54960 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations DEPARTMENT OF HEALTH AND FOR FURTHER INFORMATION CONTACT: D. Comments on Certain Terms Used in the HUMAN SERVICES Regarding substances that would be Proposed Regulatory Text used in human food: Paulette M. E. Comments on the Use of ‘‘Plain Food and Drug Administration Language’’ in the Regulatory Text Gaynor, Center for Food Safety and VIII. Definitions Applicable to a GRAS Notice Applied Nutrition (HFS–255), Food and A. Definitions We Described in the 2010 21 CFR Parts 20, 25, 170, 184, 186, and Drug Administration, 5001 Campus Notice 570 Drive, College Park, MD 20740, 240– B. Definition of ‘‘GRAS Notice’’ [Docket No. FDA–1997–N–0020 (formerly 402–1192. Regarding substances that C. Other Terms We Are Defining in the would be used in animal food: Geoffrey Rule 97N–0103)] K. Wong, Center for Veterinary IX. Opportunity to Submit a GRAS Notice RIN 0910–AH15 X. Comments on Administrative Procedures Medicine (HFV–224), Food and Drug for Submission of a GRAS Notice Administration, 7519 Standish Pl., A. How to Send a GRAS Notice to FDA Substances Generally Recognized as Rockville, MD 20855, 240–402–5838. B. Option for Submission of Electronic or Safe SUPPLEMENTARY INFORMATION: Paper Copies of a GRAS Notice AGENCY: Food and Drug Administration, C. Incorporation into a GRAS Notice HHS. Table of Contents XI. General Requirements Applicable to a ACTION: Final rule. Executive Summary GRAS Notice XII. Comments on Part 1 of a GRAS Notice: SUMMARY: The Food and Drug Purpose and Coverage of the Rule Signed Statements and Certification Administration (FDA or we) is issuing a Summary of the Major Provisions of the Rule A. Exclusion of Trade Secret and Confidential Commercial Information final rule that amends and clarifies the Costs and Benefits From the Signed Statements criteria in our regulations for when the B. Name of the Notified Substance, Using I. Introduction use of a substance in food for humans A. History of FDA’s Approach to the GRAS an Appropriately Descriptive Term or animals is not subject to the Provision of the FD&C Act C. Intended Conditions of Use of the premarket approval requirements of the B. Report by the Government Notified Substance Federal Food, Drug, and Cosmetic Act Accountability Office and How We Are D. Statutory Basis for the Conclusion of (the FD&C Act) because the substance is Addressing Its Recommendations GRAS Status E. Agreement to Make Data and generally recognized as safe (GRAS) C. Issues Regarding the Legal and Information Available Upon Request under the conditions of its intended use. Regulatory Framework for Substances F. Statements and Any Applicable We also are amending our regulations to Added to Food Explanation Regarding Data and replace the voluntary GRAS affirmation D. Recent FDA Actions Related to GRAS Information That a Notifier Views as Criteria petition process with a voluntary E. Moving Forward Under This Final Rule Exempt From Disclosure Under FOIA notification procedure under which any G. Certification Statement II. Background H. Person Signing Part 1 of the GRAS person may notify us of a conclusion A. The Proposed Rule that a substance is GRAS under the Notice B. Interim Pilot Program I. Authorization for FDA to Send Trade conditions of its intended use. The C. 2010 Report of the Government Secret Information to FSIS clarified criteria for GRAS status should Accountability Office XIII. Comments on Part 2 of a GRAS Notice: help stakeholders draw more informed D. 2010 Notice Reopening the Comment Identity, Method of Manufacture, conclusions about whether the intended Period Specifications, and Physical or Technical conditions of use of a substance in food E. Public Comments Effect F. Applicability of Discussions in This A. Scientific Information About the for humans or animals complies with Document to Both the Human Food the FD&C Act, and the notification Identity of a Notified Substance Regulations and the Animal Food B. Method of Manufacture procedure will enable stakeholders to be Regulations C. Specifications for the Notified Substance aware of whether we have questioned G. Use of Pronouns in This Document D. Data and Information Bearing on the the basis of a conclusion of GRAS H. Summary of Principal Changes to the Physical or Other Technical Effect of the status. Proposed Notification Procedure Notified Substance III. Legal Authority XIV. Comments on Part 3 of a GRAS Notice: DATES: This rule is effective October 17, IV. General Comments on the Proposed Rule Dietary Exposure 2016. Submit comments on information V. Comments on the Definition of Scientific XV. Comments on Part 4 of a GRAS Notice: collection issues under the Paperwork Procedures Self-Limiting Levels of Use Reduction Act of 1995 by October 17, VI. Comments on the Criteria for Eligibility XVI. Comments on Part 5 of a GRAS Notice: 2016 (see section XXIX, the ‘‘Paperwork for Classification as GRAS Common Use in Food Before 1958 Reduction Act of 1995’’ section of this A. General Criteria for Eligibility for XVII. Comments on Parts 6 and 7 of a GRAS document). Classification as GRAS Notice: Narrative and List of Supporting B. Criteria for Eligibility for Classification Data and Information ADDRESSES: To ensure that comments on as GRAS Through Scientific Procedures XVIII. Comments on Steps a Notifier May the information collection are received, C. Criteria for Eligibility for Classification Take Before We Respond to a GRAS the Office of Management and Budget as GRAS Through Experience Based on Notice (OMB) recommends that written Common Use in Food A. Communicating With a Notifier Before comments be faxed to the Office of D. Other Comments on the Criteria for We Respond to a GRAS Notice Information and Regulatory Affairs, Eligibility for Classification as GRAS B. Submitting an Amendment OMB, Attn: FDA Desk Officer, FAX: E. GRAS Status of Certain Food Substances C. Notifier’s Request That We Cease To 202–395–7285, or emailed to oira_ VII. Comments on the Substitution of a GRAS Evaluate a GRAS Notice mstockstill on DSK3G9T082PROD with RULES2 submission@omb.eop.gov. All Notification Procedure for the GRAS XIX. Comments on What We Will Do With comments should be identified with the Affirmation Petition Process a GRAS Notice A. Affirmation on the Initiative of the A. Filing Decision OMB control number 0910–0342 and Commissioner B. Our Response to a GRAS Notice titled ‘‘Substances Generally Recognized B. Deletion of the GRAS Affirmation C. Additional Correspondence as as Safe.’’ Also include the FDA docket Petition Process Circumstances Warrant number found in brackets in the C. General Comments on the Proposed D. Procedures If a Notifier Disagrees With heading of this document. GRAS Notification Procedure Our Response VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00002 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 54961 XX. Coordinating Our Evaluation of a GRAS XXIX. Paperwork Reduction Act of 1995 • General recognition of safety Notice With FSIS XXX. Federalism requires common knowledge, XXI. Comments on Public Disclosure of a XXXI. References throughout the expert scientific GRAS Notice Executive Summary community knowledgeable about the A. Data and Information in a GRAS Notice Are Available for Public Disclosure on safety of substances directly or Purpose and Coverage of the Rule indirectly added to food, that there is a the Date That We Receive It B. We Will Make a List of Filed GRAS Although we have premarket review reasonable certainty that the substance Notices and Our Responses to GRAS authority over food additives, a food is not harmful under the conditions of Notices Readily Accessible manufacturer can intentionally add a its intended use; C. Public Disclosure of a GRAS Notice Is substance to human food or animal food • ‘‘Common knowledge’’ can be based in Accordance With Our Public on either ‘‘scientific procedures’’ or on Information Regulations in Part 20 without our premarket review or approval if the substance is generally experience based on common use of a XXII. Submission of a Supplement XXIII. Comments on the Administrative recognized, among qualified experts, to substance in food prior to January 1, Process for Pending GRAS Affirmation be safe under the conditions of its 1958; and Petitions intended use (GRAS). Since the 1970s, • General recognition of safety XXIV. Other Comments we have had regulations clarifying the through scientific procedures must be A. GRAS Panels and Conflict of Interest statutory provision for eligibility for based upon the application of generally B. Guidance on Documenting Conclusions classification as GRAS. We also have available and accepted scientific data, of GRAS Status information, or methods, which C. Compliance With Other FDA had regulations governing a procedure for any person to voluntarily submit to ordinarily are published, as well as the Regulations application of scientific principles, and D. Impact on Other Federal Agencies us a petition asking us to affirm the E. Impact on International Trade GRAS status of a substance under the may be corroborated by the application F. Audits conditions of its intended use, and for of unpublished scientific data, G. Lack of an Environmental Assessment us to engage in an intensive rulemaking information, or methods. H. Substances Affirmed as GRAS With process in response to that petition. With respect to the procedure for Specific Limitations Experience has shown that our submitting a GRAS notice, we provide: XXV. Comments on Substances Intended for regulations need further clarification to • Definitions for certain terms, Use in Animal Food help stakeholders understand when a including amendment, GRAS notice, A. Issues in the 2010 Notice Specific to notified substance, notifier, qualified Animal Food substance is eligible for classification as GRAS in human food or animal food expert, supplement, we/our/us, and B. Criteria for Eligibility for Classification you/your; as GRAS for a Substance Intended for under the conditions of its intended use. • A clear statement of the opportunity Use in Animal Food (§ 570.30) Experience also has shown that C. Part 1 of a GRAS Notice for a Substance for any person to submit a GRAS notice; streamlining our evaluation of Intended for Use in Animal Food: Name • Information on available formats conclusions of GRAS status will enable of the Notified Substance (electronic and paper) and where to us to evaluate more, and higher priority, (§ 570.225(c)(3)) send a GRAS notice; substances. We are issuing this final • What data and other information D. Part 1 of a GRAS Notice for a Substance Intended for Use in Animal Food: rule to amend and clarify the criteria in may be incorporated into a GRAS Intended Conditions of Use our regulations for when a substance is notice; (§ 570.225(c)(4)) GRAS under the conditions of its • General provisions applicable to a E. Part 2 of a GRAS Notice for a Substance intended use in human food or animal GRAS notice; Intended for Use in Animal Food: Data food, and to replace the voluntary • Specific information you must and Information Bearing on the Physical administrative procedure for petitioning provide in your GRAS notice, including: or Other Technical Effect of the Notified us to affirm the GRAS status of a use of Æ Signed statements and a Substance (§ 570.230(d)) a substance in human food or animal F. Part 3 of a GRAS Notice for a Substance certification (Part 1); food with a voluntary administrative Æ The identity, method of Intended for Use in Animal Food: Target Animal and Human Exposures procedure for notifying us about a manufacture, specifications, and (§ 570.235) conclusion that a substance is GRAS physical or technical effect of the G. Data and Information in a GRAS Notice under the conditions of its intended use notified substance (Part 2); About Safety for the Target Animal in human food or animal food. Æ Dietary exposure (Part 3); (§ 570.250) Æ Self-limiting levels of use, in H. Data and Information in a GRAS Notice Summary of the Major Provisions of the Rule circumstances where the amount of the About the Safety for Humans Consuming notified substance that can be added to Human Food Derived From a Food- The final rule clarifies the criteria for human food or animal food is limited Producing Animal (§§ 570.235 and the use of a substance to be eligible for 570.250) because the food containing levels of the classification as GRAS and establishes a notified substance above a particular I. Filing Decision, Opportunity for a Notifier to Submit an Amendment, and new administrative procedure for any level would become unpalatable or Asking Us to Cease to Evaluate a GRAS person to notify us of the basis for a technologically impractical (Part 4); Notice for a Substance Intended for Use conclusion that a substance is GRAS Æ The history of consumption of the in Animal Food (§§ 570.260 and 570.265) under the conditions of its intended use. substance for food use by a significant J. Opportunity for a Notifier to Submit a With respect to criteria for eligibility for number of consumers (or animals in the Supplement to a GRAS Notice for a classification as GRAS, in the final rule case of animal food) prior to January 1, mstockstill on DSK3G9T082PROD with RULES2 Substance Intended for Use in Animal we clarify that: 1958, if a conclusion of GRAS status is Food (§ 570.280) • A substance cannot be classified as based on common use of the substance K. GRAS Affirmation Petitions for Substances Used in Animal Food GRAS under the conditions of its in food prior to 1958 (Part 5); XXVI. Editorial, Clarifying, and Conforming intended use if the available data and Æ A narrative that provides the basis Amendments information do not satisfy the safety for your conclusion of GRAS status, XXVII. Economic Analysis of Impacts standard for a food additive under the including why the scientific data, XXVIII. Analysis of Environmental Impact FD&C Act; information, methods, and principles VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00003 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 54962 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations described in the notice provide a basis with a potential to extend our response intended use and replaces that petition for your conclusion that the notified timeframe by another 90 days; process with a GRAS notification substance is generally recognized, • Our procedures in the event the procedure. We estimate that over 10 among qualified experts, to be safe intended conditions of use of the years with a 7 percent discount rate, the under the conditions of its intended use notified substance include use in a present value of the total costs of the (Part 6); and product subject to regulation by the final rule range from $0.9 million to Æ A list of the data and information Food Safety and Inspection Service $3.3 million; with a 3 percent discount that you discuss in the narrative of your (FSIS) of the U.S. Department of rate, the present value of the total costs GRAS notice, specifying which of these Agriculture (USDA); and range from $0.9 million to $3.4 million. data and information are generally • Provisions governing the public The annualized costs of the rule range available, and which of these data and disclosure of a GRAS notice, including from $0.1 million to $0.4 million with information are not generally available the actions we take to make some a 7 percent discount rate and range from (Part 7); and information regarding a GRAS notice $0.1 million to $0.5 million with a 3 • Process for you to submit an readily accessible to the public. percent discount rate. We do not amendment to your GRAS notice; and As of the effective date of the final quantify the benefits of the final rule, rule, we will close the docket for any but assume that firms will only • Process for you to request that we pending GRAS affirmation petition. The participate in the GRAS notification cease to evaluate your GRAS notice. petitioner may incorporate the procedure when they expect to receive With respect to our administration of applicable petition into a new GRAS a non-negative private benefit. The a GRAS notice, we specify: notice. GRAS notification procedure will allow • Information about how we will file us to complete our evaluation within a GRAS notice, respond to it, and send Costs and Benefits the timelines specified in the final rule. subsequent correspondence about it; The final rule eliminates the petition The following table includes a summary • Our commitment to respond within process to affirm that a substance is of the benefits and costs of the final 180 days of filing of a GRAS notice, GRAS under the conditions of its rule. SUMMARY OF BENEFITS AND COSTS OF THE FINAL RULE Present value of total Present value of total Total annualized costs Total annualized costs Total benefits costs with 7 percent costs with 3 percent over 10 years with 7 per- over 10 years with 3 per- discount rate ($ mil) discount rate ($ mil) cent discount rate ($ mil) cent discount rate ($ mil) Not estimated .................... $0.9 to $3.3 ....................... $0.9 to $3.4 ....................... $0.1 to $0.4 ....................... $0.1 to $0.5. TABLE OF ABBREVIATIONS AND ACRONYMS Abbreviation/acronym What it means 1958 amendment ............... 1958 Food Additives Amendment to the Federal Food, Drug, and Cosmetic Act. AAFCO ............................... Association of American Feed Control Officials. Affected petitioner .............. Any person who had submitted a pending petition. BATF .................................. Bureau of Alcohol, Tobacco, and Firearms. CFSAN ............................... Center for Food Safety and Applied Nutrition. CVM .................................... Center for Veterinary Medicine. EPA .................................... U.S. Environmental Protection Agency. FDA .................................... U.S. Food and Drug Administration. FDAMA ............................... 1997 Food and Drug Administration Modernization Act. FD&C Act ........................... Federal Food, Drug, and Cosmetic Act. FOIA ................................... Freedom of Information Act. FSIS .................................... Food Safety and Inspection Service of the U.S. Department of Agriculture. GAO .................................... Government Accountability Office. GRAS ................................. Generally Recognized as Safe. JECFA ................................ Joint Expert Committee on Food Additives. MOU ................................... Memorandum of Understanding. N/A ...................................... Not Applicable. OMB ................................... Office of Management and Budget. Pdf ...................................... Portable document format. Pending petition .................. A filed GRAS affirmation petition that is pending on the date that the petition process is replaced with a notification procedure. PHO .................................... Partially hydrogenated oil. PRA .................................... Paperwork Reduction Act. TTB ..................................... Alcohol and Tobacco Tax and Trade Bureau. USDA .................................. U.S. Department of Agriculture. mstockstill on DSK3G9T082PROD with RULES2 I. Introduction foods and food processing and with the could be used in food, its sponsor support of the food industry, Congress demonstrate the safety of the substance A. History of FDA’s Approach to the enacted the Food Additives Amendment to FDA, and that we establish a GRAS Provision of the FD&C Act (the 1958 amendment) to the FD&C Act. regulation prescribing the conditions In 1958, in response to public concern The basic thrust of the 1958 amendment under which the substance may be about the increased use of chemicals in was to require that, before a substance safely used. The 1958 amendment VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00004 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 54963 defined the terms ‘‘food additive’’ (21 their intended use. Importantly, under render an informal opinion on the U.S.C. 321(s)) and ‘‘unsafe food section 201(s) of the FD&C Act, it is the GRAS status of use of a substance. additive’’ (21 U.S.C. 348(a)), established use of a substance, rather than the Although convenient and expedient, a premarket approval process for food substance itself, that is eligible for these opinion letters were often additives (21 U.S.C. 348(b) through (g)), GRAS status. It is on the basis of the available only to the requestor. and amended the food adulteration GRAS provision within the food Moreover, these opinion letters were not provisions of the FD&C Act to deem additive definition that many binding on us even at the time they adulterated any food that is, or bears or substances (such as vinegar, vegetable were issued and letters issued before contains, any food additive that is oil, baking powder, and many spices, April 9, 1970, were in fact revoked (21 unsafe within the meaning of 21 U.S.C. flavors, gums, and preservatives) are CFR 170.6; 35 FR 5810; April 9, 1970). 