Federal Register: April 17, 1997 (Volume 62, Number 74)
Proposed Rules
Page 18937-18964
From the Federal Register Online via GPO Access wais.access.gpo.gov
DOCID:fr17ap97_dat-17
Page 18937
_______________________________________________________________________
Part III
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
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21 CFR Parts 170, et al.
Substances Generally Recognized as Safe; Proposed Rule
Page 18938
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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
Page 18940
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.<SUP>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
Page 18941
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 ``safety 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:
substantial 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, ``strategies 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), ``safety evaluation of foods produced by modern
biotechnology: Concepts and principles'' (Ref. 8); and a report of a
WHO workshop, ``application 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. <SUP>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.<SUP>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.<SUP>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).
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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,
<SUP>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.
---------------------------------------------------------------------------
<SUP>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.
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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