18938 federal register /vol. 62, no. 74/thursday, april … federal register/vol. 62, no....

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

DEPARTMENT OF HEALTH ANDHUMAN SERVICES

Food and Drug Administration

21 CFR Parts 170, 184, 186, and 570

[Docket No. 97N–0103]

Substances Generally Recognized asSafe

AGENCY: Food and Drug Administration,HHS.ACTION: Proposed rule.

SUMMARY: The Food and DrugAdministration (FDA) is proposing toclarify the criteria for exempting the useof a substance in human food or inanimal feed from the premarketapproval requirements of the FederalFood, Drug, and Cosmetic Act (the act)because such use is generallyrecognized as safe (GRAS). FDA is alsoproposing to replace the current GRASaffirmation process with a notificationprocedure whereby any person maynotify FDA of a determination that aparticular use of a substance is GRAS.Under the proposed notificationprocedure, the agency intends toevaluate whether the submitted noticeprovides a sufficient basis for a GRASdetermination and whether informationin the notice or otherwise available toFDA raises issues that lead the agencyto question whether use of the substanceis GRAS. This proposal reflects FDA’scommitment to achieving the goals forthe Reinventing Food Regulations partof the President’s National PerformanceReview (hereinafter referred to asReinventing Food Regulations). Theproposed notification procedure wouldallow FDA to direct its resources toquestions about GRAS status that are apriority with respect to public healthprotection.DATES: Written comments by July 16,1997, except that comments regardinginformation collection should besubmitted by May 19, 1997. The agencyproposes that any final rule that mayissue based on this proposal becomeeffective 60 days after its date ofpublication.ADDRESSES: Submit written commentsto the Dockets Management Branch(HFA–305), Food and DrugAdministration, 12420 Parklawn Dr.,rm. 1–23, Rockville, MD 20857. Submitwritten comments on the informationcollection requirements to the Office ofInformation and Regulatory Affairs,Office of Management and Budget(OMB), New Executive Office Bldg., 72517th 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 andApplied Nutrition (HFS–206), Foodand Drug Administration, 200 C St.SW., Washington, DC 20204, 202–418–3101.

Regarding Animal Feed Issues: GeorgeGraber, Center for VeterinaryMedicine (HFV–220), Food and DrugAdministration, 7500 Standish Pl.,Rockville, MD 20855, 301–594–1731.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. BackgroundA. The 1958 AmendmentB. History of FDA’s Approach to the GRAS

Exemption1. The GRAS List2. Opinion Letters3. Agency-initiated GRAS Review4. GRAS Criteria and the GRAS

Affirmation Process5. The Plant Policy StatementC. Elements of the GRAS StandardD. The GRAS Petition Process

II. Scope of the Proposed RegulationsIII. Proposed Revisions to § 170.30—

Eligibility for Classification as GRASA. General CriteriaB. Scientific Procedures GRAS

Determination1. Establishing General Recognition of

Safety2. Corroboration of SafetyC. Common Use GRAS DeterminationD. Other Provisions of Current § 170.30

IV. The Technical Element of a GRASDetermination Through ScientificProcedures

A. Consideration of Dietary ExposureB. Substantial Equivalence to a GRAS

SubstanceV. Proposed Revisions to § 170.35—

Affirmation of GRAS StatusVI. Proposed Establishment of a Notification

ProcedureA. General RequirementsB. Specific Requirements1. GRAS Exemption Claim2. Identity and Specifications3. Self-limiting Levels of Use4. Scientific Procedures GRAS

Determination5. Common Use GRAS DeterminationC. Agency Response1. Acknowledgment of Receipt2. 90-day Response Letter3. Subsequent Agency ActionD. AppealsE. Public Disclosure and Accessibility1. Public Disclosure2. Public AccessibilityF. Inventory

VII. Effect of the Proposed NotificationProcedure on Existing GRAS Petitions

VIII. Interim PolicyIX. Conforming AmendmentsX. International HarmonizationXI. Food Substances Used in Animal FeedXII. Summary of the ProposalXIII. Paperwork ReductionXIV. Analysis of Impacts

A. Regulatory OptionsB. Costs and Benefits1. Option One: Take No Action2. Option Two: Adopt Proposed GRAS

Notification Procedure3. Option Three: Adopt a GRAS

Notification Procedure Allowing FDAFeedback on Independent GRASDeterminations of Either a Higher orLower Level of Authoritativeness thanthe Proposed Notification System

4. Option Four: Eliminate AgencyParticipation in Independent GRASDeterminations

C. Regulatory Flexibility AnalysisD. Conclusions

XV. Environmental ImpactXVI. References

I. Background

A. The 1958 AmendmentIn 1958, in response to public concern

about the increased use of chemicals infoods and food processing and with thesupport of the food industry, Congressenacted the Food Additives Amendment(the 1958 amendment) to the act. Thebasic thrust of the 1958 amendment wasto require that, before a new additivecould be used in food, its producerdemonstrate the safety of the additive toFDA. The 1958 amendment defined theterms ‘‘food additive’’ (section 201(s) ofthe act (21 U.S.C. 321(s))) and ‘‘unsafefood additive’’ (section 409(a) of the act(21 U.S.C. 348(a))), established apremarket approval process for foodadditives (section 409(b) through (h)),and amended the food adulterationprovisions of the act to deemadulterated any food that is, or bears orcontains, any food additive that isunsafe within the meaning of section409 (section 402(a)(2)(C) of the act (21U.S.C. 342(a)(2)(C))).

Congress recognized that, under thisscheme, the safety of an additive couldnot be established with absolutecertainty, and thus provided for ascience-based safety standard thatrequires producers of food additives todemonstrate to a reasonable certaintythat no harm will result from theintended use of an additive (Ref. 1).FDA has incorporated this safetystandard into its regulations (§ 170.3(i)(21 CFR 170.3(i))). If FDA finds anadditive to be safe, based ordinarily ondata submitted by the producer to theagency in a food additive petition (FAP),the agency issues a regulation specifyingthe conditions under which the additivemay be safely used.

In enacting the 1958 amendment,Congress recognized that manysubstances intentionally added to foodwould not require a formal premarketreview by FDA to assure their safety,either because their safety had beenestablished by a long history of use in

18939Federal Register / Vol. 62, No. 74 / Thursday, April 17, 1997 / Proposed Rules

food or by virtue of the nature of thesubstances, their customary or projectedconditions of use, and the informationgenerally available to scientists aboutthe substances. Congress thus adopted,in section 201(s) of the act, a two-stepdefinition of ‘‘food additive.’’ The firststep broadly includes any substance, theintended use of which results or mayreasonably be expected to result,directly or indirectly, in its becoming acomponent or otherwise affecting thecharacteristics of food. The second step,however, excludes from the definitionof ‘‘food additive’’ substances that aregenerally recognized, among expertsqualified by scientific training andexperience to evaluate their safety(‘‘qualified experts’’), as having beenadequately shown through scientificprocedures (or, in the case of asubstance used in food prior to January1, 1958, through either scientificprocedures or through experience basedon common use in food) to be safeunder the conditions of their intendeduse.

Importantly, under section 201(s) ofthe act, it is the use of a substance,rather than the substance itself, that iseligible for the GRAS exemption. Inaddition, it is well settled that a mereshowing that use of a substance is‘‘safe’’ is not sufficient to exempt thesubstance from the act’s definition of‘‘food additive’’ (United States v. AnArticle of Food * * * Coco Rico, Inc.,752 F.2d 11, 15 n. 4 (1st Cir. 1985)).Instead, the substance must be shown tobe ‘‘generally recognized’’ as safe underthe conditions of its intended use (Id.;United States v. Articles of Food andDrug * * * Coli-Trol 80, 518 F.2d 743,745 (5th Cir. 1975)). The proponent ofthe exemption has the burden ofproving that the use of the substance is‘‘generally recognized’’ as safe (Id). Toestablish such recognition, theproponent must show that there is aconsensus of expert opinion regardingthe safety of the use of the substance.(See United States v. Western SerumCo., 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.2d564 (7th Cir. 1987); United States v.Articles of Drug * * * Hormonin, 498F.Supp.2d 424, 435 (D.N.J. 1980).)Unanimity among experts regardingsafety 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. AnArticle of Drug * * * 4,680 Pails, 725F.2d 976, 990 (5th Cir. 1984); Coli-Trol80, supra, 518 F.2d at 746; PromiseToothpaste, supra, 624 F.Supp. at 782.)

However, the existence of a severeconflict among experts regarding thesafety of the use of a substanceprecludes a finding of generalrecognition (4,680 Pails, supra, 725 F.2dat 990; Premo PharmaceuticalLaboratories v. United States, 629 F.2d795, 803 (2d Cir. 1980)) (Cf. Coli-Trol80, supra, 518 F.2d at 746 (mere conflictamong experts is not enough to precludea finding of general recognition)).

It is on the basis of the GRASexemption to the food additivedefinition that many substances (such asvinegar, vegetable oil, baking powder,and many salts, spices, flavors, gums,and preservatives) are lawfullymarketed today without a food additiveregulation. Under the 1958 amendment,a substance that is GRAS for a particularuse may be marketed for that usewithout agency review and approval.However, when a use of a substancedoes not qualify for the GRASexemption or other exemptionsprovided under section 201(s) of the act,that use of the substance is a foodadditive use subject to the premarketapproval mandated by the act. In suchcircumstances, the agency can takeenforcement action to stop distributionof the food substance and foodscontaining it on the grounds that suchfoods are or contain an unlawful foodadditive.

Importantly, under section 201(s) ofthe act, the GRAS exemption applies tothe premarket approval requirements forfood additives only. There is nocorresponding exemption to thepremarket approval requirements forcolor additives, which are defined insection 201(t) of the act.

B. History of FDA’s Approach to theGRAS Exemption

1. The GRAS List

Shortly after passage of the 1958amendment, FDA clarified theregulatory status of a multitude of foodsubstances that were used in food priorto 1958 and amended its regulations toinclude a list of food substances that,when used for the purposes indicatedand in accordance with current goodmanufacturing practice, are GRAS. Thislist was incorporated into the agency’sregulations as § 121.101(d) (now parts182 and 582 (21 CFR parts 182 and 582))(24 FR 9368, November 20, 1959). Aspart of that rulemaking, however, FDAacknowledged that it would beimpracticable to list all substances thatare GRAS for their intended use(formerly § 121.101(a); current§ 182.1(a)).

Section 121.101(d) became commonlyreferred to as ‘‘the GRAS list.’’ FDA

added other categories of substances(e.g., spices, seasonings, and flavorings)to the GRAS list in subsequentrulemakings (25 FR 404, January 19,1960; and 26 FR 3991, May 9, 1961).

2. Opinion LettersMany substances that were

considered GRAS by the food industrywere not included in the agency’s GRASlist. Under the 1958 amendment, asubstance that is GRAS for a particularuse may be marketed for that usewithout agency review and approval.Nonetheless, as a practical matter,manufacturers who determined on theirown initiative that use of a substancequalified for the GRAS exemptionfrequently decided to obtain theagency’s opinion on whether theirdetermination was justified. Manymanufacturers wrote to FDA andrequested an ‘‘opinion letter,’’ in whichagency officials would render aninformal opinion on the GRAS status ofuse of a substance. Although convenientand expedient, these opinion letterswere often available only to therequestor. Moreover, these opinionletters were not binding on the agencyat the time they were issued and werein fact formally revoked in 1970 (21 CFR170.6, 35 FR 5810, April 9, 1970).

3. Agency-Initiated GRAS ReviewIn 1969 (34 FR 17063, October 21,

1969), FDA removed various cyclamatesalts, a family of nonnutritivesweeteners, from the GRAS list becausethey were implicated in the formation ofbladder tumors in rats (Ref. 2). Inresponse to the concerns raised by thenew information on cyclamates, then-President Nixon directed FDA toreexamine the safety of GRASsubstances (Ref. 3), and FDA announcedthat the agency was conducting acomprehensive study of substancespresumed to be GRAS (35 FR 18623,December 8, 1970). The purpose of thestudy was to evaluate, by contemporarystandards, the available safetyinformation regarding substancespresumed to be GRAS and to issue eachitem in a new (i.e., affirmed) GRAS list,a food additive regulation, or an interimfood additive regulation pendingcompletion of additional studies.

4. GRAS Criteria and the GRASAffirmation Process

In the notice announcing thecomprehensive agency review ofpresumed GRAS substances, FDAproposed criteria that could be used toestablish whether these substancesshould be listed as GRAS, become thesubject of a food additive regulation, orbe listed in an interim food additive


1 In issuing a food additive regulation, the agencyconsiders technical evidence of safety but does notaddress the GRAS standard of general recognition.Thus, in most cases, the agency’s issuance of a foodadditive regulation means that FDA did notconsider the possible GRAS status of that substance.In a few cases (e.g., 21 CFR 173.357, cellulosetriacetate used as a fixing agent in theimmobilization of lactase enzyme preparation),FDA concluded, in evaluating the GRAS status ofa substance, that the safety of a use of a substancewas not generally recognized and authorized its useas a food additive rather than affirm it as GRAS (59FR 36935, July 20, 1994).

regulation pending completion ofadditional studies (35 FR 18623). Thesecriteria were incorporated into theagency’s regulations as § 121.3(precursor of current § 170.30 (21 CFR170.30)) (36 FR 12093, June 25, 1971).

FDA made a second announcementthat it was conducting a study ofpresumed GRAS substances (36 FR20546, October 23, 1971) andsubsequently instituted a rulemaking toestablish procedures that the agencycould use, on its own initiative, toaffirm the GRAS status of substancesthat were the subject of that review andwere found to satisfy the criteriaestablished in § 121.3 (proposed rule, 37FR 6207, March 25, 1972; final rule, 37FR 25705, December 2, 1972). Theseprocedures were subsequently codifiedat § 170.35 (a) and (b) (21 CFR 170.35 (a)and (b)). Because the GRAS review didnot cover all GRAS substances (e.g., itdid not cover many substances thatwere marketed based on amanufacturer’s independent GRASdetermination), that rulemakingincluded a mechanism (the currentGRAS petition process; § 170.35(c))whereby an individual could petitionFDA to review the GRAS status ofsubstances not being considered as partof the agency’s GRAS review.

In 1974, the agency proposed toclarify the criteria for GRAS status, thedifferences between GRAS status andfood additive status, and the proceduresbeing used to conduct the currentreview of food substances (39 FR 34194,September 23, 1974). The finalregulations based on this proposalamended § 121.3 (current § 170.30) todistinguish a determination of GRASstatus through scientific procedures(scientific procedures GRASdetermination; current § 170.30(b)) froma determination of GRAS status throughexperience based on common use infood (common use GRAS determination;current § 170.30(c)) (41 FR 53600,December 7, 1976). Those finalregulations also established definitionsfor ‘‘common use in food’’ (current§ 170.3(f)) and ‘‘scientific procedures’’(current § 170.3(h)). FDA subsequentlyadded criteria (§ 170.30(c)(2)) for thedetermination of GRAS status throughexperience based on common use infood when that use occurred exclusivelyor primarily outside of the United States(53 FR 16544, May 10, 1988).

5. The Plant Policy StatementFDA’s ‘‘Statement of Policy: Foods

Derived From New Plant Varieties’’ (theplant policy statement) (57 FR 22984,May 29, 1992) is an example of a recentagency policy announcement regardingagency priorities in reviewing the GRAS

status of substances added to food. Inthe plant policy statement, FDAreviewed its position on theapplicability of the food additivedefinition and section 409 of the act tofoods derived from new plant varietiesin light of the intended changes in thecomposition of foods that might resultfrom the newer techniques of geneticmodification such as recombinantdeoxyribonucleic acid (rDNA)techniques:

The statutory definition of ‘‘food additive’’makes clear that it is the intended orexpected introduction of a substance intofood that makes the substance potentiallysubject to food additive regulation. Thus, inthe case of foods derived from new plantvarieties, it is the transferred genetic materialand the intended expression product orproducts that could be subject to foodadditive regulation, if such material orexpression products are not GRAS.

(57 FR 22984 at 22990)In the plant policy statement, FDA

provided extensive guidance, includingcriteria and analytical steps thatproducers could follow, on situations inwhich producers should consult withFDA to determine whether an FAP isappropriate. FDA also stated its intent touse its food additive authority inregulating foods and their byproductsderived from new plant varieties to theextent necessary to protect publichealth.

C. Elements of the GRAS StandardUnder section 201(s) of the act, a

substance is exempt from the definitionof food additive and thus, frompremarket approval requirements, if itssafety is generally recognized byqualified experts. Accordingly, adetermination that a particular use of asubstance is GRAS requires bothtechnical evidence of safety and a basisto conclude that this technical evidenceof safety is generally known andaccepted. In contrast, a determinationthat a food additive is safe requires onlytechnical evidence of safety.1 Thus, aGRAS substance is distinguished from afood additive on the basis of thecommon knowledge about the safety ofthe substance for its intended use ratherthan on the basis of what the substance

is or the types of data and informationthat are necessary to establish its safety.To emphasize this distinction between aGRAS substance and a food additive,and to simplify discussion about thestandard for general recognition ofsafety, in this document, FDA uses theterm ‘‘technical element’’ whendiscussing technical evidence of safetyand ‘‘common knowledge element’’when discussing general knowledge andacceptance of safety.

The technical element of the GRASstandard requires that information aboutthe substance establish that theintended use of the substance is safe. Asdiscussed in section I.A of thisdocument, FDA has defined ‘‘safe’’(§ 170.3(i)) as a reasonable certainty inthe minds of competent scientists thatthe substance is not harmful under itsintended conditions of use. Current§ 170.30(b) provides that generalrecognition of safety through scientificprocedures requires the same quantityand quality of scientific evidence as isrequired to obtain approval of thesubstance as a food additive. Similarly,current § 170.30(c)(1) provides thatgeneral recognition of safety throughexperience based on common use infood prior to January 1, 1958, may bedetermined without the quantity orquality of scientific procedures requiredfor approval of a food additiveregulation and must be based solely onfood use of the substance prior to thatdate. Current § 170.3(f) defines‘‘common use in food’’ as a substantialhistory of consumption for food use bya significant number of consumers.

The common knowledge element ofthe GRAS standard includes two facets:(1) The data and information relied onto establish the technical element mustbe generally available; and (2) theremust be a basis to conclude that thereis consensus among qualified expertsabout the safety of the substance for itsintended use. Neither facet is, by itself,sufficient to satisfy the commonknowledge element of the GRASstandard.

The usual mechanism to establish thatscientific information is generallyavailable is to show that the informationis published in a peer-reviewedscientific journal. However,mechanisms to establish the basis forconcluding that there is expertconsensus about the safety of asubstance are more varied. In somecases, publication in a peer-reviewedscientific journal of data (such astoxicity studies) on a test substance hasbeen used to establish expert consensusin addition to general availability. Inother cases, such publication of dataand information in the primary


scientific literature has beensupplemented by: (1) Publication of dataand information in the secondaryscientific literature, such as scientificreview articles, textbooks, andcompendia; (2) documentation of theopinion of an ‘‘expert panel’’ that isspecifically convened for this purpose;or (3) the opinion or recommendation ofan authoritative body such as theNational Academy of Sciences (NAS) orthe Committee on Nutrition of theAmerican Academy of Pediatrics (CON/AAP) on a broad or specific issue thatis related to a GRAS determination.

