18938 Federal Register / Vol. 62, No. 74 / Thursday, April 17, 1997 / Proposed Rules

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.

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 § 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 § 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 § 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 (§ 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
Federal Register / Vol. 62, No. 74 / Thursday, April 17, 1997 / Proposed Rules 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 § 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 § 121.101(a); current

§ 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, thenPresident 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
18940 Federal Register / Vol. 62, No. 74 / Thursday, April 17, 1997 / Proposed Rules

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).

regulation pending completion of

additional studies (35 FR 18623). These

criteria were incorporated into the

agency’s regulations as § 121.3

(precursor of current § 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 § 121.3 (proposed rule, 37

FR 6207, March 25, 1972; final rule, 37

FR 25705, December 2, 1972). These

procedures were subsequently codified

at § 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; § 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 § 121.3 (current § 170.30) to

distinguish a determination of GRAS

status through scientific procedures

(scientific procedures GRAS

determination; current § 170.30(b)) from

a determination of GRAS status through

experience based on common use in

food (common use GRAS determination;

current § 170.30(c)) (41 FR 53600,

December 7, 1976). Those final

regulations also established definitions

for ‘‘common use in food’’ (current

§ 170.3(f)) and ‘‘scientific procedures’’

(current § 170.3(h)). FDA subsequently

added criteria (§ 170.30(c)(2)) for the

determination of GRAS status through

experience based on common use in

food when that use occurred exclusively

or primarily outside of the United States

(53 FR 16544, May 10, 1988).

5. The Plant Policy Statement

FDA’s ‘‘Statement of Policy: Foods

Derived From New Plant Varieties’’ (the

plant policy statement) (57 FR 22984,

May 29, 1992) is an example of a recent

agency policy announcement regarding

agency priorities in reviewing the GRAS

status of substances added to food. In

the plant policy statement, FDA

reviewed its position on the

applicability of the food additive

definition and section 409 of the act to

foods derived from new plant varieties

in light of the intended changes in the

composition of foods that might result

from the newer techniques of genetic

modification such as recombinant

deoxyribonucleic acid (rDNA)

techniques:

The statutory definition of ‘‘food additive’’

makes clear that it is the intended or

expected introduction of a substance into

food that makes the substance potentially

subject to food additive regulation. Thus, in

the case of foods derived from new plant

varieties, it is the transferred genetic material

and the intended expression product or

products that could be subject to food

additive regulation, if such material or

expression products are not GRAS.

(57 FR 22984 at 22990)

In the plant policy statement, FDA

provided extensive guidance, including

criteria and analytical steps that

producers could follow, on situations in

which producers should consult with

FDA to determine whether an FAP is

appropriate. FDA also stated its intent to

use its food additive authority in

regulating foods and their byproducts

derived from new plant varieties to the

extent necessary to protect public

health.

C. Elements of the GRAS Standard

Under section 201(s) of the act, a

substance is exempt from the definition

of food additive and thus, from

premarket approval requirements, if its

safety is generally recognized by

qualified experts. Accordingly, a

determination that a particular use of a

substance is GRAS requires both

technical evidence of safety and a basis

to conclude that this technical evidence

of safety is generally known and

accepted. In contrast, a determination

that a food additive is safe requires only

technical evidence of safety.1 Thus, a

GRAS substance is distinguished from a

food additive on the basis of the

common knowledge about the safety of

the substance for its intended use rather

than on the basis of what the substance

is or the types of data and information

that are necessary to establish its safety.

To emphasize this distinction between a

GRAS substance and a food additive,

and to simplify discussion about the

standard for general recognition of

safety, in this document, FDA uses the

term ‘‘technical element’’ when

discussing technical evidence of safety

and ‘‘common knowledge element’’

when discussing general knowledge and

acceptance of safety.

The technical element of the GRAS

standard requires that information about

the substance establish that the

intended use of the substance is safe. As

discussed in section I.A of this

document, FDA has defined ‘‘safe’’

(§ 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

§ 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 § 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 § 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
Federal Register / Vol. 62, No. 74 / Thursday, April 17, 1997 / Proposed Rules 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 § 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 § 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 § 170.30, FDA is

also proposing to amend the definition

in § 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 (§ 170.35(c))

with a notification procedure (proposed

§ 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
18942 Federal Register / Vol. 62, No. 74 / Thursday, April 17, 1997 / Proposed Rules

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

§ 170.30(f), which expresses the

agency’s intent to review the GRAS

status of certain food substances,

because § 170.30(f) is redundant with

the provisions of § 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

(§ 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 (§ 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 §§ 570.30 and 570.35 (21

CFR 570.30 and 570.35), respectively.

FDA is proposing the following: (1) To

amend the provisions of § 570.30 that

are parallel to the provisions of current

§ 170.30 (i.e., § 570.30 (a) and (b)); (2) to

eliminate the GRAS affirmation petition

process provided for in § 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 § 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

§§ 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 § 170.30—

Eligibility for Classification as GRAS

A. General Criteria

FDA is proposing to expand the

description of the general criteria

provided in current § 170.30(a) for a

GRAS determination. FDA is not

proposing any changes to the first two

sentences of current § 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

§ 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 § 170.30(a) would

clarify that the safety standard for a

GRAS substance is identical to the

safety standard in § 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 § 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

§ 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 § 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 § 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 § 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 § 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 § 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 § 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 § 170.30(b), the descriptor

‘‘scientific’’ applies equally to ‘‘data,’’
Federal Register / Vol. 62, No. 74 / Thursday, April 17, 1997 / Proposed Rules 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 § 170.30(b). Thus, under

proposed § 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 § 170.30(b) on the

importance of publication in satisfying

the common knowledge element.

However, current § 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 § 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 § 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 § 170.30(c)(1), which sets out

criteria for a common use GRAS

determination. However, FDA is

proposing to amend current

§ 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

§ 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 § 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 § 170.35(c)(1)

with a notification procedure (proposed

§ 170.36). The recommendation in

proposed § 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
18944 Federal Register / Vol. 62, No. 74 / Thursday, April 17, 1997 / Proposed Rules

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 § 170.30(c)(2) is comparable

to the language of current § 170.30(c)(2)

in that it is not a requirement.

D. Other Provisions of Current § 170.30

FDA is not proposing any changes to

the remainder of current § 170.30,

except § 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 § 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 § 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 § 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 § 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 § 170.38. Therefore,

§ 170.30(f) is redundant with § 170.35

(a) and (b). Accordingly, in keeping with

the agency’s goals for the Reinventing

Food Regulations, FDA is proposing to

remove current § 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

(§ 170.3(i)). Thus, the technical element

of a scientific procedures GRAS

determination must consider the

probable consumption and cumulative

effect of the substance in the diet

because a scientific procedures GRAS

determination requires the same

quantity and quality of evidence as is

required to obtain approval of the

substance as a food additive. If the

dietary exposure to the substance under

the intended conditions of use presents

a basis for concern about the safety of

its use, data or information addressing

those concerns are necessary to satisfy

the technical element. As with other

data and information that support a

GRAS determination, data or

information addressing a safety question

raised by dietary exposure must also

satisfy the common knowledge element

by being generally available to, and

accepted by, qualified experts.

In some cases, dietary exposure is

unlikely to present a basis for a safety

concern. For example, dietary exposure

to an enzyme preparation that is derived

from a controlled fermentation of a

nonpathogenic, nontoxigenic

microorganism that does not produce

antibiotics, and that is processed using

substances that are acceptable for use in

foods generally, would not ordinarily

present a basis for a safety concern. On

the other hand, consumption of a

component of a commonly consumed

food may present a basis for a safety

concern if the dietary exposure to the

isolated component under its intended

conditions of use is many times greater

than its dietary exposure when

consumed as a component of food.

For example, a fiber may be extracted

from a vegetable that has a relatively

low dietary exposure (such as beets) and

added, at the same level, to other foods

that have a relatively high dietary

exposure. The probable cumulative

intake of the fiber likely will be many

times higher from the consumption of

the foods to which it is added than from

the consumption of beets. The probable

intake of the fiber from consumption of

foods to which it is added may present

a basis for a safety concern, especially

if the foods containing the added beet

fiber will not replace beets in the diet.

Likewise, in the case of a chemically

synthesized substance that is

structurally identical to a naturally

occurring substance in commonly

consumed food, technical evidence of

safety would include consideration of

whether the cumulative exposure to

both the synthetic and the natural

substance exceeds the exposure to the

natural substance and whether the

combined exposure presents a basis for

a safety concern.

B. Substantial Equivalence to a GRAS

Substance

A report of a joint Food and

Agriculture Organization (FAO) and

World Health Organization (WHO)

consultation (the 1996 FAO/WHO

report) recommended that ‘‘[s]afety

assessment based on the concept of

substantial equivalence * * * be applied

in establishing the safety of foods and

food components derived from

genetically modified organisms’’ (Ref.

6). The 1996 FAO/WHO report stated

that:

[s]ubstantial equivalence embodies the

concept that if a new food or food component

is found to be substantially equivalent to an

existing food or food component, it can be

treated in the same manner with respect to

safety (i.e. the food or food component can

be concluded to be as safe as the

conventional food or food component).

Account should be taken of any processing

that the food or food component may

undergo as well as the intended use and the

intake by the population.

The 1996 FAO/WHO report relied, in

part, on previous expert reports that had

discussed the concept of substantial

equivalence, including the 1990 joint

FAO/WHO consultation, ‘‘[s]trategies

for assessing the safety of foods

produced by biotechnology’’ (Ref. 7); a

report prepared by an expert group of

the Organization for Economic Cooperation and Development (OECD),

‘‘[s]afety evaluation of foods produced

by modern biotechnology: Concepts and

principles’’ (Ref. 8); and a report of a

WHO workshop, ‘‘[a]pplication of the

principles of substantial equivalence to

the safety evaluation of foods or food

components from plants derived by

modern biotechnology’’ (Ref. 9).
Federal Register / Vol. 62, No. 74 / Thursday, April 17, 1997 / Proposed Rules 18945

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.

