fulfill the technical element of a GRAS 
determination.
    c. Unfavorable information. Proposed Sec. 170.36(c)(4)(i)(B) 
requires that the notice summary of a scientific procedures GRAS 
determination include a comprehensive discussion of any reports of 
investigations or other information (e.g., adverse event reports and 
consumer complaints) that may appear to be inconsistent with the GRAS 
determination. FDA is proposing this requirement as a prelude to 
proposed Sec. 170.36(c)(4)(i)(C), which would require that the notice 
summary include a basis to conclude that there is expert consensus 
regarding the safety of use of the substance. In other words, in order 
to meet the act's general recognition standard, all information, both 
favorable and unfavorable, that bears on the safety of the substance 
for its intended use must be considered.
    Proposed Sec. 170.36(c)(4)(i)(B) is consistent with the provision 
in current Sec. 170.35(c)(1)(iv) and (c)(1)(v) (which are proposed for 
deletion) that a GRAS affirmation petition include adverse information 
or consumer complaints and be a representative and balanced submission 
that includes known information, both favorable and unfavorable. 
Proposed Sec. 170.36(c)(4)(i)(B) is also consistent with a similar 
provision (Sec. 171.1(c) (21 CFR 171.1(c))) in the FAP regulations, 
which requires that the petition must not omit without explanation any 
reports of investigations that would bias an evaluation of the safety 
of the food additive. Thus, the requirement in proposed 
Sec. 170.36(c)(4)(i)(B) is appropriate because general recognition of 
safety based upon scientific procedures requires the same quantity and 
quality of scientific evidence required to obtain approval of the 
substance as a food additive.
    d. Basis for concluding expert consensus. Proposed 
Sec. 170.36(c)(4)(i)(C) requires that the notice summary of a 
scientific procedures GRAS determination include the basis for 
concluding, in light of the data and information described in the 
notice, that there is a consensus among qualified experts that there is 
reasonable certainty that the substance is not harmful under the 
intended conditions of use. Thus, the notice summary must consider the 
totality of the publicly available and corroborative evidence about the 
safety of the substance for its intended use, including both favorable 
and potentially unfavorable information.
    As discussed in section I.C of this document, the bases for 
concluding that there is the requisite expert consensus may be quite 
varied. For example, there could be a basis to conclude that the 
necessary expert consensus exists if data published in the primary 
scientific literature establish the safety of a substance for its 
intended use and such data raise no safety questions that experts would 
need to resolve. On the other hand, data published in the primary 
scientific literature may not provide a basis for expert consensus if 
those data raise unresolved safety questions. Alternatively, the 
opinions of a specially convened expert panel or of an authoritative 
body such as NAS may provide a basis for expert consensus. However, an 
ongoing scientific discussion or controversy about safety concerns 
raised by available data would make it difficult to provide a basis for 
expert consensus about the safety of a substance for its intended use.
5. Common Use GRAS Determination
    a. Technical evidence of safety. Proposed Sec. 170.36(c)(4)(ii)(A) 
requires that the notice summary of a common use GRAS determination 
include a comprehensive discussion of, and citations to, generally 
available data and information that the notifier relies on to establish 
safety, including evidence of a substantial history of consumption of 
the substance by a significant number of consumers. Under current 
Sec. 170.30(c)(1), in evaluating whether use of a substance is GRAS 
through experience based on common use in food prior to January 1, 
1958, FDA relies on information documenting that the ``common use in 
food'' of a substance satisfies the definition in Sec. 170.3(f) such 
that adverse health effects, if they occurred, could be noted. In other 
words, a substance is not eligible for the

[[Page 18950]]

GRAS exemption merely because it was used in food before January 1, 
1958, if such use were not sufficiently widespread.5
---------------------------------------------------------------------------

    \5\ For example, subsequent to the 1958 amendment, FDA required 
that food additive petitions be submitted for several substances, 
such as polysorbates (25 FR 1727, February 27, 1960), even though 
those substances had been used in food prior to January 1, 1958, 
because the pre-1958 consumption alone was not sufficient to 
establish safety (24 FR 11079, December 31, 1959).
---------------------------------------------------------------------------

    The fact that GRAS status is determined through experience based on 
common use in food does not preclude, in addition to information 
documenting that a substance has a substantial history of consumption 
for food use by a significant number of consumers, a discussion of 
relevant data or information that bears on the safety of the substance 
under its intended conditions of use. Thus, the notice summary may also 
include a comprehensive discussion of scientific data or information 
that, in the notifier's view, corroborates the common use GRAS 
determination. With respect to toxicological studies that are viewed as 
corroborative, the comprehensive discussion should fully describe the 
studies, identify the conclusions drawn from such studies, and explain 
how these conclusions are relevant to the GRAS determination.
    As discussed in section I.A of this document, it is the use of a 
substance, rather than the substance itself, that is eligible for the 
GRAS exemption. In addition, section 201(s) of the act makes a clear 
distinction between qualifying for the GRAS exemption through 
scientific procedures and qualifying for the GRAS exemption through 
common use in food. Many substances that are GRAS for a specific use 
through a common use GRAS determination could become the subject of 
GRAS determinations for additional uses. It is important to note, 
however, that an evaluation of whether an additional use of a substance 
that is GRAS through experience based on common use in food is also 
GRAS requires a scientific procedures GRAS determination when the use 
in question was not common prior to January 1, 1958.
    b. General availability. As discussed for notifiers of a scientific 
procedures GRAS determination, notifiers of a common use GRAS 
determination should limit citations to published information to those 
that the notifier discusses and relies on to support a GRAS 
determination or that are appropriately discussed and explained because 
they appear to be inconsistent with the GRAS determination.
    c. Unfavorable information. Proposed Sec. 170.36(c)(3)(ii)(B) 
requires that the notice summary of a common use GRAS determination 
include a comprehensive discussion of any reports of investigations or 
other information that may appear to be inconsistent with the GRAS 
determination. The legislative history of the 1958 amendment 
demonstrates that Congress believed that there was no reason to conduct 
specific tests to establish the safety of substances commonly used in 
food because their history of common use established a presumption of 
such safety (Ref. 1). However, nothing in the legislative history 
suggests that Congress intended that subsequent reports of adverse 
effects associated with the use of a substance in food be ignored in 
the safety evaluation. A notice summary of a common use GRAS 
determination should also address whether use was/is sufficiently 
widespread that any substance-related adverse effects would be observed 
and recorded. Where a substance has been used by a limited population, 
6 for a limited period of time, or under circumstances that do not 
lend themselves to the observation and recording of adverse effects, 
the lack of reported adverse effects may not be meaningful.
---------------------------------------------------------------------------

     6 An exception is the use of a food substance in a limited 
population such as infants, where such limited use may be part of a 
demonstration of the safety of the substance for use by the limited 
population (e.g., as an ingredient in an infant formula).
---------------------------------------------------------------------------

    d. Basis for concluding expert consensus. Proposed 
Sec. 170.36(c)(4)(ii)(C) requires that the notice summary of a common 
use GRAS determination include the basis for concluding, in light of 
the data and information described in the notice, that there is a 
consensus among qualified experts and that there is reasonable 
certainty that the substance is not harmful under the intended 
conditions of use. Thus, the notice summary must consider the totality 
of the publicly available and corroborative evidence about the safety 
of the substance for its intended use, including both favorable 
information and potentially unfavorable information.
    FDA has previously discussed the common knowledge element as it 
applies to a common use GRAS determination which reads as follows:

    For a substance to be GRAS on the basis of a history of common 
use in food, there must be a consensus among the community of 
qualified experts that the use of the substance is safe. For such a 
consensus to be possible, information about the use of the substance 
must be generally available. General availability is the result of 
documentation of the information, usually by publication.

(50 FR 27294 at 27295, July 2, 1985)
    In addition, under Sec. 170.30(c)(2), when the common use in food 
occurred exclusively or primarily outside of the United States, a 
common use GRAS determination requires that such use be documented by 
published or other information and be corroborated by information from 
a second, independent, source that confirms the history and 
circumstances of use of the substance. Such information must be widely 
available in the country in which the use occurred and readily 
accessible to interested qualified experts in the United States.

C. Agency Response

1. Acknowledgment of Receipt
    Proposed Sec. 170.36(d) requires that, within 30 days of receipt of 
a notice, FDA acknowledge receipt of the notice by informing the 
notifier in writing of the date on which the notice was received. This 
acknowledgment would serve as a means to establish the date of receipt, 
which FDA is proposing to couple with certain aspects of the agency 
response (see discussion of proposed Sec. 170.36 (d), (e), and (f) of 
this document).
2. 90-Day Response Letter
    Under the proposed notification procedure, FDA would not receive 
the detailed data and information that support a GRAS determination. 
Therefore, FDA would not be in a position to affirm a notifier's 
conclusion that a use of a substance is GRAS, and the rulemaking part 
of the GRAS affirmation process would not be necessary or appropriate. 
Rather, FDA would evaluate whether the notice provides a sufficient 
basis for the notifier's GRAS determination. For example, FDA may 
question the GRAS status of use of a substance if the information 
provided in a notice: (1) Does not adequately establish technical 
evidence of safety; (2) is not generally available; (3) does not 
convince the agency that there is the requisite expert consensus about 
the safety of the substance for its intended use; or (4) is so poorly 
presented that the basis for the GRAS determination is not clear. FDA 
also may be aware of information that is not included in the notice but 
raises important public health issues that lead the agency to question 
GRAS status of use of the substance.
    FDA believes that this narrow agency evaluation would not have a 
negative impact on public health because the agency is replacing a 
voluntary