In this document, FDA is using theterm ‘‘consensus’’ in discussing thecommon knowledge element of theGRAS standard. Such consensus doesnot require unanimity among qualifiedexperts (5,906 boxes, supra, 745 F.2d at119 n. 22; United 4,680 Pails, supra, 725F.2d at 990; Coli-Trol 80, supra, 518F.2d at 746; Promise Toothpaste, supra,624 F.Supp. at 782). For example, FDAwould evaluate a single publishedreport questioning the safety of use of asubstance in food in the context of allthe publicly available and corroborativeinformation rather than conclude thatsuch a report automatically disqualifiesthe substance from satisfying the GRASstandard (Cf. Coli-Trol 80, supra, 518F.2d at 746).

D. The GRAS Petition Process

The rulemaking process in § 170.35(c)whereby manufacturers may petitionFDA to affirm that a substance is GRASunder certain conditions of use wasdesigned as a voluntary administrativeprocess whose purpose was to providea mechanism for official recognition oflawfully made GRAS determinations. Tothe extent that a person elected tosubmit a GRAS petition, the processcould facilitate an awareness, by theagency as well as the domestic andinternational food industry, ofindependent GRAS determinations.However, GRAS affirmation involvesthe resource-intensive rulemakingprocess, including: (1) Publishing afiling notice in the Federal Register; (2)requesting comment on the petitionedrequest; (3) conducting a comprehensivereview of the petition’s data andinformation and comments received tothe filing notice to determine whetherthe evidence establishes that thepetitioned use of the substance is GRAS;(4) drafting a detailed explanation ofwhy the use is GRAS (as opposed tosimply being safe); and (5) publishingthat explanation in the Federal Register.FDA believes that, in practice, thisresource-intensive process deters manypersons from petitioning the agency to

affirm their independent GRASdeterminations.

II. Scope of the Proposed RegulationsBased on its experience applying the

provisions of § 170.30, FDA is proposingto clarify when use of a substance isexempt from the act’s premarketapproval requirements because such useis GRAS. In proposing these changes,FDA is: (1) Emphasizing that a GRASsubstance is distinguished from a foodadditive by the common knowledgeabout the safety of the substance for itsintended use rather than by what thesubstance is, or on the basis of the typesof data and information that arenecessary to establish its safety; (2)identifying the types of technicalevidence of safety that could form thebasis of a GRAS determination; and (3)clarifying the role of publication insatisfying the general recognitionstandard. For consistency with theproposed changes to § 170.30, FDA isalso proposing to amend the definitionin § 170.3(h) of ‘‘scientific procedures.’’

In addition, in keeping with theReinventing Food Regulations, FDA isproposing to replace the current GRASaffirmation petition process (§ 170.35(c))with a notification procedure (proposed§ 170.36) whereby any person maynotify FDA of a determination that aparticular use of a substance is GRAS.The submitted notice would include a‘‘GRAS exemption claim’’ that wouldprovide specific information about aGRAS determination in a consistentformat. This GRAS exemption claimwould include a succinct description ofthe ‘‘notified substance’’ (i.e., thesubstance that is the subject of thenotice), the applicable conditions of use,and the basis for the GRASdetermination (i.e., through scientificprocedures or through experience basedon common use in food) and would bedated and signed by the notifier. TheGRAS exemption claim also wouldinclude a statement that the informationsupporting the GRAS determination wasavailable for FDA review and copying orwould be sent to FDA upon request. Inaddition to the GRAS exemption claim,the notice would include detailedinformation about the identity andproperties of the notified substance anda detailed discussion of the basis for thenotifier’s GRAS determination.

Under the proposed notificationprocedure, the agency intends toevaluate whether the notice provides asufficient basis for a GRASdetermination and whether informationin the notice or otherwise available toFDA raises issues that lead the agencyto question whether use of the substanceis GRAS. Within 90 days of receipt of

the notice, FDA would respond to thenotifier in writing and could advise thenotifier that the agency has identified aproblem with the notice. Althoughinformation in a notice would bepublicly available consistent with theFreedom of Information Act (FOIA),FDA would make readily accessible tothe public the notice’s GRAS exemptionclaim, as well as the agency’s responseto the notice. However, FDA does notintend to conduct its own detailedevaluation of the data that the notifierrelies on to support a determination thata use of a substance is GRAS or to affirmthat a substance is GRAS for itsintended use.

FDA has tentatively concluded thatthe proposed notification procedure hasadvantages over the current petitionprocess because the resource-intensiverulemaking that is associated with apetition would be eliminated. Thisstreamlining would allow FDA toredirect its resources to questions aboutGRAS status that are a priority withrespect to public health protection. Inaddition, the proposed notice is simplerthan a GRAS affirmation petition andtherefore conceivably would provide anincentive for manufacturers to informFDA of their GRAS determinations. Thiswould result in increased agencyawareness of the composition of thenation’s food supply and the cumulativedietary exposure to GRAS substances.FDA has also tentatively concluded thatthe public health would be better servedif some resources that are currentlydirected to the GRAS petition processwere redirected to the preparation ofdocuments that would provide theindustry with guidance on certain foodsafety issues for complex substances(e.g., macroingredients or biologicalpolymers, such as proteins,carbohydrates, and fats and oils).Finally, the reduction in resourcesdevoted to the evaluation of GRASsubstances would allow FDA to shiftresources to its statutorily mandatedtask of reviewing food and coloradditive petitions.

In light of its experience in reviewingGRAS petitions, FDA believes that thesubstitution of the proposed notificationprocedure for the current GRAS petitionprocess would not adversely affect thepublic health because the agency wouldbe replacing one voluntaryadministrative process with a differentvoluntary administrative procedure thatwould utilize FDA’s resources moreeffectively and efficiently. Under boththe current and the proposedprocedures, a manufacturer may marketa substance that the manufacturerdetermines is GRAS without informingthe agency or, if the agency is so


informed, while the agency is reviewingthat information. Thus, from a legal andregulatory perspective, this substitutionis neutral.

FDA is also proposing to remove§ 170.30(f), which expresses theagency’s intent to review the GRASstatus of certain food substances,because § 170.30(f) is redundant withthe provisions of § 170.35 (a) and (b)that the agency may, on its owninitiative, affirm the GRAS status ofsubstances that directly or indirectlybecome components of food(§ 170.35(a)) or publish a noticeannouncing its conclusion that there isa lack of convincing evidence that thesubstance is GRAS and that it should beconsidered a food additive (§ 170.35(b)).

FDA’s regulations regarding theeligibility of substances used in animalfood or feeds for classification as GRAS,and the procedures for affirmation ofGRAS status for such substances, arecodified at §§ 570.30 and 570.35 (21CFR 570.30 and 570.35), respectively.FDA is proposing the following: (1) Toamend the provisions of § 570.30 thatare parallel to the provisions of current§ 170.30 (i.e., § 570.30 (a) and (b)); (2) toeliminate the GRAS affirmation petitionprocess provided for in § 570.35 (a) and(c); and (3) to provide the option of aGRAS notification procedure for animalfood or feeds that would be parallel toproposed § 170.36. FDA is proposingthese changes because the regulations inpart 570 (21 CFR part 570) implementthe same statutory provisions as theregulations in part 170 (21 CFR part170).

Finally, FDA is proposing to makecertain conforming amendments to§§ 170.38, 184.1, 186.1, and 570.38.

As FDA gains experience with thequestions raised by industry inpreparing notices, FDA expects, fromtime to time, to prepare guidancedocuments on issues of particularinterest. However, such guidancedocuments are not a subject of thisproposal.

III. Proposed Revisions to § 170.30—Eligibility for Classification as GRAS

A. General Criteria

FDA is proposing to expand thedescription of the general criteriaprovided in current § 170.30(a) for aGRAS determination. FDA is notproposing any changes to the first twosentences of current § 170.30(a), whichreflect the language of the GRASexemption as set out in section 201(s) ofthe act.

The final sentence of current§ 170.30(a) provides that generalrecognition of safety requires that there

be common knowledge about thesubstance throughout the scientificcommunity knowledgeable about thesafety of substances directly orindirectly added to food. FDA isproposing to amend this provision todefine what that common knowledge is(i.e., that there is reasonable certaintythat the substance is not harmful underthe intended conditions of use). In otherwords, proposed § 170.30(a) wouldclarify that the safety standard for aGRAS substance is identical to thesafety standard in § 170.3(i) and that aGRAS substance is neither more safe norless safe than an approved foodadditive. Rather, the distinctionbetween a GRAS substance and anapproved food additive is that, for aGRAS substance, there is commonknowledge of safety within the expertcommunity.

B. Scientific Procedures GRASDetermination

1. Establishing General Recognition ofSafety

Current § 170.30(b) describes thetechnical element of a scientificprocedures GRAS determination (i.e.,that it requires the same quantity andquality of scientific evidence as isrequired to obtain approval of thesubstance as a food additive). Current§ 170.30(b) also describes the commonknowledge element of a scientificprocedures GRAS determination (i.e.,that it ordinarily is based uponpublished studies, which may becorroborated by unpublished studiesand other data and information).

FDA is proposing two changes to thedescription of the common knowledgeelement in current § 170.30(b). First,FDA is proposing to broaden thisdescription to clarify the types oftechnical evidence of safety (currentlydescribed only as ‘‘studies’’) that couldform the basis of a GRAS determination.FDA is proposing this change becausethe quantity and quality of scientificevidence required to obtain approval ofa substance as a food additive varyconsiderably depending upon theestimated dietary exposure to thesubstance and the chemical, physical,and physiological properties of thesubstance; there can likewise be acomparable variation in the scientificevidence that forms the basis of a GRASdetermination. Second, FDA isproposing to amend this description toclarify the role of publication insatisfying the common knowledgeelement. FDA is proposing this changebecause publication is ordinarilyrequired, but may not always besufficient, to satisfy the common

knowledge element of the GRASstandard.

Specifically, FDA is proposing torevise § 170.30(b) to provide that generalrecognition of safety through scientificprocedures be based upon generallyavailable 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 ofscientific ‘‘data and information’’ thatcould support the technical element ofa scientific procedures GRASdetermination. However, depending onthe circumstances, other scientific dataand scientific information such as thatrelating to chemical identity orcharacteristic properties of a substance,as well as methods of manufacture,could support, and in some cases besufficient to satisfy that element.

In addition, under this proposedrevision of § 170.30(b), generallyavailable and accepted scientificprinciples could be applied to, andrelied on as part of, the technicalelement of a scientific procedures GRASdetermination. Webster’s New WorldDictionary of the American Languagedefines a ‘‘principle’’ as ‘‘a fundamentaltruth, law, doctrine or motivating forceupon which others are based.’’ Forexample, the common scientificprinciple ‘‘the dose makes the poison,’’underlies a determination that asubstance is safe for use in food atcertain levels even if it exhibits toxicitywhen present at higher levels. A relatedscientific principle is that the toxicity ofa substance may vary between animalspecies. FDA relies on both of thesescientific principles when determiningwhether the proposed use of a substanceadded to food is safe within themeaning of section 409 of the act.

For consistency with this proposedamendment, FDA is also proposing toamend the current definition of‘‘scientific procedures’’ in § 170.3(h).Under the current definition, scientificprocedures include those human,animal, analytical, and other scientificstudies, whether published orunpublished, appropriate to establishthe safety of a substance. FDA isproposing to amend § 170.3(h) bybroadening it so that scientificprocedures would include scientificdata (such as human, animal, analytical,and other scientific studies),information, methods, or principles,whether published or unpublished,appropriate to establish the safety of asubstance. In both this proposeddefinition and the proposed amendmentto § 170.30(b), the descriptor‘‘scientific’’ applies equally to ‘‘data,’’


‘‘information,’’ ‘‘methods,’’ and‘‘principles.’’

FDA is proposing to clarify the role ofpublication in satisfying the commonknowledge element of the GRASstandard by adding the phrases‘‘generally available and accepted’’ and‘‘which ordinarily are published’’ asdescriptors of ‘‘scientific data,information, methods, or principles’’ inproposed § 170.30(b). Thus, underproposed § 170.30(b), publication ofdata and information about a GRASsubstance is usually necessary, but maynot always be sufficient, to satisfy thecommon knowledge element of theGRAS standard.

The descriptor ‘‘which ordinarily arepublished’’ reflects that the usualmechanism to establish that scientificinformation is generally available is toshow that the information is publishedin a peer-reviewed scientific journal.This descriptor maintains the explicitemphasis of current § 170.30(b) on theimportance of publication in satisfyingthe common knowledge element.However, current § 170.30(b) does notexplicitly emphasize the second facet ofthe common knowledge element (i.e.,that there is a basis to conclude thatthere is the requisite expert consensusthat the generally available data andinformation establish the safety of thesubstance for its intended use). Forexample, there could be a basis toconclude that there is expert consensusthat the published results of a particularsafety study (i.e., the primary scientificliterature) establish the safety of asubstance for its intended use if thestudy raises no safety questions thatexperts would need to interpret andresolve. On the other hand, thepublished results of a particular safetystudy may not be sufficient to satisfy thecommon knowledge element if thestudy raises safety questions that requireadditional data to be resolved. In suchcases, the general recognition standardusually requires more than a publicationin the primary scientific literature. Asmentioned, the basis for concluding thatthere is expert consensus historicallyhas included publication in secondarysources, convening an expert panel, orrelying on an opinion orrecommendation of an authoritativebody.

The body of information published insecondary sources (such as reviewarticles, articles describing scientificmethods, general reference materials,and textbooks) can be more useful thanthe primary scientific literature forshowing a basis for a conclusion that thenecessary expert consensus existsbecause the existence of the secondarysources implies that the primary

scientific literature has been evaluatedafter its publication. For example, FDAsometimes relies on generally availableand accepted compendia such asBergey’s Manual of SystematicBacteriology (Ref. 4) when evaluatingthe common knowledge element of theGRAS standard for food substancesderived from a bacterial source.

The opinion of a specially-convenedexpert panel can provide a basis forshowing expert consensus when anindividual published study raises safetyquestions. The opinion of an expertpanel is also useful when multiplestudies bearing on the safety of asubstance are published but there are nosecondary sources that evaluate thesestudies and draw general conclusionsbased on this comprehensive body ofknowledge. For example, during theagency-initiated GRAS review, FDAcommissioned, through the LifeSciences Research Office of theFederation of American Societies forExperimental Biology, the ‘‘SelectCommittee on GRAS Substances’’ (theSelect Committee). The charge to theSelect Committee was to summarize theavailable scientific literature and toprovide a recommendation as to whatrestrictions, if any, on the use of thesubstance would be needed to ensure itssafe use in food.

In FDA’s view, the commonknowledge element of the GRASstandard precludes a GRASdetermination if the data andinformation evaluated by such an expertpanel are only available in files that arenot publicly accessible, such as inconfidential industry files. For example,in response to GRAS petitionsrequesting that FDA affirm the GRASstatus of lactase from Kluyveromyceslactis entrapped in cellulose triacetatefibers for use in reducing the lactosecontent of milk, FDA affirmed that thelactase enzyme was GRAS (49 FR 47384,December 4, 1984) but issued a foodadditive regulation authorizing thesecondary direct food additive use ofcellulose triacetate as an immobilizingagent because the information that thepetitioner relied on to establish thesafety of the cellulose triacetate was notgenerally available (59 FR 36935, July20, 1994).

The opinions or recommendations ofan authoritative body such as NAS orCON/AAP frequently bear on an issuethat is related to a GRAS determination.For example, CON/AAP mayrecommend the use in infant formula ofa food substance whose regulatorystatus is not explicitly identified inFDA’s regulations. Similarly, NAS’sRecommended Dietary Allowances (Ref.5) are useful in establishing the safe

level of an added nutrient source infoods, particularly when the safe levelof intake is a narrow range because thedifference between the recommendeddietary intake and the intake at whichthe substance exhibits toxic propertiesis small. In cases such as these, theopinions or recommendations of theauthoritative body may provide a basisfor concluding that there is expertconsensus regarding the safety of asubstance for its intended use in food.

2. Corroboration of SafetyFDA is proposing to retain the

concept in current § 170.30(b) thatunpublished data and information thatbear on safety may be used tocorroborate published data andinformation that establish generalrecognition of safety. FDA is proposingto amend current § 170.30(b) byremoving the phrase ‘‘unpublishedstudies and other data and information’’and substituting the phrase‘‘unpublished scientific data,information, or methods.’’ Thisproposed revision is comparable to theproposed broadening of the descriptionof the common knowledge element ofthe GRAS standard and likewise reflectsthe variation in the nature of thescientific evidence that would berequired to obtain approval of thesubstance as a food additive.

C. Common Use GRAS DeterminationFDA is not proposing any changes to

current § 170.30(c)(1), which sets outcriteria for a common use GRASdetermination. However, FDA isproposing to amend current§ 170.30(c)(2), which sets out thesecriteria in the more narrowcircumstance of that use occurringexclusively or primarily outside of theUnited States. FDA is proposing torevise the final sentence of current§ 170.30(c)(2) by replacing therecommendation that persons whoclaim GRAS status on such basis obtainFDA concurrence that the use of thesubstance is GRAS (i.e., throughsubmission of a GRAS affirmationpetition) with a recommendation thatpersons who assert such a claim for asubstance notify FDA of that claim inaccordance with proposed § 170.36.This revision is a necessary conformingamendment because, as discussed insections V and VI of this document,FDA is proposing to replace the currentaffirmation process in § 170.35(c)(1)with a notification procedure (proposed§ 170.36). The recommendation inproposed § 170.30(c)(2) is appropriatebecause notice will facilitate the lawfulentry of GRAS substances into theUnited States. FDA will be aware that a


substance offered for import is thesubject of a GRAS exemption claim andwill also be aware of the basis for suchclaim. Absent notice, the substance mayappear to be adulterated and thus, bedetained under section 801(a) of the act(21 U.S.C. 381(a)). Therefore, it isprudent for an individual who claimsthat a substance is GRAS throughexperience based on its common use infood outside of the United States tonotify FDA of that claim. The languageof proposed § 170.30(c)(2) is comparableto the language of current § 170.30(c)(2)in that it is not a requirement.

D. Other Provisions of Current § 170.30FDA 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 isproposing in this document require noconforming amendments to thosesections.

Current § 170.30(f) was issued underthe auspices of the agency-initiatedGRAS review (36 FR 12093, June 25,1971) and expresses the agency’s intentto review the GRAS status of certainfood substances. As discussed in sectionV of this document), FDA is proposingto remove the provision in § 170.35(a)that the Commissioner of Food andDrugs (the Commissioner), on thepetition of an interested person, mayaffirm the GRAS status of substancesthat directly or indirectly becomecomponents of food. The agency isproposing to retain, however, theprovision in § 170.35(a) that theCommissioner, on his/her owninitiative, may affirm the GRAS status ofsuch substances. In addition, the agencyis proposing no changes to the provisionin § 170.35(b) that if the Commissionerconcludes that there is a lack ofconvincing evidence that a substance isGRAS and that it should be considereda food additive, he/she shall publish anotice thereof in the Federal Register inaccordance with § 170.38. Therefore,§ 170.30(f) is redundant with § 170.35(a) and (b). Accordingly, in keeping withthe agency’s goals for the ReinventingFood Regulations, FDA is proposing toremove current § 170.30(f).