FDA believes that in certain instances

the concept of substantial equivalence

may have applicability to the technical

element of a GRAS determination, and

the agency has already applied this

concept when evaluating the safety of

new or modified food substances. For

example, the agency’s approach (57 FR

22984 and Ref. 10) to assessing the

safety of foods derived from new plant

varieties, including the safety of newly

introduced substances in the food

(primarily proteins, carbohydrates, and

fatty acids) and unintended changes in

the food’s composition, is similar to the

concept of substantial equivalence

posited by FAO, WHO, and OECD. 2 As

another example, FDA has applied this

concept in affirming the GRAS status of

several microbially-derived chymosin

(i.e., rennet) enzyme preparations (55

FR 10932 at 10935, March 23, 1990; 57

FR 6476 at 6479, February 25, 1992; 58

FR 27197 at 27202, May 7, 1993) and

several animal-and plant-derived

enzyme preparations (60 FR 32904 at

32911, June 26, 1995).

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 § 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 § 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 § 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 agencyinitiated GRAS review.

Proposed § 170.35(a) includes a

technical revision that amends current

§ 170.35(a) to place it in the singular.

For consistency with the language of the

statute, proposed § 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 § 170.35(c), which prescribes the

procedure for the submission of a GRAS

affirmation petition. Under proposed

§ 170.35(a), FDA will no longer be

bound to review such a petition.

Therefore, if proposed § 170.35(a)

becomes final, current § 170.35(c) will

become obsolete.

VI. Proposed Establishment of a

Notification Procedure

A. General Requirements

Proposed § 170.36(a)(1) provides that

any person may notify FDA of a claim
18946 Federal Register / Vol. 62, No. 74 / Thursday, April 17, 1997 / Proposed Rules

3FDA 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.

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

Current agency regulations

concerning the eligibility of a substance

for a health claim (§ 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 § 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

§ 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

§ 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

§ 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 § 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 § 101.14(b)(3)(ii)

or proposed § 106.120(b)(6)(ii) is

reflected in proposed § 170.36(a)(2).

Under proposed § 170.36(a)(2)(i), any

person who submits a health claim

petition under § 101.14 must comply in

full with § 101.14(b)(3)(ii), regardless of

whether the agency has been notified

under proposed § 170.36 about a

relevant GRAS determination and

regardless of the nature of the agency’s

response to that notice. Similarly,

proposed § 170.36(a)(2)(ii) provides that

any person who makes a new infant

formula submission under § 106.120

must comply in full with

§ 106.120(b)(6)(ii), regardless of whether

the agency has been notified under

proposed § 170.36 about a relevant

GRAS determination and regardless of

the nature of the agency’s response to

that notice.

Proposed § 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 § 170.36(b).

B. Specific Requirements

Proposed § 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 § 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 § 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

§ 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 § 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 § 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 § 170.36(f)(2)).

FDA has requested comment on

whether proposed § 170.36(b) should

require or recommend that an electronic

copy of the entire notice be submitted
Federal Register / Vol. 62, No. 74 / Thursday, April 17, 1997 / Proposed Rules 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

§ 170.36(c)(1).

a. Notifier. Proposed § 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 § 170.36(d)) and inform the

notifier of the agency’s response to the

notice (proposed § 170.36(e)).

b. Name of notified substance.

Proposed § 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 § 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

§ 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 § 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 § 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 § 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

§ 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

§ 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 § 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

§ 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
18948 Federal Register / Vol. 62, No. 74 / Thursday, April 17, 1997 / Proposed Rules

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 (§ 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

(§ 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 § 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 selflimiting 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 § 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 § 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

§ 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.
Federal Register / Vol. 62, No. 74 / Thursday, April 17, 1997 / Proposed Rules 18949

4For 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).

Proposed § 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;

§ 170.30(b) further provides that a

scientific procedures GRAS

determination requires the same

quantity and quality of scientific

evidence as would be required to

approve a food additive. Thus, such

information should be included in the

notice summary. Several technical

documents that discuss the practical

details of estimating consumer exposure

to a food substance are available from

the agency.4

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

§ 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 § 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 § 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

§ 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

§ 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 § 170.36(c)(4)(i)(B) is

consistent with the provision in current

§ 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

§ 170.36(c)(4)(i)(B) is also consistent

with a similar provision (§ 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 § 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 § 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 § 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

§ 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 § 170.3(f) such

that adverse health effects, if they

occurred, could be noted. In other

words, a substance is not eligible for the
18950 Federal Register / Vol. 62, No. 74 / Thursday, April 17, 1997 / Proposed Rules

5For 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).

6An 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).

GRAS exemption merely because it was

used in food before January 1, 1958, if

such use were not sufficiently

widespread.5

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

§ 170.36(c)(3)(ii)(B) requires that the

notice summary of a common use GRAS

determination include a comprehensive

discussion of any reports of

investigations or other information that

may appear to be inconsistent with the

GRAS determination. The legislative

history of the 1958 amendment

demonstrates that Congress believed

that there was no reason to conduct

specific tests to establish the safety of

substances commonly used in food

because their history of common use

established a presumption of such safety

(Ref. 1). However, nothing in the

legislative history suggests that Congress

intended that subsequent reports of

adverse effects associated with the use

of a substance in food be ignored in the

safety evaluation. A notice summary of

a common use GRAS determination

should also address whether use was/is

sufficiently widespread that any

substance-related adverse effects would

be observed and recorded. Where a

substance has been used by a limited

population, 6 for a limited period of

time, or under circumstances that do not

lend themselves to the observation and

recording of adverse effects, the lack of

reported adverse effects may not be

meaningful.

d. Basis for concluding expert

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

§ 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

§ 170.36(a)(2), any response from FDA

would not constitute compliance with

§ 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

§ 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 § 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 §§ 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

§ 106.120(b)(6)(ii); 61 FR 36154 at

36217). The agency could receive a

notice under proposed § 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

§ 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 § 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 § 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

§ 170.36.

Under § 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 § 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

§ 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 § 170.36(f)(1) provides that

any GRAS exemption claim submitted

under proposed § 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 § 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 § 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 (§ 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 § 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 § 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

§ 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 § 170.36(c)(1); (2) a copy of all
Federal Register / Vol. 62, No. 74 / Thursday, April 17, 1997 / Proposed Rules 18953

letters issued by the agency under

proposed § 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 § 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 § 170.36(f)(2) and to place that

file on public display at DMB. FDA is

planning this approach because DMB is

a common repository for publicly

available files. Alternatively, FDA could

make the file accessible for inspection at

the agency’s Freedom of Information

Office or, in keeping with the current

procedures for public inspection of the

information FDA considered and relied

on to reach a decision on an FAP, at

CFSAN. Although FDA has tentatively

concluded that it would be best to

provide for public accessibility at DMB

because the public is already

accustomed to obtaining information

relating to GRAS substances at that

location, the agency requests comment

on this matter.

FDA is not proposing to codify how

or where the information prescribed by

proposed § 170.36(f)(2) would be made

accessible because any mechanism that

appears in the agency’s regulations will

bind the agency to its provisions. In

keeping with the agency’s goals in

meeting the Reinventing Food

Regulations, FDA wishes to maintain

flexibility to improve the process for

public accessibility, particularly as the

agency gains experience with electronic

modes of information dissemination.

FDA is aware that the public review of

hard copy (i.e., paper) files in a public

reading room may become obsolete as

electronic technology for public

dissemination of information advances.

FDA requests comment on whether

proposed § 170.36(f)(2) is an effective

and efficient means to provide the

public with ready access to information

from the proposed notification

procedure.

F. Inventory

Proposed § 170.36(f)(2) would not

require that FDA maintain an inventory

of the information retained in the

publicly accessible file. Consequently,

such an inventory would be a new

record within the meaning of § 20.24

and FDA would not be required to

prepare such an inventory in response

to a FOIA request. However, FDA

recognizes the utility and importance of

an inventory of notices received under

proposed § 170.36 and of the agency’s

response to those notices, particularly

for persons without ready access to the

agency’s DMB. FDA also recognizes that

many members of the public would

prefer to access basic information

relevant to GRAS notices in a

streamlined format. FDA further

recognizes that the agency itself can

most efficiently carry out its own

responsibilities (e.g., with respect to

monitoring imports of food products) by

having basic information relevant to

GRAS notices available in such a

format.

Therefore, FDA intends to maintain

an inventory of notices received, the

agency’s response, and any subsequent

relevant agency correspondence. Such

an inventory would be an

administratively efficient mechanism of

accounting for the information residing

in the publicly accessible file. Such an

inventory also would complement the

current agency regulations tabulating

substances that are listed (part 182) or

affirmed (parts 184 and 186) as GRAS.

FDA has tentatively concluded that

any inventory of notices received

should be an adjunct to proposed

§ 170.36(f)(2), rather than the sole means

of distributing the information available

from the notification procedure, because

the agency could place the GRAS

exemption claims and the letters issued

by the agency in the publicly accessible

file faster than it could amend an

inventory. However, FDA is not

proposing to codify the inventory as an

adjunct to proposed § 170.36(f)(2)

because such an inventory would

require continuous amendment and the

administrative procedures required to

amend a codified inventory would be

too cumbersome to meet the needs of

the public and the agency efficiently.

FDA is also not proposing to mention

the availability of the inventory in its

codified regulations. In keeping with the

agency’s goals in meeting Reinventing

Food Regulations, FDA believes that

refraining from codifying any aspect of

the inventory will provide the agency

with maximum flexibility to improve

the process by which the inventory is

updated and maintained.

Initially, FDA intends that such an

inventory would be publicly accessible

in any file maintained in accordance

with proposed § 170.36(f)(2), e.g., at

DMB. FDA could also make such an

inventory available through prevailing

publicly accessible electronic modes,

such as the agency’s home page on the

contemporary World Wide Web. FDA

requests comment on making any

inventory prepared by the agency

available through such electronic

modes.

VII. Effect of the Proposed Notification

Procedure on Existing GRAS Petitions

Under the current GRAS affirmation

process, the agency conducts a

preliminary examination of the data and

information submitted in the petition. If

FDA finds that the submitted

information conforms to the

requirements established under

§§ 170.30 and 170.35, FDA makes an

administrative decision to file the

petition and publishes a notice in the

Federal Register to that effect.