[[Page 18951]]

administrative process that was developed to provide official 
recognition of a lawfully made GRAS determination with a different 
voluntary administrative procedure. From a legal and regulatory 
perspective, this substitution is neutral.
    This narrow evaluation would facilitate FDA's rapid response to the 
notifier. Accordingly, under proposed Sec. 170.36(e), FDA would respond 
to the notifier in writing within 90 days of receipt of the notice. In 
some circumstances, the agency's response would not question the GRAS 
determination. This response, however, would not be equivalent to an 
agency affirmation of GRAS status because FDA would neither receive nor 
review the detailed data and information that support the GRAS 
determination. In addition, consistent with proposed Sec. 170.36(a)(2), 
any response from FDA would not constitute compliance with 
Sec. 101.14(b)(3)(ii) or with the requirements that the agency has 
proposed (61 FR 36154) for new infant formula submissions.
    In other circumstances, the agency's response could include 
identification of a problem with the notice. However, whether FDA 
chooses to advise a notifier that the agency has identified a problem 
with the notice, where the notice raises no important public health 
issues, is a matter committed to the agency's discretion.
    FDA is proposing to respond in writing to a notifier in all 
circumstances for the following reasons. First, a written response 
would make clear that the agency's evaluation of a notice has come to 
closure. Second, as discussed more fully in section X of this document, 
FDA believes that a written response would facilitate international 
trade. Third, as discussed more fully in section VI.F of this document, 
FDA believes that a written response would be a useful element of any 
file that the agency makes publicly accessible or any inventory that 
the agency prepares of notices received under proposed Sec. 170.36.
    However, under a notification procedure, an agency response is not 
imperative in those circumstances in which the agency chooses to raise 
no question about the GRAS status of the intended use of the substance. 
As discussed in sections I.A and II of this document, a manufacturer 
may market a substance that the manufacturer determines is GRAS without 
informing the agency or, if the agency were so informed, while the 
agency is reviewing that information. Thus, FDA's proposal to respond 
to a notifier in all circumstances does not alter a notifier's 
prerogative under the statute to market a GRAS substance. Nonetheless, 
as an alternative approach, the notification program could be 
structured so that FDA responds to the notifier only when the agency 
questions the GRAS status of the intended use of the substance. FDA 
specifically requests comment on whether the agency should, in all 
cases, provide a notifier with a letter at the conclusion of the 
agency's evaluation of a notice. Such comments may result in a 
modification to proposed Sec. 170.36(e).
    FDA has also considered whether the time for the agency's response 
should be longer than 90 days, and specifically requests comment on 
whether the proposed 90-day timeframe for an agency response should be 
lengthened, e.g., to 120 days or 150 days. FDA's proposal to respond 
within 90 days reflects both a commitment to operational efficiency and 
a belief that the agency's evaluation of whether a notice provides a 
sufficient basis for a GRAS determination could likely be accomplished 
in such a period. However, FDA's expectation that it could respond 
within 90 days is in part predicated on its estimate, which is 
discussed more fully in the agency's analysis of the information 
collection requirements of this document, that the agency would receive 
approximately 50 notices per year. Accordingly, although comments on 
the information collection requirements of this document are submitted 
directly to the Office of Information and Regulatory Affairs, OMB, the 
agency also requests comment directly to FDA on the number of notices 
that manufacturers anticipate submitting on an annual basis. Such 
information may result in a modified timeframe for the agency's 
response.
3. Subsequent Agency Action
    FDA is continuously evaluating the safety of substances in the food 
supply. In some cases, FDA may consider whether an emerging body of 
scientific knowledge raises questions about the continued safe use of a 
food additive or of a substance whose use was listed as GRAS, affirmed 
as GRAS, or commonly considered to be GRAS by the food industry. 
Likewise, FDA may consider whether specific information brought to the 
agency's attention (e.g., through routine correspondence from 
interested parties or through a citizen petition) raises such safety 
questions. In most cases, the information that comes to FDA's attention 
does not demonstrate a health hazard, and the scientific issues are 
resolved upon consideration by the agency. Thus, the agency does not 
routinely publicize safety issues that it is considering, or 
reconsidering, concerning the safety of a substance or class of 
substances that is used in food unless action by the agency is 
necessary for public health protection.
    Similarly, FDA may direct resources to exploring issues raised by a 
GRAS notice even though such issues do not, on their face, appear to be 
significant public health issues. Alternatively, FDA may, at some point 
after its 90-day response to the notifier, receive additional 
information about a notified substance that raises questions about the 
safety of that substance. If, after issuing a 90-day response letter, 
questions develop for the agency regarding the GRAS status of a use of 
a substance, FDA may subsequently advise the notifier and other 
interested parties of those questions.
    In such circumstances, FDA ordinarily expects to advise a notifier 
by letter that the agency has subsequently identified a problem with 
the notice. As discussed more fully in section VI.F of this document, 
such a letter would be placed in a publicly accessible file so that 
other interested parties would become aware of the agency's position. 
Alternatively, FDA may, in accordance with Secs. 170.35(b)(4) and 
170.38, publish a notice in the Federal Register determining that use 
of a substance is not GRAS and is a food additive subject to section 
409 of the act. Importantly, however, when faced with a public health 
hazard, the existence of such rulemaking authority would not preclude 
other agency action, including seizure and injunction, to remove from 
the market a product that is an unapproved food additive.
    As discussed in section VI.A of this document, FDA has recently 
proposed that a ``new infant formula'' submission required under 
section 412 (c) and (d) of the act include the basis on which each 
ingredient is determined to be safe and suitable under the food safety 
provisions of the act (proposed Sec. 106.120(b)(6)(ii); 61 FR 36154 at 
36217). The agency could receive a notice under proposed Sec. 170.36 
concerning a GRAS determination for a broad use of a substance in foods 
and subsequently receive a new infant formula submission that lists the 
substance as an ingredient in a new infant formula and asserts that the 
use of the substance in infant formula is GRAS. In such circumstances, 
FDA could choose to reexamine the notice previously received under 
proposed Sec. 170.36. If, following such reexamination, the agency 
questions whether use of the substance in infant formula is GRAS, the 
agency could so inform the person who submitted the GRAS notice under 
proposed Sec. 170.36.

[[Page 18952]]

D. Appeals

    FDA recognizes that in some cases a notifier may disagree with the 
agency if the notifier receives a response advising that FDA has 
identified a problem with the notice. FDA has recently reviewed the 
vehicles, provided in part 10 (21 CFR part 10) of its regulations, that 
any person or firm may use to appeal an agency employee's decision (61 
FR 9181 at 9184, March 7, 1996). Although an agency response to a 
notice under proposed Sec. 170.36 does not constitute an agency 
decision on the GRAS status of a substance, FDA is advising that it 
will consider any of the existing appeals processes that are described 
below as an appropriate vehicle to engage the agency in cases where a 
notifier disagrees with a response received under proposed Sec. 170.36.
    Under Sec. 10.75, an interested person may request internal agency 
review of an agency decision made by anyone other than the 
Commissioner. Such review ordinarily would be by the employee's 
supervisor, but may move up the management ranks to the Center Director 
or to the Office of the Commissioner if the issue cannot be resolved, 
important policy matters are present, or it would be in the public 
interest. Sections 10.25 and 10.33 permit an interested person to 
petition the Commissioner to review any administrative action. The 
regulations also include less formal methods of appeal. For example, 
under Sec. 10.65, an interested person may correspond or meet with FDA 
about any matter under FDA's jurisdiction. Finally, any person with 
concerns about an agency response to a notice received under proposed 
Sec. 170.36 may contact FDA's Office of the Chief Mediator and 
Ombudsman (the Ombudsman's Office). The Ombudsman's Office, which 
reports directly to the Commissioner, works on resolving issues and 
conflicts that arise in any FDA component. The Ombudsman's staff is 
available to discuss options, explain FDA's practices and procedures, 
and suggest approaches for resolution. When appropriate, the staff of 
the Ombudsman's Office may contact FDA's staff involved in the issue 
and mediate a dispute.

E. Public Disclosure and Accessibility

1. Public Disclosure
    Proposed Sec. 170.36(f)(1) provides that any GRAS exemption claim 
submitted under proposed Sec. 170.36(c)(1) of this section be 
immediately available for public disclosure on the date the notice is 
received. As discussed in section VI.B.1 of this document, any person 
who makes a GRAS determination is responsible for ensuring that the 
determination complies with the provisions of Sec. 170.30, regardless 
of whether that person notifies the agency about the determination. 
Further, the common knowledge element of a GRAS determination signifies 
that neither the common or usual name of the substance, the intended 
use of the substance, nor the basis for the GRAS determination can be 
confidential.
    Proposed Sec. 170.36(f)(1) further provides that all remaining data 
and information in a notice be available for public disclosure, in 
accordance with part 20 (21 CFR part 20), on the date the notice is 
received. The common knowledge element of a GRAS determination 
signifies that neither the detailed information about the identity of 
the substance nor the information needed to establish technical 
evidence of safety can be confidential. Therefore, FDA assumes that a 
notice will not contain any information that is protected from public 
disclosure. Moreover, because a GRAS substance may be marketed without 
prior approval, FDA assumes that, in most cases, submission of a notice 
will not reflect the notifier's plans about the timing of 
commercialization, which is arguably confidential commercial 
information (Sec. 20.61(b)).
    A notifier who considers that certain information in a submission 
should not be available for public disclosure should identify as 
confidential the relevant portions of the submission for FDA 
consideration. FDA will review the identified information, determine 
whether that information is exempt from public disclosure under part 
20, and release or protect the information in accordance with that 
determination. FDA advises that, in most cases, the agency is likely to 
determine that all information submitted to support a GRAS 
determination is available for public disclosure.
2. Public Accessibility
    The food industry's basic need to know whether a food substance is 
in compliance with applicable provisions of the act originally 
persuaded the agency to clarify the regulatory status of a multitude of 
food substances by publishing the GRAS list. Under this proposal, the 
current GRAS list (i.e., current part 182) and the regulations listing 
uses of a substance that FDA has affirmed as GRAS (i.e., current parts 
184 and 186 (21 CFR parts 184 and 186)) would remain in the agency's 
codified regulations. In addition, FDA is retaining the process whereby 
the agency may, on its initiative, review the GRAS status of a 
substance and, if appropriate, establish a regulation in part 184 or 
part 186 affirming such use as GRAS. However, if this proposal becomes 
final, the existing process whereby an interested person may petition 
FDA to affirm the GRAS status of use of a substance and list such 
affirmed uses in part 184 or part 186 would be eliminated.
    FDA believes that there would be considerable interest, from a 
broad segment of the public, including members of the regulated 
industry, other Federal, State, and local government agencies, 
international government agencies, and public interest groups, in 
notices received under proposed Sec. 170.36. Such groups likely would 
want to know whether FDA is aware that a substance is being used in 
food on the basis of the GRAS exemption and whether FDA has advised the 
notifier that it has identified a problem with the notice. Therefore, 
FDA is proposing to establish a procedure whereby all members of the 
public could readily access such information. Moreover, such a 
procedure would be in keeping with the agency's goals in meeting the 
Reinventing Food Regulations.
    All GRAS petitions are currently on public display at the Dockets 
Management Branch (DMB) because the petition process includes informal 
rulemaking and DMB is the usual repository for information that is 
publicly available during informal rulemaking. However, FDA sees no 
need to place the entire GRAS notice on public display at DMB because, 
under the proposed notification procedure, the agency will no longer be 
engaged in rulemaking. Moreover, a process of maintaining a copy of all 
notices at DMB would require that an additional copy be submitted and 
that an administrative copy be maintained at two locations (i.e., CFSAN 
as well as DMB). Such a process would be administratively inefficient.
    Nonetheless, FDA has considered the best way to make the 
information from the proposed notification procedure readily accessible 
to the public. FDA has tentatively concluded that making both the GRAS 
exemption claim provided under proposed Sec. 170.36(c)(1) and all 
letters issued by the agency relevant to each claim easily accessible 
to the public is the most direct and administratively efficient way of 
meeting the needs of the public. Accordingly, under proposed 
Sec. 170.36(f)(2), the following information would be readily 
accessible for public review and copying: (1) A copy of all GRAS 
exemption claims received under proposed Sec. 170.36(c)(1); (2) a copy 
of all