348 (see 21 U.S.C. 342(a)(2)(C)). lawfully marketed today without a food In 1969 (34 FR 17063; October 21, Congress recognized that, under this additive regulation. Under the 1958 1969), we deleted various cyclamate scheme, the safety of a food additive amendment, a substance that is GRAS salts, a family of nonnutritive could not be established with absolute for a particular use may be marketed for sweeteners, from the GRAS list because certainty, and thus provided for a that use without our review and they were implicated in the formation of science-based safety standard that approval. However, when a use of a bladder tumors in rats (Ref. 2). In requires sponsors of food additives to substance does not qualify for GRAS response to the concerns raised by the demonstrate to a reasonable certainty status or other exceptions provided new information on cyclamates, then- that no harm will result from the under section 201(s) of the FD&C Act, President Nixon directed us to intended use of an additive (Ref. 1). We that use of the substance is a food reexamine the safety of GRAS have incorporated this safety standard additive use subject to the premarket substances (Ref. 3), and we announced into our regulations for food additives approval mandated by the FD&C Act. In that we were conducting a and GRAS substances (§ 170.3(i)) (21 such circumstances, we can take comprehensive study of substances CFR 170.3(i)). (We note that although enforcement action to stop distribution presumed to be GRAS (35 FR 18623; this rule addresses substances intended of the food substance and foods December 8, 1970). The purpose of the for use in animal food as well as containing it on the grounds that such study was to evaluate, by contemporary substances intended for use in human foods are or contain an unlawful food standards, the available safety food, in this introduction we describe additive. information regarding substances the history of the our GRAS regulations Shortly after passage of the 1958 presumed to be GRAS and to from the perspective of human food amendment, we clarified the regulatory promulgate each item in a new (i.e., only.) If we find an additive to be safe, status of a multitude of food substances affirmed) GRAS list, a food additive based ordinarily on data submitted by that were used in food prior to 1958 and regulation, or an interim food additive the sponsor to us in a food additive amended our regulations to include a regulation pending completion of petition, we promulgate a regulation list of food substances that, when used additional studies. specifying the conditions under which for the purposes indicated and in In the notice announcing the the additive may be safely used. accordance with good manufacturing comprehensive review of presumed In enacting the 1958 amendment, practice, are GRAS. This list was GRAS substances, we proposed criteria Congress recognized that many incorporated into our regulations as that could be used to establish whether substances intentionally added to food § 121.101(d) (21 CFR 121.101(d)) (now these substances should be listed as would not require a formal premarket part 182 (21 CFR part 182)) (24 FR 9368; GRAS, become the subject of a food review by FDA to assure their safety, November 20, 1959). As part of that additive regulation, or be listed in an either because their safety had been rulemaking, however, we acknowledged interim food additive regulation established by a long history of use in that it would be impracticable to list all pending completion of additional food or by virtue of the nature of the substances that are GRAS for their studies (35 FR 18623). These criteria substance, its customary or projected intended use (§ 121.101(a); current were incorporated into our regulations conditions of use, and the information § 182.1(a)). as § 121.3 (precursor of current § 170.30) generally available to scientists about Section 121.101(d) became commonly (36 FR 12093; June 25, 1971). the substance. Congress thus adopted, in referred to as ‘‘the GRAS list.’’ We We made a second announcement section 201(s) of the FD&C Act (21 added other categories of substances that we were conducting a study of U.S.C. 321(s)), a two-step definition of (e.g., spices, seasonings, and flavorings) presumed GRAS substances (36 FR ‘‘food additive.’’ The first step broadly to the GRAS list in subsequent 20546; October 23, 1971) and includes any substance, the intended rulemakings (25 FR 404, January 19, subsequently instituted a rulemaking to use of which results or may reasonably 1960; and 26 FR 3991, May 9, 1961). establish procedures that we could use, be expected to result, directly or Many substances that were on our own initiative, to affirm the indirectly, in its becoming a component considered GRAS by the food industry GRAS status of substances that were the or otherwise affecting the characteristics were not included in our GRAS list. subject of that review and were found to of food. The second step, however, Under the 1958 amendment, a substance satisfy the criteria established in § 121.3 excludes from the definition of ‘‘food that is GRAS under the conditions of its (proposed rule, 37 FR 6207, March 25, additive’’ substances that are generally intended use may be marketed for that 1972; final rule, 37 FR 25705, December recognized, among experts qualified by use without Agency review and 2, 1972). These procedures were scientific training and experience to approval. Nonetheless, as a practical subsequently codified at § 170.35(a) and evaluate their safety (‘‘qualified matter, manufacturers who concluded (b). Because the GRAS review did not mstockstill on DSK3G9T082PROD with RULES2 experts’’), as having been adequately on their own initiative that use of a cover all GRAS substances (e.g., it did shown through scientific procedures (or, substance qualified for GRAS status not cover many substances that were in the case of a substance used in food frequently decided to obtain our marketed based on a manufacturer’s prior to January 1, 1958, through either opinion on whether their conclusion independent conclusion of GRAS scientific procedures or through was justified. Many manufacturers status), that rulemaking included a experience based on common use in wrote to us and requested an ‘‘opinion mechanism (the GRAS affirmation food) to be safe under the conditions of letter,’’ in which Agency officials would petition process; § 170.35(c)) whereby VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00005 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 54964 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations an individual could petition us to on common use in food), as well as our Response 125, Response 128, and review the GRAS status of substances response to the notice. In 2010, we Response 129). not being considered as part of our reopened the comment period for the In 2012, we made available a draft GRAS review. We codified our proposed rule to update comments and guidance entitled ‘‘Draft Guidance for affirmations of GRAS status in current to solicit comment on specific issues (75 Industry: Assessing the Effects of parts 184 and 186 (21 CFR parts 184 and FR 81536, December 28, 2010; the 2010 Significant Manufacturing Process 186). notice). (See section II.D for additional Changes, Including Emerging In 1974, we proposed to clarify the information about this reopening of the Technologies, on the Safety and criteria for GRAS status, the differences comment period). Regulatory Status of Food Ingredients between GRAS status and food additive In the proposed rule, we invited and Food Contact Substances, Including status, and the procedures being used to interested persons to notify us about Food Ingredients That Are Color conduct the current review of food their conclusions of GRAS status as Additives’’ (Ref. 5) (77 FR 24722, April substances (39 FR 34194; September 23, described in the proposed rule (62 FR 25, 2012). We finalized this guidance in 1974). The final regulations based on 18938 at 18954; the ‘‘Interim Pilot 2014 (Ref. 6) (79 FR 36533, June 27, this proposal amended § 121.3 (now program’’). Our Center for Food Safety 2014). The guidance includes § 170.30) to distinguish a conclusion of and Applied Nutrition (CFSAN) filed its recommendations for assessing the GRAS status through scientific first GRAS notice in 1998 and has filed effect of a significant manufacturing procedures (§ 170.30(b)) from a 614 GRAS notices as of December 31, process change (including the use of conclusion of GRAS status through 2015. Our Center for Veterinary nanotechnology) on the safety and experience based on common use in Medicine (CVM) established its Interim regulatory status of substances used in food (§ 170.30(c)) (41 FR 53600; Pilot program more recently (75 FR human food, including those that are December 7, 1976). Those final 31800, June 4, 2010) and filed its first GRAS. In this guidance, we stated that, regulations also established definitions GRAS notice in December 2010. As of at present, for nanotechnology for ‘‘common use in food’’ (now applications in food substances, there December 31, 2015, CVM has filed 18 § 170.3(f)) and ‘‘scientific procedures’’ are questions related to the technical GRAS notices. (now § 170.3(h)). We subsequently evidence of safety as well as the general added criteria (§ 170.30(c)(2)) for the B. Report by the Government recognition of that safety, that are likely determination of GRAS status through Accountability Office and How We Are to be sufficient to warrant formal experience based on common use in Addressing Its Recommendations premarket review and approval by FDA, food when that use occurred exclusively rather than to satisfy criteria for GRAS or primarily outside of the United States From 2008 to 2010, the Government status. In addition, in 2011, we made (53 FR 16544; May 10, 1988). Accountability Office (GAO) conducted available a draft guidance entitled To the extent that a person elected to a study related to ingredients used in ‘‘Considering Whether an FDA- submit a GRAS affirmation petition, the human food on the basis of the GRAS Regulated Product Involves the GRAS affirmation process could provision in section 201(s) of the FD&C Application of Nanotechnology’’ (Ref. 7) facilitate awareness, by us as well as the Act. In 2010, GAO issued a report (Ref. (76 FR 34715, June 14, 2011). We domestic and international food 4; the GAO report) that included a finalized this guidance in 2014 (Ref. 8) industry, of independent conclusions of number of recommendations for FDA. (June 27, 2014, 79 FR 36534), which GRAS status. However, the GRAS For example, the GAO report describes our thinking on determining affirmation petition process involved recommended that we finalize the whether FDA-regulated products the resource-intensive rulemaking proposed rule to establish a notification involve the application of process. In the Federal Register of April program for GRAS substances, strive to nanotechnology. 17, 1997 (62 FR 18938; the proposed minimize the potential for conflict of rule), we proposed to: (1) Clarify the interest on ‘‘GRAS panels,’’ issue C. Issues Regarding the Legal and criteria for eligibility for classification as guidance on how to document GRAS Regulatory Framework for Substances GRAS; and (2) replace the GRAS conclusions, and obtain more Added to Food affirmation petition process with a information about the use of engineered The GAO report discussed issues notification procedure whereby any nanomaterials. (As we note in section fundamental to the legal and regulatory person may notify us of a conclusion VI.B, this document uses the term framework for our oversight of the safety that a particular use of a substance is ‘‘GRAS panel’’ to mean a panel of of substances added to food, such as the GRAS. We explained that we would individuals convened for the purpose of voluntary nature of the GRAS evaluate whether the notice provides a evaluating whether the available affirmation petition process and the sufficient basis for a GRAS conclusion scientific data, information, and proposed GRAS notification procedure. and whether information in the notice methods establish that a substance is In light of these issues, the GAO report or otherwise available to us raises issues safe under the conditions of its intended recommended that we ask any company that lead us to question whether use of use in food.) Consistent with the evaluating whether a substance is GRAS the substance is GRAS. We would recommendations in the GAO report, under the conditions of its intended use respond to the notifier in writing and this document finalizes the GRAS to provide us with basic information could advise the notifier that we had notification procedure as requested by about any conclusion of GRAS status identified a problem with the notice. GAO. It also announces our intent to (Ref. 4). Some comments to this Although information in a notice would issue guidance in the near future to: (1) rulemaking raise similar issues. For be publicly available consistent with the Provide recommendations regarding the example, some comments address the mstockstill on DSK3G9T082PROD with RULES2 Freedom of Information Act (FOIA), we use of a ‘‘GRAS panel,’’ including the voluntary nature of the GRAS would make readily accessible to the potential for conflict of interest; and (2) notification procedure or assert that we public a basic description the notified remind the food industry that the same have implied legal authority to require substance, the conditions of its intended standards apply to a conclusion of that companies notify us of a conclusion use, and the statutory basis for GRAS GRAS status regardless of whether the of GRAS status (see Comment 1 and status (i.e., through scientific conclusion is submitted to us as a GRAS Comment 28). Some comments ask us to procedures or through experience based notice or is not submitted to us. (See require companies to maintain active VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00006 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 54965 and accurate listings for all GRAS regulatory framework for our oversight scientific evidence establishing the substances, not just those that are the of the safety of substances added to food health risks associated with the subject of a GRAS regulation or a GRAS are outside the scope of this rulemaking. consumption of trans fat. In the Federal notice, in a public database (see Thus, this final rule does not address Register of June 17, 2015 (80 FR 34650), Comment 3). Some comments ask us to the possibility that we might enhance we issued a declaratory order require certain postmarket submissions our oversight through additional announcing our final determination that of exposure and safety data related to all rulemaking or other actions based on there is no longer a consensus among GRAS substances, to require our current legal authority. Nonetheless, qualified experts that PHOs are GRAS submissions for conclusions of GRAS we will continue to consider the broader for any use in human food. status that predate the final rule, and to issues raised by these comments and The GRAS list in part 182 includes require any notifier who ‘‘withdraws’’ a take further action as appropriate under the use of caffeine in cola-type GRAS notice or receives an ‘‘insufficient our existing authority through future beverages at a maximum level of 0.02 basis letter’’ to notify us about any use rulemaking. Importantly, however, this percent (§ 182.1180). In 2010, we issued of that substance (see Comment 30). One final rule does establish uniform criteria four warning letters regarding the use of comment asks us to exclude uses of for describing the basis for a conclusion caffeine under markedly different ‘‘novel’’ substances from consideration that a substance is GRAS under the conditions of use than the use listed in for eligibility for classification as GRAS conditions of its intended use, and those § 182.1180, i.e., the use of caffeine as an (see Comment 19). uniform criteria apply to all conclusions added ingredient in alcoholic beverages Some comments discuss an industry of GRAS status, not just conclusions of (Ref. 10 through Ref. 13). In our letters, practice of convening a ‘‘GRAS panel’’ GRAS status that are submitted to us as we stated that, based on the publicly of ‘‘qualified experts’’ to provide an a GRAS notice. As discussed in available literature, a number of opinion on whether a company’s Response 129, we are issuing a guidance qualified experts have concerns about evaluation of the available data and directed to any person who evaluates the safety of caffeinated alcoholic information support a conclusion that a whether the available data and beverages. We described these concerns, substance is safe under the conditions of information regarding the safety of a citing published literature. We further its intended use, and express concern substance under the conditions of its stated that FDA is not aware of data or that such a ‘‘GRAS panel’’ may base its intended use satisfy GRAS criteria. The other information to establish the safety opinion partly on confidential data and purpose of the guidance is to: (1) of caffeine as used in these products. information that are provided to the Remind such persons of their We therefore informed the companies GRAS panel, but not provided to us in responsibilities under the FD&C Act who were marketing these caffeinated a submitted GRAS notice (see Comment regarding a conclusion of GRAS status, alcoholic beverages that caffeine, as 10 through Comment 14, Comment 69, regardless of whether the conclusion of used in the companies’ products, is an and Comment 78). GRAS status is submitted to us as a unsafe food additive, and therefore the Some comments express concern that GRAS notice; and (2) refer such persons products are adulterated under section the GRAS notification procedure would to key resources, such as those 402(a)(2)(C) of the FD&C Act (21 U.S.C. be viewed as a ‘‘fast-track’’ option that discussed in Response 128, for 342(a)(2)(C)). (The Alcohol and Tobacco would tempt a company that should evaluating the safety of the substance Tax and Trade Bureau (TTB) also submit a food additive petition to under the conditions of its intended use notified the four companies that if we submit a GRAS notice instead (see and for evaluating whether the available deem their caffeinated alcohol beverage Comment 32). A published critique of data and information regarding safety products adulterated under the FD&C the GRAS notification procedure (Ref. 9) satisfy the criteria for eligibility for Act, TTB would consider them to be likewise expresses concern that industry classification as GRAS in § 170.30. mislabeled under the Federal Alcohol is simply using the GRAS notification Administration Act, making it a procedure as an alternative to the food D. Recent FDA Actions Related to GRAS violation for industry members to sell or additive petition process, contrasting Criteria ship the products in interstate or foreign the number of food additive petitions In the following paragraphs, we commerce (Ref. 14).) The companies filed in recent years with the number of describe two examples of steps we have subsequently ceased distribution of GRAS notices filed in recent years. This taken to address concerns about the these products. report also expresses concern that there safety of certain substances marketed In recent years, other food and are an indeterminate—but not under the GRAS provision. The first beverage products containing caffeine as insignificant—number of industry example is partially hydrogenated oils an added substance have been conclusions of GRAS status that are not (PHOs), which are the primary dietary introduced into the marketplace, the subject of a GRAS notice to FDA. source of industrially produced trans including so-called ‘‘energy drinks’’ that In this document, we respond to such fatty acids, or trans fat. The second are frequently marketed for their comments in the context of our example is certain uses of caffeine. stimulant properties. When there are proposed revisions to the criteria for Although we had not listed the most new uses of an added food substance eligibility for classification as GRAS and commonly used PHOs in either part 182 without FDA’s premarket engagement, our proposal to replace one voluntary or part 184, they had been used in food presumably because a manufacturer has administrative procedure, i.e., the GRAS for many years based on conclusions of concluded that such a use is GRAS, we affirmation petition process, with a GRAS status by industry. In a notice must react to the new uses after they different voluntary administrative published in the Federal Register of emerge. In such cases, it can be procedure, i.e., the GRAS notification November 8, 2013 (78 FR 67169), we challenging for FDA to accurately assess mstockstill on DSK3G9T082PROD with RULES2 procedure. (See Response 1, Response 3, described new scientific evidence and consumption patterns and intake levels Response 10 through Response 14, the findings of expert scientific panels and to determine whether those new Response 19, Response 28, Response 30, regarding trans fat and requested uses are safe and lawful in light of all Response 32, Response 69, and comments and scientific data and of the available safety data. FDA has Response 78). As we discuss in information on our tentative engaged with the National Academies of Response 28, the broader issues raised determination that PHOs are not GRAS Science (Ref. 15), trade associations, and by these comments about the legal and for any use in food based on current other industry representatives, some of VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00007 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 54966 