At this time, approximately 60 filed

GRAS affirmation petitions are pending

at FDA. These petitions were filed with

the agency under an administrative

process that the agency is proposing to

remove. Therefore, if this proposal

becomes final, the administrative

process that FDA would use to bring

these petitions to closure will no longer

be operative. Moreover, FDA is

proposing to eliminate the GRAS

affirmation process in order to increase

effectiveness and efficiency. The

continued commitment of agency

resources to complete the GRAS petition

process for pending petitions would be

contrary to one of the agency’s goals in

this rulemaking.

FDA recognizes that persons who

have a pending GRAS affirmation

petition have invested time and

resources in those petitions. Therefore,

proposed § 170.36(g)(1) stipulates that

any GRAS affirmation petition filed

under § 170.35 prior to the date that a

final rule based on this proposal

becomes effective, and still pending as

of such effective date, will be

presumptively converted to a GRAS

notice under proposed § 170.36. This

conversion will allow the agency to

bring filed GRAS affirmation petitions

to closure, albeit under a different

process than the one to which they were

submitted.

However, the proposed notification

procedure has certain requirements that

have no specific counterpart in the

petition process. In particular, under the

notification procedure a notifier

explicitly accepts full responsibility for

the GRAS determination by signing a

GRAS exemption claim (under proposed

§ 170.36(c)(1)). In contrast, under the

petition process a petitioner requests

that FDA attest to a GRAS

determination. Thus, FDA cannot

assume that all persons who submitted
18954 Federal Register / Vol. 62, No. 74 / Thursday, April 17, 1997 / Proposed Rules

a GRAS petition would in fact be

willing to accept full responsibility for

the determination.

Moreover, the GRAS exemption claim

in proposed § 170.36(c)(1) would be a

complete and separate section of a

GRAS notice that could stand alone and

would contain basic information in a

consistent format. As discussed, under

proposed § 170.36(f)(2) the agency

would use the GRAS exemption claim

to effectively and efficiently inform the

public about received notices. Thus,

logic compels that a GRAS exemption

claim filed under proposed § 170.36(g)

include all elements of the claim

required under proposed § 170.36(c)(1),

rather than only those elements that

have no counterpart in the GRAS

affirmation petition process.

Accordingly, proposed § 170.36(g)(2)

provides that any person who submitted

a GRAS affirmation petition that is

converted to a notice under the

provisions of proposed § 170.36(g)(1)

may amend such converted petition to

satisfy the requirements of proposed

§ 170.36 by submitting to the agency a

claim, dated and signed by the notifier

(i.e., the former petitioner), that a

particular use of a substance is exempt

from the premarket approval

requirements of the act because the

notifier has determined that such use is

GRAS. Proposed § 170.36 (g)(2)(i)

through (g)(2)(vi) describe the format of

the GRAS exemption claim that would

amend a converted GRAS affirmation

petition to satisfy the requirements of a

notice under proposed § 170.36. This

claim format is similar to that required

under proposed § 170.36(c)(1) but has

been modified in two particulars (i.e.,

proposed § 170.36 (g)(2)(ii) and

(g)(2)(vi)) to take into account the fact

that the data and information to support

the GRAS determination have already

been submitted to the agency in the

applicable GRAS petition.

Proposed § 170.36(g)(2)(i) requires

that the GRAS exemption claim include

the name and address of the notifier. As

with proposed § 170.36(c)(1)(i), this is

necessary for full identification of the

person who accepts responsibility for

the claim. This also is necessary so that

the agency can administer the

amendment to the converted petition

according to the provisions of proposed

§ 170.36 (d) and (e) (see proposed

§ 170.36(g)(3)(i)).

Proposed § 170.36(g)(2)(ii) requires

that the GRAS exemption claim include

the applicable GRAS affirmation

petition number. The petition number is

the simplest way to identify the

converted petition that is being

amended.

Proposed § 170.36(g)(2)(iii) requires

that the GRAS exemption claim include

the common or usual name of the

substance that was the subject of the

converted GRAS affirmation petition

(i.e., the notified substance). As with

proposed § 170.36(c)(1)(ii), this is

necessary to identify the notified

substance as well as to identify whether

there are any labeling issues that need

to be addressed. FDA is satisfied that

detailed identity information, such as

that described in proposed

§ 170.36(c)(2), will be present in the

referenced petition because, under

current § 170.35(c)(1)(i), FDA requires

that a GRAS petition contain such

information as a prerequisite to filing

the petition.

Proposed § 170.36(g)(2)(iv) requires

that the GRAS exemption claim include

the applicable conditions of use that are

supported by data and information in

the referenced GRAS petition, including

the foods in which the notified

substance is to be used, levels of use in

such foods, and the purposes for which

the notified substance is used,

including, when appropriate, a

description of the population expected

to consume the substance. As with

proposed § 170.36(c)(1)(iii), this

information describing the conditions of

use is necessary to delineate the

boundaries of the GRAS exemption

claim consistent with section 201(s) of

the act, which states that a GRAS

substance must be generally recognized

as safe ‘‘under the conditions of its

intended use.’’ Importantly, a petitioner

who amends a converted GRAS

affirmation petition to satisfy the

requirements of a notice may do so only

for the intended use that was the subject

of the GRAS affirmation petition. Any

additional use(s) would be the subject of

a separate notice under proposed

§ 170.36(c).

Proposed § 170.36(g)(2)(v) requires

that the GRAS exemption claim identify

the basis for the GRAS determination as

scientific procedures or experience

based on common use in food. As

discussed in section I.B.4 of this

document, under § 170.30, the

requirements for a scientific procedures

GRAS determination are different from

those for a common use GRAS

determination. The basis for a GRAS

determination is thus fundamental to

the GRAS exemption claim.

Proposed § 170.36(g)(2)(vi) requires

that the GRAS exemption claim include

either a statement that the complete

record that supports the GRAS

determination has already been

submitted to the agency in the relevant

GRAS petition (proposed

§ 170.36(g)(2)(vi)(A)) or a statement that

all data and information that are the

basis for the GRAS determination are

available for FDA review and copying or

will be sent to FDA upon request

(proposed § 170.36(g)(2)(vi)(B)).

Proposed § 170.36(g)(2)(vi) takes into

account the fact that, in many cases, a

petitioner has already submitted the

complete record that supports the GRAS

determination. Alternatively, proposed

§ 170.36(g)(2)(vi) provides to the person

who submitted a GRAS petition the

option of agreeing to provide upon

request any additional information that

supports the GRAS determination but

was not included in the GRAS petition.

As discussed with respect to proposed

§ 170.36(c)(1)(v), FDA might conduct

random audits of such data and

information or conduct an audit on a

broad issue or class of products if the

issue or use of a class of products raises

important public health issues.

FDA requests comment on proposed

§ 170.36(g) as a mechanism for

administering pending GRAS

affirmation petitions if the proposed

notification procedure becomes final.

Proposed § 170.36(g) would not

preclude any person who had a filed

GRAS petition prior to the effective date

of a final GRAS notification rule from

submitting a notice of a claim for

exemption according to the provisions

of proposed § 170.36(c) or from

submitting an FAP under § 171.1 and

requesting that FDA cross reference the

information contained in the filed GRAS

petition in accordance with § 171.1(b).

VIII. Interim Policy

Between the time of publication of

this proposal and any final rule based

on this proposal, FDA invites interested

persons who determine that a use of a

substance is GRAS to notify FDA of

such GRAS determinations as described

in proposed § 170.36 (b) and (c). In

general, the agency would administer

the notices as described in proposed

§ 170.36 (d) through (f) (i.e., FDA would

acknowledge receipt of the notice,

respond in writing to the notifier, and

make publicly accessible a copy of all

GRAS exemption claims and the

agency’s response). However, although

FDA would make a good faith effort to

respond within the proposed 90-day

timeframe, the agency would not be

bound by such a timeframe. FDA will

determine whether its experience in

administering such notices suggests

modifications to the proposed

procedure.

FDA realizes that some individuals

who have a filed GRAS affirmation

petition pending at the agency may be

interested in converting such petition to

a notice under proposed § 170.36(g) or
Federal Register / Vol. 62, No. 74 / Thursday, April 17, 1997 / Proposed Rules 18955

in submitting a complete notice for the

petitioned use under proposed § 170.36

(b) and (c). FDA invites such petitioners

to submit an amendment in accordance

with proposed § 170.36(g)(2) or to

submit a complete notice for the

petitioned use in accordance with

proposed § 170.36 (b) and (c). FDA

would administer such notice or

amendment as described in proposed

§ 170.36 (d) through (f). However,

during the interim period FDA would

not continue to commit resources to

review of a GRAS affirmation petition if

the agency receives an amendment in

accordance with proposed § 170.36(g)(2)

or receives a complete notice

concerning the petitioned use.

FDA will consult upon request with

interested persons who seek additional

guidance in preparing a notice because

such consultation may identify sections

of the proposed procedure that may

require clarification in any final rule

based on the proposal.

IX. Conforming Amendments

This proposal would eliminate the

GRAS petition process set out in

§ 170.35(c). Therefore, FDA is proposing

conforming amendments to revise

current §§ 184.1(b)(1) and 186.1(b)(1) by

removing the last sentence of each

paragraph. These sentences provide that

persons seeking FDA approval of an

independent determination that a use of

a food substance is GRAS may submit

a petition in accordance with § 170.35.

Consistent with the proposed

elimination of the GRAS petition

process set out in § 170.35(c), FDA is

also proposing a conforming

amendment to revise current § 170.38(a)

to: (1) Remove the provision that the

Commissioner may, in accordance with

§ 170.35(c)(5), publish a notice in the

Federal Register determining that a

substance is not GRAS and is a food

additive subject to section 409 of the act

and (2) retain the provision in

§ 170.38(a) that the Commissioner may,

in accordance with § 170.35(b)(4) (i.e.,

on his/her own initiative), publish such

a notice in the Federal Register.

Importantly, however, when faced with

a public health hazard, the existence of

such rulemaking authority would not

preclude other agency action, including

seizure and injunction, to remove from

the market a product that is an

unapproved food additive.