[[Page 18953]]

letters issued by the agency under proposed Sec. 170.36(e); and (3) a 
copy of any subsequent letter issued by the agency.
    FDA considered whether the agency should only make a GRAS exemption 
claim readily accessible if the agency has not advised a notifier that 
it has identified a problem with the notice. The agency decided to make 
all claims and responses readily accessible because such a system will 
properly underscore the notifier's acceptance of responsibility for the 
determination. Proposed Sec. 170.36(f)(2) makes explicit to notifiers 
that their notice to the agency about a GRAS determination is a public 
claim.
    Initially, FDA intends to prepare a file containing the information 
specified by proposed Sec. 170.36(f)(2) and to place that file on 
public display at DMB. FDA is planning this approach because DMB is a 
common repository for publicly available files. Alternatively, FDA 
could make the file accessible for inspection at the agency's Freedom 
of Information Office or, in keeping with the current procedures for 
public inspection of the information FDA considered and relied on to 
reach a decision on an FAP, at CFSAN. Although FDA has tentatively 
concluded that it would be best to provide for public accessibility at 
DMB because the public is already accustomed to obtaining information 
relating to GRAS substances at that location, the agency requests 
comment on this matter.
    FDA is not proposing to codify how or where the information 
prescribed by proposed Sec. 170.36(f)(2) would be made accessible 
because any mechanism that appears in the agency's regulations will 
bind the agency to its provisions. In keeping with the agency's goals 
in meeting the Reinventing Food Regulations, FDA wishes to maintain 
flexibility to improve the process for public accessibility, 
particularly as the agency gains experience with electronic modes of 
information dissemination. FDA is aware that the public review of hard 
copy (i.e., paper) files in a public reading room may become obsolete 
as electronic technology for public dissemination of information 
advances.
    FDA requests comment on whether proposed Sec. 170.36(f)(2) is an 
effective and efficient means to provide the public with ready access 
to information from the proposed notification procedure.

F. Inventory

    Proposed Sec. 170.36(f)(2) would not require that FDA maintain an 
inventory of the information retained in the publicly accessible file. 
Consequently, such an inventory would be a new record within the 
meaning of Sec. 20.24 and FDA would not be required to prepare such an 
inventory in response to a FOIA request. However, FDA recognizes the 
utility and importance of an inventory of notices received under 
proposed Sec. 170.36 and of the agency's response to those notices, 
particularly for persons without ready access to the agency's DMB. FDA 
also recognizes that many members of the public would prefer to access 
basic information relevant to GRAS notices in a streamlined format. FDA 
further recognizes that the agency itself can most efficiently carry 
out its own responsibilities (e.g., with respect to monitoring imports 
of food products) by having basic information relevant to GRAS notices 
available in such a format.
    Therefore, FDA intends to maintain an inventory of notices 
received, the agency's response, and any subsequent relevant agency 
correspondence. Such an inventory would be an administratively 
efficient mechanism of accounting for the information residing in the 
publicly accessible file. Such an inventory also would complement the 
current agency regulations tabulating substances that are listed (part 
182) or affirmed (parts 184 and 186) as GRAS.
    FDA has tentatively concluded that any inventory of notices 
received should be an adjunct to proposed Sec. 170.36(f)(2), rather 
than the sole means of distributing the information available from the 
notification procedure, because the agency could place the GRAS 
exemption claims and the letters issued by the agency in the publicly 
accessible file faster than it could amend an inventory. However, FDA 
is not proposing to codify the inventory as an adjunct to proposed 
Sec. 170.36(f)(2) because such an inventory would require continuous 
amendment and the administrative procedures required to amend a 
codified inventory would be too cumbersome to meet the needs of the 
public and the agency efficiently.
    FDA is also not proposing to mention the availability of the 
inventory in its codified regulations. In keeping with the agency's 
goals in meeting Reinventing Food Regulations, FDA believes that 
refraining from codifying any aspect of the inventory will provide the 
agency with maximum flexibility to improve the process by which the 
inventory is updated and maintained.
    Initially, FDA intends that such an inventory would be publicly 
accessible in any file maintained in accordance with proposed 
Sec. 170.36(f)(2), e.g., at DMB. FDA could also make such an inventory 
available through prevailing publicly accessible electronic modes, such 
as the agency's home page on the contemporary World Wide Web. FDA 
requests comment on making any inventory prepared by the agency 
available through such electronic modes.

VII. Effect of the Proposed Notification Procedure on Existing GRAS 
Petitions

    Under the current GRAS affirmation process, the agency conducts a 
preliminary examination of the data and information submitted in the 
petition. If FDA finds that the submitted information conforms to the 
requirements established under Secs. 170.30 and 170.35, FDA makes an 
administrative decision to file the petition and publishes a notice in 
the Federal Register to that effect.
    At this time, approximately 60 filed GRAS affirmation petitions are 
pending at FDA. These petitions were filed with the agency under an 
administrative process that the agency is proposing to remove. 
Therefore, if this proposal becomes final, the administrative process 
that FDA would use to bring these petitions to closure will no longer 
be operative. Moreover, FDA is proposing to eliminate the GRAS 
affirmation process in order to increase effectiveness and efficiency. 
The continued commitment of agency resources to complete the GRAS 
petition process for pending petitions would be contrary to one of the 
agency's goals in this rulemaking.
    FDA recognizes that persons who have a pending GRAS affirmation 
petition have invested time and resources in those petitions. 
Therefore, proposed Sec. 170.36(g)(1) stipulates that any GRAS 
affirmation petition filed under Sec. 170.35 prior to the date that a 
final rule based on this proposal becomes effective, and still pending 
as of such effective date, will be presumptively converted to a GRAS 
notice under proposed Sec. 170.36. This conversion will allow the 
agency to bring filed GRAS affirmation petitions to closure, albeit 
under a different process than the one to which they were submitted.
    However, the proposed notification procedure has certain 
requirements that have no specific counterpart in the petition process. 
In particular, under the notification procedure a notifier explicitly 
accepts full responsibility for the GRAS determination by signing a 
GRAS exemption claim (under proposed Sec. 170.36(c)(1)). In contrast, 
under the petition process a petitioner requests that FDA attest to a 
GRAS determination. Thus, FDA cannot assume that all persons who 
submitted

[[Page 18954]]

a GRAS petition would in fact be willing to accept full responsibility 
for the determination.
    Moreover, the GRAS exemption claim in proposed Sec. 170.36(c)(1) 
would be a complete and separate section of a GRAS notice that could 
stand alone and would contain basic information in a consistent format. 
As discussed, under proposed Sec. 170.36(f)(2) the agency would use the 
GRAS exemption claim to effectively and efficiently inform the public 
about received notices. Thus, logic compels that a GRAS exemption claim 
filed under proposed Sec. 170.36(g) include all elements of the claim 
required under proposed Sec. 170.36(c)(1), rather than only those 
elements that have no counterpart in the GRAS affirmation petition 
process.
    Accordingly, proposed Sec. 170.36(g)(2) provides that any person 
who submitted a GRAS affirmation petition that is converted to a notice 
under the provisions of proposed Sec. 170.36(g)(1) may amend such 
converted petition to satisfy the requirements of proposed Sec. 170.36 
by submitting to the agency a claim, dated and signed by the notifier 
(i.e., the former petitioner), that a particular use of a substance is 
exempt from the premarket approval requirements of the act because the 
notifier has determined that such use is GRAS. Proposed Sec. 170.36 
(g)(2)(i) through (g)(2)(vi) describe the format of the GRAS exemption 
claim that would amend a converted GRAS affirmation petition to satisfy 
the requirements of a notice under proposed Sec. 170.36. This claim 
format is similar to that required under proposed Sec. 170.36(c)(1) but 
has been modified in two particulars (i.e., proposed Sec. 170.36 
(g)(2)(ii) and (g)(2)(vi)) to take into account the fact that the data 
and information to support the GRAS determination have already been 
submitted to the agency in the applicable GRAS petition.
    Proposed Sec. 170.36(g)(2)(i) requires that the GRAS exemption 
claim include the name and address of the notifier. As with proposed 
Sec. 170.36(c)(1)(i), this is necessary for full identification of the 
person who accepts responsibility for the claim. This also is necessary 
so that the agency can administer the amendment to the converted 
petition according to the provisions of proposed Sec. 170.36 (d) and 
(e) (see proposed Sec. 170.36(g)(3)(i)).
    Proposed Sec. 170.36(g)(2)(ii) requires that the GRAS exemption 
claim include the applicable GRAS affirmation petition number. The 
petition number is the simplest way to identify the converted petition 
that is being amended.
    Proposed Sec. 170.36(g)(2)(iii) requires that the GRAS exemption 
claim include the common or usual name of the substance that was the 
subject of the converted GRAS affirmation petition (i.e., the notified 
substance). As with proposed Sec. 170.36(c)(1)(ii), this is necessary 
to identify the notified substance as well as to identify whether there 
are any labeling issues that need to be addressed. FDA is satisfied 
that detailed identity information, such as that described in proposed 
Sec. 170.36(c)(2), will be present in the referenced petition because, 
under current Sec. 170.35(c)(1)(i), FDA requires that a GRAS petition 
contain such information as a prerequisite to filing the petition.
    Proposed Sec. 170.36(g)(2)(iv) requires that the GRAS exemption 
claim include the applicable conditions of use that are supported by 
data and information in the referenced GRAS petition, including the 
foods in which the notified substance is to be used, levels of use in 
such foods, and the purposes for which the notified substance is used, 
including, when appropriate, a description of the population expected 
to consume the substance. As with proposed Sec. 170.36(c)(1)(iii), this 
information describing the conditions of use is necessary to delineate 
the boundaries of the GRAS exemption claim consistent with section 
201(s) of the act, which states that a GRAS substance must be generally 
recognized as safe ``under the conditions of its intended use.'' 
Importantly, a petitioner who amends a converted GRAS affirmation 
petition to satisfy the requirements of a notice may do so only for the 
intended use that was the subject of the GRAS affirmation petition. Any 
additional use(s) would be the subject of a separate notice under 
proposed Sec. 170.36(c).
    Proposed Sec. 170.36(g)(2)(v) requires that the GRAS exemption 
claim identify the basis for the GRAS determination as scientific 
procedures or experience based on common use in food. As discussed in 
section I.B.4 of this document, under Sec. 170.30, the requirements for 
a scientific procedures GRAS determination are different from those for 
a common use GRAS determination. The basis for a GRAS determination is 
thus fundamental to the GRAS exemption claim.
    Proposed Sec. 170.36(g)(2)(vi) requires that the GRAS exemption 
claim include either a statement that the complete record that supports 
the GRAS determination has already been submitted to the agency in the 
relevant GRAS petition (proposed Sec. 170.36(g)(2)(vi)(A)) or a 
statement that all data and information that are the basis for the GRAS 
determination are available for FDA review and copying or will be sent 
to FDA upon request (proposed Sec. 170.36(g)(2)(vi)(B)). Proposed 
Sec. 170.36(g)(2)(vi) takes into account the fact that, in many cases, 
a petitioner has already submitted the complete record that supports 
the GRAS determination. Alternatively, proposed Sec. 170.36(g)(2)(vi) 
provides to the person who submitted a GRAS petition the option of 
agreeing to provide upon request any additional information that 
supports the GRAS determination but was not included in the GRAS 
petition. As discussed with respect to proposed Sec. 170.36(c)(1)(v), 
FDA might conduct random audits of such data and information or conduct 
an audit on a broad issue or class of products if the issue or use of a 
class of products raises important public health issues.
    FDA requests comment on proposed Sec. 170.36(g) as a mechanism for 
administering pending GRAS affirmation petitions if the proposed 
notification procedure becomes final. Proposed Sec. 170.36(g) would not 
preclude any person who had a filed GRAS petition prior to the 
effective date of a final GRAS notification rule from submitting a 
notice of a claim for exemption according to the provisions of proposed 
Sec. 170.36(c) or from submitting an FAP under Sec. 171.1 and 
requesting that FDA cross reference the information contained in the 
filed GRAS petition in accordance with Sec. 171.1(b).