IV. The Technical Element of a GRASDetermination Through ScientificProcedures

A GRAS substance is distinguishedfrom a food additive on the basis of thecommon knowledge about the safety ofthe substance for its intended use ratherthan on the basis of what the substanceis or the types of data and informationthat are necessary to establish its safety.Nonetheless, FDA is frequently askedabout the types of data and information

that are appropriate to establish thesafety of a GRAS substance.Accordingly, FDA discusses below twotopics that pertain to the technicalelement of a scientific procedures GRASdetermination: (1) The importance ofdietary exposure; and (2) the role ofsubstantial equivalence.

A. Consideration of Dietary ExposureSection 409(c)(5) of the act requires

that, in evaluating the proposed use ofa food additive, FDA consider theprobable consumption of the substanceand of any substance formed in or onfood because of its use, as well as thecumulative effect of the substance in thediet, taking into account any chemicallyor pharmacologically related substanceor substances in such diet. FDA hasincorporated this requirement into thedefinition of ‘‘safe’’ and ‘‘safety’’ withrespect to substances added to food(§ 170.3(i)). Thus, the technical elementof a scientific procedures GRASdetermination must consider theprobable consumption and cumulativeeffect of the substance in the dietbecause a scientific procedures GRASdetermination requires the samequantity and quality of evidence as isrequired to obtain approval of thesubstance as a food additive. If thedietary exposure to the substance underthe intended conditions of use presentsa basis for concern about the safety ofits use, data or information addressingthose concerns are necessary to satisfythe technical element. As with otherdata and information that support aGRAS determination, data orinformation addressing a safety questionraised by dietary exposure must alsosatisfy the common knowledge elementby being generally available to, andaccepted by, qualified experts.

In some cases, dietary exposure isunlikely to present a basis for a safetyconcern. For example, dietary exposureto an enzyme preparation that is derivedfrom a controlled fermentation of anonpathogenic, nontoxigenicmicroorganism that does not produceantibiotics, and that is processed usingsubstances that are acceptable for use infoods generally, would not ordinarilypresent a basis for a safety concern. Onthe other hand, consumption of acomponent of a commonly consumedfood may present a basis for a safetyconcern if the dietary exposure to theisolated component under its intendedconditions of use is many times greaterthan its dietary exposure whenconsumed as a component of food.

For example, a fiber may be extractedfrom a vegetable that has a relativelylow dietary exposure (such as beets) andadded, at the same level, to other foods

that have a relatively high dietaryexposure. The probable cumulativeintake of the fiber likely will be manytimes higher from the consumption ofthe foods to which it is added than fromthe consumption of beets. The probableintake of the fiber from consumption offoods to which it is added may presenta basis for a safety concern, especiallyif the foods containing the added beetfiber will not replace beets in the diet.Likewise, in the case of a chemicallysynthesized substance that isstructurally identical to a naturallyoccurring substance in commonlyconsumed food, technical evidence ofsafety would include consideration ofwhether the cumulative exposure toboth the synthetic and the naturalsubstance exceeds the exposure to thenatural substance and whether thecombined exposure presents a basis fora safety concern.

B. Substantial Equivalence to a GRASSubstance

A report of a joint Food andAgriculture Organization (FAO) andWorld Health Organization (WHO)consultation (the 1996 FAO/WHOreport) recommended that ‘‘[s]afetyassessment based on the concept ofsubstantial equivalence * * * be appliedin establishing the safety of foods andfood components derived fromgenetically modified organisms’’ (Ref.6). The 1996 FAO/WHO report statedthat:[s]ubstantial equivalence embodies theconcept that if a new food or food componentis found to be substantially equivalent to anexisting food or food component, it can betreated in the same manner with respect tosafety (i.e. the food or food component canbe concluded to be as safe as theconventional food or food component).Account should be taken of any processingthat the food or food component mayundergo as well as the intended use and theintake by the population.

The 1996 FAO/WHO report relied, inpart, on previous expert reports that haddiscussed the concept of substantialequivalence, including the 1990 jointFAO/WHO consultation, ‘‘[s]trategiesfor assessing the safety of foodsproduced by biotechnology’’ (Ref. 7); areport prepared by an expert group ofthe Organization for Economic Co-operation and Development (OECD),‘‘[s]afety evaluation of foods producedby modern biotechnology: Concepts andprinciples’’ (Ref. 8); and a report of aWHO workshop, ‘‘[a]pplication of theprinciples of substantial equivalence tothe safety evaluation of foods or foodcomponents from plants derived bymodern biotechnology’’ (Ref. 9).


2 In the plant policy statement, FDA used the term‘‘substantial similarity,’’ rather than ‘‘substantialequivalence,’’ to avoid possible confusion with theagency’s use of the concept of ‘‘substantialequivalence’’ with respect to the premarketnotification process for medical devices. Forconsistency with current thinking frominternational expert groups such as the FAO/WHOand OECD consultation groups, FDA is now usingthe term ‘‘substantial equivalence’’ with respect tofood products.

FDA believes that in certain instancesthe concept of substantial equivalencemay have applicability to the technicalelement of a GRAS determination, andthe agency has already applied thisconcept when evaluating the safety ofnew or modified food substances. Forexample, the agency’s approach (57 FR22984 and Ref. 10) to assessing thesafety of foods derived from new plantvarieties, including the safety of newlyintroduced substances in the food(primarily proteins, carbohydrates, andfatty acids) and unintended changes inthe food’s composition, is similar to theconcept of substantial equivalenceposited by FAO, WHO, and OECD. 2 Asanother example, FDA has applied thisconcept in affirming the GRAS status ofseveral microbially-derived chymosin(i.e., rennet) enzyme preparations (55FR 10932 at 10935, March 23, 1990; 57FR 6476 at 6479, February 25, 1992; 58FR 27197 at 27202, May 7, 1993) andseveral animal-and plant-derivedenzyme preparations (60 FR 32904 at32911, June 26, 1995).

However, the concept of substantialequivalence may be of minimalrelevance in circumstances where thedifferences between two substancesoutweigh the similarities. Thus, acritical factor that must be consideredwhen applying the concept ofsubstantial equivalence is any differencein composition or characteristicproperties between the substances beingcompared. In the example of amicrobially-derived enzymepreparation, its principal enzymecomponent may show substantialequivalence in structure and function tothat of a GRAS enzyme preparationderived from an animal source butexhibit different properties such asspecific activity (i.e., the rate at whichthe enzyme catalyzes a reaction) oroptimum reaction conditions of pH andtemperature because of changes, eitherthrough natural selection or throughselective chemical modification, in theparticular amino acid sequence of theenzyme’s active site. Such differences,which are common when comparingenzyme preparations derived fromdifferent sources, generally do notoutweigh the similarities between theenzyme preparations.

On the other hand, the productresulting from the chemical reaction oftwo or more GRAS substances is adiscrete new substance that may haveproperties that are distinctly differentfrom the individual GRAS substancesfrom which it is synthesized or from asimple mixture of those GRASsubstances. The concept of substantialequivalence may not be relevant hereunless the reaction product is widelyrecognized to be metabolized in thesame way as the individual componentsfrom which it is synthesized. Likewise,in the case of a chemically synthesizedsubstance that is structurally identicalto a naturally occurring substance incommonly consumed food,compositional differences between thesynthesized and naturally occurringsubstance may include the presence ofany residues of potentially harmfulchemicals carried over to the syntheticsubstance from the manufacturingprocess.

FDA invites comment on theapplicability of the concept ofsubstantial equivalence to the technicalelement of a GRAS determination.

V. Proposed Revisions to § 170.35—Affirmation of GRAS Status

As a result of the agency’s experiencein processing FAP’s and GRASaffirmation petitions, FDA hastentatively concluded that the petitionprocess, which is the statutorilymandated process for food additives,should no longer be applied to GRASsubstances, where the conditions of safeuse of a substance have already beenrecognized by qualified experts. FDAbelieves that the lengthy rulemakingassociated with the GRAS petitionprocess deters many persons whoindependently determine that use of asubstance is GRAS from informing theagency of such determinations.Moreover, FDA believes that the currentcommitment of its resources to theGRAS petition process provides limitedpublic health benefit becausemanufacturers who submit anaffirmation petition frequently marketthe substance at issue before FDAreaches a decision on the GRAS statusof its intended use.

Accordingly, FDA is proposing toamend current § 170.35(a) to remove theprovision that FDA may review theGRAS status of a substance added tofood in response to a petition from aninterested party. FDA has tentativelyconcluded that the elimination of theGRAS petition process would notadversely affect public health becausethe agency is simultaneously proposingto establish a notification procedure forGRAS substances. FDA has also

tentatively concluded that the proposednotification procedure, discussed morefully in section VI of this document,would allow the agency to direct itsresources to the more significantquestions about GRAS status.

Proposed § 170.35(a) would continueto provide a mechanism whereby FDA,on its own initiative, may affirm theGRAS status of the use of a substancethat directly or indirectly becomes acomponent of food. FDA proposes toretain the option of agency-initiatedaffirmations for those circumstanceswhere such action is necessary oruseful. For example, FDA may proposeto revise an existing regulation affirmingthe GRAS status of a use of a substanceif the agency determines that the currentregulation is confusing or unnecessarilyrestrictive. In addition, the agency maychoose to complete a rulemakingalready begun as part of the agency-initiated GRAS review.

Proposed § 170.35(a) includes atechnical revision that amends current§ 170.35(a) to place it in the singular.For consistency with the language of thestatute, proposed § 170.35(a) also hasbeen revised to clarify that theCommissioner might affirm the GRASstatus of a use of a substance, ratherthan the substance itself.

In light of the increasing complexityof the food supply, FDA recognizes thatmembers of the food industry may wishto engage in discussions with the agencyconcerning novel issues that accompanythe technical element of some GRASdeterminations. FDA believes that theelimination of the GRAS petitionprocess will not constrain industry fromconsulting with the agency about suchnovel issues. Rather, FDA believes thatthe substitution of the proposednotification procedure for the currentpetition process will encourage industryto consult with FDA early indevelopment of food substances toidentify the critical aspects of the safetydetermination that would need generalrecognition to qualify for a GRASexemption.

FDA is also proposing to removecurrent § 170.35(c), which prescribes theprocedure for the submission of a GRASaffirmation petition. Under proposed§ 170.35(a), FDA will no longer bebound to review such a petition.Therefore, if proposed § 170.35(a)becomes final, current § 170.35(c) willbecome obsolete.

VI. Proposed Establishment of aNotification Procedure

A. General Requirements

Proposed § 170.36(a)(1) provides thatany person may notify FDA of a claim


3 FDA considers that the current voluntaryprocedure whereby developers of new plantvarieties modified through the use of rDNAtechniques notify the agency about food derivedfrom the plant is parallel to, and has someoverlapping provisions with, the proposed GRASnotification procedure but is nonetheless distinctfrom this proposed procedure. For example, currentnotices to the agency concerning new plantvarieties generally are broader in scope than theregulatory status of substances introduced into thenew plant variety and usually include a safety andnutritional assessment of food derived from the newplant variety in addition to a basis for the notifier’sdetermination that an FAP is not required for anyof the substances introduced into that food.

that a particular use of a substance isexempt from the statutory premarketapproval requirements based on thenotifier’s determination that such use isGRAS. The agency encouragesmanufacturers and developers of foodsubstances and of new processes forproducing food substances to use thisnotification procedure to inform FDA ifsuch manufacturers or developersconclude that there is generalrecognition that use of a substance issafe.3

Current agency regulationsconcerning the eligibility of a substancefor a health claim (§ 101.14(b)(3)(ii)) (21CFR 101.14(b)(3)(ii)) require that asubstance that is to be consumed as acomponent of conventional food atother than decreased dietary levels be afood, food ingredient, or a component ofa food ingredient, whose use, at thelevels necessary to justify a claim, bedemonstrated by the proponent of theclaim, to FDA’s satisfaction, to be safeand lawful under the applicable foodsafety provisions of the act. In the finalrule establishing § 101.14(b)(3)(ii) (58FR 2478 at 2502, January 6, 1993), FDAexplained that the preliminaryrequirement that a substance be safe andlawful was necessary in the health claimregulation because FDA’s authorizationof a health claim places the agency’simprimatur on the claim. FDA furtherstated that it would be a violation of theagency’s responsibility under the act toauthorize a health claim for a substancewithout the agency being satisfied thatthe particular use of the substance issafe. As discussed in detail in sectionVI.D of this document, an agencyresponse to a GRAS notice would not beequivalent to an agency affirmation ofGRAS status. Therefore, if adopted, theGRAS notification procedure proposedin this notice will not satisfy a healthclaim petitioner’s responsibilities under§ 101.14(b)(3)(ii).

In addition, FDA recently proposedthat good manufacturing practice forinfant formula requires that onlysubstances whose use in infant formulais safe and suitable under the applicablefood safety provisions of the act be used

to make this product; that is, that thesubstance be GRAS for such use, usedin accordance with the agency’s foodadditive regulations, or authorized forsuch use by a prior sanction (proposed§ 106.40(a); 61 FR 36154 at 36212, July9, 1996). FDA also proposed that a ‘‘newinfant formula’’ submission requiredunder section 412 (c) and (d) of the act(21 U.S.C. 350a (c) and (d)) include thebasis on which each ingredient meetsthe requirements of proposed§ 106.40(a), and that any claim that aningredient is GRAS be supported by acitation to the agency’s regulations or byan explanation as to why there isgeneral recognition of the safety of theuse of the ingredient in infant formula(proposed § 106.120(b)(6)(ii); 61 FR36154 at 36217). Again, as discussed indetail in section VI.D of this document,an agency response to a GRAS noticewould not be equivalent to an agencyaffirmation of GRAS status or place anagency imprimatur on the substancethat is the subject of the notice.Therefore, if adopted, this proposedGRAS notification program will notsubstitute for the requirements proposedfor new infant formula submissions.

The fact that the proposed GRASnotification program will not satisfy therequirements of either § 101.14(b)(3)(ii)or proposed § 106.120(b)(6)(ii) isreflected in proposed § 170.36(a)(2).Under proposed § 170.36(a)(2)(i), anyperson who submits a health claimpetition under § 101.14 must comply infull with § 101.14(b)(3)(ii), regardless ofwhether the agency has been notifiedunder proposed § 170.36 about arelevant GRAS determination andregardless of the nature of the agency’sresponse to that notice. Similarly,proposed § 170.36(a)(2)(ii) provides thatany person who makes a new infantformula submission under § 106.120must comply in full with§ 106.120(b)(6)(ii), regardless of whetherthe agency has been notified underproposed § 170.36 about a relevantGRAS determination and regardless ofthe nature of the agency’s response tothat notice.

Proposed § 170.36(b) requires thatnotice of a GRAS exemption claim besubmitted in triplicate and provides theaddress for such a submission. FDAplans to use one copy of the notice forthe agency’s administrative record. FDAanticipates that at least two agencyscientists, with food safety expertiserelating to identity, dietary exposureand health effects, will evaluate mostnotices. Thus, for efficientadministration of the notificationprocedure, FDA is stipulating that threecopies of a notice be submitted.

FDA is aware that there is increasinginterest in submitting an electronic copyof information prepared for regulatorypurposes. FDA requests comment onwhether it would be appropriate torequire or recommend that thesubmission include an electronic copyin addition to the three paper copiesrequired under proposed § 170.36(b).

B. Specific RequirementsProposed § 170.36(c) provides details

on information that must be included ina notice. FDA recognizes that a decisionto submit a notice is voluntary.However, as discussed (see discussionof proposed § 170.36(e)), under theproposed notification procedure, FDAwould respond to a notice within 90days. In order for the agency to meetthis timeframe, the information in thenotice needs to be presented in anorderly and consistent fashion.Moreover, FDA believes that aprescribed format and a description ofinformation that the agency considersimportant in supporting a GRASdetermination would simplify thenotifier’s task of preparing the notice.

1. GRAS Exemption ClaimA GRAS determination must comply

with the provisions of § 170.30 and theperson making such determination isresponsible for ensuring suchcompliance, regardless of whether thatperson notifies the agency about thedetermination. Accordingly, proposed§ 170.36(c)(1) requires that the noticeinclude a claim (hereinafter referred toas the ‘‘GRAS exemption claim’’), datedand signed by the notifier, that aparticular use of a substance is exemptfrom the premarket approvalrequirements of the act because thenotifier has determined that such use isGRAS. Proposed § 170.36(c)(1) woulddistinguish the notification procedure,in which the notifier explicitly acceptsresponsibility for the GRASdetermination, from the GRAS petitionprocess, in which the notifier isrequesting that the agency affirm theGRAS status of use of a substance.

Proposed § 170.36 (c)(1)(i) through(c)(1)(iv) identify specific informationrequired in a GRAS exemption claim ina prescribed format. This requirementwill simplify the notifier’s task ofpreparing this section of a notice andwill enable the agency to use thissection of a notice to effectively andefficiently inform the public aboutreceived notices (see discussion ofproposed § 170.36(f)(2)).

FDA has requested comment onwhether proposed § 170.36(b) shouldrequire or recommend that an electroniccopy of the entire notice be submitted


in addition to three paper copies. Inparticular, receiving electronic copies ofthe GRAS exemption claim may makeFDA’s administration of the GRASnotification procedure more efficient,especially if the agency uses anelectronic means to make those claimsreadily accessible to the public.Accordingly, FDA specifically requestscomment on whether the regulationshould include a recommendation orrequirement that the notice include anelectronic copy of the GRAS exemptionclaim required by proposed§ 170.36(c)(1).

a. Notifier. Proposed § 170.36(c)(1)(i)requires that the GRAS exemption claiminclude the name and address of thenotifier. This is necessary for fullidentification of the person who acceptsresponsibility for the claim. This is alsonecessary so that the agency can bothacknowledge receipt of the notice(proposed § 170.36(d)) and inform thenotifier of the agency’s response to thenotice (proposed § 170.36(e)).

b. Name of notified substance.Proposed § 170.36(c)(1)(ii) requires thatthe GRAS exemption claim include thecommon or usual name of the notifiedsubstance. This is necessary to identifythe notified substance as well as toidentify whether there are any labelingissues that need to be addressed. Thenotifier may include in the GRASexemption claim additionalinformation, such as that described inproposed § 170.36(c)(2), concerning theidentity of the substance if suchinformation is appropriate or necessaryto fully and unambiguously describe it.