X. International Harmonization

FDA is committed to international

harmonization of regulatory

requirements and guidelines that

preserve and enhance the agency’s

ability to accomplish its public health

mission, enhance regulatory

effectiveness by providing more

consumer protection with scarce

government resources, and increase

worldwide access to safe and high

quality food products (60 FR 53078,

October 11, 1995). FDA is not aware of

a provision in the laws of any other

country that is equivalent to the GRAS

exemption. On the other hand, the laws

of other countries provide exemptions

(e.g., for ‘‘natural’’ products) that have

no equivalent under the act. Thus, the

international community is already

accustomed to operating in accordance

with a variety of regulatory approaches

for substances added to food. FDA’s

proposed substitution of a GRAS

notification procedure for the current

GRAS petition process would not

impose any new requirements that

would affect imported food products.

Under the current petition process,

FDA makes a public announcement that

a petition has been filed and

incorporates an affirmed use of a

substance into a codified list. Under the

proposed notification procedure, FDA

would make readily accessible to the

public, including international agencies

and firms, the notice’s ‘‘GRAS

exemption claim,’’ which would

include a succinct description of the

notified substance, the applicable

conditions of use, and the basis for the

GRAS determination (i.e., through

scientific procedures or through

experience based on common use in

food). FDA would also make readily

accessible to the public the agency’s

response to the notice. Further, under

the act, a variety of substances that must

be declared on the food label are exempt

from premarket approval on the basis of

the GRAS exemption and are not

included on any government list or

inventory of substances that are used

lawfully in the U.S. food supply.

Operation of either the petition process

or the proposed notification procedure

does not change that fact.

FDA recognizes that interested

persons may want to know the official

regulatory status of a food substance in

the United States prior to using that

substance in foods that will enter

international commerce. FDA also

recognizes that the proposed agency

response to a GRAS notice may have

less weight in the international

community than the agency’s

affirmation of GRAS status. However, as

a practical matter, FDA has announced

only approximately 30 GRAS

affirmations in the 10 years preceding

this proposed rule. This small number

of GRAS affirmations has a minimal

impact on considerations of

international trade.

For these reasons, FDA does not

anticipate that the proposed substitution

of a GRAS notification procedure for the

GRAS petition process will have any

impact on international trade.

Nevertheless, the agency invites

comment on this matter from the

international community and from firms

who import food products into the

United States or who export U.S. made

food products.

XI. Food Substances Used in Animal

Feed

FDA’s regulations regarding the

eligibility of substances used in animal

food or feeds for classification as GRAS,

and the procedures for affirmation of

GRAS status for such substances, are

codified at §§ 570.30 and 570.35,

respectively. The requirements

described in these regulations are

parallel to the requirements for GRAS

substances that are used in human food,

although some requirements of § 170.30

have no corresponding requirement in

§ 570.30. As an example relevant to this

rulemaking, the requirements of

§ 570.30(c) are identical to the

requirements of § 170.30(c)(1), but

§ 570.30(c) has not been amended to

describe the requirements for a common

use GRAS determination based on

history of use when that history of use

occurred primarily or exclusively

outside the United States. In addition,

the agency’s GRAS review did not

extend to the use of food substances in

animal food or feeds. Thus, § 570.30

does not contain provisions analogous

to § 170.30 (e) and (f).

The general provisions in subpart A of

part 184 were issued under the auspices

of the agency’s comprehensive review of

GRAS substances. Because this agency

review did not extend to the use of food

substances in animal food or feeds, the

agency did not issue a corresponding

subpart A in part 584 (21 CFR part 584).

Therefore, any proposed rule to modify

§§ 570.30 and 570.35 would require no

conforming amendments in part 584.

FDA is also proposing to amend the

provisions of § 570.30 that are parallel

to the provisions of current § 170.30

(i.e., § 570.30 (a) and (b)) because

§§ 170.30 and 570.30 implement the

same statutory provisions. Therefore, it

is important for the agency’s standards

concerning GRAS substances to be

consistent with respect to substances

used in human food and substances

used in animal food or feeds.

FDA is also proposing to eliminate the

GRAS affirmation petition process

provided for in § 570.35 (a) and (c)

because the corresponding process for

substances used in human food is being

eliminated. Although the GRAS
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affirmation process has rarely been

employed for substances used in animal

food or feeds, FDA believes that it is

appropriate to provide the option of a

GRAS notification procedure for animal

food or feeds that would be parallel to

proposed § 170.36. Therefore, in

proposed § 570.36 the agency is

proposing a GRAS notification

procedure for substances used in animal

food or feeds. Finally, FDA is proposing

to revise current § 570.38(a) as a

conforming amendment required by

removing the current GRAS affirmation

petition process for substances used in

animal food or feeds.

With regard to the notification

procedure, FDA’s proposal for

substances that would be used in animal

food or feeds is for practical purposes

identical to FDA’s proposal for

substances that would be used in

human food. As discussed in more

detail throughout this document, FDA is

specifically requesting comment on the

following issues concerning the

proposed regulations for substances that

would be used in human food: (1)

Whether it would be appropriate to

require or recommend that the

submission include an electronic copy,

in addition to three paper copies, of

some or all of the notice; (2) the

proposed requirement that, in all cases,

FDA respond to the notifier; (3) whether

the agency should be permitted more

than 90 days to respond to a GRAS

notice; (4) the number of notices that

notifiers anticipate submitting on an

annual basis; (5) the agency’s proposal

to provide the public with ready access

to information from the proposed

notification procedure and the location

for such information; (6) whether any

inventory prepared by the agency

should be available through electronic

modes; (7) its proposal for administering

pending GRAS affirmation petitions if

the proposed notification procedure

becomes final; and (8) whether the

proposed substitution of a GRAS

notification procedure for the GRAS

petition process would have any impact

on international trade. FDA specifically

requests comments on these same issues

for the proposed regulations concerning

substances that would be used in animal

foods or feed.

In the case of substances that would

be used in animal feed, FDA is

particularly concerned about the

practical implications of a 90-day

response period, because, to date, the

agency has received fewer than 10

GRAS affirmation petitions for

substances that would be used solely in

animal food or feed. Should the number

of notices received under a GRAS

notification program exceed more than

a few notices per year, agency resources

devoted to the animal feed program

likely would be insufficient to evaluate,

within the proposed 90-day timeframe,

whether the notice provides a sufficient

basis for a GRAS determination. Thus,

comments to the proposal may justify

that the agency adopt, in a final rule, a

longer timeframe for notifications

concerning substances used in animal

feed.

The agency recognizes that notifiers

may have questions concerning the

common or usual name for a substance

that would be used in animal feeds.

FDA advises that, in such

circumstances, a notifier should consult

with the Division of Animal Feeds in

FDA’s Center for Veterinary Medicine.

XII. Summary of the Proposal

FDA is proposing to clarify current

§ 170.30 regarding the eligibility of the

use of a substance for exemption from

the act’s premarket approval

requirements based on a GRAS

determination. Specifically, FDA is

proposing to amend current § 170.30(a)

to clarify that general recognition of

safety requires that there be common

knowledge among the qualified expert

community that there is reasonable

certainty that the substance is not

harmful under the intended conditions

of use. This amendment would also

clarify that a GRAS substance is neither

more safe nor less safe than an approved

food additive, and that the distinction

between a GRAS substance and an

approved food additive is in the

common knowledge of, and expert

consensus about, that safety.

In addition, FDA is proposing two

changes to current § 170.30(b). First,

FDA is proposing to clarify the types of

technical evidence of safety that

ordinarily would constitute common

knowledge about a substance that is

GRAS through scientific procedures.

FDA is proposing this change because

the quantity and quality of scientific

evidence required to obtain approval of

a substance as a food additive vary

considerably depending upon the

estimated dietary exposure to the

substance and the chemical, physical,

and physiological properties of the

substance. Second, FDA is proposing to

clarify the role of publication in

satisfying the common knowledge

element of the GRAS standard because

publication is ordinarily required, but

may not always be sufficient, to satisfy

this element. For consistency with these

proposed amendments, FDA is also

proposing to amend the definition of

‘‘scientific procedures’’ in § 170.3(h).

In keeping with the Reinventing Food

Regulations, FDA is proposing to

replace the current voluntary GRAS

affirmation process with a voluntary

procedure whereby any person may

notify FDA of a GRAS determination.

The notice would include a ‘‘GRAS

exemption claim,’’ dated and signed by

the notifier, that would provide, in a

consistent format, specific information

about a GRAS determination. This claim

would include a succinct description of

the notified substance, the applicable

conditions of use, and the basis for the

GRAS determination. The GRAS

exemption claim would also include a

statement that the information

supporting the GRAS determination was

available for FDA review and copying or

would be sent to FDA upon request. In

addition to the GRAS exemption claim,

the notice would include detailed

information about the identity of the

notified substance and a detailed

discussion of the basis for the notifier’s

GRAS determination.

FDA would evaluate whether the

notice provides a sufficient basis for a

GRAS determination and whether

information in the notice or otherwise

available to FDA raises issues that lead

the agency to question whether use of

the substance is GRAS. Within 90 days

from the date of receipt of the notice,

FDA would respond to the notifier in

writing and could advise the notifier

that the agency has identified a problem

with the notice. A response that does

not advise that the agency has identified

a problem with the notice would not be

equivalent to an affirmation of GRAS

status by the agency.

For each notice received, FDA would

make readily accessible to the public the

GRAS exemption claim and the agency’s

response. Although FDA would

maintain a readily accessible inventory

of notices received and the agency’s

response to them, this inventory would

be neither codified nor referenced in the

agency’s regulations.

Under the proposal, all GRAS

affirmation petitions that were filed by

FDA under § 170.35 prior to the

effective date of a GRAS notification

final rule and still pending as of that

date would be presumptively converted

to a notice on that date. Any person who

had submitted a GRAS affirmation

petition that is converted to a notice

could: (1) Amend such converted

petition to satisfy the requirements of

the notification procedure by submitting

to the agency a modified GRAS

exemption claim; (2) submit an FAP for

the substance and request that FDA

cross reference the information in the

GRAS affirmation petition; or (3) submit

a complete notice in accordance with

the notification procedure.
Federal Register / Vol. 62, No. 74 / Thursday, April 17, 1997 / Proposed Rules 18957

FDA’s regulations in part 570

concerning GRAS substances for use in

animal food or feeds implement the

same statutory provisions as the

regulations in part 170 concerning

GRAS substances for use in human

food. Accordingly, FDA is proposing: (1)

To amend the provisions of § 570.30

that are parallel to the provisions of

current § 170.30 (i.e., § 570.30(a) and

(b)); (2) to eliminate the GRAS

affirmation petition process provided

for in § 570.35(a) and (c); and (3) to

provide the option of a GRAS

notification procedure for substances

used in animal food or feeds that would

be parallel to proposed § 170.36.