VIII. Interim Policy

    Between the time of publication of this proposal and any final rule 
based on this proposal, FDA invites interested persons who determine 
that a use of a substance is GRAS to notify FDA of such GRAS 
determinations as described in proposed Sec. 170.36 (b) and (c). In 
general, the agency would administer the notices as described in 
proposed Sec. 170.36 (d) through (f) (i.e., FDA would acknowledge 
receipt of the notice, respond in writing to the notifier, and make 
publicly accessible a copy of all GRAS exemption claims and the 
agency's response). However, although FDA would make a good faith 
effort to respond within the proposed 90-day timeframe, the agency 
would not be bound by such a timeframe. FDA will determine whether its 
experience in administering such notices suggests modifications to the 
proposed procedure.
    FDA realizes that some individuals who have a filed GRAS 
affirmation petition pending at the agency may be interested in 
converting such petition to a notice under proposed Sec. 170.36(g) or

[[Page 18955]]

in submitting a complete notice for the petitioned use under proposed 
Sec. 170.36 (b) and (c). FDA invites such petitioners to submit an 
amendment in accordance with proposed Sec. 170.36(g)(2) or to submit a 
complete notice for the petitioned use in accordance with proposed 
Sec. 170.36 (b) and (c). FDA would administer such notice or amendment 
as described in proposed Sec. 170.36 (d) through (f). However, during 
the interim period FDA would not continue to commit resources to review 
of a GRAS affirmation petition if the agency receives an amendment in 
accordance with proposed Sec. 170.36(g)(2) or receives a complete 
notice concerning the petitioned use.
    FDA will consult upon request with interested persons who seek 
additional guidance in preparing a notice because such consultation may 
identify sections of the proposed procedure that may require 
clarification in any final rule based on the proposal.

IX. Conforming Amendments

    This proposal would eliminate the GRAS petition process set out in 
Sec. 170.35(c). Therefore, FDA is proposing conforming amendments to 
revise current Secs. 184.1(b)(1) and 186.1(b)(1) by removing the last 
sentence of each paragraph. These sentences provide that persons 
seeking FDA approval of an independent determination that a use of a 
food substance is GRAS may submit a petition in accordance with 
Sec. 170.35.
    Consistent with the proposed elimination of the GRAS petition 
process set out in Sec. 170.35(c), FDA is also proposing a conforming 
amendment to revise current Sec. 170.38(a) to: (1) Remove the provision 
that the Commissioner may, in accordance with Sec. 170.35(c)(5), 
publish a notice in the Federal Register determining that a substance 
is not GRAS and is a food additive subject to section 409 of the act 
and (2) retain the provision in Sec. 170.38(a) that the Commissioner 
may, in accordance with Sec. 170.35(b)(4) (i.e., on his/her own 
initiative), publish such a notice in the Federal Register. 
Importantly, however, when faced with a public health hazard, the 
existence of such rulemaking authority would not preclude other agency 
action, including seizure and injunction, to remove from the market a 
product that is an unapproved food additive.

X. International Harmonization

    FDA is committed to international harmonization of regulatory 
requirements and guidelines that preserve and enhance the agency's 
ability to accomplish its public health mission, enhance regulatory 
effectiveness by providing more consumer protection with scarce 
government resources, and increase worldwide access to safe and high 
quality food products (60 FR 53078, October 11, 1995). FDA is not aware 
of a provision in the laws of any other country that is equivalent to 
the GRAS exemption. On the other hand, the laws of other countries 
provide exemptions (e.g., for ``natural'' products) that have no 
equivalent under the act. Thus, the international community is already 
accustomed to operating in accordance with a variety of regulatory 
approaches for substances added to food. FDA's proposed substitution of 
a GRAS notification procedure for the current GRAS petition process 
would not impose any new requirements that would affect imported food 
products.
    Under the current petition process, FDA makes a public announcement 
that a petition has been filed and incorporates an affirmed use of a 
substance into a codified list. Under the proposed notification 
procedure, FDA would make readily accessible to the public, including 
international agencies and firms, the notice's ``GRAS exemption 
claim,'' which would include a succinct description of the notified 
substance, the applicable conditions of use, and the basis for the GRAS 
determination (i.e., through scientific procedures or through 
experience based on common use in food). FDA would also make readily 
accessible to the public the agency's response to the notice. Further, 
under the act, a variety of substances that must be declared on the 
food label are exempt from premarket approval on the basis of the GRAS 
exemption and are not included on any government list or inventory of 
substances that are used lawfully in the U.S. food supply. Operation of 
either the petition process or the proposed notification procedure does 
not change that fact.
    FDA recognizes that interested persons may want to know the 
official regulatory status of a food substance in the United States 
prior to using that substance in foods that will enter international 
commerce. FDA also recognizes that the proposed agency response to a 
GRAS notice may have less weight in the international community than 
the agency's affirmation of GRAS status. However, as a practical 
matter, FDA has announced only approximately 30 GRAS affirmations in 
the 10 years preceding this proposed rule. This small number of GRAS 
affirmations has a minimal impact on considerations of international 
trade.
    For these reasons, FDA does not anticipate that the proposed 
substitution of a GRAS notification procedure for the GRAS petition 
process will have any impact on international trade. Nevertheless, the 
agency invites comment on this matter from the international community 
and from firms who import food products into the United States or who 
export U.S. made food products.

XI. Food Substances Used in Animal Feed

    FDA's regulations regarding the eligibility of substances used in 
animal food or feeds for classification as GRAS, and the procedures for 
affirmation of GRAS status for such substances, are codified at 
Secs. 570.30 and 570.35, respectively. The requirements described in 
these regulations are parallel to the requirements for GRAS substances 
that are used in human food, although some requirements of Sec. 170.30 
have no corresponding requirement in Sec. 570.30. As an example 
relevant to this rulemaking, the requirements of Sec. 570.30(c) are 
identical to the requirements of Sec. 170.30(c)(1), but Sec. 570.30(c) 
has not been amended to describe the requirements for a common use GRAS 
determination based on history of use when that history of use occurred 
primarily or exclusively outside the United States. In addition, the 
agency's GRAS review did not extend to the use of food substances in 
animal food or feeds. Thus, Sec. 570.30 does not contain provisions 
analogous to Sec. 170.30 (e) and (f).
    The general provisions in subpart A of part 184 were issued under 
the auspices of the agency's comprehensive review of GRAS substances. 
Because this agency review did not extend to the use of food substances 
in animal food or feeds, the agency did not issue a corresponding 
subpart A in part 584 (21 CFR part 584). Therefore, any proposed rule 
to modify Secs. 570.30 and 570.35 would require no conforming 
amendments in part 584.
    FDA is also proposing to amend the provisions of Sec. 570.30 that 
are parallel to the provisions of current Sec. 170.30 (i.e., 
Sec. 570.30 (a) and (b)) because Secs. 170.30 and 570.30 implement the 
same statutory provisions. Therefore, it is important for the agency's 
standards concerning GRAS substances to be consistent with respect to 
substances used in human food and substances used in animal food or 
feeds.
    FDA is also proposing to eliminate the GRAS affirmation petition 
process provided for in Sec. 570.35 (a) and (c) because the 
corresponding process for substances used in human food is being 
eliminated. Although the GRAS

[[Page 18956]]

affirmation process has rarely been employed for substances used in 
animal food or feeds, FDA believes that it is appropriate to provide 
the option of a GRAS notification procedure for animal food or feeds 
that would be parallel to proposed Sec. 170.36. Therefore, in proposed 
Sec. 570.36 the agency is proposing a GRAS notification procedure for 
substances used in animal food or feeds. Finally, FDA is proposing to 
revise current Sec. 570.38(a) as a conforming amendment required by 
removing the current GRAS affirmation petition process for substances 
used in animal food or feeds.
    With regard to the notification procedure, FDA's proposal for 
substances that would be used in animal food or feeds is for practical 
purposes identical to FDA's proposal for substances that would be used 
in human food. As discussed in more detail throughout this document, 
FDA is specifically requesting comment on the following issues 
concerning the proposed regulations for substances that would be used 
in human food: (1) Whether it would be appropriate to require or 
recommend that the submission include an electronic copy, in addition 
to three paper copies, of some or all of the notice; (2) the proposed 
requirement that, in all cases, FDA respond to the notifier; (3) 
whether the agency should be permitted more than 90 days to respond to 
a GRAS notice; (4) the number of notices that notifiers anticipate 
submitting on an annual basis; (5) the agency's proposal to provide the 
public with ready access to information from the proposed notification 
procedure and the location for such information; (6) whether any 
inventory prepared by the agency should be available through electronic 
modes; (7) its proposal for administering pending GRAS affirmation 
petitions if the proposed notification procedure becomes final; and (8) 
whether the proposed substitution of a GRAS notification procedure for 
the GRAS petition process would have any impact on international trade. 
FDA specifically requests comments on these same issues for the 
proposed regulations concerning substances that would be used in animal 
foods or feed.
    In the case of substances that would be used in animal feed, FDA is 
particularly concerned about the practical implications of a 90-day 
response period, because, to date, the agency has received fewer than 
10 GRAS affirmation petitions for substances that would be used solely 
in animal food or feed. Should the number of notices received under a 
GRAS notification program exceed more than a few notices per year, 
agency resources devoted to the animal feed program likely would be 
insufficient to evaluate, within the proposed 90-day timeframe, whether 
the notice provides a sufficient basis for a GRAS determination. Thus, 
comments to the proposal may justify that the agency adopt, in a final 
rule, a longer timeframe for notifications concerning substances used 
in animal feed.
    The agency recognizes that notifiers may have questions concerning 
the common or usual name for a substance that would be used in animal 
feeds. FDA advises that, in such circumstances, a notifier should 
consult with the Division of Animal Feeds in FDA's Center for 
Veterinary Medicine.

