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
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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 plannin