The agency recognizes that notifiersmay have questions concerning thecommon or usual name for a notifiedsubstance. FDA advises that in suchcircumstances, a notifier should consultwith the Office of Food Labeling inFDA’s Center for Food Safety andApplied Nutrition (CFSAN).

c. Conditions of use. Proposed§ 170.36(c)(1)(iii) requires that the GRASexemption claim identify the applicableconditions of use of the notifiedsubstance, including the foods in whichthe substance is to be used, levels of usein such foods, and the purposes forwhich the substance is used, including,when appropriate, a description of thepopulation expected to consume thesubstance (e.g., if the substance isintended for use in a limitedpopulation, such as ingredients usedmainly in infant formula, medical foods,or in specially designed food productstypically consumed as a sole source ofthe diet by persons who are unable toconsume food in conventional form).Information describing the conditions ofuse is necessary to delineate the

boundaries of the GRAS exemptionclaim consistent with section 201(s) ofthe act, which states that a GRASsubstance must be generally recognizedas safe ‘‘under the conditions of itsintended use.’’ This information is alsonecessary to determine whether dietaryexposure to the substance presents abasis for concern about the safety of itsuse.

d. Basis for the GRAS determination.Proposed § 170.36(c)(1)(iv) requires thatthe GRAS exemption claim identify thebasis for the GRAS determination aseither scientific procedures orexperience based on common use infood. The act differentiates betweenthese two bases for GRAS determinationand, under § 170.30, the requirementsfor a scientific procedures GRASdetermination are different from therequirements for a common use GRASdetermination. The basis for a GRASdetermination is thus fundamental tothe GRAS exemption claim.

e. Availability of information. AGRAS determination must comply withthe provisions of § 170.30 and theperson making such determination isresponsible for ensuring suchcompliance, regardless of whether thatperson notifies the agency about thedetermination. As discussed more fullybelow (see discussion of proposed§ 170.36(c)(4)), and in keeping with theagency’s commitment to achieving thegoals for Reinventing Food Regulations,FDA is proposing to require that anotifier supply a detailed summary ofthe information that is the basis for aGRAS determination rather than theinformation itself. Proposed§ 170.36(c)(1)(v) provides a mechanismfor FDA to verify the information thatsupports a GRAS determination byrequiring that the GRAS exemptionclaim include a statement that the dataand information that are the basis forthe determination are available forreview and copying by FDA or will besent to FDA upon request. Notifiers whovoluntarily choose to notify FDA of aGRAS determination receive as a benefita response that documents the agency’sawareness of the determination. As acondition of that benefit, the notifiermust consent to grant FDA access to thedata and information that are the basisof the GRAS determination.

There is no burden on the notifier fordeveloping the data and informationthat are the basis for the GRASdetermination because such data andinformation must already be generallyavailable in order to satisfy the commonknowledge element of a GRASdetermination. Additionally, any personwho determines that a substance isGRAS should have assembled and

evaluated the evidence that forms thebasis of such a determination, regardlessof whether the person subsequentlynotifies the agency about the claim.Therefore, FDA believes that the burdento the notifier of the proposed rule is theminimal burden of maintaining theinformation. Such preservation of thedata and information that are the basisfor the GRAS determination alsorepresents prudent practice for thosewho claim an exemption from astatutory requirement.

The new procedure that FDA isproposing to establish will involve thesubmission of a detailed summary of theinformation that forms the basis for anexemption from a statutory requirementrather than the submission of theinformation itself. It therefore is prudentthat FDA monitor compliance with theessence of the statutory requirement(i.e., that there is common knowledgeamong qualified experts that there isreasonable certainty that the substanceis not harmful under the intendedconditions of use). Accordingly, FDAintends to conduct random audits ofdata and information maintained by thenotifier. Moreover, because theproposed substitution of a notificationprocedure for the current petitionprocess would allow FDA to direct itsresources to priority questions aboutGRAS status, FDA might conduct anaudit on a broad issue or class ofproducts if the issue or use of a class ofproducts raises important public healthissues.

2. Identity and SpecificationsProposed § 170.36(c)(2) requires that

the notice include detailed informationabout the identity of the notifiedsubstance, including, as applicable, thechemical name, Chemical AbstractsService (CAS) registry number, EnzymeCommission (EC) number, empiricalformula, structural formula, quantitativecomposition, method of manufacture(excluding any trade secretinformation), characteristic properties,any potential human toxicants, andspecifications for food-grade material.This detailed information, which wouldbe in addition to the substance’scommon or usual name that would beincluded under proposed§ 170.36(c)(1)(ii), is necessary todescribe accurately the notifiedsubstance using commonly acceptedscientific nomenclature and practice.

For some substances, such as calciumacetate (21 CFR 184.1185), the mostrelevant information concerningidentity may be chemical informationsuch as its CAS registry number andempirical formula. For other substances,such as whey (21 CFR 184.1979), a


chemical formula cannot be used foridentification; instead, source andquantitative composition (e.g., percentof protein, fat, ash, lactose, andmoisture) appropriately describe thesubstance.

In many cases, the method ofmanufacture provides importantidentity information. For example, anenzyme preparation that is derived froman animal source and contains theenzyme chymosin as its principalenzyme component (§ 184.1685(a)(1) (21CFR 184.1685(a)(1))) is chemicallydifferent from an enzyme preparationthat is derived from a microbial sourceand contains the enzyme chymosin asits principal enzyme component(§ 184.1685(a)(2)) because thecomponents and contaminants derivedfrom the source material are distinctlydifferent.

In some cases, the characteristicproperties of a substance may beimportant when defining the conditionsunder which the substance may safelybe used. For example, if an isolated orchemically processed fiber is intendedfor use as a replacement for part of theflour used in baked goods, informationabout its physicochemical properties,such as its ability to swell due to highwater absorption or to bindphysiologically important ions, may beimportant in establishing a safe level ofthe fiber in baked goods.

The proposed requirement thatinformation relating to identity includeany potential human toxicants in thenotified substance derives from theknown presence of such toxicants insubstances of natural biological origin.For example, it is well known thatpotatoes contain the naturally occurringtoxicant, solanine. In the plant policystatement (57 FR 22984 at 22987), FDAdiscussed the importance of ensuringthat new plant varieties do not containsignificantly higher levels of toxicantsthan are present in other edible varietiesof the same species. This considerationapplies to all food products that derivefrom a source known to containnaturally occurring toxicants.

Specifications are an important factorin establishing food-grade quality forany substance intended for use in food.Substances that do not meet thespecifications may not be suitable foruse in food. Specifications may begeneral or particular and may relate toidentity, purity, or both.

General specifications governing bothidentity and purity are common forGRAS substances. For example, theregulations for microbially-derivedGRAS substances usually stipulate, as ageneral identity specification, that thesource microorganism be anontoxigenic, nonpathogenic strain.

Similarly, the regulations for manyGRAS substances stipulate, as a generalpurity specification, the maximumpermissible level of a heavy metaltoxicant such as lead.

In addition, GRAS substancesfrequently require a particular identityspecification to adequately define thesubstance whose safety is generallyrecognized. For example, in affirmingthat canola oil (i.e., low erucic acidrapeseed oil) is GRAS for use as anedible fat and oil, FDA only consideredthe GRAS status of oil that containslevels of a specific fatty acid (erucicacid) that are no more than 2 percent ofthe component fatty acids. Therefore,the identity specification for low erucicacid rapeseed oil (21 CFR184.1555(c)(1)) stipulates that,chemically, the oil is a mixture oftriglycerides, composed of bothsaturated and unsaturated fatty acids,with an erucic acid content of no morethan 2 percent of the component fattyacids.

In some cases, FDA expects that thespecifications for a notified substancemay be generally available in a standardreference such as the Food ChemicalsCodex (FCC), which contains generaland specific requirements for more than900 substances used in food. In othercases, the specifications for the notifiedsubstance may be the same as, or similarto, specifications in the agency’s GRASregulations but not available in anyother standard reference. For example,the specifications for an oil that issubstantially similar to hydrogenatedand partially hydrogenated menhadenoil, which FDA has affirmed as GRASfor use as an edible fat or oil, could bebased on the specifications in 21 CFR184.1472.

3. Self-limiting Levels of UseProposed § 170.36(c)(3) requires that

the notice include any self-limitinglevels of use of the substance. If asubstance is added to food above itstechnologically self-limiting level, thefood becomes unpalatable, unappealingor otherwise unfit for consumption.Information on a technologically self-limiting level of use of a substancewould be important in addressingconcerns about the level of use of thesubstance as a food component. Forexample, it is generally known that thetaste associated with many GRASsynthetic flavoring substances limits thelevels at which the flavoring substancescan be used to levels below thoseknown to exhibit toxic properties.

4. Scientific Procedures GRASDetermination

The technical element of a scientificprocedures GRAS determination

requires that information about thesubstance show that there is reasonablecertainty in the minds of competentscientists that the substance is notharmful under the intended conditionsof use. The nature of the informationthat the notifier relies on to establish thetechnical element of the GRAS standardmay vary from substance to substance.Such information may include, but isnot limited to, the identity,characteristic properties, and methodsof manufacture of the notifiedsubstance, applicable toxicologicalstudies, and information relating todietary exposure.

The common knowledge elementrequires both that the information reliedon be generally available and that therebe a basis to conclude that there isexpert consensus about the safety of thesubstance for its intended use. A noticesummary that fully describes thetechnical evidence of safety, but doesnot provide a basis to conclude that thetechnical evidence is generally availableand accepted, would be incomplete. Thecommon knowledge element applies toall of the evidence that is the basis forthe safety determination.

a. Technical evidence of safety.Proposed § 170.36(c)(4)(i)(A) requiresthat the notice include a detailedsummary of the basis for the notifier’sdetermination that a particular use ofthe substance is GRAS throughscientific procedures. This summarywould include a comprehensivediscussion of, and citations to, generallyavailable and accepted scientific data,information, methods, or principles thatthe notifier relies on to establish safety.

Proposed § 170.36 (c)(2) and (c)(3) ofthe notice would require thatinformation relating to the identity,characteristic properties, and methodsof manufacture of the notified substancebe described in detail; therefore, thecomprehensive discussion in the noticesummary should focus on how thatinformation is relevant to the GRASdetermination. Under proposed§ 170.36(c)(4), the comprehensivediscussion in the notice summary of anyapplicable toxicological studies shouldfully describe such studies, identify theconclusions drawn from such studies,and explain how these conclusions arerelevant to the GRAS determination.FDA is not proposing to require that thenotice include the raw data supportingthe conclusions of applicabletoxicological studies because the agencydoes not intend, in most cases, toconduct its own detailed evaluation ofthose data.


4 For example, ‘‘Recommendations forSubmission of Chemical and Technological Data forDirect Food Additive and GRAS Food IngredientPetitions’’ (1993); ‘‘Estimating Exposure to DirectFood Additives and Chemical Contaminants in theDiet’’ (1995); and ‘‘Recommendations for ChemistryData for Indirect Food Additive Petitions’’ (1995).

Proposed § 170.36(c)(4)(i)(A) specifiesthat the discussion in the noticesummary include a consideration of theprobable consumption of the substanceand the cumulative effect of thesubstance in the diet, taking intoaccount any chemically orpharmacologically related substances insuch diet. This consideration of dietaryexposure is mandated for food additivesby section 409(c)(5) of the act;§ 170.30(b) further provides that ascientific procedures GRASdetermination requires the samequantity and quality of scientificevidence as would be required toapprove a food additive. Thus, suchinformation should be included in thenotice summary. Several technicaldocuments that discuss the practicaldetails of estimating consumer exposureto a food substance are available fromthe agency.4

The notice summary may also includea comprehensive discussion of scientificdata, information, and methods that, inthe notifier’s view, corroborate theGRAS determination. For example, for asubstance whose safety is establishedbased on its identity, method ofmanufacture, and characteristicproperties, a notifier may describe atoxicological study and rely on thesedata as corroborative. However, as withstudies that are relied on to support aGRAS determination, thecomprehensive discussion should fullydescribe such studies, identify theconclusions drawn from such studies,and explain how these conclusions arerelevant to the GRAS determination.

b. General availability of informationsupporting safety. The inclusion ofcitations to published articles iscustomary scientific practice and is thesimplest way to demonstrate the generalavailability of the information on whichthe notifier relies. Proposed§ 170.36(c)(4)(i)(A) does not require thata notifier submit copies of publishedinformation identified in the noticesummary because, in most cases, theagency does not intend to conduct itsown detailed evaluation of the data thatthe notifier relies on to support adetermination that a use of a substanceis GRAS. Rather, the agency intends toevaluate whether the notice summaryestablishes a basis to conclude that thereis expert consensus regarding the safetyof use of the substance.

Under proposed § 170.36(c)(4)(i)(A),notifiers should limit publishedinformation citations to those that thenotifier discusses and relies on tosupport a GRAS determination or thatare appropriately discussed andexplained because they may appear tobe inconsistent with a GRASdetermination (see discussion ofproposed § 170.36(c)(4)(i)(B)).Accordingly, the notifier should not citepublished information unless the citedinformation bears directly on the GRASdetermination. For example, abibliography describing an exhaustiveliterature search about a notifiedsubstance is of limited or no value insupporting the common knowledgeelement of a GRAS determination if therelevance of the cited literature is notreadily apparent or fully discussed.Moreover, such a bibliography wouldnot, absent a discussion of the relevanceof the material cited to the GRASdetermination in question, fulfill thetechnical element of a GRASdetermination.

c. Unfavorable information. Proposed§ 170.36(c)(4)(i)(B) requires that thenotice summary of a scientificprocedures GRAS determinationinclude a comprehensive discussion ofany reports of investigations or otherinformation (e.g., adverse event reportsand consumer complaints) that mayappear to be inconsistent with the GRASdetermination. FDA is proposing thisrequirement as a prelude to proposed§ 170.36(c)(4)(i)(C), which wouldrequire that the notice summary includea basis to conclude that there is expertconsensus regarding the safety of use ofthe substance. In other words, in orderto meet the act’s general recognitionstandard, all information, both favorableand unfavorable, that bears on the safetyof the substance for its intended usemust be considered.

Proposed § 170.36(c)(4)(i)(B) isconsistent with the provision in current§ 170.35(c)(1)(iv) and (c)(1)(v) (whichare proposed for deletion) that a GRASaffirmation petition include adverseinformation or consumer complaintsand be a representative and balancedsubmission that includes knowninformation, both favorable andunfavorable. Proposed§ 170.36(c)(4)(i)(B) is also consistentwith a similar provision (§ 171.1(c) (21CFR 171.1(c))) in the FAP regulations,which requires that the petition mustnot omit without explanation anyreports of investigations that would biasan evaluation of the safety of the foodadditive. Thus, the requirement inproposed § 170.36(c)(4)(i)(B) isappropriate because general recognitionof safety based upon scientific

procedures requires the same quantityand quality of scientific evidencerequired to obtain approval of thesubstance as a food additive.

d. Basis for concluding expertconsensus. Proposed § 170.36(c)(4)(i)(C)requires that the notice summary of ascientific procedures GRASdetermination include the basis forconcluding, in light of the data andinformation described in the notice, thatthere is a consensus among qualifiedexperts that there is reasonable certaintythat the substance is not harmful underthe intended conditions of use. Thus,the notice summary must consider thetotality of the publicly available andcorroborative evidence about the safetyof the substance for its intended use,including both favorable and potentiallyunfavorable information.

As discussed in section I.C of thisdocument, the bases for concluding thatthere is the requisite expert consensusmay be quite varied. For example, therecould be a basis to conclude that thenecessary expert consensus exists if datapublished in the primary scientificliterature establish the safety of asubstance for its intended use and suchdata raise no safety questions thatexperts would need to resolve. On theother hand, data published in theprimary scientific literature may notprovide a basis for expert consensus ifthose data raise unresolved safetyquestions. Alternatively, the opinions ofa specially convened expert panel or ofan authoritative body such as NAS mayprovide a basis for expert consensus.However, an ongoing scientificdiscussion or controversy about safetyconcerns raised by available data wouldmake it difficult to provide a basis forexpert consensus about the safety of asubstance for its intended use.

5. Common Use GRAS Determinationa. Technical evidence of safety.

Proposed § 170.36(c)(4)(ii)(A) requiresthat the notice summary of a commonuse GRAS determination include acomprehensive discussion of, andcitations to, generally available data andinformation that the notifier relies on toestablish safety, including evidence of asubstantial history of consumption ofthe substance by a significant number ofconsumers. Under current§ 170.30(c)(1), in evaluating whether useof a substance is GRAS throughexperience based on common use infood prior to January 1, 1958, FDA relieson information documenting that the‘‘common use in food’’ of a substancesatisfies the definition in § 170.3(f) suchthat adverse health effects, if theyoccurred, could be noted. In otherwords, a substance is not eligible for the


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

6 An exception is the use of a food substance ina limited population such as infants, where suchlimited use may be part of a demonstration of thesafety of the substance for use by the limitedpopulation (e.g., as an ingredient in an infantformula).

GRAS exemption merely because it wasused in food before January 1, 1958, ifsuch use were not sufficientlywidespread.5

The fact that GRAS status isdetermined through experience basedon common use in food does notpreclude, in addition to informationdocumenting that a substance has asubstantial history of consumption forfood use by a significant number ofconsumers, a discussion of relevant dataor information that bears on the safetyof the substance under its intendedconditions of use. Thus, the noticesummary may also include acomprehensive discussion of scientificdata or information that, in the notifier’sview, corroborates the common useGRAS determination. With respect totoxicological studies that are viewed ascorroborative, the comprehensivediscussion should fully describe thestudies, identify the conclusions drawnfrom such studies, and explain howthese conclusions are relevant to theGRAS determination.

As discussed in section I.A of thisdocument, it is the use of a substance,rather than the substance itself, that iseligible for the GRAS exemption. Inaddition, section 201(s) of the act makesa clear distinction between qualifyingfor the GRAS exemption throughscientific procedures and qualifying forthe GRAS exemption through commonuse in food. Many substances that areGRAS for a specific use through acommon use GRAS determination couldbecome the subject of GRASdeterminations for additional uses. It isimportant to note, however, that anevaluation of whether an additional useof a substance that is GRAS throughexperience based on common use infood is also GRAS requires a scientificprocedures GRAS determination whenthe use in question was not commonprior to January 1, 1958.

b. General availability. As discussedfor notifiers of a scientific proceduresGRAS determination, notifiers of acommon use GRAS determinationshould limit citations to publishedinformation to those that the notifierdiscusses and relies on to support aGRAS determination or that areappropriately discussed and explainedbecause they appear to be inconsistentwith the GRAS determination.

c. Unfavorable information. Proposed§ 170.36(c)(3)(ii)(B) requires that thenotice summary of a common use GRASdetermination include a comprehensivediscussion of any reports ofinvestigations or other information thatmay appear to be inconsistent with theGRAS determination. The legislativehistory of the 1958 amendmentdemonstrates that Congress believedthat there was no reason to conductspecific tests to establish the safety ofsubstances commonly used in foodbecause their history of common useestablished a presumption of such safety(Ref. 1). However, nothing in thelegislative history suggests that Congressintended that subsequent reports ofadverse effects associated with the useof a substance in food be ignored in thesafety evaluation. A notice summary ofa common use GRAS determinationshould also address whether use was/issufficiently widespread that anysubstance-related adverse effects wouldbe observed and recorded. Where asubstance has been used by a limitedpopulation, 6 for a limited period oftime, or under circumstances that do notlend themselves to the observation andrecording of adverse effects, the lack ofreported adverse effects may not bemeaningful.

d. Basis for concluding expertconsensus. Proposed § 170.36(c)(4)(ii)(C)requires that the notice summary of acommon use GRAS determinationinclude the basis for concluding, in lightof the data and information described inthe notice, that there is a consensusamong qualified experts and that thereis reasonable certainty that thesubstance is not harmful under theintended conditions of use. Thus, thenotice summary must consider thetotality of the publicly available andcorroborative evidence about the safetyof the substance for its intended use,including both favorable informationand potentially unfavorableinformation.