XII. Summary of the Proposal

    FDA is proposing to clarify current Sec. 170.30 regarding the 
eligibility of the use of a substance for exemption from the act's 
premarket approval requirements based on a GRAS determination. 
Specifically, FDA is proposing to amend current Sec. 170.30(a) to 
clarify that general recognition of safety requires that there be 
common knowledge among the qualified expert community that there is 
reasonable certainty that the substance is not harmful under the 
intended conditions of use. This amendment would also clarify that a 
GRAS substance is neither more safe nor less safe than an approved food 
additive, and that the distinction between a GRAS substance and an 
approved food additive is in the common knowledge of, and expert 
consensus about, that safety.
    In addition, FDA is proposing two changes to current 
Sec. 170.30(b). First, FDA is proposing to clarify the types of 
technical evidence of safety that ordinarily would constitute common 
knowledge about a substance that is GRAS through scientific procedures. 
FDA is proposing this change because the quantity and quality of 
scientific evidence required to obtain approval of a substance as a 
food additive vary considerably depending upon the estimated dietary 
exposure to the substance and the chemical, physical, and physiological 
properties of the substance. Second, FDA is proposing to clarify the 
role of publication in satisfying the common knowledge element of the 
GRAS standard because publication is ordinarily required, but may not 
always be sufficient, to satisfy this element. For consistency with 
these proposed amendments, FDA is also proposing to amend the 
definition of ``scientific procedures'' in Sec. 170.3(h).
    In keeping with the Reinventing Food Regulations, FDA is proposing 
to replace the current voluntary GRAS affirmation process with a 
voluntary procedure whereby any person may notify FDA of a GRAS 
determination. The notice would include a ``GRAS exemption claim,'' 
dated and signed by the notifier, that would provide, in a consistent 
format, specific information about a GRAS determination. This claim 
would include a succinct description of the notified substance, the 
applicable conditions of use, and the basis for the GRAS determination. 
The GRAS exemption claim would also include a statement that the 
information supporting the GRAS determination was available for FDA 
review and copying or would be sent to FDA upon request. In addition to 
the GRAS exemption claim, the notice would include detailed information 
about the identity of the notified substance and a detailed discussion 
of the basis for the notifier's GRAS determination.
    FDA would evaluate whether the 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. Within 90 days from the 
date of receipt of the notice, FDA would respond to the notifier in 
writing and could advise the notifier that the agency has identified a 
problem with the notice. A response that does not advise that the 
agency has identified a problem with the notice would not be equivalent 
to an affirmation of GRAS status by the agency.
    For each notice received, FDA would make readily accessible to the 
public the GRAS exemption claim and the agency's response. Although FDA 
would maintain a readily accessible inventory of notices received and 
the agency's response to them, this inventory would be neither codified 
nor referenced in the agency's regulations.
    Under the proposal, all GRAS affirmation petitions that were filed 
by FDA under Sec. 170.35 prior to the effective date of a GRAS 
notification final rule and still pending as of that date would be 
presumptively converted to a notice on that date. Any person who had 
submitted a GRAS affirmation petition that is converted to a notice 
could: (1) Amend such converted petition to satisfy the requirements of 
the notification procedure by submitting to the agency a modified GRAS 
exemption claim; (2) submit an FAP for the substance and request that 
FDA cross reference the information in the GRAS affirmation petition; 
or (3) submit a complete notice in accordance with the notification 
procedure.

[[Page 18957]]

    FDA's regulations in part 570 concerning GRAS substances for use in 
animal food or feeds implement the same statutory provisions as the 
regulations in part 170 concerning GRAS substances for use in human 
food. Accordingly, FDA is proposing: (1) To amend the provisions of 
Sec. 570.30 that are parallel to the provisions of current Sec. 170.30 
(i.e., Sec. 570.30(a) and (b)); (2) to eliminate the GRAS affirmation 
petition process provided for in Sec. 570.35(a) and (c); and (3) to 
provide the option of a GRAS notification procedure for substances used 
in animal food or feeds that would be parallel to proposed Sec. 170.36.
    FDA is also proposing several amendments to parts 170, 184, 186, 
and 570 of its regulations as conforming amendments.

XIII. Paperwork Reduction

    This proposed rule contains information that is subject to review 
by OMB under the Paperwork Reduction Act of 1995 (Pub. L. 104-13). 
Therefore, in accordance with 44 U.S.C. 3506(c)(2)(B) and 5 CFR part 
1320, FDA is providing below the title, description, and respondent 
descriptions for the information collections contained in this 
proposal, along with an estimate of the resulting annual information 
collection burden. Included in the estimate is the time needed to 
review instructions, to gather the required information, and to 
disclose the information.
    FDA invites comments on the following: (1) Whether the proposed 
collection of information is necessary for the proper performance of 
the functions of the agency, including whether the information will 
have practical utility; (2) the accuracy of the agency's estimate of 
the burden of the proposed collection of information, including the 
validity of the methodology and assumptions used; (3) ways to enhance 
the quality, utility, and clarity of the information to be collected; 
and (4) ways to minimize the burden of the collection of information on 
those who are to respond, including through the use of automated 
collection techniques, where appropriate, or other forms of information 
technology.
    Title: Notice of a Claim for GRAS Exemption Based on a GRAS 
Determination
    Description: Section 409 of the act establishes a premarket 
approval requirement for ``food additives;'' section 201(s) of that act 
provides an exemption from the definition of ``food additive'' and thus 
from the premarket approval requirement, for uses of substances that 
are GRAS by qualified experts. FDA is proposing a voluntary procedure 
whereby members of the food industry who determine that use of a 
substance satisfies the statutory exemption may notify FDA of that 
determination. The notice would include a detailed summary of the data 
and information that support the GRAS determination, and the notifier 
would maintain a record of such data and information. FDA would make 
the information describing the GRAS claim, and the agency's response to 
the notice, available in a publicly accessible file; the entire GRAS 
notice would be publicly available consistent with the FOIA and other 
Federal disclosure statutes.
    Description of Respondents: Manufacturers of Substances Used in 
Food and Feed
    FDA estimates the total annual burden for this information 
collection to be 9,900 hours.

                                         Estimated Annual Report Burden                                         
----------------------------------------------------------------------------------------------------------------
                                                                 Annual                                         
                                                  Number of    frequency      Total      Hours per              
                     21 CFR                      respondents      per         annual      response   Total hours
                                                                response     response                           
----------------------------------------------------------------------------------------------------------------
170.36.........................................           50            1           50          150        7,500
570.36.........................................           10            1           10          150        1,500
----------------------------------------------------------------------------------------------------------------

    There are no operating or maintenance costs or capital costs 
associated with this collection.

                                      Estimated Annual Recordkeeping Burden                                     
----------------------------------------------------------------------------------------------------------------
                                                               Annual        Total                              
                  21 CFR                      Number of     frequency of     annual      Hours per   Total hours
                                            recordkeepers  recordkeeping    records    recordkeeper             
----------------------------------------------------------------------------------------------------------------
170.36(c)(v)..............................            50              1            50            15          750
570.36(c)(v)..............................            10              1            10            15          150
----------------------------------------------------------------------------------------------------------------

    There are no operating or maintenance costs or capital costs 
associated with this collection.
    FDA tentatively concludes that there are no anticipated capital 
costs or operating and maintenance costs associated with the proposed 
information collection requirements. However, the agency welcomes 
comments on any such anticipated costs.
    The agency has submitted copies of the proposed rule to OMB for 
review of the portions of the proposal that are subject to the 
Paperwork Reduction Act of 1995. Interested persons are requested to 
send comments regarding information collection by May 19, 1997 to the 
Office of Information and Regulatory Affairs, OMB (address above).

XIV. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612). 
Executive Order 12866 directs agencies to assess all costs and benefits 
of available regulatory alternatives and, when regulation is necessary, 
to select the regulatory approaches that maximize net benefits 
(including potential economic, environmental, public health and safety 
effects; other advantages; distributive impacts; and equity). Executive 
Order 12866 classifies a rule as significant if it meets any one of a 
number of specified conditions, including having an annual effect on 
the economy of $100 million or adversely affecting in a material way a 
sector of the economy, competition, or jobs, or if it raises novel 
legal or policy issues. If a rule has a significant economic impact on 
a

[[Page 18958]]

substantial number of small entities, the Regulatory Flexibility Act 
requires agencies to analyze regulatory options that would minimize the 
economic impact of that rule on small entities.
    FDA finds that this proposed rule is not a significant rule as 
defined by Executive Order 12866, and finds under the Regulatory 
Flexibility Act that this proposed rule will not have a significant 
impact on a substantial number of small entities. Finally, FDA, in 
conjunction with the Administrator of OMB, finds that this proposed 
rule is not a major rule for the purpose of congressional review (Pub. 
L. 104-121).

A. Regulatory Options

    FDA has the following primary options:
    (1) Take no action;
    (2) Adopt proposed GRAS notification procedure;
    (3) Adopt a GRAS notification procedure allowing FDA feedback on 
independent GRAS determinations of either a higher or lower level of 
authoritativeness than the proposed notification system; and
    (4) Eliminate agency participation in independent GRAS 
determinations.