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations whom are conducting a systematic appropriate and regarding the design, information, or methods, which review on the health effects associated conduct, and reporting of the results of ordinarily are published, as well as the with the consumption of caffeine (Ref. toxicity studies and applies to assessing application of scientific principles 16 and Ref. 17). the safety of GRAS substances. As (§ 170.30(b)). Although general discussed in section I.D, we also have recognition of safety through scientific E. Moving Forward Under This Final taken key postmarket actions such as procedures may be corroborated by the Rule issuing a declaratory order announcing application of unpublished scientific We believe that our filing of more our final determination that there is no data, information, or methods than 600 GRAS notices for substances longer a consensus among qualified (§ 170.30(b)), to satisfy GRAS criteria used in human food is evidence that the experts that PHOs are GRAS for any use qualified experts must be able to substitution of a GRAS notification in human food, as well as issuing conclude that the substance is not procedure for the GRAS affirmation warning letters regarding the use of harmful under the conditions of its petition process has benefits for caffeine as an added ingredient in intended use without access to consumers, FDA, the regulated industry, alcoholic beverages. ‘‘corroborative’’ information (see, e.g., and other stakeholders. We have For reasons such as those discussed in Response 9). For example, as discussed increased our awareness of the this section, and after fully considering in Response 69 there could be no basis composition of the nation’s food supply comments submitted to this rulemaking, for a conclusion of GRAS status if trade and the dietary exposure to GRAS this rule announces that we are secret information (or other non-public substances, which helps us to ensure replacing the former GRAS affirmation information) is necessary for qualified the safe use of substances added to food. petition process with a GRAS experts to reach a conclusion that the The ongoing submission of GRAS notification procedure. notified substance is safe under the notices provides evidence that our We strongly encourage any company conditions of its intended use. response to a GRAS notice can support considering the addition of a substance the marketing of a food substance by the to any food on the basis of a conclusion We also advise any company who regulated industry. Notified substances of GRAS status to contact us and follow intends to market a food substance on include substances that are intended to the available procedures for FDA the basis of an independent GRAS address food safety problems (e.g., oversight of such decisions. As we move conclusion that relies, in whole or in antimicrobial substances and substances forward to implement the GRAS part, on the opinion of a specially intended to reduce acrylamide notification procedure that is the subject convened ‘‘GRAS panel’’ to carefully formation) and public health issues of this rulemaking, we intend to review the discussions in this document (e.g., substances that would reduce continue to closely monitor and assess regarding whether and how the opinion levels of sodium chloride in food). In the ramifications of the use of of a GRAS panel can support an addition, the letters we issue responding substances without food additive independent conclusion of GRAS status. to GRAS notices demonstrate that we approval or evaluation by FDA through For example, as discussed in Response inform notifiers of any scientific or the GRAS notification procedure. We 10 and Response 11 whether a regulatory issues that call into question intend to take action as appropriate, published ‘‘GRAS panel’’ opinion that a notifier’s conclusion of GRAS status, such as we did in the case of PHOs and discusses data and information that are and stakeholders have ready access to caffeinated alcoholic beverages, available to the members of the GRAS those letters. As discussed in Response particularly when the available data and panel, but not generally available to 81, we intend to increase the information raise a safety concern about qualified experts, could support an transparency of our response letters the use of a substance. independent conclusion of GRAS status when a notifier asks us to cease to We advise any company that intends would depend on factors such as evaluate a GRAS notice. to market a food substance on the basis whether that publication includes In the years since we published the of an independent conclusion of GRAS details similar to details that would be proposed rule, we have taken important status (i.e., a conclusion of GRAS status included in a publication in the primary public health actions with respect to that would remain with the proponent scientific literature; the subject matter substances used in food on the basis of of the conclusion rather than be expertise of the members of the GRAS the GRAS provision of the FD&C Act. submitted to us as a GRAS notice) to panel; and whether the members of the For example, we recently announced an carefully consider whether this use fully GRAS panel would be considered initiative to establish voluntary short- satisfies the criteria for eligibility for representative of experts qualified by term and long-term goals for sodium classification as GRAS and to carefully scientific training and experience to reduction in a variety of identified review the discussions in this document evaluate the safety of the substance categories of foods to address the relevant to those criteria. Fundamental under the conditions of its intended use. excessive intake of sodium in the to all conclusions of GRAS status is the For example, a published GRAS panel current population and promote criterion that general recognition of opinion that includes a very general improvements in public health (81 FR safety requires common knowledge statement that a study was conducted 35363, June 2, 2016). In addition, we throughout the scientific community and reported no adverse findings would recently held a public meeting in which knowledgeable about the safety of not suffice to make the study ‘‘generally we invited public comment on what substances directly or indirectly added available’’ as required by the criteria for should be included, changed, or even to food that there is reasonable certainty eligibility for classification as GRAS and excluded from our guidance entitled that the substance is not harmful under would merely be a generally available ‘‘Guidance for Industry and Other the conditions of its intended use (see opinion about data and information that mstockstill on DSK3G9T082PROD with RULES2 Stakeholders: Toxicological Principles § 170.30(a)). In addition, the criteria for are not generally available. As another for the Safety Assessment of Food eligibility for classification as GRAS example, a ‘‘GRAS panel’’ opinion Ingredients’’ (79 FR 64603, October 30, through scientific procedures require published by scientists without 2014); that guidance is intended to help that general recognition of safety expertise appropriate to address the interested parties understand our through scientific procedures be based applicable safety questions could not expectations regarding how to upon the application of generally provide evidence that the conclusions determine which toxicity studies are available and accepted scientific data, in the publication are ‘‘generally VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00008 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 54967 accepted.’’ Unless both criteria, i.e., knowledge element’’ of the GRAS use of a substance is GRAS to notify us ‘‘generally available’’ as well as standard (i.e., general recognition) (62 of those determinations as described in ‘‘generally accepted’’, are satisfied, there FR 18938 at 18940 to 18941); the proposed rule (62 FR 18938 at would be no basis for a conclusion of • Proposed the submission 18954). We explained that we would GRAS status. requirements for the GRAS notification administer the notices as described in procedure, including: (1) A ‘‘GRAS the proposed rule (i.e., we would II. Background exemption claim,’’ in which a notifier acknowledge receipt of the notice, A. The Proposed Rule would take responsibility for a GRAS respond in writing to the notifier, and determination; (2) information about the We proposed to: (1) Clarify the criteria make publicly accessible a copy of all identity of the notified substance; (3) for eligibility for classification as GRAS; ‘‘GRAS exemption claims’’ and our information about any self-limiting and (2) replace the GRAS affirmation response). Although we would make a levels of use; and (4) a comprehensive petition process with a notification good faith effort to respond within the discussion of the basis for the GRAS procedure through which any interested proposed 90-day timeframe, we would determination (proposed §§ 170.36 (c) person may notify us of a determination not be bound by such a timeframe. We and 570.36(c)); that a particular use of a substance is • Proposed what we would do when stated that we would determine whether GRAS (62 FR 18938). In the proposed we received a GRAS notice, including: our experience in administering such rule, we: (1) Acknowledge receipt of the GRAS notices suggests modifications to the • Discussed the 1958 amendment, notice; (2) evaluate whether the notice proposed procedure. including judicial decisions bearing on provides a sufficient basis for a GRAS GRAS criteria and the burden on the CFSAN received its first GRAS notice determination and respond to the in 1998. CFSAN wrote a memorandum proponent of a conclusion of GRAS notifier in writing; (3) make readily status to show that there is a consensus documenting its experience in accessible to the public the notice’s of expert opinion regarding the safety of evaluating GRAS notices during the ‘‘GRAS exemption claim’’ and our the use of the substance (62 FR 18938 period 1998–2009 (Ref. 18, ‘‘CFSAN’s response to the notice; and (4) disclose at 18939); other releasable information in a notice 2010 experience document’’) and added • Described the history of our in accordance with our regulations, in that memorandum to the docket for this approach to the GRAS provision, part 20 (21 CFR part 20), implementing rulemaking in 2010. Unless we say including: (1) A GRAS list, first the FOIA (proposed §§ 170.36 (d) otherwise, the discussions in this established in 1959, in which we through (f) and 570.36(d) through (f)); document referring to FDA’s experience clarified the regulatory status of a and during the Interim Pilot program refer to multitude of food substances that were • Proposed to: (1) Convert any GRAS CFSAN’s experience. used in food prior to 1958; (2) opinion affirmation petition that was pending on During the Interim Pilot program, letters in which Agency officials the effective date of the rule establishing rendered an informal, non-binding CFSAN’s response to a GRAS notice fell the notification procedure to a GRAS into three categories as shown in table opinion on the GRAS status of a use of notice; and (2) require the petitioner to a substance; (3) an FDA-initiated GRAS 1 in this document. We refer to these submit an amendment to the converted categories of response throughout this review to evaluate the available safety petition to satisfy the procedural information regarding substances document. Table 1 in CFSAN’s 2010 requirements of the GRAS notification presumed to be GRAS; and (4) GRAS experience document shows the procedure (proposed §§ 170.36(g) and criteria and the GRAS affirmation category of response for CFSAN’s GRAS 570.36(g)). petition process (62 FR 18938 at 18939 We requested comments on the notices that came to closure by to 18940); proposed rule by July 16, 1997. December 31, 2009. CFSAN has now • Discussed ‘‘elements of the GRAS written an updated memorandum standard,’’ in which we distinguished B. Interim Pilot Program showing the category of response for the ‘‘technical element’’ of the GRAS In the proposed rule, we invited CFSAN’s GRAS notices that came to standard (i.e., safety) from the ‘‘common interested persons who determine that a closure by December 31, 2015 (Ref. 19). TABLE 1—CATEGORIES OF LETTERS RESPONDING TO A GRAS NOTICE DURING THE INTERIM PILOT PROGRAM Category of response letter Typical text of the response ‘‘No questions letter’’ ....................... Based on the information provided by the notifier, as well as other information available to FDA, the Agen- cy has no questions at this time regarding the notifier’s conclusion that the notified substance is GRAS under the intended conditions of use. The Agency has not, however, made its own determination regard- ing the GRAS status of the subject use of the notified substance. As always, it is the continuing respon- sibility of the notifier to ensure that food ingredients that the firm markets are safe, and are otherwise in compliance with all applicable legal and regulatory requirements. ‘‘Insufficient basis letter’’ ................. FDA has evaluated the information that the notifier discusses in its GRAS notice as well as other data and information that are available to us. The notice does not provide a sufficient basis for a determination that the notified substance is GRAS under the conditions of its intended use. ‘‘Cease to evaluate letter’’ .............. In correspondence dated [month, day, year], you asked that we cease to evaluate your notice. We ceased to evaluate your GRAS notice, effective the date we received your correspondence. mstockstill on DSK3G9T082PROD with RULES2 In this document, we frequently cite of the rule, as well as state our intent to Nonetheless, we intend to adapt our CFSAN’s experience during the Interim continue the applicable practice in the practices, consistent with the provisions Pilot program when responding to future, because this experience is of this rule, as circumstances warrant comments asking us to clarify how we relevant to our administration of the and as necessary to administer the intend to administer various provisions GRAS notification program. GRAS notification program consistent VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00009 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 54968 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations with appropriate public health policy, during the Interim Pilot program, another example, one comment asks us current scientific information, our comments we received on the proposed to prepare an alphabetical index of food available resources, and the scientific rule, and GAO’s recommendations (75 additive and GRAS regulations and cites and regulatory issues raised by specific FR 81536 at 81537). These issues related the alphabetical list in our GRAS notices. For example, as to the proposed revisions to the criteria Investigations Operations Manual as discussed in Response 92 we intend to for eligibility for classification as GRAS evidence that it is feasible to develop continue to include standard language (Issue 1), the proposed establishment of such a list. Regardless of whether it is such as that shown in table 1 in a notification procedure (Issues 2 feasible to develop such a list, doing so responding to GRAS notices. However, through 16), and the effect of the is not within the scope of our proposal this language may evolve over time. proposed notification procedure on to establish a notification procedure for CVM established its Interim Pilot existing GRAS affirmation petitions uses of substances that are not listed in program in June, 2010 (75 FR 31800, (Issue 17). Accordingly, we requested our regulations. We do not discuss such Docket No. FDA–2010–N–0215) and comments, by March 28, 2011, on the comments in this document. filed its first GRAS notice in December entire proposed rule as well as on the 2010. CVM did not have any experience specific issues identified in the 2010 F. Applicability of Discussions in This to document as of 2010 and, thus, had notice. Document to Both the Human Food not written its own experience In Issue 2 in the 2010 notice, we Regulations and the Animal Food document at that time. As of December explained our reasons for tentatively Regulations 31, 2015, CVM had responded to 18 concluding that the terms ‘‘conclude’’ To simplify the discussion in this GRAS notices, and has now and ‘‘conclusion’’ would be more document, in general we refer to documented its experience with those appropriate in lieu of ‘‘determine’’ and provisions of the proposed rule and the 18 GRAS notices with respect to some ‘‘determination’’ and requested 2010 notice from the perspective of the comments specifically directed to the comment on these terms. In the regulations that would be established in GRAS notification procedure remainder of this document, we part 170. Unless we say otherwise, administered by CVM (Ref. 20; ‘‘CVM’s generally use the terms ‘‘conclude’’ and however, the issues discussed also experience document’’). We discuss ‘‘conclusion’’ in lieu of ‘‘determine’’ and apply to the corresponding provisions CVM’s experience with GRAS notices ‘‘determination’’ except when we are for part 570. Any reference to CFSAN submitted for substances intended for describing provisions of the proposed documents (such as guidance use in animal food in section XXV. rule (see Response 41). documents) is specific to CFSAN. See We are ending both the CFSAN E. Public Comments section XXV for a discussion of Interim Pilot program announced in the comments and issues specifically proposed rule, and the CVM pilot We received submissions, each containing one or more comments, from directed to substances used in animal program announced in Docket No. food. FDA–2010–N–0215, as of October 17, diverse members of the public, 2016. On that date, the final rule including manufacturers; trade G. Use of Pronouns in This Document becomes effective and will govern the organizations; consulting firms; law firms; public advocacy groups; non- In this document, terms such as ‘‘we,’’ GRAS notification procedure. profit organizations; individuals; a ‘‘our,’’ and ‘‘us’’ refer to FDA. The C. 2010 Report of the Government Federal Agency; and other regulatory text of the final rule for the Accountability Office organizations. In the remainder of this GRAS notification procedure specifies As noted in section I.B, from 2008 to document, we describe these comments, that the terms ‘‘you’’ and ‘‘your’’ refer to 2010 GAO conducted a study related to respond to them, and explain any a notifier (i.e., a person who is ingredients used in human food on the revisions we made to the proposed rule. responsible for a GRAS notice). To basis of the GRAS provision of section Some comments address issues that simplify the discussion in this 201(s) of the FD&C Act. In 2010, GAO are outside the scope of this rule. For document, in general we use pronouns issued a report (Ref. 4) that included a example, some comments ask us to add such as ‘‘you’’ and ‘‘your’’ to refer to a number of recommendations for FDA. a new definition to part 170, to define notifier, even though some persons who We responded to the GAO’s the term ‘‘harm’’ that is used in our read this document may not be notifiers. recommendations, and that response is current definition of ‘‘safe’’ or ‘‘safety’’ H. Summary of Principal Changes to the also included in the GAO report. (§ 170.3(e)(i)) (where ‘‘safe’’ or ‘‘safety’’ Proposed Notification Procedure means that there is a reasonable D. 2010 Notice Reopening the Comment certainty in the minds of competent In table 2, we briefly describe the Period scientists that the substance is not principal changes to the GRAS As noted in section I.A, we reopened harmful under the intended conditions notification procedure in the final rule the comment period for the proposed of use). We did not propose to add a compared to the proposed rule. In the rule to update comments (75 FR 81536). definition of the term ‘‘harm’’ or ask for remainder of this document, we discuss We did so because of the length of time comment on whether we should do so, each of these changes in more detail, that had elapsed since publication of the and adding a new definition in the final including our response to comments proposed rule and because we had rule for a term that is used in the relevant to these changes. See table 28 identified a number of issues within the definition of ‘‘safe’’ and ‘‘safety’’ would for principal changes that are specific to scope of the proposed rule that may broadly affect our regulations for food the GRAS notification procedure for require further clarification based on additives and GRAS substances without substances used in animal food in part mstockstill on DSK3G9T082PROD with RULES2 CFSAN’s experience with GRAS notices opportunity for public comment. As 570. VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00010 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 54969 TABLE 2—SUMMARY OF PRINCIPAL CHANGES TO THE PROPOSED NOTIFICATION PROCEDURE Proposed rule Final rule Would not define any terms ..................................................................... Defines the terms ‘‘amendment,’’ ‘‘GRAS,’’ ‘‘GRAS notice,’’ ‘‘notified substance,’’ ‘‘notifier,’’ ‘‘qualified expert,’’ ‘‘supplement,’’ ‘‘we, our, and us,’’ and ‘‘you and your.’’ Referred to a ‘‘GRAS determination’’ ....................................................... Refers to a ‘‘GRAS conclusion’’ or ‘‘conclusion of GRAS status.’’ Referred to the statutory GRAS provision as an ‘‘exemption’’ ................ Refers to the statutory GRAS provision as an ‘‘exclusion.’’ Would not use ‘‘Plain Language’’ techniques as outlined in a Presi- Uses ‘‘Plain Language’’ techniques such as pronouns and short regu- dential Memorandum dated June 1, 1998 (Ref. 21) and in ‘‘Improving latory sections. Electronic Dockets on Regulations.gov and the Federal Docket Man- agement System: Best Practices for Federal Agencies’’ (Ref. 22). Was silent on whether you could incorporate into your GRAS notice Expressly provides for you to incorporate into your GRAS notice spe- specifically identified data and information previously submitted to cifically identified data and information previously submitted to CFSAN or CVM. CFSAN or CVM. Would not specify individual parts of a GRAS notice .............................. Specifies the seven parts of a GRAS notice. Would require three paper copies of a GRAS notice .............................. Provides that you may submit a GRAS notice either in electronic for- mat that is accessible for our evaluation or on paper. If you send your GRAS notice on paper, a single paper copy is sufficient. Referred to dated and signed statements in a GRAS notice as a Refers to dated and signed statements in a GRAS notice as ‘‘signed ‘‘claim’’. statements.’’ Assumed that a notice will not contain any information that is protected Specifies that you must not include any information that is trade secret from public disclosure under the FOIA. or confidential commercial information in certain sections of the signed statements in your GRAS notice, but does not otherwise pro- hibit the submission of information that is protected from public dis- closure under the FOIA. Would require that you inform us of the ‘‘common or usual name’’ of Requires that you provide an ‘‘appropriately descriptive term’’ for the the notified substance. notified substance. Would not require that you state your view as to whether any data and Requires that you state your view as to whether any of the data and in- information in your GRAS notice are exempt from disclosure under formation in your GRAS notice are exempt from disclosure under the the FOIA. FOIA (e.g., as trade secret or as commercial or financial information that is privileged or confidential). Would not expressly require a signed certification regarding the rep- Expressly requires a signed certification that to the best of your knowl- resentative and balanced nature of the GRAS notice. edge, your GRAS notice is a complete, representative, and balanced submission that includes unfavorable information, as well as favor- able information, known to you and pertinent to the evaluation of the safety and GRAS status of the use of the substance. For a notified substance of natural biological origin, would require For a notified substance of natural biological origin, requires source in- source information such as genus and species. formation that includes applicable data and information at the sub- species level (e.g., variety, strain) in addition to genus and species. Would require the method of manufacture (excluding any trade secrets) Requires a description of the method of manufacture of the notified substance in sufficient detail to evaluate the safety of the notified substance as manufactured; you may include trade secret informa- tion. Would not expressly require relevant data and information bearing on When necessary to demonstrate safety, expressly requires relevant the physical or other technical effect the notified substance is in- data and information bearing on the physical or other technical effect tended to produce. the notified substance is intended to produce, including the quantity of the notified substance required to produce such effect. Would require consideration of dietary exposure as part of a com- Separates the statutory language of section 409(c)(5)(A) and (B) of the prehensive discussion of the data and information that you rely on to FD&C Act into two distinct parts of the GRAS notice: (1) Part 3, establish safety, using the statutory language of section 409(c)(5)(A) which addresses how much of the notified substance consumers and (B) of the FD&C Act. would eat as part of the total diet (including exposure from its in- tended use and all sources in the diet), as well as how much con- sumers would eat of other substances (e.g., contaminants or by- products); and (2) Part 6, which requires that you address, in your narrative, the safety of the notified substance, considering all dietary sources and taking into account any chemically or pharmacologically related substances in such diet. Would require a ‘‘comprehensive discussion’’ of, and citations to, gen- Requires a narrative (Part 6 of a GRAS notice) and a list of supporting erally available and accepted scientific data, information, methods, or data and information (Part 7 of a GRAS notice). principles that you rely on to establish safety. Would not require consideration of dietary exposure as part of a com- Expressly requires consideration of dietary exposure, regardless of prehensive discussion of the data and information that you rely on to whether your conclusion of GRAS status is through scientific proce- establish safety for a conclusion of GRAS status through experience dures or through experience based on common use in food. based on common use in food. Would require a comprehensive discussion of any reports of investiga- Requires that you either: (1) Identify, discuss, and place in context, mstockstill on DSK3G9T082PROD with RULES2 tions or other information that may appear to be inconsistent with the data and information that are, or may appear to be, inconsistent with GRAS determination. your conclusion of GRAS status; or (2) state that you have reviewed the available data and information and are not aware of any data and information that are, or may appear to be, inconsistent with your conclusion of GRAS status. Would not require that you identify data and information that you view If you view any of the data and information in your notice as exempt as exempt from disclosure under the FOIA. from disclosure under the FOIA, requires that you identify the spe- cific data and information. VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00011 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 54970 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations TABLE 2—SUMMARY OF PRINCIPAL CHANGES TO THE PROPOSED NOTIFICATION PROCEDURE—Continued Proposed rule Final rule Would not require that you explain how there could be a basis for a Requires that you explain how there could be a basis for a conclusion conclusion of GRAS status if qualified experts generally do not have of GRAS status if qualified experts generally do not have access to access to non-public, safety-related data and information. non-public, safety-related data and information. Would require that the comprehensive discussion include the basis for Uses the term ‘‘generally recognized’’ rather than the term ‘‘con- concluding that there is consensus among qualified experts that sensus.’’ there is reasonable certainty that the substance is not harmful under the intended conditions of use. Was silent on whether you could submit an amendment to a GRAS no- Expressly provides for you to submit a timely ‘‘amendment’’ to a GRAS tice. notice before we respond to your GRAS notice or cease to evaluate your GRAS notice. Considered that it was implicit that you could ask us to cease to evalu- Expressly provides that you may ask us to cease to evaluate your ate a GRAS notice. GRAS notice, and expressly provides that we will inform you of our decision regarding your request. We would acknowledge receipt of a GRAS notice within 30 days of re- We will conduct an initial evaluation of your submission to determine ceipt. whether to file it as a GRAS notice for evaluation of your view that the notified substance is GRAS under the conditions of its intended use. If we file your submission as a GRAS notice, we will send you a letter that informs you of the date of filing. If we do not file your sub- mission as a GRAS notice, we will send you a letter that informs you of that fact and provides our reasons for not filing the submission as a GRAS notice. We would respond to you in writing within 90 days of receipt of the no- Within 180 days of filing, we will respond to you by letter based on our tice. evaluation of your notice. We may extend the 180 day timeframe by 90 days on an as needed basis. If we extend the timeframe, we will inform you of the extension as soon as practicable but no later than within 180 days of filing. Was silent on procedures that apply when the intended conditions of Specifies procedures that apply when the intended conditions of use of use of a notified substance include use in a product or products sub- a notified substance in human food include use in a product or prod- ject to regulation by USDA’s FSIS. ucts subject to regulation by USDA’s FSIS. We noted that, although the decision to submit a GRAS notice would The regulatory text of the final rule specifies that the data and informa- be voluntary, the provisions governing the GRAS notification proce- tion in a GRAS notice are considered a mandatory, rather than vol- dure, including the information to be submitted, would be mandatory. untary, submission for purposes of its status under the FOIA and our public information requirements in part 20. Was silent on whether you could submit additional information to a Expressly provides for you to submit a ‘‘supplement’’ to a GRAS notice GRAS notice after we respond to it. after we respond to your GRAS notice or cease to evaluate it. Would presumptively convert any filed, pending GRAS affirmation peti- On the effective date of the rule, we will close the docket for any tion to a notice on the effective date of the rule. If we did not receive GRAS affirmation petition that is still pending. Any person who sub- an amendment from the petitioner within 90 days of the effective mitted a GRAS affirmation petition that is closed may submit a date of the rule, with information and statements analogous to those GRAS notice and request that we incorporate the GRAS affirmation in the proposed ‘‘GRAS exemption claim,’’ we would consider the petition. converted petition to be inadequate as a notice and would send the petitioner a letter to that effect.. III. Legal Authority of the FD&C Act) be approved by FDA of the GRAS criteria and provide a more We are amending our regulations in before they are marketed (sections efficient procedure. 21 CFR parts 170 and 570 to replace the 402(a)(2)(C) and 409 of the FD&C Act). As an error, the authority citation that voluntary GRAS affirmation petition Section 201(s) excludes from the we listed for the proposed amendments process with a voluntary GRAS definition of a food additive a substance to part 570 did not include an existing notification procedure and to clarify generally recognized, among experts authority citation, i.e., section 408 of the when the intended conditions of use of qualified by scientific training and FD&C Act (21 U.S.C. 346a). Nothing in a substance are eligible for classification experience to evaluate its safety, as the proposed rule would alter the as GRAS under our authority in sections having been adequately shown through citation to section 408. Therefore, the 201, 402, 409, and 701 of the FD&C Act scientific procedures (or, in the case of authority citation for 21 CFR part 570 (21 U.S.C. 321, 342, 348, and 371). a substance used in food prior to continues to include section 408. Section 701(a) of the FD&C Act January 1, 1958, through either As an error, the authority citation that authorizes the Secretary of the scientific procedures or experience we listed for the proposed amendments Department of Health and Human based on common use in food) to be safe to part 170 stated that we were revising Services (the Secretary) to issue under the conditions of its intended use. the authority citation. Nothing in the regulations for the efficient These regulations will help FDA proposed rule would alter the authority administration of the FD&C Act; under administer efficiently the FD&C Act’s citation for part 170. Therefore, the mstockstill on DSK3G9T082PROD with RULES2 section 1003(d) of the FD&C Act (21 various provisions that apply to the use authority citation for 21 CFR part 170 U.S.C. 393(d)), the Secretary is of substances added to food, specifically states that the authority citation responsible for executing the FD&C Act, on the question of whether a substance ‘‘continues to read’’ rather than ‘‘is including section 701(a), through the is GRAS under the conditions of its revised to read.’’ Commissioner of Food and Drugs. The intended use or is a food additive (Comment 1) Some comments state FD&C Act requires that all food subject to FDA’s premarket review. that the proposed rule violates the 1958 additives (as defined by section 201(s) These regulations provide clarification amendment because FDA would not be VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00012 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 54971 fulfilling its statutory duty to oversee on common use in food). In the past, available letters responding to GRAS food additives, and, therefore, FDA’s outside parties who have accessed this notices. interpretation of the GRAS provision is information have made us aware of (Comment 5) One comment notes that arbitrary and capricious. The comments dissenting views about whether the experience highlighted in CFSAN’s state that the proposed rule violates the available data and information support experience document (Ref. 18) can 1958 amendment because it would not a conclusion that a notified substance is provide valuable learning that can be of require companies to notify FDA of a safe under the conditions of its intended benefit to CVM and asks CFSAN and conclusion that the use of a substance use (see sections III.C.2, III.E, and III.I.1 CVM to strive for harmonization of their is GRAS. One comment states that in CFSAN’s 2010 experience document) requirements and policies in all areas, without mandatory submissions FDA (Ref. 18). We continue to welcome so the process is not more stringent for lacks a ‘‘comprehensive catalog’’ of such substantive information from one industry than the other. substances and their dietary exposure, stakeholders regarding the safety of a (Response 5) We agree that CFSAN and therefore cannot ‘‘police the border notified substance. We advise and CVM can learn from each other’s between food additives and GRAS stakeholders who wish to provide us experience with the implementation of substances’’ and that FDA and food with such substantive information to the GRAS notification procedure and manufacturers do not have access to submit it to the same address where a that procedural and scientific accurate exposure data and cannot notifier would send a GRAS notice and requirements should be consistent as assess the cumulative effect of similar ask us to add it to the administrative file much as is feasible and appropriate. As substances. The comment further states for the applicable GRAS notice. This noted in section II.B, CVM has now that because the proposed rule administrative file is maintained by the documented its experience with 18 ‘‘establishes no real oversight over the responsible Center (i.e., CFSAN or GRAS notices with respect to some safety of GRAS substances’’ it violates CVM). We would consider the comments specifically directed to the the 1958 amendment. submitted information, along with other GRAS notification procedure (Response 1) We disagree that the information that is available to us, on a administered by CVM (Ref. 20). voluntary nature of the GRAS (Comment 6) One comment urges case-by-case basis. notification procedure violates the 1958 CFSAN and CVM to put forth similar (Comment 3) One comment asks us to amendment. The FD&C Act provides for training and resources for staff assigned require companies to maintain active premarket review by FDA of a food to evaluate GRAS notices to decrease and accurate registrations for GRAS additive, and excludes from this review the time necessary to complete the substances in a public database. evaluation of a GRAS notice. any substance that is generally (Response 3) We decline this request. (Response 6) We staff, equip, and recognized, among qualified experts, to This comment is suggesting a process train our employees consistent with our be safe under the conditions of its not within our regulatory framework priorities and budgets, which are intended use. Although the FD&C Act and does not provide a legal basis specific to each Center. As a practical specifically provides for our review of whereby we could require companies to matter, our current organizational food additives, it is silent with respect maintain registrations in a public framework, in which CFSAN and CVM to industry submissions to us on the use database for substances that are used in are both components of the Office of of GRAS substances. To administer the food on the basis of the GRAS provision Foods and Veterinary Medicine, provisions of the FD&C Act with respect in section 201(s) of the FD&C Act. We promotes interactions between staff in to the use of GRAS substances, we are retaining the voluntary nature of the note, however, that the final rule the two Centers. GRAS administrative procedure. This provides a framework for making the GRAS notices, and our responses to V. Comments on the Definition of rule replaces one longstanding Scientific Procedures voluntary administrative procedure these notices, available to the public. with a different voluntary (Comment 4) One comment asks us to We proposed to amend the definition administrative procedure. specify whether the notified substance of ‘‘scientific procedures’’ to specify that would be for human or animal scientific procedures include scientific IV. General Comments on the Proposed consumption. Another comment notes data (such as human, animal, analytical, Rule that specifying whether the notified or other scientific studies), information, (Comment 2) One comment states that substance is intended for human or methods, and principles, whether the rule does not give consumers an animal consumption is important published or unpublished, appropriate opportunity to participate in the process because food for humans is not to establish the safety of a substance. In before a substance is used in food. necessarily appropriate for animals and the 2010 notice, we described comments Another comment asserts that the lack vice versa. relevant to this proposed amendment, of an opportunity for public comment or (Response 4) We agree with these including comments that support it and participation is a ‘‘major flaw’’ in the comments. This rule establishes a comment that objected to it because, rule. requirements for a GRAS notice about under the proposed amendment, an (Response 2) We disagree that the the intended use of a notified substance ‘‘unpublished principle’’ could GRAS notification procedure does not in human food in part 170 and inappropriately be considered a allow for public participation. We establishes separate requirements for a sufficient scientific procedure for proactively disclose to the public GRAS notice about the intended use of demonstrating the safety of a food information about each GRAS notice a notified substance in animal food in substance. We also noted that we had that we have filed for evaluation, part 570. Regardless of whether the reviewed our use of the term ‘‘study’’ in mstockstill on DSK3G9T082PROD with RULES2 including the name and address of the notified substance would be used in the proposed companion change to the notifier; the name of the notified human food or in animal food, the definition of scientific procedures and substance; the intended conditions of notifier must specify the intended explained our view that, to be a use of the notified substance; and the conditions of use (see §§ 170.225(c)(4) ‘‘procedure,’’ data, information, statutory basis for the conclusion of and 570.225(c)(4)). As discussed in methods, or principles would need to be GRAS status (i.e., through scientific Response 90, we include the intended acquired or applied. We stated that we procedures or through experience based conditions of use in our publicly were considering whether to revise the VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00013 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 54972 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations definition of scientific procedures in fundamental cause or basis of GRAS for use of a substance in human § 170.3(h) to include the application of something; a primary element, force, or food as proposed, with the modification scientific data (including, as law determining a particular result; or a we described in the 2010 notice and appropriate, data from human, animal, fundamental truth or proposition on with editorial, clarifying, and analytical, and other scientific studies), which others depend. Thus, a principle conforming changes as shown in table information, and methods, whether is a different genre than data, 29. See section XXV.B for a description published or unpublished, as well as the information, and methods. Therefore, of additional changes we made to the application of scientific principles, although we agree that ‘‘scientific criteria for eligibility for classification as appropriate to establish the safety of a procedures’’ encompass consideration GRAS for use of a substance in animal substance (see Issue 1, 75 FR 81536 at of both the data supporting the safety of food. 81537–81538). We requested comment the substance and the probable dietary A. General Criteria for Eligibility for on this issue. exposure, we disagree that the data Several comments support the Classification as GRAS supporting the safety of the substance proposed amendment to the definition and the probable dietary exposure are We proposed to revise the final of scientific procedures as described in ‘‘scientific principles.’’ sentence of § 170.30(a) to specify that the proposed rule, with the potential general recognition of safety requires modifications described in the 2010 VI. Comments on the Criteria for common knowledge throughout the notice, because the revised definition Eligibility for Classification as GRAS scientific community knowledgeable would more accurately reflect the state Section 170.30 specifies three types of about the safety of substances directly or of contemporary science than the criteria for eligibility for classification as indirectly added to food that there is definition it would replace. Some GRAS: (1) General criteria; (2) criteria reasonable certainty that the substance comments express the view that for classification as GRAS through is not harmful under the intended specifying that it is ‘‘the application’’ of scientific procedures; and (3) criteria for conditions of use. As discussed in the unpublished scientific data, classification as GRAS through proposed rule, we proposed this information, or methods that would experience based on common use in revision to clarify that the safety corroborate GRAS status would make it food. We proposed to amend all three standard for a GRAS substance is clear that a submission to us regarding criteria to: (1) Clarify that the safety identical to the safety standard for food a conclusion of GRAS status may standard for a GRAS substance is additives (see § 170.3(i)) and that a include discussions of unpublished identical to the safety standard for a GRAS substance is neither more safe, studies. In the following paragraphs, we food additive; (2) clarify the types of nor less safe, than an approved food discuss comments that suggest technical evidence of safety that could additive (62 FR 18938 at 18942). We additional changes to the definition of form the basis for classification as GRAS received no comments that disagreed ‘‘scientific procedures.’’ After through scientific procedures, and with this proposed revision and are considering these comments, we are clarify the role of publication in finalizing § 170.30(a) as proposed with finalizing the definition of scientific establishing general recognition of conforming changes as shown in table procedures as proposed, with the safety through scientific procedures; 29. modifications described in the 2010 and (3) make conforming changes to the See section XXV.B regarding revisions notice and with editorial changes as criteria for eligibility for classification as to the general criteria for eligibility for shown in table 29. GRAS through experience based on classification as GRAS for a substance (Comment 7) One comment that common use in food. We proposed these used in animal food. supports the potential modifications to amendments in association with our B. Criteria for Eligibility for the definition of ‘‘scientific procedures’’ concurrent proposal to replace the Classification as GRAS Through as described in the 2010 notice asks us GRAS affirmation petition process with a GRAS notification procedure. In the Scientific Procedures to incorporate an additional clarification that ‘‘scientific principles appropriate to 2010 notice, we stated that we were We proposed to amend the criteria for establishing the safety of a substance’’ considering an additional revision to eligibility for classification as GRAS encompass consideration of both the correspond with the revision to the through scientific procedures to: (1) data supporting the safety of the definition of scientific procedures (see Require that the data and information substance and the probable dietary section V in this document and Issue 1, for general recognition of safety be exposure. 75 FR 81536 at 81537–81538 in the 2010 ‘‘generally available and accepted,’’ and (Response 7) To the extent that the notice). (2) broaden the types of acceptable data comment means that ‘‘scientific In the following sections, we discuss and information by replacing ‘‘studies’’ procedures’’ (rather than ‘‘scientific comments that disagree with one or with ‘‘data, information, methods, or principles’’) encompass consideration of more aspects of our proposal to amend principles.’’ In the 2010 notice, we both the data supporting the safety of the criteria for eligibility for stated that we were considering whether the substance and the probable dietary classification as GRAS, with the to revise these criteria with respect to exposure, we agree. However, it is not potential modifications described in the the types of acceptable data and necessary to revise the definition of 2010 notice (see, e.g., Comment 9 and information to include ‘‘the scientific procedures to make that clear. Comment 13); ask us to clarify how we application’’ of generally available and The definition of ‘‘scientific will interpret the revised criteria or offer accepted scientific data, information, or procedures’’ already specifies the suggestions for how we should interpret methods, as well as ‘‘the application’’ of application of data from human, animal, the revised criteria (see, e.g., Comment scientific principles’’ (see section V in mstockstill on DSK3G9T082PROD with RULES2 analytical, or other scientific studies, 12, Comment 16, Comment 17, and this document and Issue 1, 75 FR 81536 and the definition of ‘‘safe’’ or ‘‘safety’’ Comment 18); or suggest one or more at 81537–81538 in the 2010 notice). in § 170.3(i) includes probable dietary changes to the revised criteria (see, e.g., See section XXV.B regarding revisions exposure as a factor that must be Comment 10, Comment 19, and to the criteria for eligibility for considered in determining safety. Comment 20). After considering these classification as GRAS through As discussed in the 2010 notice, comments, we are establishing the scientific procedures for a substance ‘‘principle’’ can be defined as a criteria for eligibility for classification as used in animal food. VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00014 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 54973 (Comment 8) One comment asserts the Internet may avoid Internet of these comments cited the placement that the criterion for the generally ‘‘publications’’ about a scientific topic of the word ‘‘ordinarily’’ in the criteria available data or information when the ‘‘publication’’ is not for classification as GRAS through establishing safety to ordinarily be associated with a reputable scientific scientific procedures as support for this published is artificial. Other comments institution. interpretation. Several comments urge point out that information that is not We have not changed our position on us to interpret, in a flexible manner, the published can nonetheless be the importance of peer review. The basis proposed criteria for the scientific data, considered ‘‘generally available.’’ Some for GRAS status continues to be the information, methods or principles that comments object to the proposed application of generally available establish safety to be ‘‘generally amendment to the criteria for eligibility scientific data, information, and available and accepted’’ and ‘‘ordinarily for classification as GRAS through methods, which ordinarily are . . . published.’’ scientific procedures and assert that it published (and, thus, are subject to peer (Response 9) We agree that all would de-emphasize or eliminate the review as part of the scientific relevant data should be used in existing criterion for peer-reviewed publication process for most journals). evaluating GRAS status, including studies. We continue to believe that whether unpublished data. However, regardless (Response 8) Regardless of whether scientific data, information, and of whether data and information are the data and information are published methods have been peer reviewed published or unpublished, a GRAS or unpublished, under the revised before publication in a scientific journal conclusion based on scientific that is representative of scientific procedures must be based on data and criteria a GRAS conclusion must be publications accessed by the expert information that are generally available based on data and information that are scientific community is a factor that and accepted, and as such, are publicly generally available and accepted, and as bears on the objectivity and scientific available (see Response 8). The GRAS such, are publicly available. As we merit of study, and is a variable we criteria for scientific procedures, as stated in the proposed rule, the common consider in determining whether established in 1976, state that the knowledge element of the GRAS experts accept the report of a scientific applicable data and information are standard precludes a GRAS conclusion investigation as a credible report and ‘‘ordinarily’’ published and may be if the data and information (e.g., as whether there is general knowledge of ‘‘corroborated’’ by unpublished data and evaluated by a ‘‘GRAS panel’’) are only the scientific investigation. information, and this rule retains these available in files that are not publicly CFSAN’s 2010 experience document criteria. The common meaning of accessible, such as in confidential (Ref. 18) provides factual information on ‘‘corroborate’’ is to make more certain or industry files (62 FR 18938 at 18943). how CFSAN already has interpreted the confirm (Ref. 23). Although We disagree that the criterion for the criteria for eligibility for classification of unpublished data and information can generally available data or information GRAS status through scientific confirm a conclusion of GRAS status, to establishing safety to ordinarily be procedures for GRAS notices CFSAN satisfy GRAS criteria qualified experts published is artificial. Publication in a received during the Interim Pilot must be able to conclude that the peer-reviewed scientific journal is the program (see section III.A.1 of CFSAN’s substance is not harmful under the usual mechanism to establish that 2010 experience document), and we conditions of its intended use without scientific information is generally intend to continue this approach in the access to ‘‘corroborative’’ information available, provided that the journal is future. In most cases, a submitted GRAS (see § 170.30(a)). Under this rule, a representative of scientific publications notice described a mixture of notifier is required to explain how there accessed by the expert scientific information published in peer-reviewed could be a basis for a conclusion of community (62 FR 18938 at 18943). journals, information (such as in GRAS status if qualified experts do not Nonetheless, the revised criteria provide textbooks) that was generally available have access to non-public safety-related flexibility for supporting a conclusion of in a form other than a peer-reviewed data and information considered in GRAS status through the application of journal, and unpublished information. reaching a conclusion of GRAS status scientific data, information, or methods As shown in table 1 in CFSAN’s 2016 (see § 170.250(e)). that are generally available through a experience document, CFSAN had no Whether data and information are mechanism other than publication in a questions about GRAS status based on corroborative of safety, rather than peer-reviewed scientific journal, such as this mixture of information in establish safety, depends on what those publication in a textbook and other approximately 81 percent of the GRAS data and information are and how they sources of technical literature. One notices CFSAN evaluated between 1998 relate to the safety assessment, not just example of another source of technical and 2015 (Ref. 19). Importantly, whether they are published or otherwise literature is the Joint Expert Committee CFSAN’s evaluation of the basis for a publicly available. Whereas on Food Additives (JECFA, a joint conclusion that a use of a food unpublished data and information that committee of the Food and Agriculture substance is GRAS in addition to being have a bearing on a safety conclusion, Organization/World Health safe was a case-by-case evaluation. As and therefore could help confirm a Organization). We note, however, that discussed in section III.A.4 of CFSAN’s safety conclusion based on other data the mere fact that data and information 2010 experience document, in some and information, in general, can only be are published or otherwise publicly cases it was CFSAN’s view that the considered as corroborative in the available does not satisfy the criteria for available data and information were context of a GRAS conclusion, general recognition of safety. Regardless sufficient to demonstrate safety, but not published data and information may be of the mechanism of making data and GRAS status, and CFSAN established a either the basis for a safety conclusion mstockstill on DSK3G9T082PROD with RULES2 information generally available to food additive regulation for the use of or corroborative of a safety conclusion, qualified experts, it must be plausible the substance in response to a food depending on the nature of the data and that qualified experts would be additive petition for that use (Ref. 18). information. For example, a published accessing those data and information (Comment 9) Some comments state 90-day toxicology study could be the using that mechanism. For example, that all available relevant data, basis for a safety conclusion, but a scientists who routinely access peer- including unpublished data, should be preliminary toxicology study conducted reviewed journals in electronic form on used in evaluating GRAS status. Some primarily for the purpose of selecting VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00015 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 54974 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations the doses to be used in that 90-day through scientific procedures would representative of experts qualified by toxicology study is unlikely to be the depend on the nature and extent of the scientific training and experience to basis for a safety conclusion, regardless discussion in the publication. For evaluate the safety of the substance of whether that preliminary toxicology example, a very general statement that under the conditions of its intended use. study is published. a study was conducted and reported no For example, a ‘‘GRAS panel’’ opinion See also the discussion in Response adverse findings would not suffice to published by scientists without 58 regarding the requirement for you to make the study ‘‘generally available’’; expertise appropriate to address the submit a signed statement certifying instead, such a statement would merely applicable safety questions could not that, to the best of your knowledge, your be a generally available opinion about provide evidence that the conclusions GRAS notice is a complete, data and information, in that study, that in the publication are ‘‘generally representative, and balanced submission are not generally available. Such a accepted.’’ that includes unfavorable information, publication may satisfy the ‘‘generally If a published ‘‘GRAS panel’’ opinion as well as favorable information, known accepted’’ aspect of the criteria for discusses data and information that are to you and pertinent to the evaluation GRAS status through scientific available to the members of the GRAS of the safety and GRAS status of the use procedures for that study, but would be panel, but not generally available to of the substance (§ 170.225(c)(9)). See insufficient, by itself, to satisfy the qualified experts, whether that also the discussion in section XVII ‘‘generally available’’ aspect of those publication could satisfy the ‘‘generally regarding the requirement for your criteria. However, a comprehensive available’’ aspect of the criteria for narrative to identify, and place in description in the secondary scientific eligibility for GRAS status through context, data and information that are, literature of a previously unpublished scientific procedures would depend on or may appear to be, inconsistent with study, including details similar to the nature and extent of the discussion your conclusion of GRAS status, details that would be included in a in the publication (see Response 10). regardless of whether those data and publication in the primary scientific Unless both criteria, i.e., ‘‘generally information are generally available literature, may suffice to make the study available’’ and ‘‘generally accepted’’, are (§ 170.250(c)). published in the secondary scientific satisfied, there would be no basis for a (Comment 10) One comment asks us literature ‘‘generally available.’’ In such conclusion of GRAS status based on a to explicitly acknowledge publication of circumstances, the publication in the published ‘‘GRAS panel’’ opinion. information in the secondary scientific secondary scientific literature may be (Comment 12) One comment states literature as a mechanism to satisfy the able to satisfy both the ‘‘generally that all available relevant data, standard for general availability. available’’ and ‘‘generally accepted’’ including unpublished data, should be (Response 10) We decline this aspects of the criteria for eligibility for used in evaluating GRAS status, as long request. In general, the secondary GRAS status through scientific as any unpublished data are generated scientific literature includes procedures for certain data and by appropriate and valid scientific publications (such as review articles, information. methods as judged and reviewed by an textbooks, and compendia) which (Comment 11) One comment asks us external qualified GRAS panel and are disseminate the views of scientists who to recognize that publication of an accessible to FDA for review. are critically evaluating a primary body opinion of a specially convened ‘‘expert (Response 12) We agree that all of data and information already panel’’ would satisfy the standard for available relevant data should be used published in peer-reviewed scientific general availability because, in the in evaluating whether a use of a journals that are representative of comment’s view, review by such a panel substance in food is GRAS through scientific publications accessed by the would be equivalent to, or exceed, peer scientific procedures. By ‘‘all relevant expert scientific community (i.e., the review. (By ‘‘expert panel,’’ we assume data,’’ we mean data that support a primary scientific literature). Whether a that the comment is referring to a conclusion of GRAS status as well as publication in the secondary scientific ‘‘GRAS panel’’, i.e., a panel of data that are inconsistent with a literature satisfies the criteria for GRAS individuals convened for the purpose of conclusion of GRAS status, not just status through scientific procedures is a evaluating whether the available whether the data are published. (See case-by-case determination that depends scientific data, information, and §§ 170.225(c)(9) and 170.250(c) and the on the circumstances. See section III.A.1 methods establish that a substance is discussion in Response 58, Response 69, of CFSAN’s 2010 experience document safe under the conditions of its intended and Response 78.) We also agree that it (Ref. 18) for examples of how CFSAN use in food. See the discussion in is appropriate for unpublished data to considered publications in the section III.A.1 of CFSAN’s 2010 be generated by valid scientific methods secondary scientific literature during experience document (Ref. 18).) and to be accessible to FDA for review the Interim Pilot program. When the (Response 11) We would consider (e.g., when such data are cited in a underlying data being reviewed in the publication of an opinion of a specially submission to FDA). In addition, we secondary scientific literature are convened ‘‘GRAS panel’’ to be part of have acknowledged the practice of themselves generally available, a the secondary scientific literature as convening an external ‘‘GRAS panel’’ to publication in the secondary scientific discussed in Response 10. As with any evaluate whether the available scientific literature can provide evidence that the publication in the secondary scientific data, information, and methods data and information discussed in the literature, when the underlying data demonstrate that a substance is safe publication are generally accepted as being reviewed in a published ‘‘GRAS under the conditions of its intended use well as generally available. If a panel’’ opinion are themselves generally in food (see section III.A.1 of CFSAN’s publication in the secondary scientific available, a published ‘‘GRAS panel’’ 2010 experience document) (Ref. 18). mstockstill on DSK3G9T082PROD with RULES2 