FDA is also proposing several

amendments to parts 170, 184, 186, and

570 of its regulations as conforming

amendments.

XIII. Paperwork Reduction

This proposed rule contains

information that is subject to review by

OMB under the Paperwork Reduction

Act of 1995 (Pub. L. 104–13). Therefore,

in accordance with 44 U.S.C.

3506(c)(2)(B) and 5 CFR part 1320, FDA

is providing below the title, description,

and respondent descriptions for the

information collections contained in

this proposal, along with an estimate of

the resulting annual information

collection burden. Included in the

estimate is the time needed to review

instructions, to gather the required

information, and to disclose the

information.

FDA invites comments on the

following: (1) Whether the proposed

collection of information is necessary

for the proper performance of the

functions of the agency, including

whether the information will have

practical utility; (2) the accuracy of the

agency’s estimate of the burden of the

proposed collection of information,

including the validity of the

methodology and assumptions used; (3)

ways to enhance the quality, utility, and

clarity of the information to be

collected; and (4) ways to minimize the

burden of the collection of information

on those who are to respond, including

through the use of automated collection

techniques, where appropriate, or other

forms of information technology.

Title: Notice of a Claim for GRAS

Exemption Based on a GRAS

Determination

Description: Section 409 of the act

establishes a premarket approval

requirement for ‘‘food additives;’’

section 201(s) of that act provides an

exemption from the definition of ‘‘food

additive’’ and thus from the premarket

approval requirement, for uses of

substances that are GRAS by qualified

experts. FDA is proposing a voluntary

procedure whereby members of the food

industry who determine that use of a

substance satisfies the statutory

exemption may notify FDA of that

determination. The notice would

include a detailed summary of the data

and information that support the GRAS

determination, and the notifier would

maintain a record of such data and

information. FDA would make the

information describing the GRAS claim,

and the agency’s response to the notice,

available in a publicly accessible file;

the entire GRAS notice would be

publicly available consistent with the

FOIA and other Federal disclosure

statutes.

Description of Respondents:

Manufacturers of Substances Used in

Food and Feed

FDA estimates the total annual

burden for this information collection to

be 9,900 hours.

ESTIMATED ANNUAL REPORT BURDEN

21 CFR Number of

respondents

Annual frequency per

response

Total annual

response

Hours per

response Total hours

170.36 ....................................................................................................... 50 1 50 150 7,500

570.36 ....................................................................................................... 10 1 10 150 1,500

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

ESTIMATED ANNUAL RECORDKEEPING BURDEN

21 CFR

Number of

recordkeepers

Annual frequency of

recordkeeping

Total annual

records

Hours per

recordkeeperTotal hours

170.36(c)(v) ............................................................................................... 50 1 50 15 750

570.36(c)(v) ............................................................................................... 10 1 10 15 150

There are no operating or

maintenance costs or capital costs

associated with this collection.

FDA tentatively concludes that there

are no anticipated capital costs or

operating and maintenance costs

associated with the proposed

information collection requirements.

However, the agency welcomes

comments on any such anticipated

costs.

The agency has submitted copies of

the proposed rule to OMB for review of

the portions of the proposal that are

subject to the Paperwork Reduction Act

of 1995. Interested persons are

requested to send comments regarding

information collection by May 19, 1997

to the Office of Information and

Regulatory Affairs, OMB (address

above).

XIV. Analysis of Impacts

FDA has examined the impacts of the

proposed rule under Executive Order

12866 and the Regulatory Flexibility Act

(5 U.S.C. 601–612). Executive Order

12866 directs agencies to assess all costs

and benefits of available regulatory

alternatives and, when regulation is

necessary, to select the regulatory

approaches that maximize net benefits

(including potential economic,

environmental, public health and safety

effects; other advantages; distributive

impacts; and equity). Executive Order

12866 classifies a rule as significant if

it meets any one of a number of

specified conditions, including having

an annual effect on the economy of $100

million or adversely affecting in a

material way a sector of the economy,

competition, or jobs, or if it raises novel

legal or policy issues. If a rule has a

significant economic impact on a
18958 Federal Register / Vol. 62, No. 74 / Thursday, April 17, 1997 / Proposed Rules

substantial number of small entities, the

Regulatory Flexibility Act requires

agencies to analyze regulatory options

that would minimize the economic

impact of that rule on small entities.

FDA finds that this proposed rule is

not a significant rule as defined by

Executive Order 12866, and finds under

the Regulatory Flexibility Act that this

proposed rule will not have a significant

impact on a substantial number of small

entities. Finally, FDA, in conjunction

with the Administrator of OMB, finds

that this proposed rule is not a major

rule for the purpose of congressional

review (Pub. L. 104–121).

A. Regulatory Options

FDA has the following primary

options:

(1) Take no action;

(2) Adopt proposed GRAS notification

procedure;

(3) Adopt a GRAS notification

procedure allowing FDA feedback on

independent GRAS determinations of

either a higher or lower level of

authoritativeness than the proposed

notification system; and

(4) Eliminate agency participation in

independent GRAS determinations.

B. Costs and Benefits

1. Option One: Take No Action

Neither costs nor benefits are

associated with taking no action. This

option is the baseline case in

comparison with which the costs and

benefits of the other options are

determined.

The existing GRAS petition process is

a government service provided to

industry by which firms may

voluntarily submit information to FDA

for agency review and affirmation of the

GRAS status of the use of a substance

in food. Although FDA does not charge

a fee to review material submitted under

the GRAS petition process, participation

in that process is not without cost

because the required information must

either be generated or gathered, and

submitted to FDA. The fact that some

firms participate in this voluntary

process implies that for some firms, the

benefit of participation must be greater

than the cost of participation, and also

that the net benefit of participation must

be greater than the net benefit of

existing alternatives, such as private

third-party review of independent

GRAS determinations. However, the fact

that the cost of participation does not

reflect the costs involved in actually

administering the GRAS petition

process means that participation in that

process cannot support inferences

regarding the net social benefits of the

petition process.

The benefit firms receive from

participation in the existing GRAS

petition process appears to involve a

reduction in the cost of marketing foods

containing substances independently

determined to be GRAS because FDA

affirmation of GRAS status would likely

facilitate marketing of such substances.

Manufacturers of these foods and retail

establishments buying these foods for

subsequent resale to consumers may be

reluctant to offer them for sale in the

absence of assurance that FDA will not

subsequently conclude that ingredients

independently determined to be GRAS

are unapproved food additives. If these

substances were subsequently found not

to be GRAS, any ensuing seizure of

foods containing the unapproved food

additive might damage the credibility of

those manufacturers and retail

establishments, and might lead to

economic losses. If there were no

process for agency GRAS affirmation,

firms making independent GRAS

determinations may attempt to

substitute for GRAS affirmations by

doing additional research, contracting

with third party research organizations,

or taking other steps to provide

adequate assurances to other firms that

FDA will probably not subsequently

challenge their independent GRAS

determinations.

In addition to providing a desired

good or service, the GRAS petition

process may result in some benefit in

terms of reducing the health risks from

substances independently determined to

be GRAS if FDA review of the

information supporting independent

GRAS determinations uncovers an

erroneous determination which, if

undetected, could lead to health risks.

2. Option Two: Adopt Proposed GRAS

Notification Procedure

The chief benefit of eliminating the

existing GRAS petition process and

replacing it with the proposed GRAS

notification procedure is that the

notification procedure will enable

industry to obtain a limited degree of

FDA feedback on independent GRAS

determinations more quickly and at

lower cost, to both industry and FDA,

than the GRAS petition process. Under

the proposed notification procedure,

FDA will determine whether the notice

provides a sufficient basis for a GRAS

determination or whether information

in the notice, or otherwise available to

FDA, raises issues that lead the agency

to question whether use of the substance

is GRAS.

The proposed notification procedure

will come to closure more quickly and

generate less uncertainty than the GRAS

petition process because the notification

procedure is based on a 90-day review

period rather than on the open-ended

review period of the GRAS petition

process. In some cases, the GRAS

petition process involves a number of

iterative steps in which FDA asks for

and receives additional supporting

information. Under the notification

procedure, FDA will base its response

on the notifier’s initial submission.

In addition to the time advantage, the

cost of participation in the proposed

notification procedure will probably be

less than the cost of participation in the

GRAS petition process because the

notification procedure will require the

submission of only a summary of the

information used to support the

independent GRAS determination,

rather than the full supporting

information required under the GRAS

petition process. For example, the

notification procedure will not require

the submission of references or material

relating to methods of detection in

foods, which are required under the

GRAS petition process. Submissions

under the notification procedure will

probably be about 25 to 30 pages, while

submissions under the current GRAS

petition process can have hundreds or

even thousands of pages.

On the other hand, the same

underlying information will be required

under the notification procedure as

under the GRAS petition process, so the

potential cost savings will be confined

to the relatively modest costs of

assembling, copying, and mailing

information. The more significant cost

of generating or locating the requisite

underlying information will not be

affected. In addition, the summary

required under the proposed

notification procedure may fairly be

viewed as a step beyond simply

providing the supporting information as

required under the GRAS petition

process. Therefore, although

participation in the proposed

notification procedure will probably be

somewhat less costly than participation

in the GRAS petition process, the cost

reduction is likely to be relatively

modest.

The primary cost of replacing the

existing GRAS petition process with the

proposed notification procedure is that

it reduces the options available to

industry for obtaining FDA feedback on

independent GRAS determinations at a

level of authoritativeness comparable to

that currently offered under the GRAS

petition process. Currently, feedback at

this level of authoritativeness is

available through both the GRAS

petition process and the FAP process.

The fact that FDA receives both GRAS

petitions and FAP’s suggests that some
Federal Register / Vol. 62, No. 74 / Thursday, April 17, 1997 / Proposed Rules 18959

firms find participation in the GRAS

petition process less costly than

participation in the FAP process.