FDA has previously discussed thecommon knowledge element as itapplies to a common use GRASdetermination which reads as follows:

For a substance to be GRAS on the basisof a history of common use in food, theremust be a consensus among the communityof qualified experts that the use of thesubstance is safe. For such a consensus to bepossible, information about the use of thesubstance must be generally available.General availability is the result of

documentation of the information, usually bypublication.

(50 FR 27294 at 27295, July 2, 1985)In addition, under § 170.30(c)(2),

when the common use in food occurredexclusively or primarily outside of theUnited States, a common use GRASdetermination requires that such use bedocumented by published or otherinformation and be corroborated byinformation from a second,independent, source that confirms thehistory and circumstances of use of thesubstance. Such information must bewidely available in the country inwhich the use occurred and readilyaccessible to interested qualified expertsin 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 noticeby informing the notifier in writing ofthe date on which the notice wasreceived. This acknowledgment wouldserve as a means to establish the date ofreceipt, which FDA is proposing tocouple with certain aspects of theagency response (see discussion ofproposed § 170.36 (d), (e), and (f) of thisdocument).

2. 90-Day Response Letter

Under the proposed notificationprocedure, FDA would not receive thedetailed data and information thatsupport a GRAS determination.Therefore, FDA would not be in aposition to affirm a notifier’s conclusionthat a use of a substance is GRAS, andthe rulemaking part of the GRASaffirmation process would not benecessary or appropriate. Rather, FDAwould evaluate whether the noticeprovides a sufficient basis for thenotifier’s GRAS determination. Forexample, FDA may question the GRASstatus of use of a substance if theinformation provided in a notice: (1)Does not adequately establish technicalevidence of safety; (2) is not generallyavailable; (3) does not convince theagency that there is the requisite expertconsensus about the safety of thesubstance for its intended use; or (4) isso poorly presented that the basis for theGRAS determination is not clear. FDAalso may be aware of information that isnot included in the notice but raisesimportant public health issues that leadthe agency to question GRAS status ofuse of the substance.

FDA believes that this narrow agencyevaluation would not have a negativeimpact on public health because theagency is replacing a voluntary


administrative process that wasdeveloped to provide officialrecognition of a lawfully made GRASdetermination with a different voluntaryadministrative procedure. From a legaland regulatory perspective, thissubstitution is neutral.

This narrow evaluation wouldfacilitate FDA’s rapid response to thenotifier. Accordingly, under proposed§ 170.36(e), FDA would respond to thenotifier in writing within 90 days ofreceipt of the notice. In somecircumstances, the agency’s responsewould not question the GRASdetermination. This response, however,would not be equivalent to an agencyaffirmation of GRAS status because FDAwould neither receive nor review thedetailed data and information thatsupport the GRAS determination. Inaddition, consistent with proposed§ 170.36(a)(2), any response from FDAwould not constitute compliance with§ 101.14(b)(3)(ii) or with therequirements that the agency hasproposed (61 FR 36154) for new infantformula submissions.

In other circumstances, the agency’sresponse could include identification ofa problem with the notice. However,whether FDA chooses to advise anotifier that the agency has identified aproblem with the notice, where thenotice raises no important public healthissues, is a matter committed to theagency’s discretion.

FDA is proposing to respond inwriting to a notifier in all circumstancesfor the following reasons. First, awritten response would make clear thatthe agency’s evaluation of a notice hascome to closure. Second, as discussedmore fully in section X of thisdocument, FDA believes that a writtenresponse would facilitate internationaltrade. Third, as discussed more fully insection VI.F of this document, FDAbelieves that a written response wouldbe a useful element of any file that theagency makes publicly accessible or anyinventory that the agency prepares ofnotices received under proposed§ 170.36.

However, under a notificationprocedure, an agency response is notimperative in those circumstances inwhich the agency chooses to raise noquestion about the GRAS status of theintended use of the substance. Asdiscussed in sections I.A and II of thisdocument, a manufacturer may market asubstance that the manufacturerdetermines is GRAS without informingthe agency or, if the agency were soinformed, while the agency is reviewingthat information. Thus, FDA’s proposalto respond to a notifier in allcircumstances does not alter a notifier’s

prerogative under the statute to marketa GRAS substance. Nonetheless, as analternative approach, the notificationprogram could be structured so thatFDA responds to the notifier only whenthe agency questions the GRAS status ofthe intended use of the substance. FDAspecifically requests comment onwhether the agency should, in all cases,provide a notifier with a letter at theconclusion of the agency’s evaluation ofa notice. Such comments may result ina modification to proposed § 170.36(e).

FDA has also considered whether thetime for the agency’s response should belonger than 90 days, and specificallyrequests comment on whether theproposed 90-day timeframe for anagency response should be lengthened,e.g., to 120 days or 150 days. FDA’sproposal to respond within 90 daysreflects both a commitment tooperational efficiency and a belief thatthe agency’s evaluation of whether anotice provides a sufficient basis for aGRAS determination could likely beaccomplished in such a period.However, FDA’s expectation that itcould respond within 90 days is in partpredicated on its estimate, which isdiscussed more fully in the agency’sanalysis of the information collectionrequirements of this document, that theagency would receive approximately 50notices per year. Accordingly, althoughcomments on the information collectionrequirements of this document aresubmitted directly to the Office ofInformation and Regulatory Affairs,OMB, the agency also requests commentdirectly to FDA on the number ofnotices that manufacturers anticipatesubmitting on an annual basis. Suchinformation may result in a modifiedtimeframe for the agency’s response.

3. Subsequent Agency ActionFDA is continuously evaluating the

safety of substances in the food supply.In some cases, FDA may considerwhether an emerging body of scientificknowledge raises questions about thecontinued safe use of a food additive orof a substance whose use was listed asGRAS, affirmed as GRAS, or commonlyconsidered to be GRAS by the foodindustry. Likewise, FDA may considerwhether specific information brought tothe agency’s attention (e.g., throughroutine correspondence from interestedparties or through a citizen petition)raises such safety questions. In mostcases, the information that comes toFDA’s attention does not demonstrate ahealth hazard, and the scientific issuesare resolved upon consideration by theagency. Thus, the agency does notroutinely publicize safety issues that itis considering, or reconsidering,

concerning the safety of a substance orclass of substances that is used in foodunless action by the agency is necessaryfor public health protection.

Similarly, FDA may direct resourcesto exploring issues raised by a GRASnotice even though such issues do not,on their face, appear to be significantpublic health issues. Alternatively, FDAmay, at some point after its 90-dayresponse to the notifier, receiveadditional information about a notifiedsubstance that raises questions about thesafety of that substance. If, after issuinga 90-day response letter, questionsdevelop for the agency regarding theGRAS status of a use of a substance,FDA may subsequently advise thenotifier and other interested parties ofthose questions.

In such circumstances, FDAordinarily expects to advise a notifier byletter that the agency has subsequentlyidentified a problem with the notice. Asdiscussed more fully in section VI.F ofthis document, such a letter would beplaced in a publicly accessible file sothat other interested parties wouldbecome aware of the agency’s position.Alternatively, FDA may, in accordancewith §§ 170.35(b)(4) and 170.38, publisha notice in the Federal Registerdetermining that use of a substance isnot GRAS and is a food additive subjectto section 409 of the act. Importantly,however, when faced with a publichealth hazard, the existence of suchrulemaking authority would notpreclude other agency action, includingseizure and injunction, to remove fromthe market a product that is anunapproved food additive.

As discussed in section VI.A of thisdocument, FDA has recently proposedthat a ‘‘new infant formula’’ submissionrequired under section 412 (c) and (d)of the act include the basis on whicheach ingredient is determined to be safeand suitable under the food safetyprovisions of the act (proposed§ 106.120(b)(6)(ii); 61 FR 36154 at36217). The agency could receive anotice under proposed § 170.36concerning a GRAS determination for abroad use of a substance in foods andsubsequently receive a new infantformula submission that lists thesubstance as an ingredient in a newinfant formula and asserts that the useof the substance in infant formula isGRAS. In such circumstances, FDAcould choose to reexamine the noticepreviously received under proposed§ 170.36. If, following suchreexamination, the agency questionswhether use of the substance in infantformula is GRAS, the agency could soinform the person who submitted theGRAS notice under proposed § 170.36.


D. AppealsFDA recognizes that in some cases a

notifier may disagree with the agency ifthe notifier receives a response advisingthat FDA has identified a problem withthe notice. FDA has recently reviewedthe vehicles, provided in part 10 (21CFR part 10) of its regulations, that anyperson or firm may use to appeal anagency employee’s decision (61 FR 9181at 9184, March 7, 1996). Although anagency response to a notice underproposed § 170.36 does not constitutean agency decision on the GRAS statusof a substance, FDA is advising that itwill consider any of the existing appealsprocesses that are described below as anappropriate vehicle to engage the agencyin cases where a notifier disagrees witha response received under proposed§ 170.36.

Under § 10.75, an interested personmay request internal agency review ofan agency decision made by anyoneother than the Commissioner. Suchreview ordinarily would be by theemployee’s supervisor, but may moveup the management ranks to the CenterDirector or to the Office of theCommissioner if the issue cannot beresolved, important policy matters arepresent, or it would be in the publicinterest. Sections 10.25 and 10.33permit an interested person to petitionthe Commissioner to review anyadministrative action. The regulationsalso include less formal methods ofappeal. For example, under § 10.65, aninterested person may correspond ormeet with FDA about any matter underFDA’s jurisdiction. Finally, any personwith concerns about an agency responseto a notice received under proposed§ 170.36 may contact FDA’s Office of theChief Mediator and Ombudsman (theOmbudsman’s Office). TheOmbudsman’s Office, which reportsdirectly to the Commissioner, works onresolving issues and conflicts that arisein any FDA component. TheOmbudsman’s staff is available todiscuss options, explain FDA’s practicesand procedures, and suggest approachesfor resolution. When appropriate, thestaff of the Ombudsman’s Office maycontact FDA’s staff involved in the issueand mediate a dispute.

E. Public Disclosure and Accessibility

1. Public DisclosureProposed § 170.36(f)(1) provides that

any GRAS exemption claim submittedunder proposed § 170.36(c)(1) of thissection be immediately available forpublic disclosure on the date the noticeis received. As discussed in sectionVI.B.1 of this document, any personwho makes a GRAS determination is

responsible for ensuring that thedetermination complies with theprovisions of § 170.30, regardless ofwhether that person notifies the agencyabout the determination. Further, thecommon knowledge element of a GRASdetermination signifies that neither thecommon or usual name of thesubstance, the intended use of thesubstance, nor the basis for the GRASdetermination can be confidential.

Proposed § 170.36(f)(1) furtherprovides that all remaining data andinformation in a notice be available forpublic disclosure, in accordance withpart 20 (21 CFR part 20), on the date thenotice is received. The commonknowledge element of a GRASdetermination signifies that neither thedetailed information about the identityof the substance nor the informationneeded to establish technical evidenceof safety can be confidential. Therefore,FDA assumes that a notice will notcontain any information that isprotected from public disclosure.Moreover, because a GRAS substancemay be marketed without priorapproval, FDA assumes that, in mostcases, submission of a notice will notreflect the notifier’s plans about thetiming of commercialization, which isarguably confidential commercialinformation (§ 20.61(b)).

A notifier who considers that certaininformation in a submission should notbe available for public disclosure shouldidentify as confidential the relevantportions of the submission for FDAconsideration. FDA will review theidentified information, determinewhether that information is exemptfrom public disclosure under part 20,and release or protect the information inaccordance with that determination.FDA advises that, in most cases, theagency is likely to determine that allinformation submitted to support aGRAS determination is available forpublic disclosure.

2. Public AccessibilityThe food industry’s basic need to

know whether a food substance is incompliance with applicable provisionsof the act originally persuaded theagency to clarify the regulatory status ofa multitude of food substances bypublishing the GRAS list. Under thisproposal, the current GRAS list (i.e.,current part 182) and the regulationslisting uses of a substance that FDA hasaffirmed as GRAS (i.e., current parts 184and 186 (21 CFR parts 184 and 186))would remain in the agency’s codifiedregulations. In addition, FDA isretaining the process whereby theagency may, on its initiative, review theGRAS status of a substance and, if

appropriate, establish a regulation inpart 184 or part 186 affirming such useas GRAS. However, if this proposalbecomes final, the existing processwhereby an interested person maypetition FDA to affirm the GRAS statusof use of a substance and list suchaffirmed uses in part 184 or part 186would be eliminated.

FDA believes that there would beconsiderable interest, from a broadsegment of the public, includingmembers of the regulated industry,other Federal, State, and localgovernment agencies, internationalgovernment agencies, and publicinterest groups, in notices receivedunder proposed § 170.36. Such groupslikely would want to know whetherFDA is aware that a substance is beingused in food on the basis of the GRASexemption and whether FDA hasadvised the notifier that it has identifieda problem with the notice. Therefore,FDA is proposing to establish aprocedure whereby all members of thepublic could readily access suchinformation. Moreover, such aprocedure would be in keeping with theagency’s goals in meeting theReinventing Food Regulations.

All GRAS petitions are currently onpublic display at the DocketsManagement Branch (DMB) because thepetition process includes informalrulemaking and DMB is the usualrepository for information that ispublicly available during informalrulemaking. However, FDA sees no needto place the entire GRAS notice onpublic display at DMB because, underthe proposed notification procedure, theagency will no longer be engaged inrulemaking. Moreover, a process ofmaintaining a copy of all notices atDMB would require that an additionalcopy be submitted and that anadministrative copy be maintained attwo locations (i.e., CFSAN as well asDMB). Such a process would beadministratively inefficient.

Nonetheless, FDA has considered thebest way to make the information fromthe proposed notification procedurereadily accessible to the public. FDAhas tentatively concluded that makingboth the GRAS exemption claimprovided under proposed § 170.36(c)(1)and all letters issued by the agencyrelevant to each claim easily accessibleto the public is the most direct andadministratively efficient way ofmeeting the needs of the public.Accordingly, under proposed§ 170.36(f)(2), the following informationwould be readily accessible for publicreview and copying: (1) A copy of allGRAS exemption claims received underproposed § 170.36(c)(1); (2) a copy of all


letters issued by the agency underproposed § 170.36(e); and (3) a copy ofany subsequent letter issued by theagency.

FDA considered whether the agencyshould only make a GRAS exemptionclaim readily accessible if the agencyhas not advised a notifier that it hasidentified a problem with the notice.The agency decided to make all claimsand responses readily accessiblebecause such a system will properlyunderscore the notifier’s acceptance ofresponsibility for the determination.Proposed § 170.36(f)(2) makes explicit tonotifiers that their notice to the agencyabout a GRAS determination is a publicclaim.

Initially, FDA intends to prepare a filecontaining the information specified byproposed § 170.36(f)(2) and to place thatfile on public display at DMB. FDA isplanning this approach because DMB isa common repository for publiclyavailable files. Alternatively, FDA couldmake the file accessible for inspection atthe agency’s Freedom of InformationOffice or, in keeping with the currentprocedures for public inspection of theinformation FDA considered and reliedon to reach a decision on an FAP, atCFSAN. Although FDA has tentativelyconcluded that it would be best toprovide for public accessibility at DMBbecause the public is alreadyaccustomed to obtaining informationrelating to GRAS substances at thatlocation, the agency requests commenton this matter.

FDA is not proposing to codify howor where the information prescribed byproposed § 170.36(f)(2) would be madeaccessible because any mechanism thatappears in the agency’s regulations willbind the agency to its provisions. Inkeeping with the agency’s goals inmeeting the Reinventing FoodRegulations, FDA wishes to maintainflexibility to improve the process forpublic accessibility, particularly as theagency gains experience with electronicmodes of information dissemination.FDA is aware that the public review ofhard copy (i.e., paper) files in a publicreading room may become obsolete aselectronic technology for publicdissemination of information advances.

FDA requests comment on whetherproposed § 170.36(f)(2) is an effectiveand efficient means to provide thepublic with ready access to informationfrom the proposed notificationprocedure.

F. InventoryProposed § 170.36(f)(2) would not

require that FDA maintain an inventoryof the information retained in thepublicly accessible file. Consequently,

such an inventory would be a newrecord within the meaning of § 20.24and FDA would not be required toprepare such an inventory in responseto a FOIA request. However, FDArecognizes the utility and importance ofan inventory of notices received underproposed § 170.36 and of the agency’sresponse to those notices, particularlyfor persons without ready access to theagency’s DMB. FDA also recognizes thatmany members of the public wouldprefer to access basic informationrelevant to GRAS notices in astreamlined format. FDA furtherrecognizes that the agency itself canmost efficiently carry out its ownresponsibilities (e.g., with respect tomonitoring imports of food products) byhaving basic information relevant toGRAS notices available in such aformat.

Therefore, FDA intends to maintainan inventory of notices received, theagency’s response, and any subsequentrelevant agency correspondence. Suchan inventory would be anadministratively efficient mechanism ofaccounting for the information residingin the publicly accessible file. Such aninventory also would complement thecurrent agency regulations tabulatingsubstances that are listed (part 182) oraffirmed (parts 184 and 186) as GRAS.

FDA has tentatively concluded thatany inventory of notices receivedshould be an adjunct to proposed§ 170.36(f)(2), rather than the sole meansof distributing the information availablefrom the notification procedure, becausethe agency could place the GRASexemption claims and the letters issuedby the agency in the publicly accessiblefile faster than it could amend aninventory. However, FDA is notproposing to codify the inventory as anadjunct to proposed § 170.36(f)(2)because such an inventory wouldrequire continuous amendment and theadministrative procedures required toamend a codified inventory would betoo cumbersome to meet the needs ofthe public and the agency efficiently.

FDA is also not proposing to mentionthe availability of the inventory in itscodified regulations. In keeping with theagency’s goals in meeting ReinventingFood Regulations, FDA believes thatrefraining from codifying any aspect ofthe inventory will provide the agencywith maximum flexibility to improvethe process by which the inventory isupdated and maintained.

Initially, FDA intends that such aninventory would be publicly accessiblein any file maintained in accordancewith proposed § 170.36(f)(2), e.g., atDMB. FDA could also make such aninventory available through prevailing

publicly accessible electronic modes,such as the agency’s home page on thecontemporary World Wide Web. FDArequests comment on making anyinventory prepared by the agencyavailable through such electronicmodes.

VII. Effect of the Proposed NotificationProcedure on Existing GRAS Petitions

Under the current GRAS affirmationprocess, the agency conducts apreliminary examination of the data andinformation submitted in the petition. IfFDA finds that the submittedinformation conforms to therequirements established under§§ 170.30 and 170.35, FDA makes anadministrative decision to file thepetition and publishes a notice in theFederal Register to that effect.