B. Costs and Benefits

1. Option One: Take No Action
    Neither costs nor benefits are associated with taking no action. 
This option is the baseline case in comparison with which the costs and 
benefits of the other options are determined.
    The existing GRAS petition process is a government service provided 
to industry by which firms may voluntarily submit information to FDA 
for agency review and affirmation of the GRAS status of the use of a 
substance in food. Although FDA does not charge a fee to review 
material submitted under the GRAS petition process, participation in 
that process is not without cost because the required information must 
either be generated or gathered, and submitted to FDA. The fact that 
some firms participate in this voluntary process implies that for some 
firms, the benefit of participation must be greater than the cost of 
participation, and also that the net benefit of participation must be 
greater than the net benefit of existing alternatives, such as private 
third-party review of independent GRAS determinations. However, the 
fact that the cost of participation does not reflect the costs involved 
in actually administering the GRAS petition process means that 
participation in that process cannot support inferences regarding the 
net social benefits of the petition process.
    The benefit firms receive from participation in the existing GRAS 
petition process appears to involve a reduction in the cost of 
marketing foods containing substances independently determined to be 
GRAS because FDA affirmation of GRAS status would likely facilitate 
marketing of such substances. Manufacturers of these foods and retail 
establishments buying these foods for subsequent resale to consumers 
may be reluctant to offer them for sale in the absence of assurance 
that FDA will not subsequently conclude that ingredients independently 
determined to be GRAS are unapproved food additives. If these 
substances were subsequently found not to be GRAS, any ensuing seizure 
of foods containing the unapproved food additive might damage the 
credibility of those manufacturers and retail establishments, and might 
lead to economic losses. If there were no process for agency GRAS 
affirmation, firms making independent GRAS determinations may attempt 
to substitute for GRAS affirmations by doing additional research, 
contracting with third party research organizations, or taking other 
steps to provide adequate assurances to other firms that FDA will 
probably not subsequently challenge their independent GRAS 
determinations.
    In addition to providing a desired good or service, the GRAS 
petition process may result in some benefit in terms of reducing the 
health risks from substances independently determined to be GRAS if FDA 
review of the information supporting independent GRAS determinations 
uncovers an erroneous determination which, if undetected, could lead to 
health risks.
2. Option Two: Adopt Proposed GRAS Notification Procedure
    The chief benefit of eliminating the existing GRAS petition process 
and replacing it with the proposed GRAS notification procedure is that 
the notification procedure will enable industry to obtain a limited 
degree of FDA feedback on independent GRAS determinations more quickly 
and at lower cost, to both industry and FDA, than the GRAS petition 
process. Under the proposed notification procedure, FDA will determine 
whether the notice provides a sufficient basis for a GRAS determination 
or 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.
    The proposed notification procedure will come to closure more 
quickly and generate less uncertainty than the GRAS petition process 
because the notification procedure is based on a 90-day review period 
rather than on the open-ended review period of the GRAS petition 
process. In some cases, the GRAS petition process involves a number of 
iterative steps in which FDA asks for and receives additional 
supporting information. Under the notification procedure, FDA will base 
its response on the notifier's initial submission.
    In addition to the time advantage, the cost of participation in the 
proposed notification procedure will probably be less than the cost of 
participation in the GRAS petition process because the notification 
procedure will require the submission of only a summary of the 
information used to support the independent GRAS determination, rather 
than the full supporting information required under the GRAS petition 
process. For example, the notification procedure will not require the 
submission of references or material relating to methods of detection 
in foods, which are required under the GRAS petition process. 
Submissions under the notification procedure will probably be about 25 
to 30 pages, while submissions under the current GRAS petition process 
can have hundreds or even thousands of pages.
    On the other hand, the same underlying information will be required 
under the notification procedure as under the GRAS petition process, so 
the potential cost savings will be confined to the relatively modest 
costs of assembling, copying, and mailing information. The more 
significant cost of generating or locating the requisite underlying 
information will not be affected. In addition, the summary required 
under the proposed notification procedure may fairly be viewed as a 
step beyond simply providing the supporting information as required 
under the GRAS petition process. Therefore, although participation in 
the proposed notification procedure will probably be somewhat less 
costly than participation in the GRAS petition process, the cost 
reduction is likely to be relatively modest.
    The primary cost of replacing the existing GRAS petition process 
with the proposed notification procedure is that it reduces the options 
available to industry for obtaining FDA feedback on independent GRAS 
determinations at a level of authoritativeness comparable to that 
currently offered under the GRAS petition process. Currently, feedback 
at this level of authoritativeness is available through both the GRAS 
petition process and the FAP process. The fact that FDA receives both 
GRAS petitions and FAP's suggests that some

[[Page 18959]]

firms find participation in the GRAS petition process less costly than 
participation in the FAP process. However, this difference in cost is 
probably relatively modest because the systems are quite similar. For 
example, substances that are GRAS may be marketed without prior agency 
approval and thus may be marketed during the period in which either a 
GRAS petition or an FAP on that substance is under review.
    The net benefit or cost of the proposed notification procedure will 
depend largely on whether the value of participation in the proposed 
notification procedure is or is not comparable to that of participation 
in the GRAS petition process. If the value of participation in the two 
systems is roughly comparable, then the time and cost advantages of the 
proposed notification procedure will probably lead to modest net 
benefits. However, if participation in the proposed notification 
procedure is significantly less valuable than participation in the GRAS 
petition process because of the lower level of authoritativeness of FDA 
feedback available through the notification procedure, then the 
proposed procedure could lead to net costs because firms may submit 
relatively more costly FAP's or take other steps to compensate for the 
lack of more authoritative FDA feedback on independent GRAS 
determinations.
3. Option Three: Adopt a GRAS Notification Procedure Allowing FDA 
Feedback on Independent GRAS Determinations of Either a Higher or Lower 
Level of Authoritativeness Than the Proposed Notification System
    The benefits and costs of replacing the existing GRAS petition 
process with notification procedures allowing FDA feedback on 
independent GRAS determinations at either higher or lower levels of 
authoritativeness than the proposed notification procedure are 
qualitatively similar to the benefits and costs of adopting the 
proposed notification procedure.
    The net benefits or costs of notification procedures allowing more 
or less authoritative FDA feedback depend largely on the cost of 
participation in those systems and the value of the feedback provided 
to participating firms under those systems. The value of FDA feedback 
to participating firms involves the degree to which that feedback 
facilitates the marketing of substances that have been subject to 
independent GRAS determinations. A system providing more authoritative 
feedback than the proposed GRAS notification procedure would either 
require submission of more information or more detailed information, or 
would involve more detailed agency review of the same amount of 
information. Thus, participation in such a system would arguably 
provide more valuable feedback than participation in the proposed 
notification procedure but would also be more costly than participation 
in the proposed notification procedure. A system providing less 
authoritative feedback than the proposed GRAS notification procedure 
would either require submission of less information or less detailed 
information, or would involve less detailed agency review of the same 
amount of information. Thus, participation in such a system would 
arguably provide less valuable feedback than participation in the 
proposed notification procedure but would probably also be less costly 
than participation in the proposed notification procedure.
    In both cases, it is difficult to determine whether the resulting 
changes in the value of FDA feedback available through the notification 
procedure would compensate firms for the resulting changes in the cost 
of participation in such procedures, or to compare the net social 
benefits of offering such procedures with the net benefits of the 
existing GRAS petition process.
4. Option Four: Eliminate Agency Participation in Independent GRAS 
Determinations
    The costs and benefits of this option are qualitatively similar to 
those of adopting a notification procedure allowing FDA feedback of 
only a minimal level of authoritativeness. In general, the same results 
will occur if the value of participation in a notification procedure 
drops below the costs involved in participation, or if a notification 
procedure is not available. In both cases, industry will either submit 
relatively costly FAP's or take other steps to compensate for the lack 
of a GRAS notification procedure or petition process, or simply forgo 
government oversight of their independent GRAS determinations.
    If FDA no longer participates in independent GRAS determinations, 
FDA will not be aware of substances that have been the subject of 
independent GRAS determinations unless firms choose to submit FAP's for 
those substances. Any public health benefits associated with FDA 
awareness of these substances will be lost. However, if firms take 
other steps to confirm independent GRAS determinations, then these 
other steps will be associated with countervailing public health 
benefits.
    Again, it is difficult to determine whether this option would 
result in net social costs or benefits because of the difficulty of 
estimating the value of various levels of FDA and non FDA feedback on 
independent GRAS determinations. However, the distinctive role of FDA 
in GRAS issues suggests that FDA feedback may be more valuable to 
industry than other, equally costly, activity designed to confirm 
independent GRAS determinations. Therefore, it is likely that the 
availability of some type of notification procedure will lead to 
greater net benefits than no notification procedure.

C. Regulatory Flexibility Analysis

    The proposed action will affect any firm that may have chosen to 
participate in the existing GRAS petition process or may choose to 
participate in the proposed GRAS notification process, including 
manufacturers of both human and animal food, food additives, and feed 
additives. The Dun's Market Identifiers database lists 27,989 firms in 
Standard Industry Code (SIC) 20, Food and Kindred Products. This 
includes dog and cat food, and prepared feeds not elsewhere classified. 
In addition, this database lists 113 firms in SIC 2869, Industrial 
Organic Chemicals, Not Elsewhere Classified, the SIC code that includes 
manufacturers of food additives. Therefore, a total of 28,102 firms 
will potentially be affected by this proposed rule.
    The Small Business Administration (SBA) guidelines on the 
definition of a small business for SIC 20 identify a small business as 
being a business having no more than 1,000, 750, or 500 employees, 
depending on the more precise four-digit SIC code associated with the 
firm in question. However, there is no easy way to distribute the total 
number of firms in SIC 20 into the appropriate four-digit SIC 
categories because more than one primary four-digit SIC code may be 
associated with any given firm. To avoid missing any small firms, the 
least restrictive size definition of 1,000 or fewer employees was used 
for all firms. The SBA definition of a small business in SIC 2869 is a 
business with 1,000 or fewer employees. Based on these definitions, and 
assuming that the distribution of employment for firms for which no 
employee data are available is the same as the distribution for firms 
for which data are available, a total of 27,531 firms could potentially 
be affected by this proposed rule.

[[Page 18960]]

    Although this proposal may affect a substantial number of firms 
that manufacture food or food additives, many of which are small firms, 
this proposal will not have a significant impact on these firms for two 
reasons. First, this proposal replaces one voluntary program with 
another voluntary program. Therefore, small firms will not be required 
to undertake any additional activity or bear any additional costs. 
Second, participation in the proposed GRAS notification procedure 
should be somewhat less costly than participation in the GRAS petition 
process. Therefore, small firms should be better able to participate in 
the notification procedure than the petition process.

D. Conclusions

    In accordance with Executive Order 12866, FDA has analyzed this 
proposed rule and finds that this proposed rule is neither economically 
significant nor a significant action, as defined by that order. FDA has 
also analyzed this proposed rule in accordance with the Regulatory 
Flexibility Act and finds that this proposed rule will not have a 
significant impact on a substantial number of small businesses. 
Accordingly, under the Regulatory Flexibility Act, 5 U.S.C. 605(b), the 
Commissioner certifies that this proposed rule will not have a 
significant economic impact on a substantial number of small entities.
    The net costs and benefits of replacing the GRAS petition process 
with the proposed GRAS notification procedure are indeterminate. 
However, any increase in net costs or benefits relative to the current 
system will probably be modest. FDA requests comments on the costs and 
benefits of replacing the GRAS petition process with the proposed GRAS 
notification procedure.

XV. Environmental Impact

    The agency has determined under 21 CFR 25.24(a)(8) that this action 
is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

XVI. References

    The following references have been placed on display at DMB 
(address above) and may be seen by interested persons between 9 a.m. 
and 4 p.m., Monday through Friday.

    1. House Report No. 2284, July 28, 1958.
    2. Price, J. M., C. G. Biava, B. L. Oser, E. E. Vogin, J. 
Steinfeld, and H. L. Ley, ``Bladder Tumors in Rats Fed 
Cyclohexylamine or High Doses of a Mixture of Cyclamate and 
Saccharin,'' Science, 167:1131-1132, 1970.
    3. New York Times, p. 22, October 31, 1969.
    4. Sneath, P. H. A. et. al., Bergey's Manual of Systematic 
Bacteriology, Williams & Wilkins, Baltimore, 1984.
    5. Subcommittee on the 10th Edition of the Recommended Dietary 
Allowances, Food and Nutrition Board, Commission on Life Sciences, 
National Research Council, Recommended Dietary Allowances, 10th ed., 
Washington, DC, National Academy Press, 1989.
    6. ``Biotechnology and Food Safety,'' (Food and Agriculture 
Organization, Rome, 1996).
    7. ``Strategies for Assessing the Safety of Foods Produced by 
Biotechnology'' (World Health Organization, Geneva, 1991).
    8. ``Safety Evaluation of Foods Derived by Modern Biotechnology: 
Concepts and Principles'' (Organization for Economic Cooperation and 
Development, Paris, 1993).
    9. ``Application of the Principles of Substantial Equivalence to 
the Safety Evaluation of Foods or Food Components from Plants 
Derived by Modern Biotechnology'' (World Health Organization, 
Geneva, 1995).
    10. Kessler, D. A., M. R. Taylor, J. H. Maryanski, E. L. Flamm, 
and L. S. Kahl, ``The Safety of Foods Developed by Biotechnology,'' 
Science, 256:1747-1749 and 1832, 1992.