However, this difference in cost is

probably relatively modest because the

systems are quite similar. For example,

substances that are GRAS may be

marketed without prior agency approval

and thus may be marketed during the

period in which either a GRAS petition

or an FAP on that substance is under

review.

The net benefit or cost of the

proposed notification procedure will

depend largely on whether the value of

participation in the proposed

notification procedure is or is not

comparable to that of participation in

the GRAS petition process. If the value

of participation in the two systems is

roughly comparable, then the time and

cost advantages of the proposed

notification procedure will probably

lead to modest net benefits. However, if

participation in the proposed

notification procedure is significantly

less valuable than participation in the

GRAS petition process because of the

lower level of authoritativeness of FDA

feedback available through the

notification procedure, then the

proposed procedure could lead to net

costs because firms may submit

relatively more costly FAP’s or take

other steps to compensate for the lack of

more authoritative FDA feedback on

independent GRAS determinations.

3. Option Three: Adopt a GRAS

Notification Procedure Allowing FDA

Feedback on Independent GRAS

Determinations of Either a Higher or

Lower Level of Authoritativeness Than

the Proposed Notification System

The benefits and costs of replacing the

existing GRAS petition process with

notification procedures allowing FDA

feedback on independent GRAS

determinations at either higher or lower

levels of authoritativeness than the

proposed notification procedure are

qualitatively similar to the benefits and

costs of adopting the proposed

notification procedure.

The net benefits or costs of

notification procedures allowing more

or less authoritative FDA feedback

depend largely on the cost of

participation in those systems and the

value of the feedback provided to

participating firms under those systems.

The value of FDA feedback to

participating firms involves the degree

to which that feedback facilitates the

marketing of substances that have been

subject to independent GRAS

determinations. A system providing

more authoritative feedback than the

proposed GRAS notification procedure

would either require submission of

more information or more detailed

information, or would involve more

detailed agency review of the same

amount of information. Thus,

participation in such a system would

arguably provide more valuable

feedback than participation in the

proposed notification procedure but

would also be more costly than

participation in the proposed

notification procedure. A system

providing less authoritative feedback

than the proposed GRAS notification

procedure would either require

submission of less information or less

detailed information, or would involve

less detailed agency review of the same

amount of information. Thus,

participation in such a system would

arguably provide less valuable feedback

than participation in the proposed

notification procedure but would

probably also be less costly than

participation in the proposed

notification procedure.

In both cases, it is difficult to

determine whether the resulting

changes in the value of FDA feedback

available through the notification

procedure would compensate firms for

the resulting changes in the cost of

participation in such procedures, or to

compare the net social benefits of

offering such procedures with the net

benefits of the existing GRAS petition

process.

4. Option Four: Eliminate Agency

Participation in Independent GRAS

Determinations

The costs and benefits of this option

are qualitatively similar to those of

adopting a notification procedure

allowing FDA feedback of only a

minimal level of authoritativeness. In

general, the same results will occur if

the value of participation in a

notification procedure drops below the

costs involved in participation, or if a

notification procedure is not available.

In both cases, industry will either

submit relatively costly FAP’s or take

other steps to compensate for the lack of

a GRAS notification procedure or

petition process, or simply forgo

government oversight of their

independent GRAS determinations.

If FDA no longer participates in

independent GRAS determinations,

FDA will not be aware of substances

that have been the subject of

independent GRAS determinations

unless firms choose to submit FAP’s for

those substances. Any public health

benefits associated with FDA awareness

of these substances will be lost.

However, if firms take other steps to

confirm independent GRAS

determinations, then these other steps

will be associated with countervailing

public health benefits.

Again, it is difficult to determine

whether this option would result in net

social costs or benefits because of the

difficulty of estimating the value of

various levels of FDA and non FDA

feedback on independent GRAS

determinations. However, the

distinctive role of FDA in GRAS issues

suggests that FDA feedback may be

more valuable to industry than other,

equally costly, activity designed to

confirm independent GRAS

determinations. Therefore, it is likely

that the availability of some type of

notification procedure will lead to

greater net benefits than no notification

procedure.

C. Regulatory Flexibility Analysis

The proposed action will affect any

firm that may have chosen to participate

in the existing GRAS petition process or

may choose to participate in the

proposed GRAS notification process,

including manufacturers of both human

and animal food, food additives, and

feed additives. The Dun’s Market

Identifiers database lists 27,989 firms in

Standard Industry Code (SIC) 20, Food

and Kindred Products. This includes

dog and cat food, and prepared feeds

not elsewhere classified. In addition,

this database lists 113 firms in SIC 2869,

Industrial Organic Chemicals, Not

Elsewhere Classified, the SIC code that

includes manufacturers of food

additives. Therefore, a total of 28,102

firms will potentially be affected by this

proposed rule.

The Small Business Administration

(SBA) guidelines on the definition of a

small business for SIC 20 identify a

small business as being a business

having no more than 1,000, 750, or 500

employees, depending on the more

precise four-digit SIC code associated

with the firm in question. However,

there is no easy way to distribute the

total number of firms in SIC 20 into the

appropriate four-digit SIC categories

because more than one primary fourdigit SIC code may be associated with

any given firm. To avoid missing any

small firms, the least restrictive size

definition of 1,000 or fewer employees

was used for all firms. The SBA

definition of a small business in SIC

2869 is a business with 1,000 or fewer

employees. Based on these definitions,

and assuming that the distribution of

employment for firms for which no

employee data are available is the same

as the distribution for firms for which

data are available, a total of 27,531 firms

could potentially be affected by this

proposed rule.
18960 Federal Register / Vol. 62, No. 74 / Thursday, April 17, 1997 / Proposed Rules

Although this proposal may affect a

substantial number of firms that

manufacture food or food additives,

many of which are small firms, this

proposal will not have a significant

impact on these firms for two reasons.

First, this proposal replaces one

voluntary program with another

voluntary program. Therefore, small

firms will not be required to undertake

any additional activity or bear any

additional costs. Second, participation

in the proposed GRAS notification

procedure should be somewhat less

costly than participation in the GRAS

petition process. Therefore, small firms

should be better able to participate in

the notification procedure than the

petition process.

D. Conclusions

In accordance with Executive Order

12866, FDA has analyzed this proposed

rule and finds that this proposed rule is

neither economically significant nor a

significant action, as defined by that

order. FDA has also analyzed this

proposed rule in accordance with the

Regulatory Flexibility Act and finds that

this proposed rule will not have a

significant impact on a substantial

number of small businesses.

Accordingly, under the Regulatory

Flexibility Act, 5 U.S.C. 605(b), the

Commissioner certifies that this

proposed rule will not have a significant

economic impact on a substantial

number of small entities.

The net costs and benefits of replacing

the GRAS petition process with the

proposed GRAS notification procedure

are indeterminate. However, any

increase in net costs or benefits relative

to the current system will probably be

modest. FDA requests comments on the

costs and benefits of replacing the GRAS

petition process with the proposed

GRAS notification procedure.

XV. Environmental Impact

The agency has determined under 21

CFR 25.24(a)(8) that this action is of a

type that does not individually or

cumulatively have a significant effect on

the human environment. Therefore,

neither an environmental assessment

nor an environmental impact statement

is required.

XVI. References

The following references have been

placed on display at DMB (address

above) and may be seen by interested

persons between 9 a.m. and 4 p.m.,

Monday through Friday.

1. House Report No. 2284, July 28, 1958.

2. Price, J. M., C. G. Biava, B. L. Oser, E.

E. Vogin, J. Steinfeld, and H. L. Ley, ‘‘Bladder

Tumors in Rats Fed Cyclohexylamine or High

Doses of a Mixture of Cyclamate and

Saccharin,’’ Science, 167:1131–1132, 1970.

3. New York Times, p. 22, October 31,

1969.

4. Sneath, P. H. A. et. al., Bergey’s Manual

of Systematic Bacteriology, Williams &

Wilkins, Baltimore, 1984.

5. Subcommittee on the 10th Edition of the

Recommended Dietary Allowances, Food and

Nutrition Board, Commission on Life

Sciences, National Research Council,

Recommended Dietary Allowances, 10th ed.,

Washington, DC, National Academy Press,

1989.

6. ‘‘Biotechnology and Food Safety,’’ (Food

and Agriculture Organization, Rome, 1996).

7. ‘‘Strategies for Assessing the Safety of

Foods Produced by Biotechnology’’ (World

Health Organization, Geneva, 1991).

8. ‘‘Safety Evaluation of Foods Derived by

Modern Biotechnology: Concepts and

Principles’’ (Organization for Economic

Cooperation and Development, Paris, 1993).

9. ‘‘Application of the Principles of

Substantial Equivalence to the Safety

Evaluation of Foods or Food Components

from Plants Derived by Modern

Biotechnology’’ (World Health Organization,

Geneva, 1995).

10. Kessler, D. A., M. R. Taylor, J. H.

Maryanski, E. L. Flamm, and L. S. Kahl, ‘‘The

Safety of Foods Developed by

Biotechnology,’’ Science, 256:1747–1749 and

1832, 1992.

List of Subjects

21 CFR Part 170

Administrative practice and

procedure, Food additives, Reporting

and recordkeeping requirements.

21 CFR Part 184

Food ingredients.

21 CFR Part 186

Food ingredients, Food packaging.

21 CFR Part 570

Animal feeds, Animal foods, Food

additives.

Therefore, under the Federal Food,

Drug, and Cosmetic Act and under

authority delegated to the Commissioner

of Food and Drugs, it is proposed that

21 CFR parts 170, 184, 186, and 570 be

amended as follows:

PART 170—FOOD ADDITIVES

1. The authority citation for 21 CFR

part 170 is revised to read as follows:

Authority: Secs. 201, 401, 402, 409, 701 of

the Federal Food, Drug, and Cosmetic Act (21

U.S.C. 321, 341, 342, 348, and 371).

2. Section 170.3 is amended by

revising paragraph (h) to read as

follows:

§ 170.3 Definitions.

* * * * *

(h) Scientific procedures include

scientific data (such as human, animal,

analytical, or other scientific studies),

information, methods, and principles,

whether published or unpublished,

appropriate to establish the safety of a

substance.