literature discusses data and opinion could provide evidence that the However, we disagree that information information that are available to the data and information discussed in the that is not generally available to authors, but not previously published in publication are generally accepted, qualified experts could be used as the primary scientific literature, depending on factors such as the subject evidence for a GRAS conclusion merely whether that publication could satisfy matter expertise of the members of the because a GRAS panel has reviewed it. the ‘‘generally available’’ aspect of the GRAS panel and whether the members Such information would need to be criteria for eligibility for GRAS status of the GRAS panel would be considered considered, but generally would only be VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00016 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 54975 corroborative of safety. (See Response 9 expected of any GRAS panel. This in the GRAS notice are subject to the and Response 11.) comment suggests that such guidelines public disclosure provisions of this rule (Comment 13) One comment asserts could include recommendations for: (1) (see § 170.275) and, thus, would be that the proposed rule treats the Number of panel members; (2) measures available to the expert scientific findings of GRAS panels as equivalent of ‘‘general acceptance,’’ such as a community. However, when the to determinations by authoritative majority (rather than unanimous) proponent of GRAS status does not bodies and peer reviewed published opinion and the impact of a dissenting submit a GRAS notice, the expert articles. opinion; and (3) the content of a letter scientific community that does not have (Response 13) We disagree. In the from a GRAS panel. access to the specific food categories proposed rule, we noted that the basis (Response 14) See Response 125. We and associated levels of use would not for concluding there is expert consensus intend to issue for public comment a be able to calculate an estimated dietary about the safety of a substance under the draft guidance to address GRAS panels. exposure. When the available data and conditions of its intended use may be (Comment 15) Some comments assert information suggest that the specific quite varied, and described common it can be difficult to publish data and food categories and associated levels of mechanisms that have been used to do information that do not raise an issue of use must be carefully chosen to keep so. We stated that these common concern. consumption of the substance in a safe mechanisms included publication in the (Response 15) We infer this comment range (e.g., when fortifying food with primary, peer-reviewed scientific to refer primarily to toxicology studies. certain vitamins), the expert scientific literature; publication in the secondary Toxicology studies are designed to community that does not have access to scientific literature; documentation of provide information about potential the specific food categories and the opinion of an ‘‘expert panel’’ that is adverse effects from exposure to a associated levels of use would not be specifically convened for this purpose; substance and any dose-response able to reach a conclusion about and the opinion or recommendation of relationship. Although studies that fail whether the substance is safe under the an authoritative body such as the to identity any adverse effects may be conditions of its intended use, and National Academy of Sciences or the difficult to publish, some scientific GRAS criteria would not be satisfied. Committee on Nutrition of the American journals report the findings of such Academy of Pediatrics on a broad or studies. (See section III.A.1 of CFSAN’s After market entry of the substance, it specific issue that is related to a 2010 experience document (Ref. 18)). may be appropriate to re-assess dietary conclusion of GRAS status (62 FR 18938 (Comment 16) One comment asks us exposure. For example, dietary exposure at 18940–18941). We also stated that to require that both toxicology and may need to be reassessed when a key there could be a basis to conclude that exposure data be published because a assumption in the methodology is there is expert consensus that the safety assessment for the use of a changed; as dietary consumption published results of a particular safety substance in food requires consideration patterns change; when there is an study (i.e., the primary scientific of both. unresolved question about consumer literature) establish the safety of a (Response 16) We agree that a safety intake; when there is a small margin of substance for its intended use if the assessment for the use of a substance in exposure; or when other new study raises no safety questions that food requires consideration of both information becomes available. As with experts would need to interpret and safety information (such as toxicology a premarket exposure assessment, a resolve (62 FR 18938 at 18943). In studies) and dietary exposure (i.e., the postmarket exposure assessment addition, technical literature from amount of the substance that consumers typically would be calculated by JECFA can provide evidence that are likely to eat or drink). Toxicology applying generally available and generally available safety data and data are ordinarily published. accepted methods to two types of data information are generally accepted (see A premarket exposure assessment and information: (1) Generally available section III.A.1 of CFSAN’s 2010 typically would be calculated by and accepted data about food experience document (Ref. 18)). applying generally available and consumption; and (2) specific food However, acknowledging that the accepted methods to two types of data categories, and levels of use in those opinion of an ‘‘expert panel’’ (which we and information: (1) Generally available food categories. In some cases, now refer to as a ‘‘GRAS panel’’) has and accepted data about food postmarket exposure assessments have been used to provide evidence that consumption; and (2) specific food been published so that the expert safety data and information are categories, and levels of use in those scientific community has access to generally accepted does not mean that food categories, projected by the them. For example, exposure these mechanisms are ‘‘equivalent.’’ sponsor of a food additive petition or by assessments have been published for Whether the findings of a GRAS panel, the proponent of GRAS status (Ref. 24 some sweeteners using relative a determination by an authoritative and Ref. 25). Using generally available sweetness as the basis of the estimate body, or a peer-reviewed scientific and accepted data about food (Ref. 26). As another example, estimates study provide sufficient evidence that consumption, a qualified expert who of dietary exposure to caffeine have safety data and information are has access to the specific food categories been published to address consumer generally accepted would depend on the and associated levels of use intended by intake and patterns of use (Ref. 27 specific findings of the GRAS panel, the the proponent of GRAS status can through Ref. 29). However, as with a specific determination by the calculate an estimated dietary exposure. premarket exposure assessment, when a authoritative body, and the data and When the proponent of GRAS status postmarket exposure assessment is not information in the peer-reviewed submits a GRAS notice, the proponent publicly available, the expert scientific mstockstill on DSK3G9T082PROD with RULES2 scientific study rather than on the must: (1) Provide data and information community that does not have access to classification of the mechanism for about dietary exposure (see § 170.235); the specific food categories and providing evidence that safety data and and (2) include a narrative that associated levels of use would not be information are generally accepted. addresses the safety of the notified able to reach a conclusion about (Comment 14) One comment asks us substance, considering all dietary whether the substance is safe under the to develop and publish guidelines sources (see § 170.250). Those conditions of its intended use when the regarding specific duties that would be calculations and discussions included available data and information suggest VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00017 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 54976 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations that the specific food categories and generally available and generally establish that the substance is safe associated levels of use must be accepted—rather than on the amount of under the conditions of its intended use. carefully chosen to keep consumption of time that a food additive has been used However, a conclusion of GRAS status the substance in a safe range. in food. However, in general, much of must be based on common knowledge (Comment 17) One comment asks us the data submitted for our review of a throughout the scientific community to recognize that published literature food additive contains unpublished data knowledgeable about the safety of does not need to address a specific and trade secret or confidential substances added to food that there is substance, but could involve information that is neither published reasonable certainty that the substance publications on a class of substances or nor otherwise generally available. is not harmful under the conditions of a related substance to support a Although the safety data are available its intended use (§ 170.30(a)), and a conclusion that the use of a substance for public disclosure under 21 CFR substance cannot be considered GRAS is GRAS through scientific procedures. 171.1(h)(1), they typically are based on when its characteristics are known to (Response 17) We agree that unpublished studies sponsored by the only a few experts (Final rule published information for a specific petitioner. establishing GRAS criteria, 41 FR 53600, substance is not always necessary to See also the discussion in Response December 7, 1976). In addition, the support a conclusion that the use of a 19 regarding the impact of the passage passage of time is relevant in an substance is GRAS through scientific of time and the discussion in Response evaluation of whether a substance is procedures. For example, there may be 79 that the qualified experts who GRAS under the conditions of its situations where the safety of the use of evaluate the basis for a conclusion that intended use. In our 1974 proposed rule the substance in food can be the notified substance is safe under the on general recognition of safety and demonstrated by relevant published conditions of its intended use must not prior sanctions for food ingredients, we information on a closely, structurally exclusively be ‘‘FDA’s experts.’’ acknowledged that there would be at related compound. In such cases, the least some gap between the gathering of (Comment 19) One comment asks us analysis leading to the conclusion of the scientific knowledge necessary to to exclude uses of ‘‘novel’’ substances GRAS status should explain how the provide the toxicological underpinning from consideration for eligibility for information on the closely, structurally for general recognition of safety and the classification as GRAS. The comment related compound is relevant to the dissemination to and assimilation by the asserts that novel or newly discovered safety assessment of the substance being scientific community of this material evaluated. In other cases, there may a uses of substances that are the subject of that is necessary for general recognition body of information published in the a conclusion of GRAS status are in of safety to exist.’’ (39 FR 34194 at primary or secondary literature about a conflict with the original intent of the 34194, September 23, 1974). More class of substances, which reflect 1958 amendment and the plain meaning recently, the discussions in sections generally available and accepted data of ‘‘generally recognized,’’ because there III.A.4 and IV.K of CFSAN’s 2010 and information that can be called to is no history of safe use for these experience document (Ref. 18) show our bear on the safety assessment of a substances. The comment also states approach to the time gap between the specific substance. For example, that similar ‘‘general recognition’’ publication of safety data and the use of generally available metabolism provisions for new drugs are not the published safety data to support a information about commonly consumed interpreted to allow industry-made conclusion of GRAS status during the components of food, such as safety determinations for new or novel Interim Pilot program. See also carbohydrates, lipids, and proteins, drugs. Response 67 regarding nanotechnology could support a conclusion that a (Response 19) We do not have a applications in food substances. specific substance is GRAS under the regulatory definition for a ‘‘novel’’ (Comment 20) One comment asserts conditions of its intended use. substance. As a general matter, section that we must define the extent of To help ensure that the data are, in 201(s) of the FD&C Act provides two agreement needed to establish a fact, relevant to the safety assessment of alternatives for general recognition of consensus among qualified experts, and the substance being evaluated, we safety—through scientific procedures, or that we must exclude from eligibility for strongly encourage any person who through experience based on common classification as GRAS any substance intends to rely on data and information use in food. Section 201(s) does not whose safety has been called into regarding a class of substances, or a limit eligibility, or otherwise exclude, question by expert authorities or specific substance related to the the use of a substance from authoritative entities within the substance that would be added to food, classification as GRAS through scientific community. to submit any conclusion of GRAS scientific procedures if there is no (Response 20) The proponent of a status to FDA via the GRAS notification history of use. Likewise, section 201(s) GRAS conclusion for a food substance procedure. does not limit eligibility, or otherwise must demonstrate that the conditions of (Comment 18) One comment states exclude, the use of a substance from use of the substance satisfy the that the use of an approved food classification as GRAS through definition of ‘‘safe’’ in our regulations additive can, through the passage of scientific procedures based on other (i.e., that there is reasonable certainty time, become GRAS as the substance criteria, such as whether a substance or that the substance is not harmful under becomes widely used and as its use in food is ‘‘novel’’ or ‘‘newly the conditions of its intended use (see information about the substance discovered.’’ Unlike the definition of a § 170.3(i)). The proponent of GRAS becomes publicly available. ‘‘new drug’’ in section 201(p) of the status also must demonstrate that there (Response 18) We disagree that FD&C Act, section 201(s) does not is common knowledge about this safety mstockstill on DSK3G9T082PROD with RULES2 widespread use of an approved food require that a food ingredient be used throughout the knowledgeable scientific additive as time passes has any bearing ‘‘to a material extent or for a material community (§ 170.30(a)). Although on the eligibility of this use for time under such conditions’’ before it courts have established that general classification as GRAS. Eligibility for can become GRAS. Rather, the criteria recognition of safety requires a classification as GRAS through for eligibility for classification as GRAS consensus of expert opinion regarding scientific procedures would depend on depend on whether generally available the safety of the use of the substance, the status of the information—as and accepted data and information (see, e.g., United States v. Western VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00018 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 54977 Serum Co., Inc., 666 F.2d 335, 338 (9th expert authorities or authoritative 2010 experience document, GRAS Cir. 1982) (citing Weinberger v. Hynson, entities within the scientific community notices filed during the Interim Pilot Westcott & Dunning, 412 U.S. 609, 629– to raise a concern about the safety of the program that relied on the concept of 32 (1973)), we disagree that we must substance under the conditions of its ‘‘substantial equivalence’’ generally define the extent of agreement needed to intended use in food would have addressed alternative sources of establish such a consensus. Courts have reduced significance if the concern was enzymes already used in food (Ref. 18). established that general recognition of related to a contaminant in the Most of these notices both emphasized safety does not require unanimous substance and scientifically valid data the similarities of the new enzyme agreement. See, e.g., United States v. and information supplied by the preparations to existing enzyme Articles of Drug * * * 5,906 Boxes, 745 proponent of GRAS status provide preparations and explained the F.2d 105, 119 n. 22 (1st Cir. 1984); evidence that an improved method of differences between the new enzyme United States v. Articles of Food and manufacture eliminates that preparation and currently used enzyme Drug (Coli-Trol 80), 518 F.2d 743, 746 contaminant. preparations. However, none of these (5th Cir. 1975) (‘‘What is required is not See also Response 77, in which we GRAS notices relied solely on the unanimous recognition but general explain that we proposed to provide the concept of ‘‘substantial equivalence.’’ recognition’’). Importantly, general judicial interpretation of section 201(s) Instead, these notices also described recognition of safety does not exist if of the FD&C Act in the requirement for other applicable data and information, there is a genuine dispute among the comprehensive discussion of the such as data and information about the qualified experts that the use of a notifier’s basis for a conclusion of GRAS biological source of the enzyme substance is safe. See, e.g., Premo status to provide more context to preparation; the method of manufacture Pharmaceutical Laboratories v. United notifiers than merely repeating the of the enzyme preparation; constituents States, 629 F.2d 795, 803–4 (2nd Cir. statutory language. However, as of the enzyme preparation that derive 1980) (‘‘genuine dispute among discussed in Response 77, we have from the source organism or the qualified experts’’ precludes finding of decided to use the statutory language manufacturing process; the technical general recognition, and no general (i.e., ‘‘generally recognized’’) rather than effect of the enzyme preparation; dietary recognition existed as a matter of law the proposed term ‘‘consensus’’ in the exposure to the enzyme preparation; where there was a ‘‘sharp difference’’ of submission requirements for a GRAS specifications for the enzyme expert opinion); United States v. Article notice to mirror the GRAS criteria in preparation; and applicable safety of Food * * * Coco Rico, 752 F.2d 11, § 170.30, which continue to use the studies. 