At this time, approximately 60 filedGRAS affirmation petitions are pendingat FDA. These petitions were filed withthe agency under an administrativeprocess that the agency is proposing toremove. Therefore, if this proposalbecomes final, the administrativeprocess that FDA would use to bringthese petitions to closure will no longerbe operative. Moreover, FDA isproposing to eliminate the GRASaffirmation process in order to increaseeffectiveness and efficiency. Thecontinued commitment of agencyresources to complete the GRAS petitionprocess for pending petitions would becontrary to one of the agency’s goals inthis rulemaking.

FDA recognizes that persons whohave a pending GRAS affirmationpetition have invested time andresources in those petitions. Therefore,proposed § 170.36(g)(1) stipulates thatany GRAS affirmation petition filedunder § 170.35 prior to the date that afinal rule based on this proposalbecomes effective, and still pending asof such effective date, will bepresumptively converted to a GRASnotice under proposed § 170.36. Thisconversion will allow the agency tobring filed GRAS affirmation petitionsto closure, albeit under a differentprocess than the one to which they weresubmitted.

However, the proposed notificationprocedure has certain requirements thathave no specific counterpart in thepetition process. In particular, under thenotification procedure a notifierexplicitly accepts full responsibility forthe GRAS determination by signing aGRAS exemption claim (under proposed§ 170.36(c)(1)). In contrast, under thepetition process a petitioner requeststhat FDA attest to a GRASdetermination. Thus, FDA cannotassume that all persons who submitted


a GRAS petition would in fact bewilling to accept full responsibility forthe determination.

Moreover, the GRAS exemption claimin proposed § 170.36(c)(1) would be acomplete and separate section of aGRAS notice that could stand alone andwould contain basic information in aconsistent format. As discussed, underproposed § 170.36(f)(2) the agencywould use the GRAS exemption claimto effectively and efficiently inform thepublic about received notices. Thus,logic compels that a GRAS exemptionclaim filed under proposed § 170.36(g)include all elements of the claimrequired under proposed § 170.36(c)(1),rather than only those elements thathave no counterpart in the GRASaffirmation petition process.

Accordingly, proposed § 170.36(g)(2)provides that any person who submitteda GRAS affirmation petition that isconverted to a notice under theprovisions of proposed § 170.36(g)(1)may amend such converted petition tosatisfy the requirements of proposed§ 170.36 by submitting to the agency aclaim, dated and signed by the notifier(i.e., the former petitioner), that aparticular use of a substance is exemptfrom the premarket approvalrequirements of the act because thenotifier has determined that such use isGRAS. Proposed § 170.36 (g)(2)(i)through (g)(2)(vi) describe the format ofthe GRAS exemption claim that wouldamend a converted GRAS affirmationpetition to satisfy the requirements of anotice under proposed § 170.36. Thisclaim format is similar to that requiredunder proposed § 170.36(c)(1) but hasbeen modified in two particulars (i.e.,proposed § 170.36 (g)(2)(ii) and(g)(2)(vi)) to take into account the factthat the data and information to supportthe GRAS determination have alreadybeen submitted to the agency in theapplicable GRAS petition.

Proposed § 170.36(g)(2)(i) requiresthat the GRAS exemption claim includethe name and address of the notifier. Aswith proposed § 170.36(c)(1)(i), this isnecessary for full identification of theperson who accepts responsibility forthe claim. This also is necessary so thatthe agency can administer theamendment to the converted petitionaccording to the provisions of proposed§ 170.36 (d) and (e) (see proposed§ 170.36(g)(3)(i)).

Proposed § 170.36(g)(2)(ii) requiresthat the GRAS exemption claim includethe applicable GRAS affirmationpetition number. The petition number isthe simplest way to identify theconverted petition that is beingamended.

Proposed § 170.36(g)(2)(iii) requiresthat the GRAS exemption claim includethe common or usual name of thesubstance that was the subject of theconverted GRAS affirmation petition(i.e., the notified substance). As withproposed § 170.36(c)(1)(ii), this isnecessary to identify the notifiedsubstance as well as to identify whetherthere are any labeling issues that needto be addressed. FDA is satisfied thatdetailed identity information, such asthat described in proposed§ 170.36(c)(2), will be present in thereferenced petition because, undercurrent § 170.35(c)(1)(i), FDA requiresthat a GRAS petition contain suchinformation as a prerequisite to filingthe petition.

Proposed § 170.36(g)(2)(iv) requiresthat the GRAS exemption claim includethe applicable conditions of use that aresupported by data and information inthe referenced GRAS petition, includingthe foods in which the notifiedsubstance is to be used, levels of use insuch foods, and the purposes for whichthe notified substance is used,including, when appropriate, adescription of the population expectedto consume the substance. As withproposed § 170.36(c)(1)(iii), thisinformation describing the conditions ofuse is necessary to delineate theboundaries of the GRAS exemptionclaim consistent with section 201(s) ofthe act, which states that a GRASsubstance must be generally recognizedas safe ‘‘under the conditions of itsintended use.’’ Importantly, a petitionerwho amends a converted GRASaffirmation petition to satisfy therequirements of a notice may do so onlyfor the intended use that was the subjectof the GRAS affirmation petition. Anyadditional use(s) would be the subject ofa separate notice under proposed§ 170.36(c).

Proposed § 170.36(g)(2)(v) requiresthat the GRAS exemption claim identifythe basis for the GRAS determination asscientific procedures or experiencebased on common use in food. Asdiscussed in section I.B.4 of thisdocument, under § 170.30, therequirements for a scientific proceduresGRAS determination are different fromthose for a common use GRASdetermination. The basis for a GRASdetermination is thus fundamental tothe GRAS exemption claim.

Proposed § 170.36(g)(2)(vi) requiresthat the GRAS exemption claim includeeither a statement that the completerecord that supports the GRASdetermination has already beensubmitted to the agency in the relevantGRAS petition (proposed§ 170.36(g)(2)(vi)(A)) or a statement that

all data and information that are thebasis for the GRAS determination areavailable for FDA review and copying orwill be sent to FDA upon request(proposed § 170.36(g)(2)(vi)(B)).Proposed § 170.36(g)(2)(vi) takes intoaccount the fact that, in many cases, apetitioner has already submitted thecomplete record that supports the GRASdetermination. Alternatively, proposed§ 170.36(g)(2)(vi) provides to the personwho submitted a GRAS petition theoption of agreeing to provide uponrequest any additional information thatsupports the GRAS determination butwas not included in the GRAS petition.As discussed with respect to proposed§ 170.36(c)(1)(v), FDA might conductrandom audits of such data andinformation or conduct an audit on abroad issue or class of products if theissue or use of a class of products raisesimportant public health issues.

FDA requests comment on proposed§ 170.36(g) as a mechanism foradministering pending GRASaffirmation petitions if the proposednotification procedure becomes final.Proposed § 170.36(g) would notpreclude any person who had a filedGRAS petition prior to the effective dateof a final GRAS notification rule fromsubmitting a notice of a claim forexemption according to the provisionsof proposed § 170.36(c) or fromsubmitting an FAP under § 171.1 andrequesting that FDA cross reference theinformation contained in the filed GRASpetition in accordance with § 171.1(b).

VIII. Interim PolicyBetween the time of publication of

this proposal and any final rule basedon this proposal, FDA invites interestedpersons who determine that a use of asubstance is GRAS to notify FDA ofsuch GRAS determinations as describedin proposed § 170.36 (b) and (c). Ingeneral, the agency would administerthe notices as described in proposed§ 170.36 (d) through (f) (i.e., FDA wouldacknowledge receipt of the notice,respond in writing to the notifier, andmake publicly accessible a copy of allGRAS exemption claims and theagency’s response). However, althoughFDA would make a good faith effort torespond within the proposed 90-daytimeframe, the agency would not bebound by such a timeframe. FDA willdetermine whether its experience inadministering such notices suggestsmodifications to the proposedprocedure.

FDA realizes that some individualswho have a filed GRAS affirmationpetition pending at the agency may beinterested in converting such petition toa notice under proposed § 170.36(g) or


in submitting a complete notice for thepetitioned use under proposed § 170.36(b) and (c). FDA invites such petitionersto submit an amendment in accordancewith proposed § 170.36(g)(2) or tosubmit a complete notice for thepetitioned use in accordance withproposed § 170.36 (b) and (c). FDAwould administer such notice oramendment as described in proposed§ 170.36 (d) through (f). However,during the interim period FDA wouldnot continue to commit resources toreview of a GRAS affirmation petition ifthe agency receives an amendment inaccordance with proposed § 170.36(g)(2)or receives a complete noticeconcerning the petitioned use.

FDA will consult upon request withinterested persons who seek additionalguidance in preparing a notice becausesuch consultation may identify sectionsof the proposed procedure that mayrequire clarification in any final rulebased on the proposal.

IX. Conforming AmendmentsThis proposal would eliminate the

GRAS petition process set out in§ 170.35(c). Therefore, FDA is proposingconforming amendments to revisecurrent §§ 184.1(b)(1) and 186.1(b)(1) byremoving the last sentence of eachparagraph. These sentences provide thatpersons seeking FDA approval of anindependent determination that a use ofa food substance is GRAS may submita petition in accordance with § 170.35.

Consistent with the proposedelimination of the GRAS petitionprocess set out in § 170.35(c), FDA isalso proposing a conformingamendment to revise current § 170.38(a)to: (1) Remove the provision that theCommissioner may, in accordance with§ 170.35(c)(5), publish a notice in theFederal Register determining that asubstance is not GRAS and is a foodadditive subject to section 409 of the actand (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 sucha notice in the Federal Register.Importantly, however, when faced witha public health hazard, the existence ofsuch rulemaking authority would notpreclude other agency action, includingseizure and injunction, to remove fromthe market a product that is anunapproved food additive.

X. International HarmonizationFDA is committed to international

harmonization of regulatoryrequirements and guidelines thatpreserve and enhance the agency’sability to accomplish its public healthmission, enhance regulatory

effectiveness by providing moreconsumer protection with scarcegovernment resources, and increaseworldwide access to safe and highquality food products (60 FR 53078,October 11, 1995). FDA is not aware ofa provision in the laws of any othercountry that is equivalent to the GRASexemption. On the other hand, the lawsof other countries provide exemptions(e.g., for ‘‘natural’’ products) that haveno equivalent under the act. Thus, theinternational community is alreadyaccustomed to operating in accordancewith a variety of regulatory approachesfor substances added to food. FDA’sproposed substitution of a GRASnotification procedure for the currentGRAS petition process would notimpose any new requirements thatwould affect imported food products.

Under the current petition process,FDA makes a public announcement thata petition has been filed andincorporates an affirmed use of asubstance into a codified list. Under theproposed notification procedure, FDAwould make readily accessible to thepublic, including international agenciesand firms, the notice’s ‘‘GRASexemption claim,’’ which wouldinclude a succinct description of thenotified substance, the applicableconditions of use, and the basis for theGRAS determination (i.e., throughscientific procedures or throughexperience based on common use infood). FDA would also make readilyaccessible to the public the agency’sresponse to the notice. Further, underthe act, a variety of substances that mustbe declared on the food label are exemptfrom premarket approval on the basis ofthe GRAS exemption and are notincluded on any government list orinventory of substances that are usedlawfully in the U.S. food supply.Operation of either the petition processor the proposed notification proceduredoes not change that fact.

FDA recognizes that interestedpersons may want to know the officialregulatory status of a food substance inthe United States prior to using thatsubstance in foods that will enterinternational commerce. FDA alsorecognizes that the proposed agencyresponse to a GRAS notice may haveless weight in the internationalcommunity than the agency’saffirmation of GRAS status. However, asa practical matter, FDA has announcedonly approximately 30 GRASaffirmations in the 10 years precedingthis proposed rule. This small numberof GRAS affirmations has a minimalimpact on considerations ofinternational trade.

For these reasons, FDA does notanticipate that the proposed substitutionof a GRAS notification procedure for theGRAS petition process will have anyimpact on international trade.Nevertheless, the agency invitescomment on this matter from theinternational community and from firmswho import food products into theUnited States or who export U.S. madefood products.

XI. Food Substances Used in AnimalFeed

FDA’s regulations regarding theeligibility of substances used in animalfood or feeds for classification as GRAS,and the procedures for affirmation ofGRAS status for such substances, arecodified at §§ 570.30 and 570.35,respectively. The requirementsdescribed in these regulations areparallel to the requirements for GRASsubstances that are used in human food,although some requirements of § 170.30have no corresponding requirement in§ 570.30. As an example relevant to thisrulemaking, the requirements of§ 570.30(c) are identical to therequirements of § 170.30(c)(1), but§ 570.30(c) has not been amended todescribe the requirements for a commonuse GRAS determination based onhistory of use when that history of useoccurred primarily or exclusivelyoutside the United States. In addition,the agency’s GRAS review did notextend to the use of food substances inanimal food or feeds. Thus, § 570.30does not contain provisions analogousto § 170.30 (e) and (f).

The general provisions in subpart A ofpart 184 were issued under the auspicesof the agency’s comprehensive review ofGRAS substances. Because this agencyreview did not extend to the use of foodsubstances in animal food or feeds, theagency did not issue a correspondingsubpart A in part 584 (21 CFR part 584).Therefore, any proposed rule to modify§§ 570.30 and 570.35 would require noconforming amendments in part 584.

FDA is also proposing to amend theprovisions of § 570.30 that are parallelto the provisions of current § 170.30(i.e., § 570.30 (a) and (b)) because§§ 170.30 and 570.30 implement thesame statutory provisions. Therefore, itis important for the agency’s standardsconcerning GRAS substances to beconsistent with respect to substancesused in human food and substancesused in animal food or feeds.

FDA is also proposing to eliminate theGRAS affirmation petition processprovided for in § 570.35 (a) and (c)because the corresponding process forsubstances used in human food is beingeliminated. Although the GRAS


affirmation process has rarely beenemployed for substances used in animalfood or feeds, FDA believes that it isappropriate to provide the option of aGRAS notification procedure for animalfood or feeds that would be parallel toproposed § 170.36. Therefore, inproposed § 570.36 the agency isproposing a GRAS notificationprocedure for substances used in animalfood or feeds. Finally, FDA is proposingto revise current § 570.38(a) as aconforming amendment required byremoving the current GRAS affirmationpetition process for substances used inanimal food or feeds.

With regard to the notificationprocedure, FDA’s proposal forsubstances that would be used in animalfood or feeds is for practical purposesidentical to FDA’s proposal forsubstances that would be used inhuman food. As discussed in moredetail throughout this document, FDA isspecifically requesting comment on thefollowing issues concerning theproposed regulations for substances thatwould be used in human food: (1)Whether it would be appropriate torequire or recommend that thesubmission include an electronic copy,in addition to three paper copies, ofsome or all of the notice; (2) theproposed requirement that, in all cases,FDA respond to the notifier; (3) whetherthe agency should be permitted morethan 90 days to respond to a GRASnotice; (4) the number of notices thatnotifiers anticipate submitting on anannual basis; (5) the agency’s proposalto provide the public with ready accessto information from the proposednotification procedure and the locationfor such information; (6) whether anyinventory prepared by the agencyshould be available through electronicmodes; (7) its proposal for administeringpending GRAS affirmation petitions ifthe proposed notification procedurebecomes final; and (8) whether theproposed substitution of a GRASnotification procedure for the GRASpetition process would have any impacton international trade. FDA specificallyrequests comments on these same issuesfor the proposed regulations concerningsubstances that would be used in animalfoods or feed.

In the case of substances that wouldbe used in animal feed, FDA isparticularly concerned about thepractical implications of a 90-dayresponse period, because, to date, theagency has received fewer than 10GRAS affirmation petitions forsubstances that would be used solely inanimal food or feed. Should the numberof notices received under a GRASnotification program exceed more than

a few notices per year, agency resourcesdevoted to the animal feed programlikely would be insufficient to evaluate,within the proposed 90-day timeframe,whether the notice provides a sufficientbasis for a GRAS determination. Thus,comments to the proposal may justifythat the agency adopt, in a final rule, alonger timeframe for notificationsconcerning substances used in animalfeed.

The agency recognizes that notifiersmay have questions concerning thecommon or usual name for a substancethat would be used in animal feeds.FDA advises that, in suchcircumstances, a notifier should consultwith the Division of Animal Feeds inFDA’s Center for Veterinary Medicine.

XII. Summary of the ProposalFDA is proposing to clarify current

§ 170.30 regarding the eligibility of theuse of a substance for exemption fromthe act’s premarket approvalrequirements based on a GRASdetermination. Specifically, FDA isproposing to amend current § 170.30(a)to clarify that general recognition ofsafety requires that there be commonknowledge among the qualified expertcommunity that there is reasonablecertainty that the substance is notharmful under the intended conditionsof use. This amendment would alsoclarify that a GRAS substance is neithermore safe nor less safe than an approvedfood additive, and that the distinctionbetween a GRAS substance and anapproved food additive is in thecommon knowledge of, and expertconsensus about, that safety.

In addition, FDA is proposing twochanges to current § 170.30(b). First,FDA is proposing to clarify the types oftechnical evidence of safety thatordinarily would constitute commonknowledge about a substance that isGRAS through scientific procedures.FDA is proposing this change becausethe quantity and quality of scientificevidence required to obtain approval ofa substance as a food additive varyconsiderably depending upon theestimated dietary exposure to thesubstance and the chemical, physical,and physiological properties of thesubstance. Second, FDA is proposing toclarify the role of publication insatisfying the common knowledgeelement of the GRAS standard becausepublication is ordinarily required, butmay not always be sufficient, to satisfythis element. For consistency with theseproposed amendments, FDA is alsoproposing to amend the definition of‘‘scientific procedures’’ in § 170.3(h).

In keeping with the Reinventing FoodRegulations, FDA is proposing to

replace the current voluntary GRASaffirmation process with a voluntaryprocedure whereby any person maynotify FDA of a GRAS determination.The notice would include a ‘‘GRASexemption claim,’’ dated and signed bythe notifier, that would provide, in aconsistent format, specific informationabout a GRAS determination. This claimwould include a succinct description ofthe notified substance, the applicableconditions of use, and the basis for theGRAS determination. The GRASexemption claim would also include astatement that the informationsupporting the GRAS determination wasavailable for FDA review and copying orwould be sent to FDA upon request. Inaddition to the GRAS exemption claim,the notice would include detailedinformation about the identity of thenotified substance and a detaileddiscussion of the basis for the notifier’sGRAS determination.

FDA would evaluate whether thenotice provides a sufficient basis for aGRAS determination and whetherinformation in the notice or otherwiseavailable to FDA raises issues that leadthe agency to question whether use ofthe substance is GRAS. Within 90 daysfrom the date of receipt of the notice,FDA would respond to the notifier inwriting and could advise the notifierthat the agency has identified a problemwith the notice. A response that doesnot advise that the agency has identifieda problem with the notice would not beequivalent to an affirmation of GRASstatus by the agency.

For each notice received, FDA wouldmake readily accessible to the public theGRAS exemption claim and the agency’sresponse. Although FDA wouldmaintain a readily accessible inventoryof notices received and the agency’sresponse to them, this inventory wouldbe neither codified nor referenced in theagency’s regulations.