* * * * *

3. Section 170.30 is amended by

revising the last sentence of paragraphs

(a), (b), and (c)(2); and by removing and

reserving paragraph (f) to read as

follows:

§ 170.30 Eligibility for classification as

generally recognized as safe (GRAS).

(a) * * * General recognition of safety

requires common knowledge throughout

the scientific community knowledgeable

about the safety of substances directly or

indirectly added to food that there is

reasonable certainty that the substance

is not harmful under the intended

conditions of use.

(b) * * * General recognition of

safety through scientific procedures

shall be based upon generally available

and accepted scientific data,

information, methods, or principles,

which ordinarily are published and may

be corroborated by unpublished

scientific data, information, or methods.

(c)(1) * * *

(2) * * * Persons who claim that use

of a substance is GRAS through

experience based on its common use in

food outside of the United States should

notify FDA of that claim in accordance

with proposed § 170.36.

* * * * *

4. Section 170.35 is amended by

revising paragraph (a) and by removing

paragraph (c) to read as follows:

§ 170.35 Affirmation of generally

recognized as safe (GRAS) status.

(a) The Commissioner, on his own

initiative, may affirm the GRAS status of

the use of a substance that directly or

indirectly becomes a component of

food.

* * * * *

5. New § 170.36 is added to subpart B

to read as follows:

§ 170.36 Notice of a claim for exemption

based on a GRAS determination.

(a)(1) Any person may notify FDA of

a claim that a particular use of a

substance is exempt from the statutory

premarket approval requirements based

on the notifier’s determination that such

use is generally recognized as safe

(GRAS).

(2) Notice to the agency of this section

shall not constitute compliance with:

(i) Section 101.14(b)(3)(ii) of this

chapter. Any person who submits a

health claim petition under § 101.14 of

this chapter shall comply in full with

§ 101.14(b)(3)(ii) regardless of whether
Federal Register / Vol. 62, No. 74 / Thursday, April 17, 1997 / Proposed Rules 18961

the agency has been notified under this

section about a substance and regardless

of the nature of the agency’s response.

(ii) Section 106.120(b)(6)(ii) of this

chapter. Any person who submits a new

infant formula submission under

proposed § 106.120 of this chapter shall

comply in full with proposed

§ 106.120(b)(6)(ii) regardless of whether

the agency has been notified under this

section about a substance and regardless

of the nature of the agency’s response.

(b) A notice of a GRAS exemption

claim shall be submitted in triplicate to

the Office of Premarket Approval (HFS–

200), Center for Food Safety and

Applied Nutrition, Food and Drug

Administration, 200 C St. SW.,

Washington, DC 20204.

(c) Notifiers shall submit the

following information:

(1) A claim, dated and signed by the

notifier, or by the notifier’s attorney or

agent, or (if the notifier is a corporation)

by an authorized official, that a

particular use of a substance is exempt

from the premarket approval

requirements of the Federal Food, Drug,

and Cosmetic Act (the act) because the

notifier has determined that such use is

GRAS. Such GRAS exemption claim

shall include:

(i) The name and address of the

notifier;

(ii) The common or usual name of the

substance that is the subject of the

GRAS exemption claim (i.e., the

‘‘notified substance’’);

(iii) The applicable conditions of use

of the notified substance, including the

foods in which the substance is to be

used, levels of use in such foods, and

the purposes for which the substance is

used, including, when appropriate, a

description of the population expected

to consume the substance;

(iv) The basis for the GRAS

determination (i.e., through scientific

procedures or through experience based

on common use in food); and

(v) A statement that the data and

information that are the basis for the

notifier’s GRAS determination are

available for the Food and Drug

Administration’s (FDA) review and

copying at reasonable times at a specific

address set out in the notice or will be

sent to FDA upon request.

(2) Detailed information about the

identity of the notified substance,

including, as applicable, its chemical

name, Chemical Abstracts Service (CAS)

Registry Number, Enzyme Commission

number, empirical formula, structural

formula, quantitative composition,

method of manufacture (excluding any

trade secrets and including, for

substances of natural biological origin,

source information such as genus and

species), characteristic properties, any

content of potential human toxicants,

and specifications for food-grade

material;

(3) Information on any self-limiting

levels of use; and

(4) A detailed summary of the basis

for the notifier’s determination that a

particular use of the notified substance

is exempt from the premarket approval

requirements of the act because such

use is GRAS. Such determination may

be based either on scientific procedures

or on common use in food.

(i) For a GRAS determination through

scientific procedures, such summary

shall include:

(A) A comprehensive discussion of,

and citations to, generally available and

accepted scientific data, information,

methods, or principles that the notifier

relies on to establish safety, including a

consideration of the probable

consumption of the substance and the

probable consumption of any substance

formed in or on food because of its use

and the cumulative effect of the

substance in the diet, taking into

account any chemically or

pharmacologically related substances in

such diet;

(B) A comprehensive discussion of

any reports of investigations or other

information that may appear to be

inconsistent with the GRAS

determination; and

(C) The basis for concluding, in light

of the data and information described

under paragraphs (c)(1), (c)(2), (c)(3),

(c)(4)(i)(A), and (c)(4)(i)(B) of this

section, that there is consensus among

experts qualified by scientific training

and experience to evaluate the safety of

substances added to food that there is

reasonable certainty that the substance

is not harmful under the intended

conditions of use.

(ii) For a GRAS determination through

experience based on common use in

food, such summary shall include:

(A) A comprehensive discussion of,

and citations to, generally available data

and information that the notifier relies

on to establish safety, including

evidence of a substantial history of

consumption of the substance by a

significant number of consumers;

(B) A comprehensive discussion of

any reports of investigations or other

information that may appear to be

inconsistent with the GRAS

determination;

(C) The basis for concluding, in light

of the data and information described

under paragraphs (c)(1), (c)(2), (c)(3),

(c)(4)(ii)(A), and (c)(4)(ii)(B) of this

section, that there is consensus among

experts qualified by scientific training

and experience to evaluate the safety of

substances added to food that there is

reasonable certainty that the substance

is not harmful under the intended

conditions of use.

(d) Within 30 days of receipt of the

notice, FDA shall acknowledge receipt

of a notice by informing the notifier in

writing of the date on which the notice

was received.

(e) Within 90 days of receipt of the

notice, FDA shall respond to the notifier

in writing.

(f)(1) Any GRAS exemption claim

submitted under paragraph (c)(1) of this

section shall be immediately available

for public disclosure on the date the

notice is received. All remaining data

and information in the notice shall be

available for public disclosure, in

accordance with part 20 of this chapter,

on the date the notice is received.

(2) For each GRAS notice submitted

under this section, the following

information shall be readily accessible

for public review and copying:

(i) A copy of the GRAS exemption

claim submitted under paragraph (c)(1)

of this section.

(ii) A copy of any letter issued by the

agency under paragraph (e) of this

section.

(iii) A copy of any subsequent letter

issued by the agency regarding such

notice.

(g)(1) Any GRAS affirmation petition

that was filed by FDA under § 170.35

prior to (date the final rule becomes

effective) and is still pending as of (date

the final rule becomes effective) shall be

presumptively converted to a notice

under the provisions of this section on

(date the final rule becomes effective).

(2) Any person who submitted a

GRAS affirmation petition that is

converted to a notice under paragraph

(g)(1) of this section may amend such

converted petition to meet the

requirements of this section by

submitting to the agency a claim, dated

and signed by the notifier (i.e., the

former petitioner), or by the notifier’s

attorney or agent, or (if the notifier is a

corporation) by an authorized official,

that a particular use of a substance is

exempt from the premarket approval

requirements of the act because the

notifier has determined that such use is

GRAS. Such GRAS exemption claim

shall include:

(i) The name and address of the

notifier;

(ii) The applicable GRAS affirmation

petition number;

(iii) The common or usual name of the

substance that was the subject of the

converted GRAS affirmation petition

(i.e., the notified substance);

(iv) The applicable conditions of use

of the notified substance that are
18962 Federal Register / Vol. 62, No. 74 / Thursday, April 17, 1997 / Proposed Rules

supported by data and information in

the referenced GRAS petition, including

the foods in which the substance is to

be used, levels of use in such foods, and

the purposes for which the substance is

used, including, when appropriate, a

description of the population expected

to consume the substance;

(v) The basis for the GRAS

determination (i.e., through scientific

procedures or through experience based

on common use in food); and

(vi)(A) A statement that the complete

record that supports the GRAS

determination has been submitted to the

agency in the applicable GRAS petition;

or

(B) A statement that the data and

information that are the basis for the

notifier’s GRAS determination are

available for FDA review and copying at

reasonable times at a specific address

set out in the claim or will be sent to

FDA upon request.

(3)(i) A petition that is converted to a

notice under the provisions of

paragraph (g)(1) of this section and that

is amended according to the provisions

of paragraph (g)(2) of this section shall

be reviewed and administered according

to the provisions of paragraphs (d), (e),

and (f) of this section. For the purposes

of paragraphs (d), (e), and (f) of this

section, the date of receipt of the

amendment described in paragraph

(g)(2) of this section shall be the date of

receipt of the notice.

(3)(ii) After (date 90 days after date of

publication of the final rule), FDA will

inform any person who submitted a

GRAS affirmation petition that is

converted to a notice under the

provisions of paragraph (g)(1) of this

section, and who has not amended such

petition according to the provisions of

paragraph (g)(2) of this section, that the

converted petition is inadequate as a

notice under this section.

6. Section 170.38 is amended by

revising paragraph (a) to read as follows:

§ 170.38 Determination of food additive

status.

(a) The Commissioner may, in

accordance with § 170.35(b)(4), publish

a notice in the Federal Register

determining that a substance is not

GRAS and is a food additive subject to

section 409 of the act.

* * * * *

PART 184—DIRECT FOOD

SUBSTANCES AFFIRMED AS

GENERALLY RECOGNIZED AS SAFE

7. The authority citation for 21 CFR

part 184 continues to read as follows:

Authority: Secs. 201, 402, 409, 701 of the

Federal Food, Drug, and Cosmetic Act (21

U.S.C. 321, 342, 348, and 371).