15 n 6 (1st Cir. 1985) (substance was not statutory language rather than the consensus standard applied by the C. Criteria for Eligibility for GRAS as a matter of law based on courts in applying the statutory Classification as GRAS Through existence of ‘‘genuine dispute among language to specific situations. Experience Based on Common Use in qualified experts’’ regarding safety of (Comment 21) In the proposed rule, Food use). For discussions of additional we asked for comment on the potential judicial decisions bearing on the criteria We proposed to amend the criteria for for a conclusion of GRAS status through for eligibility for classification as GRAS, eligibility for classification as GRAS scientific procedures to be based in part see the notice of declaratory order through experience based on common on the ‘‘substantial equivalence’’ of the providing our final determination use in food (§ 170.30(c)(2)) to state that applicable substance to a substance that regarding partially hydrogenated oils persons who claim that use of a is GRAS through experience based on (80 FR 34650). substance is GRAS through experience common use in food. One comment A conclusion of GRAS status must be agrees with the view, expressed in a based on its common use in food based on the totality of the publicly 1996 JECFA Report (Ref. 30) and outside of the United States should available and corroborative evidence reported in the proposed rule (62 FR notify FDA of that claim in accordance about the safety of the substance under 18938 at 18944), that ‘‘substantial with the GRAS notification procedure. the conditions of its intended use, equivalence’’ embodies the concept that We received no comments that including both favorable and potentially if a new food component is found to be disagreed with this proposed unfavorable information. Thus, reports substantially equivalent to an existing amendment and are finalizing it as of expert authorities or authoritative food component, the food component proposed, with conforming changes as entities within the scientific community could be considered to be as safe as the shown in table 29. may indicate that there is no general existing food component, after taking See section XXV.B regarding revisions recognition of safety when the reports into account any processing that the to the criteria for eligibility for call into question the safety of a food component may undergo as well as classification as GRAS through substance for use in food. However, we the intended use and the intake by the experience based on common use in disagree that the outcome of an population. Several comments assert food for a substance used in animal evaluation of such information can be that the concept of substantial food. predetermined as suggested by the equivalence, although useful, is D. Other Comments on the Criteria for comments. Regardless of whether nonetheless ambiguous. One comment Eligibility for Classification as GRAS particular scientific data and asks us to clearly state our interpretation information lead experts to conclude of this concept in the final rule. (Comment 22) One comment asserts that a substance is safe under the (Response 21) We have decided not to that the proposed rule would add conditions of its intended use, or raise include the term ‘‘substantial unnecessary complexity to continued mstockstill on DSK3G9T082PROD with RULES2 questions about the safety of the equivalence’’ in the regulatory text of use of substances currently presumed to substance under the conditions of its this rule, because whether, and to what be GRAS. This comment also asserts intended use, the evaluation of whether extent, similarity between two that the proposed rule would remove a use of a substance in food is safe, and substances could support a conclusion the ‘‘pre-1958 exemption’’ and, as a whether safety is generally recognized, of GRAS status depends on too many result, would place an unnecessary is a case-by-case evaluation. For situation-specific variables. As burden on food producers and example, data and information that lead discussed in section IV.N of CFSAN’s processors with respect to substances VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00019 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 54978 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations that are the subject of previous in the formation of bladder tumors in on the types of data and information in conclusions of GRAS status. rats; as discussed in section I.D, we support of a food additive petition, and (Response 22) These comments are recently issued a declaratory order these types of data and information unclear. By ‘‘pre-1958 exemption’’ these making a final determination that there would be useful in the evaluation of the comments could mean a conclusion of is no longer a consensus among safety of a substance when the GRAS status through experience based qualified experts that PHOs are GRAS proponent of the substance seeks to on common use in food, which requires for any use in human food (80 FR demonstrate that the substance is GRAS common use in food before January 1, 34650). under the conditions of its intended use 1958. Alternatively, these comments (Comment 23) One comment asks us (see Response 37 and Response 66). could be referring to the statutory to require minimum safety or short-term For a safety assessment of a chemical, exception from the definition of ‘‘food toxicology studies for all conclusions of the specific types of data and additive’’ for a substance that is the GRAS status, regardless of whether the information generally follow from the subject of a prior sanction within the conclusion is through scientific chemical structure and estimated meaning of section 201(s)(4) of the procedures or through experience based dietary exposure of the substance. For FD&C Act and part 181 (21 CFR part on common use in food before 1958. example, chemistry data, including 181). Either way, nothing in this rule This comment explains that such manufacturing information, as well as would affect a lawful use of a food studies could corroborate safety when information sufficient to estimate substance that is GRAS based on GRAS status is based on common use on exposure, are necessary to consider in common use in food prior to January 1, food, e.g., by taking into account any arriving at a conclusion of GRAS status. 1958 or that is the subject of a prior impact of the manufacturing process on Whether toxicological studies are sanction. This rule does not remove food safety. necessary to demonstrate safety depends GRAS status based on common use in (Response 23) We decline this on the properties of the substance such food prior to January 1, 1958. Likewise, request. We agree that the method of as the presence or absence of chemical the lawful use of a substance listed in manufacture can impact safety, alerts, physical properties, and part 181 as being the subject of a prior regardless of whether GRAS status is physiological fate of the substance. For sanction is not affected by this rule. through experience based on common example, well understood and accepted However, any person who relies on a use on food or through scientific metabolism information about a conclusion of GRAS status through procedures. See, e.g., our guidance substance that is a component of experience based on common use in entitled ‘‘Assessing the Effects of commonly consumed foods (such as food prior to 1958 or on a prior sanction Significant Manufacturing Process vegetables or fruits) may provide within the meaning of section 201(s)(4) Changes, Including Emerging sufficient safety information to arrive at of the FD&C Act needs to consider Technologies, on the Safety and a conclusion of GRAS status at a whether the conditions of use associated Regulatory Status of Food Ingredients specified level of the use of that with the applicable substance, such as and Food Contact Substances, Including substance in food. As discussed in the foods in which the substance would Food Ingredients that Are Color section III.A.2 of CFSAN’s 2010 be used and the levels of use of the Additives’’ (Ref. 6). The rule requires experience document, during the substance, are within the scope of these submission of a description of the Interim Pilot program it was CFSAN’s statutory provisions. As discussed in method of manufacture in sufficient view that toxicological studies were not section I.D, in 2010 we issued warning detail to evaluate the safety of the necessary to evaluate the safety of letters informing four companies notified substance as manufactured, substances such as carrot fiber and dried marketing caffeinated alcoholic regardless of whether the basis for the orange pulp (Ref. 18). Likewise, for beverages that caffeine, as used in the conclusion of GRAS status is through simple substances (such as minerals and companies’ products, is an unsafe food scientific procedures or through their salts) that are readily dissociated to additive, and therefore the products are experience based on common use in components that have long been viewed adulterated under section 402(a)(2)(C) of food (see § 170.230(b)). If the method of as GRAS (e.g., by a listing in part 182 the FD&C Act, and the companies manufacture has changed over time, a or by a GRAS affirmation regulation in subsequently ceased distribution of new evaluation of GRAS status based on part 184), toxicological studies would these products. Thus, we advise any scientific procedures may be warranted. likely not be necessary. As discussed in manufacturer or distributor to carefully We advise any manufacturer of a section III.A.2 of CFSAN’s 2010 consider whether there is adequate substance that is used in food based on experience document, during the support for concluding that a substance a conclusion of GRAS status to carefully Interim Pilot program it was CFSAN’s is GRAS under the conditions of its consider the impact of its method of view that toxicological studies were not intended use and to submit a GRAS manufacture on the safety of the necessary to evaluate the safety of notice to us if it intends to manufacture substance before introducing the substances such as potassium bisulfate or distribute a food product containing substance into commerce. and seaweed-derived calcium (with a substance that has been used in food We disagree that the rule must require calcium carbonate as the major as a GRAS substance under conditions minimum safety or short-term component) (Ref. 18). of use different from those in the toxicology studies for all conclusions of For a safety assessment of a substance manufacturer’s or distributor’s product. GRAS status because the kinds of data produced from a microorganism, the In addition, new data and information and information needed to demonstrate specific types of data and information may call into question the safety of a safety (or that could be used to generally follow from the identity of the substance used in food as a GRAS corroborate safety) will vary based on microorganism and how the substance mstockstill on DSK3G9T082PROD with RULES2 substance, whether the basis for a the substance and its intended use. A is produced from that microorganism in conclusion of GRAS status is through conclusion of GRAS status based on addition to the substance itself. For experience based on common use in scientific procedures must be based on example, the safety of a substance food or through scientific procedures. the same quantity and quality of produced from a microorganism As discussed in section I.A, in 1969 we scientific evidence as is required to generally considers generally available deleted various cyclamate salts from the obtain approval of a food additive microbiological data and information GRAS list because they were implicated (§ 170.30(b)). We have issued guidance about the potential toxigenicity and VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00020 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 54979 pathogenicity of the microorganism. VII. Comments on the Substitution of a sufficient basis for a GRAS Whether toxicological studies would be GRAS Notification Procedure for the determination and whether information necessary to demonstrate the safety of GRAS Affirmation in the notice or otherwise available to us the substance as manufactured would Petition Process raises issues that lead us to question depend on what the substance is and its whether use of the substance is GRAS. intended use in food. Our regulations specify procedures for We also proposed to presumptively us to affirm the GRAS status of the use convert any filed GRAS affirmation E. GRAS Status of Certain Food of a food substance, whether on our own petition that is pending on the date that Substances initiative (§ 170.35(a) and (b)) or on the the petition process is replaced with a petition of an interested person notification procedure (‘‘pending We proposed to remove § 170.30(f), (§ 170.35(c)). We proposed to eliminate which expresses our intent to review the petition’’) to a GRAS notice and provide the GRAS affirmation petition process GRAS status of certain food substances. an opportunity for the person who had in § 170.35(c) and replace it with a We received no comments that submitted a pending petition (‘‘affected GRAS notification procedure (proposed disagreed with our proposal to remove § 170.36) in which any person may petitioner’’) to amend the petition to notify us of a claim that a particular use meet the requirements for a GRAS § 170.30(f) and are removing it as of a substance is exempt from the notice. proposed. statutory premarket approval In the 2010 notice, we discussed requirements based on the notifier’s several issues broadly applicable to the determination that such use is GRAS. proposed substitution of a GRAS Under the proposed notification notification procedure for the GRAS procedure, we would evaluate whether affirmation petition process (see table the submitted notice provides a 3). TABLE 3—ISSUES IN THE 2010 NOTICE BROADLY APPLICABLE TO THE PROPOSED SUBSTITUTION OF A GRAS NOTIFICATION PROCEDURE FOR THE GRAS AFFIRMATION PETITION PROCESS Issue Description of our request for comment Reference No. N/A .... Our intent to use ‘‘Plain Language’’ tools such as pronouns in the final rule ....................................... 75 FR 81536 at 81537. 2 ........ Our reasons for tentatively concluding that the terms ‘‘conclude’’ and ‘‘conclusion’’ would be more 75 FR 81536 at 81538. appropriate in lieu of ‘‘determine’’ and ‘‘determination’’. 17 ...... Alternative approach to administering pending GRAS affirmation petitions .......................................... 75 FR 81536 at 81542–81543. Several comments support the and Comment 32); ask us to clarify how definition of ‘‘GRAS notice’’ means a proposed replacement of the GRAS we generally will administer the submission that informs us of your view affirmation petition process with a proposed GRAS notification procedure that a specified use of a substance is not GRAS notification procedure. For (see, e.g., Comment 31); or suggest one subject to the premarket approval example, several comments support the or more general changes to the proposed requirements of the FD&C Act based on expectation we expressed in the GRAS notification procedure (see, e.g., your conclusion that such use is GRAS. proposed rule (62 FR 18938 at 18941) Comment 27, Comment 28, Comment The singular term ‘‘use’’ is employed for that the substitution of a GRAS 30, Comment 31, and Comment 36). a simple and consistent presentation in notification procedure for the GRAS After considering these comments, we the regulatory text and does not mean, affirmation petition process would are replacing the GRAS affirmation for example, that you are limited to result in our increased awareness of the petition process with a GRAS notifying us about a single use of the composition of the nation’s food supply notification procedure, using the terms notified substance. and the cumulative dietary exposure to ‘‘conclude’’ and ‘‘conclusion’’ as We also are establishing in new GRAS substances. Most of these described in the 2010 notice. As noted subpart E the process we described in comments agree that such increased in the 2010 notice, the final rule uses the 2010 notice for administering awareness could be an advantage of the Plain Language tools such as pronouns. pending GRAS affirmation petitions. notification procedure if manufacturers To improve clarity and readability we Finally, we made editorial, clarifying, view our response to a GRAS notice as used another Plain Language tool, i.e., and conforming changes as shown in an incentive to participate in the the use of short regulatory sections that table 29. Because the editorial changes program. Many comments that support have limited subparagraph designations. associated with the redesignation of the the proposed replacement of the GRAS To do so we redesignated the single notification procedure in subpart E are affirmation petition process with a proposed section (i.e., proposed extensive, we do not list them in table GRAS notification procedure § 170.36) into several distinct, short 29. nonetheless raise questions about how sections of regulatory text in a newly we would administer the pending GRAS A. Affirmation on the Initiative of the established subpart E (GRAS Notice), affirmation petitions. We discuss those Commissioner with editorial changes associated with mstockstill on DSK3G9T082PROD with RULES2 comments in section XXIII. the new structure of the redesignated We proposed to amend current In the following sections, we discuss regulations. See table 4 for the section § 170.35(a) to clarify that the comments that disagree with one or numbers and titles of the regulatory text Commissioner would affirm the GRAS more aspects of our proposal to replace in subpart E. Many provisions of the status of a use of a substance, rather the GRAS affirmation petition process regulatory text in subpart E use singular than the substance itself, and to include with a GRAS notification procedure nouns when discussing the intended a grammatical change to place (see, e.g., Comment 24, Comment 25, use of the notified substance, e.g., the § 170.35(a) in the singular. The single VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00021 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 54980 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations comment that expressly addressed this data supporting the safety of the affirmation regulation, which would proposed amendment concurred with us ingredient and that the public should require rulemaking to revoke. on this point and we are finalizing it as also have access to these data. These We acknowledge that the term (i.e., proposed. comments also assert that the GRAS ‘‘evaluate’’) we use to describe our We also proposed to amend current affirmation petition process, in which actions when we receive a GRAS notice § 170.35(a) to remove the provision that we conduct a review of supporting data, is different from the term (i.e., ‘‘review’’) we may review the GRAS status of a provides an incentive to manufacturers we use to describe our actions when we substance added to food in response to to fully research each substance and that receive a petition (whether a food or a petition from an interested party. removing this incentive would color additive petition or a GRAS Under current § 170.35, such a petition compromise safety. Other comments affirmation petition). We decided to use would be submitted in accordance with assert that the GRAS notification a different term because, as already the provisions of the GRAS affirmation procedure would be less thorough than noted, the data and information we will petition process established in current the GRAS affirmation petition process. receive in a GRAS notice (i.e., summary § 170.35(c). We are deleting this data and discussions) are different from One comment states that consumers are provision as proposed. The comments the data and information we receive in concerned about the safety and we received relevant to our proposed a petition (which generally includes the wholesomeness of substances added to deletion of the petition-related underlying data from studies described provision in § 170.35(a) are directed to food and criticizes the proposed rule as in the petition). our proposed deletion of the GRAS not being ‘‘rigorous enough’’ and as not As discussed in Response 120, we affirmation petition process in current creating a ‘‘meaningful process for currently make a hyperlink to an § 170.35(c), and we discuss those adequately reviewing the safety of electronic copy of each GRAS notice comments in section VII.B. substances used in human and animal accessible from our Internet site and, food.’’ thus, the public has access to each B. Deletion of the GRAS Affirmation GRAS notice. We also make our (Response 25) We disagree that the Petition Process response to each GRAS notice accessible notification procedure is less protective We proposed to eliminate the GRAS of food safety than the affirmation from our Internet site (see § 170.275(b), affirmation petition process in current petition process. In the proposed rule, Response 115, and Response 116). We § 170.35(c). we stated that our response to a GRAS acknowledge that supporting data and (Comment 24) Several comments notice would not be equivalent to an information that are provided to us in oppose our proposal to eliminate the agency affirmation of GRAS status the form of a petition can provide the GRAS affirmation petition process. In because we would neither receive nor public with ready access to such data general, these comments assert that we review the detailed data and and information (e.g., through a FOIA should provide manufacturers the request), but disagree that substitution information that support the GRAS option of seeking GRAS affirmation of the GRAS notification procedure for determination (62 FR 18938 at 18951). even though we would be establishing the GRAS affirmation petition process These comments may have a new notification procedure. The has a fundamental impact on the misinterpreted that statement to mean comments assert that such an option is public’s access to supporting data and that we would not conduct a substantive essential to support the marketing of a information, because a conclusion of evaluation of the summary information product in certain situations, such as GRAS status must be based on generally that we receive in a GRAS notice. This when recognition of GRAS status is available data and information. Under is not the case. CFSAN’s 2010 needed by international standard-setting the notification procedure, the publicly bodies. experience document (Ref. 18) accessible GRAS notice both (Response 24) We acknowledge that a demonstrates that we have conducted a summarizes the available data and regulation listing the use of a substance substantive evaluation of the GRAS information and provides a list of in food could provide some support for notices that we received during the publicly available data and information marketing a product in certain Interim Pilot program. For example, (see §§ 170.250 and 170.255). Under the situations, but disagree that we should section III.C.1 of CFSAN’s 2010 GRAS affirmation petition process, we retain the GRAS affirmation petition experience document describes placed a copy of each publication process. We note that CFSAN filed more examples of situations in which we provided by the petitioner to support a than 600 GRAS notices during the time contacted a notifier to request conclusion of GRAS status in the public period 1998 through 