Under the proposal, all GRASaffirmation petitions that were filed byFDA under § 170.35 prior to theeffective date of a GRAS notificationfinal rule and still pending as of thatdate would be presumptively convertedto a notice on that date. Any person whohad submitted a GRAS affirmationpetition that is converted to a noticecould: (1) Amend such convertedpetition to satisfy the requirements ofthe notification procedure by submittingto the agency a modified GRASexemption claim; (2) submit an FAP forthe substance and request that FDAcross reference the information in theGRAS affirmation petition; or (3) submita complete notice in accordance withthe notification procedure.


FDA’s regulations in part 570concerning GRAS substances for use inanimal food or feeds implement thesame statutory provisions as theregulations in part 170 concerningGRAS substances for use in humanfood. Accordingly, FDA is proposing: (1)To amend the provisions of § 570.30that are parallel to the provisions ofcurrent § 170.30 (i.e., § 570.30(a) and(b)); (2) to eliminate the GRASaffirmation petition process providedfor in § 570.35(a) and (c); and (3) toprovide the option of a GRASnotification procedure for substancesused in animal food or feeds that wouldbe parallel to proposed § 170.36.

FDA is also proposing severalamendments to parts 170, 184, 186, and570 of its regulations as conformingamendments.

XIII. Paperwork ReductionThis proposed rule contains

information that is subject to review byOMB under the Paperwork ReductionAct of 1995 (Pub. L. 104–13). Therefore,in accordance with 44 U.S.C.3506(c)(2)(B) and 5 CFR part 1320, FDAis providing below the title, description,and respondent descriptions for theinformation collections contained in

this proposal, along with an estimate ofthe resulting annual informationcollection burden. Included in theestimate is the time needed to reviewinstructions, to gather the requiredinformation, and to disclose theinformation.

FDA invites comments on thefollowing: (1) Whether the proposedcollection of information is necessaryfor the proper performance of thefunctions of the agency, includingwhether the information will havepractical utility; (2) the accuracy of theagency’s estimate of the burden of theproposed collection of information,including the validity of themethodology and assumptions used; (3)ways to enhance the quality, utility, andclarity of the information to becollected; and (4) ways to minimize theburden of the collection of informationon those who are to respond, includingthrough the use of automated collectiontechniques, where appropriate, or otherforms of information technology.

Title: Notice of a Claim for GRASExemption Based on a GRASDetermination

Description: Section 409 of the actestablishes a premarket approvalrequirement for ‘‘food additives;’’

section 201(s) of that act provides anexemption from the definition of ‘‘foodadditive’’ and thus from the premarketapproval requirement, for uses ofsubstances that are GRAS by qualifiedexperts. FDA is proposing a voluntaryprocedure whereby members of the foodindustry who determine that use of asubstance satisfies the statutoryexemption may notify FDA of thatdetermination. The notice wouldinclude a detailed summary of the dataand information that support the GRASdetermination, and the notifier wouldmaintain a record of such data andinformation. FDA would make theinformation describing the GRAS claim,and the agency’s response to the notice,available in a publicly accessible file;the entire GRAS notice would bepublicly available consistent with theFOIA and other Federal disclosurestatutes.

Description of Respondents:Manufacturers of Substances Used inFood and Feed

FDA estimates the total annualburden for this information collection tobe 9,900 hours.

ESTIMATED ANNUAL REPORT BURDEN

21 CFR Number ofrespondents

Annual fre-quency perresponse

Total annualresponse

Hours perresponse Total hours

170.36 ....................................................................................................... 50 1 50 150 7,500570.36 ....................................................................................................... 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 CFRNumber of

record-keepers

Annual fre-quency of

record-keeping

Total annualrecords

Hours perrecord-keeper

Total hours

170.36(c)(v) ............................................................................................... 50 1 50 15 750570.36(c)(v) ............................................................................................... 10 1 10 15 150

There are no operating ormaintenance costs or capital costsassociated with this collection.

FDA tentatively concludes that thereare no anticipated capital costs oroperating and maintenance costsassociated with the proposedinformation collection requirements.However, the agency welcomescomments on any such anticipatedcosts.

The agency has submitted copies ofthe proposed rule to OMB for review ofthe portions of the proposal that aresubject to the Paperwork Reduction Act

of 1995. Interested persons arerequested to send comments regardinginformation collection by May 19, 1997to the Office of Information andRegulatory Affairs, OMB (addressabove).

XIV. Analysis of Impacts

FDA has examined the impacts of theproposed rule under Executive Order12866 and the Regulatory Flexibility Act(5 U.S.C. 601–612). Executive Order12866 directs agencies to assess all costsand benefits of available regulatoryalternatives and, when regulation is

necessary, to select the regulatoryapproaches that maximize net benefits(including potential economic,environmental, public health and safetyeffects; other advantages; distributiveimpacts; and equity). Executive Order12866 classifies a rule as significant ifit meets any one of a number ofspecified conditions, including havingan annual effect on the economy of $100million or adversely affecting in amaterial way a sector of the economy,competition, or jobs, or if it raises novellegal or policy issues. If a rule has asignificant economic impact on a


substantial number of small entities, theRegulatory Flexibility Act requiresagencies to analyze regulatory optionsthat would minimize the economicimpact of that rule on small entities.

FDA finds that this proposed rule isnot a significant rule as defined byExecutive Order 12866, and finds underthe Regulatory Flexibility Act that thisproposed rule will not have a significantimpact on a substantial number of smallentities. Finally, FDA, in conjunctionwith the Administrator of OMB, findsthat this proposed rule is not a majorrule for the purpose of congressionalreview (Pub. L. 104–121).

A. Regulatory OptionsFDA has the following primary

options:(1) Take no action;(2) Adopt proposed GRAS notification

procedure;(3) Adopt a GRAS notification

procedure allowing FDA feedback onindependent GRAS determinations ofeither a higher or lower level ofauthoritativeness than the proposednotification system; and

(4) Eliminate agency participation inindependent GRAS determinations.

B. Costs and Benefits

1. Option One: Take No ActionNeither costs nor benefits are

associated with taking no action. Thisoption is the baseline case incomparison with which the costs andbenefits of the other options aredetermined.

The existing GRAS petition process isa government service provided toindustry by which firms mayvoluntarily submit information to FDAfor agency review and affirmation of theGRAS status of the use of a substancein food. Although FDA does not chargea fee to review material submitted underthe GRAS petition process, participationin that process is not without costbecause the required information musteither be generated or gathered, andsubmitted to FDA. The fact that somefirms participate in this voluntaryprocess implies that for some firms, thebenefit of participation must be greaterthan the cost of participation, and alsothat the net benefit of participation mustbe greater than the net benefit ofexisting alternatives, such as privatethird-party review of independentGRAS determinations. However, the factthat the cost of participation does notreflect the costs involved in actuallyadministering the GRAS petitionprocess means that participation in thatprocess cannot support inferencesregarding the net social benefits of thepetition process.

The benefit firms receive fromparticipation in the existing GRASpetition process appears to involve areduction in the cost of marketing foodscontaining substances independentlydetermined to be GRAS because FDAaffirmation of GRAS status would likelyfacilitate marketing of such substances.Manufacturers of these foods and retailestablishments buying these foods forsubsequent resale to consumers may bereluctant to offer them for sale in theabsence of assurance that FDA will notsubsequently conclude that ingredientsindependently determined to be GRASare unapproved food additives. If thesesubstances were subsequently found notto be GRAS, any ensuing seizure offoods containing the unapproved foodadditive might damage the credibility ofthose manufacturers and retailestablishments, and might lead toeconomic losses. If there were noprocess for agency GRAS affirmation,firms making independent GRASdeterminations may attempt tosubstitute for GRAS affirmations bydoing additional research, contractingwith third party research organizations,or taking other steps to provideadequate assurances to other firms thatFDA will probably not subsequentlychallenge their independent GRASdeterminations.

In addition to providing a desiredgood or service, the GRAS petitionprocess may result in some benefit interms of reducing the health risks fromsubstances independently determined tobe GRAS if FDA review of theinformation supporting independentGRAS determinations uncovers anerroneous determination which, ifundetected, could lead to health risks.

2. Option Two: Adopt Proposed GRASNotification Procedure

The chief benefit of eliminating theexisting GRAS petition process andreplacing it with the proposed GRASnotification procedure is that thenotification procedure will enableindustry to obtain a limited degree ofFDA feedback on independent GRASdeterminations more quickly and atlower cost, to both industry and FDA,than the GRAS petition process. Underthe proposed notification procedure,FDA will determine whether the noticeprovides a sufficient basis for a GRASdetermination or whether informationin the notice, or otherwise available toFDA, raises issues that lead the agencyto question whether use of the substanceis GRAS.

The proposed notification procedurewill come to closure more quickly andgenerate less uncertainty than the GRASpetition process because the notification

procedure is based on a 90-day reviewperiod rather than on the open-endedreview period of the GRAS petitionprocess. In some cases, the GRASpetition process involves a number ofiterative steps in which FDA asks forand receives additional supportinginformation. Under the notificationprocedure, FDA will base its responseon the notifier’s initial submission.

In addition to the time advantage, thecost of participation in the proposednotification procedure will probably beless than the cost of participation in theGRAS petition process because thenotification procedure will require thesubmission of only a summary of theinformation used to support theindependent GRAS determination,rather than the full supportinginformation required under the GRASpetition process. For example, thenotification procedure will not requirethe submission of references or materialrelating to methods of detection infoods, which are required under theGRAS petition process. Submissionsunder the notification procedure willprobably be about 25 to 30 pages, whilesubmissions under the current GRASpetition process can have hundreds oreven thousands of pages.

On the other hand, the sameunderlying information will be requiredunder the notification procedure asunder the GRAS petition process, so thepotential cost savings will be confinedto the relatively modest costs ofassembling, copying, and mailinginformation. The more significant costof generating or locating the requisiteunderlying information will not beaffected. In addition, the summaryrequired under the proposednotification procedure may fairly beviewed as a step beyond simplyproviding the supporting information asrequired under the GRAS petitionprocess. Therefore, althoughparticipation in the proposednotification procedure will probably besomewhat less costly than participationin the GRAS petition process, the costreduction is likely to be relativelymodest.

The primary cost of replacing theexisting GRAS petition process with theproposed notification procedure is thatit reduces the options available toindustry for obtaining FDA feedback onindependent GRAS determinations at alevel of authoritativeness comparable tothat currently offered under the GRASpetition process. Currently, feedback atthis level of authoritativeness isavailable through both the GRASpetition process and the FAP process.The fact that FDA receives both GRASpetitions and FAP’s suggests that some


firms find participation in the GRASpetition process less costly thanparticipation in the FAP process.However, this difference in cost isprobably relatively modest because thesystems are quite similar. For example,substances that are GRAS may bemarketed without prior agency approvaland thus may be marketed during theperiod in which either a GRAS petitionor an FAP on that substance is underreview.

The net benefit or cost of theproposed notification procedure willdepend largely on whether the value ofparticipation in the proposednotification procedure is or is notcomparable to that of participation inthe GRAS petition process. If the valueof participation in the two systems isroughly comparable, then the time andcost advantages of the proposednotification procedure will probablylead to modest net benefits. However, ifparticipation in the proposednotification procedure is significantlyless valuable than participation in theGRAS petition process because of thelower level of authoritativeness of FDAfeedback available through thenotification procedure, then theproposed procedure could lead to netcosts because firms may submitrelatively more costly FAP’s or takeother steps to compensate for the lack ofmore authoritative FDA feedback onindependent GRAS determinations.

3. Option Three: Adopt a GRASNotification Procedure Allowing FDAFeedback on Independent GRASDeterminations of Either a Higher orLower Level of Authoritativeness Thanthe Proposed Notification System

The benefits and costs of replacing theexisting GRAS petition process withnotification procedures allowing FDAfeedback on independent GRASdeterminations at either higher or lowerlevels of authoritativeness than theproposed notification procedure arequalitatively similar to the benefits andcosts of adopting the proposednotification procedure.

The net benefits or costs ofnotification procedures allowing moreor less authoritative FDA feedbackdepend largely on the cost ofparticipation in those systems and thevalue of the feedback provided toparticipating firms under those systems.The value of FDA feedback toparticipating firms involves the degreeto which that feedback facilitates themarketing of substances that have beensubject to independent GRASdeterminations. A system providingmore authoritative feedback than theproposed GRAS notification procedure

would either require submission ofmore information or more detailedinformation, or would involve moredetailed agency review of the sameamount of information. Thus,participation in such a system wouldarguably provide more valuablefeedback than participation in theproposed notification procedure butwould also be more costly thanparticipation in the proposednotification procedure. A systemproviding less authoritative feedbackthan the proposed GRAS notificationprocedure would either requiresubmission of less information or lessdetailed information, or would involveless detailed agency review of the sameamount of information. Thus,participation in such a system wouldarguably provide less valuable feedbackthan participation in the proposednotification procedure but wouldprobably also be less costly thanparticipation in the proposednotification procedure.

In both cases, it is difficult todetermine whether the resultingchanges in the value of FDA feedbackavailable through the notificationprocedure would compensate firms forthe resulting changes in the cost ofparticipation in such procedures, or tocompare the net social benefits ofoffering such procedures with the netbenefits of the existing GRAS petitionprocess.

4. Option Four: Eliminate AgencyParticipation in Independent GRASDeterminations

The costs and benefits of this optionare qualitatively similar to those ofadopting a notification procedureallowing FDA feedback of only aminimal level of authoritativeness. Ingeneral, the same results will occur ifthe value of participation in anotification procedure drops below thecosts involved in participation, or if anotification procedure is not available.In both cases, industry will eithersubmit relatively costly FAP’s or takeother steps to compensate for the lack ofa GRAS notification procedure orpetition process, or simply forgogovernment oversight of theirindependent GRAS determinations.

If FDA no longer participates inindependent GRAS determinations,FDA will not be aware of substancesthat have been the subject ofindependent GRAS determinationsunless firms choose to submit FAP’s forthose substances. Any public healthbenefits associated with FDA awarenessof these substances will be lost.However, if firms take other steps toconfirm independent GRAS

determinations, then these other stepswill be associated with countervailingpublic health benefits.

Again, it is difficult to determinewhether this option would result in netsocial costs or benefits because of thedifficulty of estimating the value ofvarious levels of FDA and non FDAfeedback on independent GRASdeterminations. However, thedistinctive role of FDA in GRAS issuessuggests that FDA feedback may bemore valuable to industry than other,equally costly, activity designed toconfirm independent GRASdeterminations. Therefore, it is likelythat the availability of some type ofnotification procedure will lead togreater net benefits than no notificationprocedure.

C. Regulatory Flexibility AnalysisThe proposed action will affect any

firm that may have chosen to participatein the existing GRAS petition process ormay choose to participate in theproposed GRAS notification process,including manufacturers of both humanand animal food, food additives, andfeed additives. The Dun’s MarketIdentifiers database lists 27,989 firms inStandard Industry Code (SIC) 20, Foodand Kindred Products. This includesdog and cat food, and prepared feedsnot elsewhere classified. In addition,this database lists 113 firms in SIC 2869,Industrial Organic Chemicals, NotElsewhere Classified, the SIC code thatincludes manufacturers of foodadditives. Therefore, a total of 28,102firms will potentially be affected by thisproposed rule.

The Small Business Administration(SBA) guidelines on the definition of asmall business for SIC 20 identify asmall business as being a businesshaving no more than 1,000, 750, or 500employees, depending on the moreprecise four-digit SIC code associatedwith the firm in question. However,there is no easy way to distribute thetotal number of firms in SIC 20 into theappropriate four-digit SIC categoriesbecause more than one primary four-digit SIC code may be associated withany given firm. To avoid missing anysmall firms, the least restrictive sizedefinition of 1,000 or fewer employeeswas used for all firms. The SBAdefinition of a small business in SIC2869 is a business with 1,000 or feweremployees. Based on these definitions,and assuming that the distribution ofemployment for firms for which noemployee data are available is the sameas the distribution for firms for whichdata are available, a total of 27,531 firmscould potentially be affected by thisproposed rule.


Although this proposal may affect asubstantial number of firms thatmanufacture food or food additives,many of which are small firms, thisproposal will not have a significantimpact on these firms for two reasons.First, this proposal replaces onevoluntary program with anothervoluntary program. Therefore, smallfirms will not be required to undertakeany additional activity or bear anyadditional costs. Second, participationin the proposed GRAS notificationprocedure should be somewhat lesscostly than participation in the GRASpetition process. Therefore, small firmsshould be better able to participate inthe notification procedure than thepetition process.

D. ConclusionsIn accordance with Executive Order

12866, FDA has analyzed this proposedrule and finds that this proposed rule isneither economically significant nor asignificant action, as defined by thatorder. FDA has also analyzed thisproposed rule in accordance with theRegulatory Flexibility Act and finds thatthis proposed rule will not have asignificant impact on a substantialnumber of small businesses.Accordingly, under the RegulatoryFlexibility Act, 5 U.S.C. 605(b), theCommissioner certifies that thisproposed rule will not have a significanteconomic impact on a substantialnumber of small entities.

The net costs and benefits of replacingthe GRAS petition process with theproposed GRAS notification procedureare indeterminate. However, anyincrease in net costs or benefits relativeto the current system will probably bemodest. FDA requests comments on thecosts and benefits of replacing the GRASpetition process with the proposedGRAS notification procedure.

XV. Environmental ImpactThe agency has determined under 21

CFR 25.24(a)(8) that this action is of atype that does not individually orcumulatively have a significant effect onthe human environment. Therefore,neither an environmental assessmentnor an environmental impact statementis required.

XVI. ReferencesThe following references have been

placed on display at DMB (addressabove) and may be seen by interestedpersons 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, ‘‘BladderTumors in Rats Fed Cyclohexylamine or High

Doses of a Mixture of Cyclamate andSaccharin,’’ Science, 167:1131–1132, 1970.

3. New York Times, p. 22, October 31,1969.

4. Sneath, P. H. A. et. al., Bergey’s Manualof Systematic Bacteriology, Williams &Wilkins, Baltimore, 1984.

5. Subcommittee on the 10th Edition of theRecommended Dietary Allowances, Food andNutrition Board, Commission on LifeSciences, National Research Council,Recommended Dietary Allowances, 10th ed.,Washington, DC, National Academy Press,1989.

6. ‘‘Biotechnology and Food Safety,’’ (Foodand Agriculture Organization, Rome, 1996).

7. ‘‘Strategies for Assessing the Safety ofFoods Produced by Biotechnology’’ (WorldHealth Organization, Geneva, 1991).

8. ‘‘Safety Evaluation of Foods Derived byModern Biotechnology: Concepts andPrinciples’’ (Organization for EconomicCooperation and Development, Paris, 1993).

9. ‘‘Application of the Principles ofSubstantial Equivalence to the SafetyEvaluation of Foods or Food Componentsfrom Plants Derived by ModernBiotechnology’’ (World Health Organization,Geneva, 1995).

10. Kessler, D. A., M. R. Taylor, J. H.Maryanski, E. L. Flamm, and L. S. Kahl, ‘‘TheSafety of Foods Developed byBiotechnology,’’ Science, 256:1747–1749 and1832, 1992.