List of Subjects

21 CFR Part 170

    Administrative practice and procedure, Food additives, Reporting 
and recordkeeping requirements.

21 CFR Part 184

    Food ingredients.

21 CFR Part 186

    Food ingredients, Food packaging.

21 CFR Part 570

    Animal feeds, Animal foods, Food additives.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR parts 170, 184, 186, and 570 be amended as 
follows:

PART 170--FOOD ADDITIVES

    1. The authority citation for 21 CFR part 170 is revised to read as 
follows:

    Authority: Secs. 201, 401, 402, 409, 701 of the Federal Food, 
Drug, and Cosmetic Act (21 U.S.C. 321, 341, 342, 348, and 371).

    2. Section 170.3 is amended by revising paragraph (h) to read as 
follows:


Sec. 170.3  Definitions.

* * * * *
    (h) Scientific procedures include scientific data (such as human, 
animal, analytical, or other scientific studies), information, methods, 
and principles, whether published or unpublished, appropriate to 
establish the safety of a substance.
* * * * *
    3. Section 170.30 is amended by revising the last sentence of 
paragraphs (a), (b), and (c)(2); and by removing and reserving 
paragraph (f) to read as follows:


Sec. 170.30  Eligibility for classification as generally recognized as 
safe (GRAS).

    (a) * * * General recognition of safety requires common knowledge 
throughout the scientific community knowledgeable about the safety of 
substances directly or indirectly added to food that there is 
reasonable certainty that the substance is not harmful under the 
intended conditions of use.
    (b) * * * General recognition of safety through scientific 
procedures shall be based upon generally available and accepted 
scientific data, information, methods, or principles, which ordinarily 
are published and may be corroborated by unpublished scientific data, 
information, or methods.
    (c)(1) * * *
    (2) * * * Persons who claim that use of a substance is GRAS through 
experience based on its common use in food outside of the United States 
should notify FDA of that claim in accordance with proposed 
Sec. 170.36.
* * * * *
    4. Section 170.35 is amended by revising paragraph (a) and by 
removing paragraph (c) to read as follows:


Sec. 170.35  Affirmation of generally recognized as safe (GRAS) status.

    (a) The Commissioner, on his own initiative, may affirm the GRAS 
status of the use of a substance that directly or indirectly becomes a 
component of food.
* * * * *
    5. New Sec. 170.36 is added to subpart B to read as follows:


Sec. 170.36  Notice of a claim for exemption based on a GRAS 
determination.

    (a)(1) Any person may notify FDA of a claim that a particular use 
of a substance is exempt from the statutory premarket approval 
requirements based on the notifier's determination that such use is 
generally recognized as safe (GRAS).
    (2) Notice to the agency of this section shall not constitute 
compliance with:
    (i) Section 101.14(b)(3)(ii) of this chapter. Any person who 
submits a health claim petition under Sec. 101.14 of this chapter shall 
comply in full with Sec. 101.14(b)(3)(ii) regardless of whether

[[Page 18961]]

the agency has been notified under this section about a substance and 
regardless of the nature of the agency's response.
    (ii) Section 106.120(b)(6)(ii) of this chapter. Any person who 
submits a new infant formula submission under proposed Sec. 106.120 of 
this chapter shall comply in full with proposed Sec. 106.120(b)(6)(ii) 
regardless of whether the agency has been notified under this section 
about a substance and regardless of the nature of the agency's 
response.
    (b) A notice of a GRAS exemption claim shall be submitted in 
triplicate to the Office of Premarket Approval (HFS-200), Center for 
Food Safety and Applied Nutrition, Food and Drug Administration, 200 C 
St. SW., Washington, DC 20204.
    (c) Notifiers shall submit the following information:
    (1) A claim, dated and signed by the notifier, or by the notifier's 
attorney or agent, or (if the notifier is a corporation) by an 
authorized official, that a particular use of a substance is exempt 
from the premarket approval requirements of the Federal Food, Drug, and 
Cosmetic Act (the act) because the notifier has determined that such 
use is GRAS. Such GRAS exemption claim shall include:
    (i) The name and address of the notifier;
    (ii) The common or usual name of the substance that is the subject 
of the GRAS exemption claim (i.e., the ``notified substance'');
    (iii) The applicable conditions of use of the notified substance, 
including the foods in which the substance is to be used, levels of use 
in such foods, and the purposes for which the substance is used, 
including, when appropriate, a description of the population expected 
to consume the substance;
    (iv) The basis for the GRAS determination (i.e., through scientific 
procedures or through experience based on common use in food); and
    (v) A statement that the data and information that are the basis 
for the notifier's GRAS determination are available for the Food and 
Drug Administration's (FDA) review and copying at reasonable times at a 
specific address set out in the notice or will be sent to FDA upon 
request.
    (2) Detailed information about the identity of the notified 
substance, including, as applicable, its chemical name, Chemical 
Abstracts Service (CAS) Registry Number, Enzyme Commission number, 
empirical formula, structural formula, quantitative composition, method 
of manufacture (excluding any trade secrets and including, for 
substances of natural biological origin, source information such as 
genus and species), characteristic properties, any content of potential 
human toxicants, and specifications for food-grade material;
    (3) Information on any self-limiting levels of use; and
    (4) A detailed summary of the basis for the notifier's 
determination that a particular use of the notified substance is exempt 
from the premarket approval requirements of the act because such use is 
GRAS. Such determination may be based either on scientific procedures 
or on common use in food.
    (i) For a GRAS determination through scientific procedures, such 
summary shall include:
    (A) A comprehensive discussion of, and citations to, generally 
available and accepted scientific data, information, methods, or 
principles that the notifier relies on to establish safety, including a 
consideration of the probable consumption of the substance and the 
probable consumption of any substance formed in or on food because of 
its use and the cumulative effect of the substance in the diet, taking 
into account any chemically or pharmacologically related substances in 
such diet;
    (B) A comprehensive discussion of any reports of investigations or 
other information that may appear to be inconsistent with the GRAS 
determination; and
    (C) The basis for concluding, in light of the data and information 
described under paragraphs (c)(1), (c)(2), (c)(3), (c)(4)(i)(A), and 
(c)(4)(i)(B) of this section, that there is consensus among experts 
qualified by scientific training and experience to evaluate the safety 
of substances added to food that there is reasonable certainty that the 
substance is not harmful under the intended conditions of use.
    (ii) For a GRAS determination through experience based on common 
use in food, such summary shall include:
    (A) A comprehensive discussion of, and citations to, generally 
available data and information that the notifier relies on to establish 
safety, including evidence of a substantial history of consumption of 
the substance by a significant number of consumers;
    (B) A comprehensive discussion of any reports of investigations or 
other information that may appear to be inconsistent with the GRAS 
determination;
    (C) The basis for concluding, in light of the data and information 
described under paragraphs (c)(1), (c)(2), (c)(3), (c)(4)(ii)(A), and 
(c)(4)(ii)(B) of this section, that there is consensus among experts 
qualified by scientific training and experience to evaluate the safety 
of substances added to food that there is reasonable certainty that the 
substance is not harmful under the intended conditions of use.
    (d) Within 30 days of receipt of the notice, FDA shall acknowledge 
receipt of a notice by informing the notifier in writing of the date on 
which the notice was received.
    (e) Within 90 days of receipt of the notice, FDA shall respond to 
the notifier in writing.
    (f)(1) Any GRAS exemption claim submitted under paragraph (c)(1) of 
this section shall be immediately available for public disclosure on 
the date the notice is received. All remaining data and information in 
the notice shall be available for public disclosure, in accordance with 
part 20 of this chapter, on the date the notice is received.
    (2) For each GRAS notice submitted under this section, the 
following information shall be readily accessible for public review and 
copying:
    (i) A copy of the GRAS exemption claim submitted under paragraph 
(c)(1) of this section.
    (ii) A copy of any letter issued by the agency under paragraph (e) 
of this section.
    (iii) A copy of any subsequent letter issued by the agency 
regarding such notice.
    (g)(1) Any GRAS affirmation petition that was filed by FDA under 
Sec. 170.35 prior to (date the final rule becomes effective) and is 
still pending as of (date the final rule becomes effective) shall be 
presumptively converted to a notice under the provisions of this 
section on (date the final rule becomes effective).
    (2) Any person who submitted a GRAS affirmation petition that is 
converted to a notice under paragraph (g)(1) of this section may amend 
such converted petition to meet the requirements of this section by 
submitting to the agency a claim, dated and signed by the notifier 
(i.e., the former petitioner), or by the notifier's attorney or agent, 
or (if the notifier is a corporation) by an authorized official, that a 
particular use of a substance is exempt from the premarket approval 
requirements of the act because the notifier has determined that such 
use is GRAS. Such GRAS exemption claim shall include:
    (i) The name and address of the notifier;
    (ii) The applicable GRAS affirmation petition number;
    (iii) The common or usual name of the substance that was the 
subject of the converted GRAS affirmation petition (i.e., the notified 
substance);
    (iv) The applicable conditions of use of the notified substance 
that are

[[Page 18962]]

supported by data and information in the referenced GRAS petition, 
including the foods in which the substance is to be used, levels of use 
in such foods, and the purposes for which the substance is used, 
including, when appropriate, a description of the population expected 
to consume the substance;
    (v) The basis for the GRAS determination (i.e., through scientific 
procedures or through experience based on common use in food); and
    (vi)(A) A statement that the complete record that supports the GRAS 
determination has been submitted to the agency in the applicable GRAS 
petition; or
    (B) A statement that the data and information that are the basis 
for the notifier's GRAS determination are available for FDA review and 
copying at reasonable times at a specific address set out in the claim 
or will be sent to FDA upon request.
    (3)(i) A petition that is converted to a notice under the 
provisions of paragraph (g)(1) of this section and that is amended 
according to the provisions of paragraph (g)(2) of this section shall 
be reviewed and administered according to the provisions of paragraphs 
(d), (e), and (f) of this section. For the purposes of paragraphs (d), 
(e), and (f) of this section, the date of receipt of the amendment 
described in paragraph (g)(2) of this section shall be the date of 
receipt of the notice.
    (3)(ii) After (date 90 days after date of publication of the final 
rule), FDA will inform any person who submitted a GRAS affirmation 
petition that is converted to a notice under the provisions of 
paragraph (g)(1) of this section, and who has not amended such petition 
according to the provisions of paragraph (g)(2) of this section, that 
the converted petition is inadequate as a notice under this section.
    6. Section 170.38 is amended by revising paragraph (a) to read as 
follows:


Sec. 170.38  Determination of food additive status.