§ 184.1 [Amended]

8. Section 184.1 Substances added

directly to human food affirmed as

generally recognized as safe (GRAS) is

amended in paragraph (b)(1) by

removing the last sentence.

PART 186—INDIRECT FOOD

SUBSTANCES AFFIRMED AS

GENERALLY RECOGNIZED AS SAFE

9. The authority citation for 21 CFR

part 186 continues to read as follows:

Authority: Secs. 201, 402, 409, 701 of the

Federal Food, Drug, and Cosmetic Act (21

U.S.C. 321, 342, 348, and 371).

§ 186.1 [Amended]

10. Section 186.1 Substances added

indirectly to human food affirmed as

generally recognized as safe (GRAS) is

amended in paragraph (b)(1) by

removing the last sentence.

PART 570—FOOD ADDITIVES

11. The authority citation for 21 CFR

part 570 is revised to read as follows:

Authority: Secs. 201, 401, 402, 409, 701 of

the Federal Food, Drug, and Cosmetic Act (21

U.S.C. 321, 341, 342, 348, and 371).

12. Section 570.3 is amended by

revising paragraph (h) to read as

follows:

§ 570.3 Definitions.

* * * * *

(h) Scientific procedures include

scientific data (such as human, animal,

analytical, or other scientific studies),

information, methods, and principles,

whether published or unpublished,

appropriate to establish the safety of a

substance.

* * * * *

13. Section 570.30 is amended by

revising the last sentence of paragraphs

(a) and (b) to read as follows:

§ 570.30 Eligibility for classification as

generally recognized as safe (GRAS).

(a) * * * General recognition of safety

requires common knowledge throughout

the scientific community knowledgeable

about the safety of substances directly or

indirectly added to food that there is

reasonable certainty that the substance

is not harmful under the intended

conditions of use.

(b) * * * General recognition of

safety through scientific procedures

shall be based upon generally available

and accepted scientific data,

information, methods, or principles,

which ordinarily are published and may

be corroborated by unpublished

scientific data, information, or methods.

* * * * *

14. Section 570.35 is amended by

revising paragraph (a) and by removing

paragraph (c) to read as follows:

§ 570.35 Affirmation of generally

recognized as safe (GRAS) status.

(a) The Commissioner, on his own

initiative, may affirm the GRAS status of

the use of a substance that directly or

indirectly becomes a component of

food.

* * * * *

15. New § 570.36 is added to subpart

B to read as follows:

§ 570.36 Notice of a claim for exemption

based on a GRAS determination.

(a) Any person may notify FDA of a

claim that a particular use of a

substance is exempt from the statutory

premarket approval requirements based

on the notifier’s determination that such

use is generally recognized as safe

(GRAS).

(b) A notice of a GRAS exemption

claim shall be submitted in triplicate to

the Division of Animal Feeds (HFV–

220), Center for Veterinary Medicine,

Food and Drug Administration, 7500

Standish Pl., Rockville, MD 20855.

(c) Notifiers shall submit the

following information:

(1) A claim, dated and signed by the

notifier, or by the notifier’s attorney or

agent, or (if the notifier is a corporation)

by an authorized official, that a

particular use of a substance is exempt

from the premarket approval

requirements of the Federal Food, Drug,

and Cosmetic Act (the act) because the

notifier has determined that such use is

GRAS. Such GRAS exemption claim

shall include:

(i) The name and address of the

notifier;

(ii) The common or usual name of the

substance that is the subject of the

GRAS exemption claim (i.e., the notified

substance);

(iii) The applicable conditions of use

of the notified substance, including the

foods in which the substance is to be

used, levels of use in such foods, and

the purposes for which the substance is

used, including, when appropriate, a

description of the population expected

to consume the substance;

(iv) The basis for the GRAS

determination (i.e., through scientific

procedures or through experience based

on common use in food); and

(v) A statement that the data and

information that are the basis for the

notifier’s GRAS determination are

available for the Food and Drug

Administration’s (FDA) review and

copying at reasonable times at a specific

address set out in the notice or will be

sent to FDA upon request.
Federal Register / Vol. 62, No. 74 / Thursday, April 17, 1997 / Proposed Rules 18963

(2) Detailed information about the

identity of the notified substance,

including, as applicable, its chemical

name, Chemical Abstracts Service (CAS)

Registry Number, Enzyme Commission

number, empirical formula, structural

formula, quantitative composition,

method of manufacture (excluding any

trade secrets and including, for

substances of natural biological origin,

source information such as genus and

species), characteristic properties, any

content of potential human or animal

toxicants, and specifications for feedgrade material;

(3) Information on any self-limiting

levels of use; and

(4) A detailed summary of the basis

for the notifier’s determination that a

particular use of the notified substance

is exempt from the premarket approval

requirements of the act because such

use is GRAS. Such determination may

be based either on scientific procedures

or on common use in food.

(i) For a GRAS determination through

scientific procedures, such summary

shall include:

(A) A comprehensive discussion of,

and citations to, generally available and

accepted scientific data, information,

methods, or principles that the notifier

relies on to establish safety, including a

consideration of the probable

consumption of the substance and the

probable consumption of any substance

formed in or on food because of its use

and the cumulative effect of the

substance in the diet, taking into

account any chemically or

pharmacologically related substances in

such diet;

(B) A comprehensive discussion of

any reports of investigations or other

information that may appear to be

inconsistent with the GRAS

determination; and

(C) The basis for concluding, in light

of the data and information described

under paragraphs (c)(1), (c)(2), (c)(3),

(c)(4)(i)(A), and (c)(4)(i)(B) of this

section, that there is consensus among

experts qualified by scientific training

and experience to evaluate the safety of

substances added to food that there is

reasonable certainty that the substance

is not harmful under the intended

conditions of use.

(ii) For a GRAS determination through

experience based on common use in

food, such summary shall include:

(A) A comprehensive discussion of,

and citations to, generally available data

and information that the notifier relies

on to establish safety, including

evidence of a substantial history of

consumption of the substance by a

significant number of consumers;

(B) A comprehensive discussion of

any reports of investigations or other

information that may appear to be

inconsistent with the GRAS

determination;

(C) The basis for concluding, in light

of the data and information described

under paragraphs (c)(1), (c)(2), (c)(3),

(c)(4)(ii)(A), and (c)(4)(ii)(B) of this

section, that there is consensus among

experts qualified by scientific training

and experience to evaluate the safety of

substances added to food that there is

reasonable certainty that the substance

is not harmful under the intended

conditions of use.

(d) Within 30 days of receipt of the

notice, FDA shall acknowledge receipt

of a notice by informing the notifier in

writing of the date on which the notice

was received.

(e) Within 90 days of receipt of the

notice, FDA shall respond to the notifier

in writing.

(f)(1) Any GRAS exemption claim

submitted under paragraph (c)(1) of this

section shall be immediately available

for public disclosure on the date the

notice is received. All remaining data

and information in the notice shall be

available for public disclosure, in

accordance with part 20 of this chapter,

on the date the notice is received.

(2) For each GRAS notice submitted

under this section, the following

information shall be readily accessible

for public review and copying:

(i) A copy of the GRAS exemption

claim submitted under paragraph (c)(1)

of this section.

(ii) A copy of any letter issued by the

agency under paragraph (e) of this

section.

(iii) A copy of any subsequent letter

issued by the agency regarding such

notice.

(g)(1) Any GRAS affirmation petition

that was filed by FDA under § 570.35

prior to (date the final rule becomes

effective) and is still pending as of (date

the final rule becomes effective) shall be

presumptively converted to a notice

under the provisions of this section on

(date the final rule becomes effective).

(2) Any person who submitted a

GRAS affirmation petition that is

converted to a notice under paragraph

(g)(1) of this section may amend such

converted petition to meet the

requirements of this section by

submitting to the agency a claim, dated

and signed by the notifier (i.e., the

former petitioner), or by the notifier’s

attorney or agent, or (if the notifier is a

corporation) by an authorized official,

that a particular use of a substance is

exempt from the premarket approval

requirements of the act because the

notifier has determined that such use is

GRAS. Such GRAS exemption claim

shall include:

(i) The name and address of the

notifier;

(ii) The applicable GRAS affirmation

petition number;

(iii) The common or usual name of the

substance that was the subject of the

converted GRAS affirmation petition

(i.e., the notified substance);

(iv) The applicable conditions of use

of the notified substance that are

supported by data and information in

the referenced GRAS petition, including

the foods in which the substance is to

be used, levels of use in such foods, and

the purposes for which the substance is

used, including, when appropriate, a

description of the population expected

to consume the substance;

(v) The basis for the GRAS

determination (i.e., through scientific

procedures or through experience based

on common use in food); and

(vi)(A) A statement that the complete

record that supports the GRAS

determination has been submitted to the

agency in the applicable GRAS petition;

or

(B) A statement that the data and

information that are the basis for the

GRAS determination are available for

FDA’s review and copying at reasonable

times at a specific address set out in the

claim or will be sent to FDA upon

request.

(3)(i) A petition that is converted to a

notice under the provisions of

paragraph (g)(1) of this section and that

is amended according to the provisions

of paragraph (g)(2) of this section shall

be reviewed and administered according

to the provisions of paragraphs (d), (e),

and (f) of this section. For the purposes

of paragraphs (d), (e), and (f) of this

section, the date of receipt of the

amendment described in paragraph

(g)(2) of this section shall be the date of

receipt of the notice.

(ii) After (date 90 days after date of

publication of the final rule), FDA will

inform any person who submitted a

GRAS affirmation petition that is

converted to a notice under the

provisions of paragraph (g)(1) of this

section, and who has not amended such

petition according to the provisions of

paragraph (g)(2) of this section, that the

converted petition is inadequate as a

notice under this section.

§ 570.38 [Amended]

16. Section 570.38 Determination of

food additive status is amended in

paragraph (a) by removing ‘‘or (c)(5)’’.
18964 Federal Register / Vol. 62, No. 74 / Thursday, April 17, 1997 / Proposed Rules

Dated: April 8, 1997.

William B. Schultz,

Deputy Commissioner for Policy.

[FR Doc. 97–9706 Filed 4–16–97; 8:45 am]

BILLING CODE 4160–01–P