List of Subjects

21 CFR Part 170

Administrative practice andprocedure, Food additives, Reportingand recordkeeping requirements.

21 CFR Part 184

Food ingredients.

21 CFR Part 186

Food ingredients, Food packaging.

21 CFR Part 570

Animal feeds, Animal foods, Foodadditives.

Therefore, under the Federal Food,Drug, and Cosmetic Act and underauthority delegated to the Commissionerof Food and Drugs, it is proposed that21 CFR parts 170, 184, 186, and 570 beamended as follows:

PART 170—FOOD ADDITIVES

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

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

2. Section 170.3 is amended byrevising paragraph (h) to read asfollows:

§ 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 asubstance.* * * * *

3. Section 170.30 is amended byrevising the last sentence of paragraphs(a), (b), and (c)(2); and by removing andreserving paragraph (f) to read asfollows:

§ 170.30 Eligibility for classification asgenerally recognized as safe (GRAS).

(a) * * * General recognition of safetyrequires common knowledge throughoutthe scientific community knowledgeableabout the safety of substances directly orindirectly added to food that there isreasonable certainty that the substanceis not harmful under the intendedconditions of use.

(b) * * * General recognition ofsafety through scientific proceduresshall be based upon generally availableand accepted scientific data,information, methods, or principles,which ordinarily are published and maybe corroborated by unpublishedscientific data, information, or methods.

(c)(1) * * *(2) * * * Persons who claim that use

of a substance is GRAS throughexperience based on its common use infood outside of the United States shouldnotify FDA of that claim in accordancewith proposed § 170.36.* * * * *

4. Section 170.35 is amended byrevising paragraph (a) and by removingparagraph (c) to read as follows:

§ 170.35 Affirmation of generallyrecognized as safe (GRAS) status.

(a) The Commissioner, on his owninitiative, may affirm the GRAS status ofthe use of a substance that directly orindirectly becomes a component offood.* * * * *

5. New § 170.36 is added to subpart Bto read as follows:

§ 170.36 Notice of a claim for exemptionbased on a GRAS determination.

(a)(1) Any person may notify FDA ofa claim that a particular use of asubstance is exempt from the statutorypremarket approval requirements basedon the notifier’s determination that suchuse is generally recognized as safe(GRAS).

(2) Notice to the agency of this sectionshall not constitute compliance with:

(i) Section 101.14(b)(3)(ii) of thischapter. Any person who submits ahealth claim petition under § 101.14 ofthis chapter shall comply in full with§ 101.14(b)(3)(ii) regardless of whether


the agency has been notified under thissection about a substance and regardlessof the nature of the agency’s response.

(ii) Section 106.120(b)(6)(ii) of thischapter. Any person who submits a newinfant formula submission underproposed § 106.120 of this chapter shallcomply in full with proposed§ 106.120(b)(6)(ii) regardless of whetherthe agency has been notified under thissection about a substance and regardlessof the nature of the agency’s response.

(b) A notice of a GRAS exemptionclaim shall be submitted in triplicate tothe Office of Premarket Approval (HFS–200), Center for Food Safety andApplied Nutrition, Food and DrugAdministration, 200 C St. SW.,Washington, DC 20204.

(c) Notifiers shall submit thefollowing information:

(1) A claim, dated and signed by thenotifier, or by the notifier’s attorney oragent, or (if the notifier is a corporation)by an authorized official, that aparticular use of a substance is exemptfrom the premarket approvalrequirements of the Federal Food, Drug,and Cosmetic Act (the act) because thenotifier has determined that such use isGRAS. Such GRAS exemption claimshall include:

(i) The name and address of thenotifier;

(ii) The common or usual name of thesubstance that is the subject of theGRAS exemption claim (i.e., the‘‘notified substance’’);

(iii) The applicable conditions of useof the notified substance, including thefoods in which the substance is to beused, levels of use in such foods, andthe purposes for which the substance isused, including, when appropriate, adescription of the population expectedto consume the substance;

(iv) The basis for the GRASdetermination (i.e., through scientificprocedures or through experience basedon common use in food); and

(v) A statement that the data andinformation that are the basis for thenotifier’s GRAS determination areavailable for the Food and DrugAdministration’s (FDA) review andcopying at reasonable times at a specificaddress set out in the notice or will besent to FDA upon request.

(2) Detailed information about theidentity of the notified substance,including, as applicable, its chemicalname, Chemical Abstracts Service (CAS)Registry Number, Enzyme Commissionnumber, empirical formula, structuralformula, quantitative composition,method of manufacture (excluding anytrade secrets and including, forsubstances of natural biological origin,source information such as genus and

species), characteristic properties, anycontent of potential human toxicants,and specifications for food-gradematerial;

(3) Information on any self-limitinglevels of use; and

(4) A detailed summary of the basisfor the notifier’s determination that aparticular use of the notified substanceis exempt from the premarket approvalrequirements of the act because suchuse is GRAS. Such determination maybe based either on scientific proceduresor on common use in food.

(i) For a GRAS determination throughscientific procedures, such summaryshall include:

(A) A comprehensive discussion of,and citations to, generally available andaccepted scientific data, information,methods, or principles that the notifierrelies on to establish safety, including aconsideration of the probableconsumption of the substance and theprobable consumption of any substanceformed in or on food because of its useand the cumulative effect of thesubstance in the diet, taking intoaccount any chemically orpharmacologically related substances insuch diet;

(B) A comprehensive discussion ofany reports of investigations or otherinformation that may appear to beinconsistent with the GRASdetermination; and

(C) The basis for concluding, in lightof the data and information describedunder paragraphs (c)(1), (c)(2), (c)(3),(c)(4)(i)(A), and (c)(4)(i)(B) of thissection, that there is consensus amongexperts qualified by scientific trainingand experience to evaluate the safety ofsubstances added to food that there isreasonable certainty that the substanceis not harmful under the intendedconditions of use.

(ii) For a GRAS determination throughexperience based on common use infood, such summary shall include:

(A) A comprehensive discussion of,and citations to, generally available dataand information that the notifier relieson to establish safety, includingevidence of a substantial history ofconsumption of the substance by asignificant number of consumers;

(B) A comprehensive discussion ofany reports of investigations or otherinformation that may appear to beinconsistent with the GRASdetermination;

(C) The basis for concluding, in lightof the data and information describedunder paragraphs (c)(1), (c)(2), (c)(3),(c)(4)(ii)(A), and (c)(4)(ii)(B) of thissection, that there is consensus amongexperts qualified by scientific trainingand experience to evaluate the safety of

substances added to food that there isreasonable certainty that the substanceis not harmful under the intendedconditions of use.

(d) Within 30 days of receipt of thenotice, FDA shall acknowledge receiptof a notice by informing the notifier inwriting of the date on which the noticewas received.

(e) Within 90 days of receipt of thenotice, FDA shall respond to the notifierin writing.

(f)(1) Any GRAS exemption claimsubmitted under paragraph (c)(1) of thissection shall be immediately availablefor public disclosure on the date thenotice is received. All remaining dataand information in the notice shall beavailable for public disclosure, inaccordance with part 20 of this chapter,on the date the notice is received.

(2) For each GRAS notice submittedunder this section, the followinginformation shall be readily accessiblefor public review and copying:

(i) A copy of the GRAS exemptionclaim submitted under paragraph (c)(1)of this section.

(ii) A copy of any letter issued by theagency under paragraph (e) of thissection.

(iii) A copy of any subsequent letterissued by the agency regarding suchnotice.

(g)(1) Any GRAS affirmation petitionthat was filed by FDA under § 170.35prior to (date the final rule becomeseffective) and is still pending as of (datethe final rule becomes effective) shall bepresumptively converted to a noticeunder the provisions of this section on(date the final rule becomes effective).

(2) Any person who submitted aGRAS affirmation petition that isconverted to a notice under paragraph(g)(1) of this section may amend suchconverted petition to meet therequirements of this section bysubmitting to the agency a claim, datedand signed by the notifier (i.e., theformer petitioner), or by the notifier’sattorney or agent, or (if the notifier is acorporation) by an authorized official,that a particular use of a substance isexempt from the premarket approvalrequirements of the act because thenotifier has determined that such use isGRAS. Such GRAS exemption claimshall include:


(ii) The applicable GRAS affirmationpetition number;

(iii) The common or usual name of thesubstance that was the subject of theconverted GRAS affirmation petition(i.e., the notified substance);

(iv) The applicable conditions of useof the notified substance that are


supported by data and information inthe referenced GRAS petition, includingthe foods in which the substance is tobe used, levels of use in such foods, andthe purposes for which the substance isused, including, when appropriate, adescription of the population expectedto consume the substance;

(v) The basis for the GRASdetermination (i.e., through scientificprocedures or through experience basedon common use in food); and

(vi)(A) A statement that the completerecord that supports the GRASdetermination has been submitted to theagency in the applicable GRAS petition;or

(B) A statement that the data andinformation that are the basis for thenotifier’s GRAS determination areavailable for FDA review and copying atreasonable times at a specific addressset out in the claim or will be sent toFDA upon request.

(3)(i) A petition that is converted to anotice under the provisions ofparagraph (g)(1) of this section and thatis amended according to the provisionsof paragraph (g)(2) of this section shallbe reviewed and administered accordingto the provisions of paragraphs (d), (e),and (f) of this section. For the purposesof paragraphs (d), (e), and (f) of thissection, the date of receipt of theamendment described in paragraph(g)(2) of this section shall be the date ofreceipt of the notice.

(3)(ii) After (date 90 days after date ofpublication of the final rule), FDA willinform any person who submitted aGRAS affirmation petition that isconverted to a notice under theprovisions of paragraph (g)(1) of thissection, and who has not amended suchpetition according to the provisions ofparagraph (g)(2) of this section, that theconverted petition is inadequate as anotice under this section.

6. Section 170.38 is amended byrevising paragraph (a) to read as follows:

§ 170.38 Determination of food additivestatus.

(a) The Commissioner may, inaccordance with § 170.35(b)(4), publisha notice in the Federal Registerdetermining that a substance is notGRAS and is a food additive subject tosection 409 of the act.* * * * *

PART 184—DIRECT FOODSUBSTANCES AFFIRMED ASGENERALLY RECOGNIZED AS SAFE

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

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

§ 184.1 [Amended]

8. Section 184.1 Substances addeddirectly to human food affirmed asgenerally recognized as safe (GRAS) isamended in paragraph (b)(1) byremoving the last sentence.

PART 186—INDIRECT FOODSUBSTANCES AFFIRMED ASGENERALLY RECOGNIZED AS SAFE

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

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

§ 186.1 [Amended]

10. Section 186.1 Substances addedindirectly to human food affirmed asgenerally recognized as safe (GRAS) isamended in paragraph (b)(1) byremoving the last sentence.

PART 570—FOOD ADDITIVES

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

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

12. Section 570.3 is amended byrevising paragraph (h) to read asfollows:

§ 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 asubstance.* * * * *

13. Section 570.30 is amended byrevising the last sentence of paragraphs(a) and (b) to read as follows:

§ 570.30 Eligibility for classification asgenerally recognized as safe (GRAS).

(a) * * * General recognition of safetyrequires common knowledge throughoutthe scientific community knowledgeableabout the safety of substances directly orindirectly added to food that there isreasonable certainty that the substanceis not harmful under the intendedconditions of use.

(b) * * * General recognition ofsafety through scientific proceduresshall be based upon generally availableand accepted scientific data,information, methods, or principles,which ordinarily are published and maybe corroborated by unpublishedscientific data, information, or methods.* * * * *

14. Section 570.35 is amended byrevising paragraph (a) and by removingparagraph (c) to read as follows:

§ 570.35 Affirmation of generallyrecognized as safe (GRAS) status.

(a) The Commissioner, on his owninitiative, may affirm the GRAS status ofthe use of a substance that directly orindirectly becomes a component offood.* * * * *

15. New § 570.36 is added to subpartB to read as follows:

§ 570.36 Notice of a claim for exemptionbased on a GRAS determination.

(a) Any person may notify FDA of aclaim that a particular use of asubstance is exempt from the statutorypremarket approval requirements basedon the notifier’s determination that suchuse is generally recognized as safe(GRAS).

(b) A notice of a GRAS exemptionclaim shall be submitted in triplicate tothe Division of Animal Feeds (HFV–220), Center for Veterinary Medicine,Food and Drug Administration, 7500Standish Pl., Rockville, MD 20855.

(c) Notifiers shall submit thefollowing information:

(1) A claim, dated and signed by thenotifier, or by the notifier’s attorney oragent, or (if the notifier is a corporation)by an authorized official, that aparticular use of a substance is exemptfrom the premarket approvalrequirements of the Federal Food, Drug,and Cosmetic Act (the act) because thenotifier has determined that such use isGRAS. Such GRAS exemption claimshall include:


(ii) The common or usual name of thesubstance that is the subject of theGRAS exemption claim (i.e., the notifiedsubstance);

(iii) The applicable conditions of useof the notified substance, including thefoods in which the substance is to beused, levels of use in such foods, andthe purposes for which the substance isused, including, when appropriate, adescription of the population expectedto consume the substance;

(iv) The basis for the GRASdetermination (i.e., through scientificprocedures or through experience basedon common use in food); and

(v) A statement that the data andinformation that are the basis for thenotifier’s GRAS determination areavailable for the Food and DrugAdministration’s (FDA) review andcopying at reasonable times at a specificaddress set out in the notice or will besent to FDA upon request.


(2) Detailed information about theidentity of the notified substance,including, as applicable, its chemicalname, Chemical Abstracts Service (CAS)Registry Number, Enzyme Commissionnumber, empirical formula, structuralformula, quantitative composition,method of manufacture (excluding anytrade secrets and including, forsubstances of natural biological origin,source information such as genus andspecies), characteristic properties, anycontent of potential human or animaltoxicants, and specifications for feed-grade material;

(3) Information on any self-limitinglevels of use; and

(4) A detailed summary of the basisfor the notifier’s determination that aparticular use of the notified substanceis exempt from the premarket approvalrequirements of the act because suchuse is GRAS. Such determination maybe based either on scientific proceduresor on common use in food.

(i) For a GRAS determination throughscientific procedures, such summaryshall include:

(A) A comprehensive discussion of,and citations to, generally available andaccepted scientific data, information,methods, or principles that the notifierrelies on to establish safety, including aconsideration of the probableconsumption of the substance and theprobable consumption of any substanceformed in or on food because of its useand the cumulative effect of thesubstance in the diet, taking intoaccount any chemically orpharmacologically related substances insuch diet;

(B) A comprehensive discussion ofany reports of investigations or otherinformation that may appear to beinconsistent with the GRASdetermination; and

(C) The basis for concluding, in lightof the data and information describedunder paragraphs (c)(1), (c)(2), (c)(3),(c)(4)(i)(A), and (c)(4)(i)(B) of thissection, that there is consensus amongexperts qualified by scientific trainingand experience to evaluate the safety ofsubstances added to food that there isreasonable certainty that the substanceis not harmful under the intendedconditions of use.

(ii) For a GRAS determination throughexperience based on common use infood, such summary shall include:

(A) A comprehensive discussion of,and citations to, generally available dataand information that the notifier relieson to establish safety, includingevidence of a substantial history ofconsumption of the substance by asignificant number of consumers;

(B) A comprehensive discussion ofany reports of investigations or otherinformation that may appear to beinconsistent with the GRASdetermination;

(C) The basis for concluding, in lightof the data and information describedunder paragraphs (c)(1), (c)(2), (c)(3),(c)(4)(ii)(A), and (c)(4)(ii)(B) of thissection, that there is consensus amongexperts qualified by scientific trainingand experience to evaluate the safety ofsubstances added to food that there isreasonable certainty that the substanceis not harmful under the intendedconditions of use.

(d) Within 30 days of receipt of thenotice, FDA shall acknowledge receiptof a notice by informing the notifier inwriting of the date on which the noticewas received.

(e) Within 90 days of receipt of thenotice, FDA shall respond to the notifierin writing.

(f)(1) Any GRAS exemption claimsubmitted under paragraph (c)(1) of thissection shall be immediately availablefor public disclosure on the date thenotice is received. All remaining dataand information in the notice shall beavailable for public disclosure, inaccordance with part 20 of this chapter,on the date the notice is received.

(2) For each GRAS notice submittedunder this section, the followinginformation shall be readily accessiblefor public review and copying:

(i) A copy of the GRAS exemptionclaim submitted under paragraph (c)(1)of this section.

(ii) A copy of any letter issued by theagency under paragraph (e) of thissection.

(iii) A copy of any subsequent letterissued by the agency regarding suchnotice.

(g)(1) Any GRAS affirmation petitionthat was filed by FDA under § 570.35prior to (date the final rule becomeseffective) and is still pending as of (datethe final rule becomes effective) shall bepresumptively converted to a noticeunder the provisions of this section on(date the final rule becomes effective).

(2) Any person who submitted aGRAS affirmation petition that isconverted to a notice under paragraph(g)(1) of this section may amend suchconverted petition to meet therequirements of this section bysubmitting to the agency a claim, datedand signed by the notifier (i.e., theformer petitioner), or by the notifier’sattorney or agent, or (if the notifier is acorporation) by an authorized official,that a particular use of a substance isexempt from the premarket approvalrequirements of the act because thenotifier has determined that such use is

GRAS. Such GRAS exemption claimshall include:


(ii) The applicable GRAS affirmationpetition number;

(iii) The common or usual name of thesubstance that was the subject of theconverted GRAS affirmation petition(i.e., the notified substance);

(iv) The applicable conditions of useof the notified substance that aresupported by data and information inthe referenced GRAS petition, includingthe foods in which the substance is tobe used, levels of use in such foods, andthe purposes for which the substance isused, including, when appropriate, adescription of the population expectedto consume the substance;

(v) The basis for the GRASdetermination (i.e., through scientificprocedures or through experience basedon common use in food); and

(vi)(A) A statement that the completerecord that supports the GRASdetermination has been submitted to theagency in the applicable GRAS petition;or

(B) A statement that the data andinformation that are the basis for theGRAS determination are available forFDA’s review and copying at reasonabletimes at a specific address set out in theclaim or will be sent to FDA uponrequest.

(3)(i) A petition that is converted to anotice under the provisions ofparagraph (g)(1) of this section and thatis amended according to the provisionsof paragraph (g)(2) of this section shallbe reviewed and administered accordingto the provisions of paragraphs (d), (e),and (f) of this section. For the purposesof paragraphs (d), (e), and (f) of thissection, the date of receipt of theamendment described in paragraph(g)(2) of this section shall be the date ofreceipt of the notice.

(ii) After (date 90 days after date ofpublication of the final rule), FDA willinform any person who submitted aGRAS affirmation petition that isconverted to a notice under theprovisions of paragraph (g)(1) of thissection, and who has not amended suchpetition according to the provisions ofparagraph (g)(2) of this section, that theconverted petition is inadequate as anotice under this section.

§ 570.38 [Amended]

16. Section 570.38 Determination offood additive status is amended inparagraph (a) by removing ‘‘or (c)(5)’’.


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

18938 federal register /vol. 62, no. 74/thursday, april … federal register/vol. 62, no....

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