    (a) The Commissioner may, in accordance with Sec. 170.35(b)(4), 
publish a notice in the Federal Register determining that a substance 
is not GRAS and is a food additive subject to section 409 of the act.
* * * * *

PART 184--DIRECT FOOD SUBSTANCES AFFIRMED AS GENERALLY RECOGNIZED 
AS SAFE

    7. The authority citation for 21 CFR part 184 continues to read as 
follows:

    Authority: Secs. 201, 402, 409, 701 of the Federal Food, Drug, 
and Cosmetic Act (21 U.S.C. 321, 342, 348, and 371).


Sec. 184.1  [Amended]

    8. Section 184.1 Substances added directly to human food affirmed 
as generally recognized as safe (GRAS) is amended in paragraph (b)(1) 
by removing the last sentence.

PART 186--INDIRECT FOOD SUBSTANCES AFFIRMED AS GENERALLY RECOGNIZED 
AS SAFE

    9. The authority citation for 21 CFR part 186 continues to read as 
follows:

    Authority: Secs. 201, 402, 409, 701 of the Federal Food, Drug, 
and Cosmetic Act (21 U.S.C. 321, 342, 348, and 371).


Sec. 186.1  [Amended]

    10. Section 186.1 Substances added indirectly to human food 
affirmed as generally recognized as safe (GRAS) is amended in paragraph 
(b)(1) by removing the last sentence.

PART 570--FOOD ADDITIVES

    11. The authority citation for 21 CFR part 570 is revised to read 
as follows:

    Authority: Secs. 201, 401, 402, 409, 701 of the Federal Food, 
Drug, and Cosmetic Act (21 U.S.C. 321, 341, 342, 348, and 371).

    12. Section 570.3 is amended by revising paragraph (h) to read as 
follows:


Sec. 570.3  Definitions.

* * * * *
    (h) Scientific procedures include scientific data (such as human, 
animal, analytical, or other scientific studies), information, methods, 
and principles, whether published or unpublished, appropriate to 
establish the safety of a substance.
* * * * *
    13. Section 570.30 is amended by revising the last sentence of 
paragraphs (a) and (b) to read as follows:


Sec. 570.30  Eligibility for classification as generally recognized as 
safe (GRAS).

    (a) * * * General recognition of safety requires common knowledge 
throughout the scientific community knowledgeable about the safety of 
substances directly or indirectly added to food that there is 
reasonable certainty that the substance is not harmful under the 
intended conditions of use.
    (b) * * * General recognition of safety through scientific 
procedures shall be based upon generally available and accepted 
scientific data, information, methods, or principles, which ordinarily 
are published and may be corroborated by unpublished scientific data, 
information, or methods.
* * * * *
    14. Section 570.35 is amended by revising paragraph (a) and by 
removing paragraph (c) to read as follows:


Sec. 570.35  Affirmation of generally recognized as safe (GRAS) status.

    (a) The Commissioner, on his own initiative, may affirm the GRAS 
status of the use of a substance that directly or indirectly becomes a 
component of food.
* * * * *
    15. New Sec. 570.36 is added to subpart B to read as follows:


Sec. 570.36  Notice of a claim for exemption based on a GRAS 
determination.

    (a) Any person may notify FDA of a claim that a particular use of a 
substance is exempt from the statutory premarket approval requirements 
based on the notifier's determination that such use is generally 
recognized as safe (GRAS).
    (b) A notice of a GRAS exemption claim shall be submitted in 
triplicate to the Division of Animal Feeds (HFV-220), Center for 
Veterinary Medicine, Food and Drug Administration, 7500 Standish Pl., 
Rockville, MD 20855.
    (c) Notifiers shall submit the following information:
    (1) A claim, dated and signed by the notifier, or by the notifier's 
attorney or agent, or (if the notifier is a corporation) by an 
authorized official, that a particular use of a substance is exempt 
from the premarket approval requirements of the Federal Food, Drug, and 
Cosmetic Act (the act) because the notifier has determined that such 
use is GRAS. Such GRAS exemption claim shall include:
    (i) The name and address of the notifier;
    (ii) The common or usual name of the substance that is the subject 
of the GRAS exemption claim (i.e., the notified substance);
    (iii) The applicable conditions of use of the notified substance, 
including the foods in which the substance is to be used, levels of use 
in such foods, and the purposes for which the substance is used, 
including, when appropriate, a description of the population expected 
to consume the substance;
    (iv) The basis for the GRAS determination (i.e., through scientific 
procedures or through experience based on common use in food); and
    (v) A statement that the data and information that are the basis 
for the notifier's GRAS determination are available for the Food and 
Drug Administration's (FDA) review and copying at reasonable times at a 
specific address set out in the notice or will be sent to FDA upon 
request.

[[Page 18963]]

    (2) Detailed information about the identity of the notified 
substance, including, as applicable, its chemical name, Chemical 
Abstracts Service (CAS) Registry Number, Enzyme Commission number, 
empirical formula, structural formula, quantitative composition, method 
of manufacture (excluding any trade secrets and including, for 
substances of natural biological origin, source information such as 
genus and species), characteristic properties, any content of potential 
human or animal toxicants, and specifications for feed-grade material;
    (3) Information on any self-limiting levels of use; and
    (4) A detailed summary of the basis for the notifier's 
determination that a particular use of the notified substance is exempt 
from the premarket approval requirements of the act because such use is 
GRAS. Such determination may be based either on scientific procedures 
or on common use in food.
    (i) For a GRAS determination through scientific procedures, such 
summary shall include:
    (A) A comprehensive discussion of, and citations to, generally 
available and accepted scientific data, information, methods, or 
principles that the notifier relies on to establish safety, including a 
consideration of the probable consumption of the substance and the 
probable consumption of any substance formed in or on food because of 
its use and the cumulative effect of the substance in the diet, taking 
into account any chemically or pharmacologically related substances in 
such diet;
    (B) A comprehensive discussion of any reports of investigations or 
other information that may appear to be inconsistent with the GRAS 
determination; and
    (C) The basis for concluding, in light of the data and information 
described under paragraphs (c)(1), (c)(2), (c)(3), (c)(4)(i)(A), and 
(c)(4)(i)(B) of this section, that there is consensus among experts 
qualified by scientific training and experience to evaluate the safety 
of substances added to food that there is reasonable certainty that the 
substance is not harmful under the intended conditions of use.
    (ii) For a GRAS determination through experience based on common 
use in food, such summary shall include:
    (A) A comprehensive discussion of, and citations to, generally 
available data and information that the notifier relies on to establish 
safety, including evidence of a substantial history of consumption of 
the substance by a significant number of consumers;
    (B) A comprehensive discussion of any reports of investigations or 
other information that may appear to be inconsistent with the GRAS 
determination;
    (C) The basis for concluding, in light of the data and information 
described under paragraphs (c)(1), (c)(2), (c)(3), (c)(4)(ii)(A), and 
(c)(4)(ii)(B) of this section, that there is consensus among experts 
qualified by scientific training and experience to evaluate the safety 
of substances added to food that there is reasonable certainty that the 
substance is not harmful under the intended conditions of use.
    (d) Within 30 days of receipt of the notice, FDA shall acknowledge 
receipt of a notice by informing the notifier in writing of the date on 
which the notice was received.
    (e) Within 90 days of receipt of the notice, FDA shall respond to 
the notifier in writing.
    (f)(1) Any GRAS exemption claim submitted under paragraph (c)(1) of 
this section shall be immediately available for public disclosure on 
the date the notice is received. All remaining data and information in 
the notice shall be available for public disclosure, in accordance with 
part 20 of this chapter, on the date the notice is received.
    (2) For each GRAS notice submitted under this section, the 
following information shall be readily accessible for public review and 
copying:
    (i) A copy of the GRAS exemption claim submitted under paragraph 
(c)(1) of this section.
    (ii) A copy of any letter issued by the agency under paragraph (e) 
of this section.
    (iii) A copy of any subsequent letter issued by the agency 
regarding such notice.
    (g)(1) Any GRAS affirmation petition that was filed by FDA under 
Sec. 570.35 prior to (date the final rule becomes effective) and is 
still pending as of (date the final rule becomes effective) shall be 
presumptively converted to a notice under the provisions of this 
section on (date the final rule becomes effective).
    (2) Any person who submitted a GRAS affirmation petition that is 
converted to a notice under paragraph (g)(1) of this section may amend 
such converted petition to meet the requirements of this section by 
submitting to the agency a claim, dated and signed by the notifier 
(i.e., the former petitioner), or by the notifier's attorney or agent, 
or (if the notifier is a corporation) by an authorized official, that a 
particular use of a substance is exempt from the premarket approval 
requirements of the act because the notifier has determined that such 
use is GRAS. Such GRAS exemption claim shall include:
    (i) The name and address of the notifier;
    (ii) The applicable GRAS affirmation petition number;
    (iii) The common or usual name of the substance that was the 
subject of the converted GRAS affirmation petition (i.e., the notified 
substance);
    (iv) The applicable conditions of use of the notified substance 
that are supported by data and information in the referenced GRAS 
petition, including the foods in which the substance is to be used, 
levels of use in such foods, and the purposes for which the substance 
is used, including, when appropriate, a description of the population 
expected to consume the substance;
    (v) The basis for the GRAS determination (i.e., through scientific 
procedures or through experience based on common use in food); and
    (vi)(A) A statement that the complete record that supports the GRAS 
determination has been submitted to the agency in the applicable GRAS 
petition; or
    (B) A statement that the data and information that are the basis 
for the GRAS determination are available for FDA's review and copying 
at reasonable times at a specific address set out in the claim or will 
be sent to FDA upon request.
    (3)(i) A petition that is converted to a notice under the 
provisions of paragraph (g)(1) of this section and that is amended 
according to the provisions of paragraph (g)(2) of this section shall 
be reviewed and administered according to the provisions of paragraphs 
(d), (e), and (f) of this section. For the purposes of paragraphs (d), 
(e), and (f) of this section, the date of receipt of the amendment 
described in paragraph (g)(2) of this section shall be the date of 
receipt of the notice.
    (ii) After (date 90 days after date of publication of the final 
rule), FDA will inform any person who submitted a GRAS affirmation 
petition that is converted to a notice under the provisions of 
paragraph (g)(1) of this section, and who has not amended such petition 
according to the provisions of paragraph (g)(2) of this section, that 
the converted petition is inadequate as a notice under this section.


Sec. 570.38  [Amended]

    16. Section 570.38 Determination of food additive status is amended 
in paragraph (a) by removing ``or (c)(5)''.


[[Page 18964]]


    Dated: April 8, 1997.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 97-9706 Filed 4-16-97; 8:45 am]
BILLING CODE 4160-01-P