2015 (Ref. 19), for clarification about data and information docket for that petition, but our current an average of approximately 34 GRAS in the notice. CFSAN’s 2010 experience practice with respect to copyrighted notices per year, including 69 GRAS document also demonstrates that during publications is to refer the public to the notices filed during 2014 and 51 GRAS the period 1998–2009 CFSAN had primary records (see § 20.51, Referral to notices filed during 2015. By contrast, questions about 21 percent of GRAS primary source of records). during that time CFSAN finalized six notices, such that CFSAN either We cannot say whether a petition GRAS affirmation regulations. We responded to the notifier that the process would provide an incentive for believe that the ongoing submission of submitted GRAS notice did not provide a manufacturer to more fully research GRAS notices is evidence that our a basis for a conclusion of GRAS status the safety of a substance before sending response to a GRAS notice can support or the notifier asked us to cease to a GRAS notice to us. However, we the marketing of a food substance. evaluate the GRAS notice (see section advise a manufacturer who intends to (Comment 25) Some comments assert III.B of CFSAN’s 2010 experience submit a GRAS notice to expect a mstockstill on DSK3G9T082PROD with RULES2 that the proposed GRAS notification document). Furthermore, we believe substantive evaluation of that GRAS procedure would be less protective of that the GRAS notification procedure notice by us. Likewise, we advise a food safety than the GRAS affirmation provides us with greater flexibility to manufacturer who reaches a conclusion petition process it would replace. Some respond to safety concerns that may that a substance is GRAS under the comments assert that our role in arise about a substance that is the conditions of its intended use, but does ensuring the safety of food ingredients subject of a GRAS notice, compared to not submit a GRAS notice to us, that is best carried out by a review of the a substance that is the subject of a GRAS when a substance is not GRAS under VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00022 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 54981 the conditions of its intended use (or is One comment asserts that the relative to the proposed rule, see table not otherwise excepted from the notification procedure would in no 2. definition of ‘‘food additive’’ in section manner be equivalent to the GRAS (Comment 27) One comment asks us 201(s) of the FD&C Act), that use of the affirmation petition process, and the to require the submission of a GRAS substance is a food additive use subject substitution of a notification procedure affirmation petition on a random basis to our premarket review as mandated by for a petition process would be anything for 20 percent of the GRAS notices we the FD&C Act. In such circumstances, but neutral. This comment asserts that receive. This comment states that such we can take various actions, including the proposed substitution of a a requirement would be essential in issuing a warning letter (which we make notification process for the affirmation light of our concurrent proposal to public on our Web site) to companies process would actually reduce the broaden the types of safety information that manufacture or distribute the food incentive for producers to notify FDA, that could support GRAS status in the additive and/or food containing the food because notification would invite criteria for eligibility for classification as additive; issuing a public alert; taking regulatory scrutiny without requiring GRAS through scientific procedures. enforcement action to stop distribution FDA to attest to a conclusion of GRAS The comment refers to this procedure as of the food substance and foods status. a ‘‘verification audit’’ and describes a containing it on the grounds that such (Response 26) We disagree that the ‘‘verification audit’’ as a detailed foods are or contain an unlawful food notification procedure we are evaluation of the scientific data and additive; and issuing a declaratory order establishing in this rule will reduce the other technical information. The determining that the substance is not incentive for producers to notify us. As comment asks that the final rule give GRAS under the conditions of its already noted in Response 24, CFSAN FDA such ‘‘verification authority’’ and intended use and is a food additive has filed more than 600 GRAS notices asserts that such a verification system subject to section 409 of the FD&C Act. between 1998 and 2015, for an average would give consumers greater For example, as already discussed in of approximately 34 GRAS notices per confidence that the new notification section I.D, we recently issued a year. In contrast, as discussed in section system was not just a system of declaratory order making a final IV.L of CFSAN’s 2010 experience deregulation. determination that there is no longer a document (Ref. 18), between 1987 and (Response 27) We decline this consensus among qualified experts that 1996 CFSAN received a total of fewer request. Both the GRAS notification PHOs are GRAS for any use in human than 100 GRAS affirmation petitions, procedure and the GRAS affirmation food (80 FR 34650). As another example with an average of approximately 8 petition process that it is replacing are discussed in section I.D, we have issued GRAS affirmation petitions per year. voluntary procedures and, thus, the warning letters informing four These data support the expectation we comment’s position that we could expressed in the proposed rule that the require a GRAS affirmation petition—on companies marketing caffeinated substitution of a GRAS notification a random or any other basis—is alcoholic beverages that caffeine, as procedure for the GRAS affirmation incorrect. Moreover, we disagree that used in the companies’ products, is an petition process would result in our the revised criteria for eligibility for unsafe food additive, and therefore the increased awareness of the composition GRAS status through scientific products are adulterated under section of the nation’s food supply and the procedures have any bearing on whether 402(a)(2)(C) of the FD&C Act (Ref. 10 cumulative dietary exposure to GRAS we should evaluate a conclusion of through Ref. 13), and the companies substances. GRAS status through a notification subsequently ceased distribution of The comments that predict that we procedure or a petition process. The these products. Thus, we advise any would need to modify the final rule revised criteria reflect the nature of manufacturer or distributor to carefully substantially to achieve increased substances being added to food, and the consider whether there is adequate awareness of the nation’s food supply fact that the quantity and quality of support for concluding that a substance did not suggest specific modifications scientific evidence required to is GRAS under the conditions of its for this purpose. However, this demonstrate safety vary considerably intended use and to submit its document discusses the changes we depending upon the estimated dietary conclusion of GRAS status to us in the have made to the proposed notification exposure to the substance and the form of a GRAS notice. procedure as a result of comments, chemical, physical, and physiological (Comment 26) A few comments described in this document and the properties of the substance. See express skepticism that the substitution 2010 notice, that raised specific issues Response 23. of a GRAS notification procedure for the and concerns regarding the proposed GRAS affirmation petition process notification procedure. For example, the C. General Comments on the Proposed would result in our increased awareness final rule defines the term GRAS Notification Procedure of the composition of the nation’s food ‘‘amendment’’ (§ 170.203) and expressly (Comment 28) Some comments ask us supply and the cumulative dietary provides that a notifier may submit a to require that companies notify us of a exposure to GRAS substances. These timely amendment to address our conclusion of GRAS status and assert comments assert that the proposed questions (§ 170.260(a)). As another that we have implied legal authority to notification procedure offered a risk example, the final rule expressly require such notification. These (i.e., the risk of a publicly available provides that a notifier may ask us to comments express concern that ‘‘insufficient basis letter’’) without the cease to evaluate a GRAS notice potentially dangerous substances could potential benefit that was available (§ 170.260(b)). In addition, see Response enter the food supply without our under the petition process (i.e., a 80 regarding our willingness to engage knowledge or supervision. Other mstockstill on DSK3G9T082PROD with RULES2 regulation affirming GRAS status). with a notifier to clarify particular comments emphasize that the GRAS These comments predict that, unless we aspects of the notice and Response 96 notification procedure should remain modify the proposed rule substantially, and Response 97 regarding comments voluntary and assert that we lack we likely would have less awareness of that raise concerns about a publicly express statutory authority to require GRAS substances under the notification available insufficient basis letter. For a companies to submit GRAS notices. procedure than we currently have under summary of the principal changes to the (Response 28) We agree that we lack the GRAS affirmation petition process. notification procedure in this final rule express statutory authority to require VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00023 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 54982 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations companies to submit GRAS notices. In the food industry is actively submitting petition because they have concluded creating the premarket approval GRAS notices. As already noted in that the substance is GRAS under the requirement for food additives in the Response 26, we believe that our filing conditions of its intended use; this 1958 amendment, Congress excluded a of more than 600 GRAS notices for possibility exists regardless of how we substance that is GRAS under the substances used in human food is structure the GRAS notification conditions of its intended use from the evidence that we have increased our procedure. However, a manufacturer’s definition of food additive. The creation awareness of the composition of the decision that a food additive petition is of this GRAS provision reflected nation’s food supply and the dietary not required must be based on the Congress’ determination that many exposure to GRAS substances. extent to which the manufacturer has substances intentionally added to food (Comment 30) Some comments ask us information both that the intended for a specific use do not need premarket to require certain postmarket conditions of use of a substance in food review by FDA to ensure their safety, submissions of exposure and safety data are ‘‘safe,’’ and that there is ‘‘general either because their safety has been related to all GRAS substances, to recognition’’ of that safety. In this rule, established by a long history of use in require submissions for conclusions of we clarify the criteria (§ 170.30) that food, or because their safety has been GRAS status that predate the final rule, govern when the intended conditions of established by information that is and to require any notifier who use of a substance in food are more generally available to and accepted by ‘‘withdraws’’ a GRAS notice or receives properly the subject of a food additive qualified experts, regarding the an ‘‘insufficient basis letter’’ to notify us petition than a GRAS notice. intended conditions of use of a about any use of that substance. The record of our actions during the substance in food. Subsequently, in (Response 30) We decline this request Interim Pilot program demonstrates that 1997, the Food and Drug Administration for the same reasons that we discuss in we will, when appropriate, issue an Modernization Act (FDAMA) amended Response 28. See also the discussions in ‘‘insufficient basis letter’’ or a ‘‘cease to section 409 of the FD&C Act to require Response 25 and Response 35 regarding evaluate letter’’ signaling that a petition the establishment of a mandatory food the responsibility of a manufacturer to to obtain a regulation is more contact notification program for human ensure that a substance added to food appropriate than a GRAS notice. As food. By contrast, Congress has not complies with the FD&C Act, and the described in sections III.A.4 and III.N.2 amended section 409 of the FD&C Act potential that we may disagree with a of CFSAN’s 2010 experience document to require the establishment of a conclusion of GRAS status and take (Ref. 18), in several cases during the premarket GRAS notification regulatory action against use of the food Interim Pilot program the outcome of procedure—either voluntary or substance when we do so. CFSAN’s review of a GRAS notice was mandatory. (Comment 31) Some comments ask us the notifier’s subsequent submission of We did not propose to require the to clarify all the information we expect a food additive petition. submission to FDA of notices to be submitted in a GRAS notice. One (Comment 33) One comment concerning all conclusions of GRAS comment states its opposition for the expresses the opinion that a GRAS status. We recognize that some proposed GRAS notification procedure, notice could be an appropriate comments suggest that such a but also states that if we implement mechanism to inform us of a view that requirement might be within our legal such a program we should establish the an additional use of an approved food authority, even if not expressly required framework and criteria for the voluntary additive is GRAS. by the FD&C Act. We will consider submission of GRAS notices. Another (Response 33) We agree, provided that these comments and our experience comment asks us to include core the available data and information under this final rule in evaluating what, requirements in the final rule. Another demonstrate that the criteria for GRAS if any, further action is needed with comment asks us to provide more status are satisfied. Whether an respect to ensuring the safety of the food explicit instructions concerning the additional use of a food additive is supply. However, mandating level of detail necessary within the GRAS depends on both whether that submission of GRAS notices would required elements of a GRAS notice. additional use is safe and on whether need to be done in a separate (Response 31) Subpart E of part 170 the safety of that additional use is rulemaking to ensure adequate notice (subpart E) establishes a comprehensive generally recognized by qualified and comment. framework for the submission of GRAS experts. To support a conclusion of (Comment 29) One comment notes notices, describing in detail ‘‘core GRAS status for the additional use of that the proposed rule did not requirements’’ such as the seven distinct the substance, there must be evidence specifically ask members of the food parts of a GRAS notice. Subpart E also that qualified experts generally (not industry to notify us of all conclusions includes provisions that will govern solely FDA experts who conducted a of GRAS status. This comment suggests what we will do when we receive a premarket review of a food additive that the final rule include such a GRAS notice, as well as provisions that petition) have evaluated generally request, explaining that such a will govern disclosure of a GRAS notice. available data and information about the provision would help us to achieve our Section 170.30 establishes the revised intended conditions of use of the goal of increasing our awareness of criteria for eligibility for classification of substance, and reached agreement that substances added to food. the food use of a substance as GRAS. those generally available data and (Response 29) We view our (Comment 32) One comment information establish the safety of the establishment of the GRAS notification expresses concern that the proposed additional use of the substance. During procedure in this final rule, as well as GRAS notification procedure would be the Interim Pilot program, CFSAN our announcement of the Interim Pilot viewed as a ‘‘fast-track’’ option that received several GRAS notices mstockstill on DSK3G9T082PROD with RULES2 program in the proposed rule, as an would tempt a company that should informing CFSAN of a conclusion that invitation to industry to submit GRAS submit a food additive petition to an additional use of an approved food notices to us for evaluation. See also submit a GRAS notice instead. additive is GRAS. As discussed in § 170.205, entitled ‘‘Opportunity to (Response 32) We recognize that there section III.A.4 of CFSAN’s 2010 submit a GRAS notice.’’ The ongoing is a possibility that some manufacturers experience document (Ref. 18), submission of GRAS notices during the of food ingredients may decide that they CFSAN’s response to these GRAS Interim Pilot program demonstrates that do not need to submit a food additive notices has been a case-by-case response VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00024 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 54983 that depends on the circumstances. In additive, and we may take action to visit these scientific guidance several cases, CFSAN had no questions remove the substance from the food documents to determine whether and about the notifier’s conclusion of GRAS supply. how to modify them to clarify that our status for an additional use of a food See also the discussion in Response guidance on evaluating the safety of a additive; in one case, the GRAS notice 80. Our experience during the Interim food substance generally applies did not support GRAS status for the Pilot program demonstrates that we are regardless of whether the substance additional use of the food additive, and willing to contact a notifier to clarify would be used in food as a food additive the notifier subsequently submitted a particular aspects of a GRAS notice. As or as a GRAS substance. food additive petition for the additional also discussed in Response 80, under Recently, we issued a notice (79 FR use of the substance. the final rule, we intend to contact a 64603, October 30, 2014) announcing a (Comment 34) One comment suggests notifier when we identify a safety public meeting, and requesting that the GRAS notification procedure concern. However, whether the purpose comments, on our intent to update our would shift the burden of proof to FDA of the contact is to provide an guidance entitled ‘‘Guidance for to demonstrate that a use of a substance opportunity to address that concern Industry and Other Stakeholders: is not safe or not GRAS after the (e.g., in an amendment or in a newly Toxicological Principles for the Safety substance is already on the market. submitted GRAS notice), or to alert the Assessment of Food Ingredients’’ (Ref. (Response 34) We disagree. Under the notifier to our concerns while we 35; commonly referred to as our FD&C Act, the burden of supporting a prepare an ‘‘insufficient basis letter,’’ ‘‘Redbook’’). In that notice, we reiterated conclusion that a substance is GRAS has been, and will continue to be, a that general recognition of safety based under the conditions of its intended use matter committed to our discretion upon scientific procedures requires the is on the proponent of this conclusion. depending on the totality of the same quantity and quality of evidence United States v. An Article of Food, 752 circumstances. as is required to approve a food F.2d 11, 15 (1st Cir. P.R. 1985). This (Comment 36) One comment suggests additive. We also asked for comment on burden of proof remains after the that we ask notifiers who previously how we should balance the desire for substance is on the market regardless of received a ‘‘no questions letter’’ under transparency and consistency in risk whether the proponent asks FDA to the Interim Pilot program to review their assessment, as described in the evaluate that GRAS conclusion, and our prior submissions and align them with Redbook, with the goal of flexibility in rule does not change this. By the requirements of the final rule. applying the most appropriate analysis establishing a process for the (Response 36) We decline this for specific contexts. submission of GRAS notices for FDA to suggestion. The final rule does not pose any substantially different data (Comment 38) One comment states review, our rule encourages firms to requirements than did the Interim Pilot that the resource-intensive petition seek our evaluation of their conclusions, before they introduce the substance into program in terms of data quality and process would be reserved for the market. quantity to support the conclusion of ingredients not eligible to meet GRAS (Comment 35) A few comments note GRAS status. We do not anticipate, as a criteria, or those which pose questions that a notifier who markets a food general matter, the need to ask previous necessitating indepth review by FDA substance before we issue our letter notifiers who received a ‘‘no questions scientists, even though the safety responding to the notice runs the risk letter’’ to provide any supplemental standard for GRAS ingredients and food that we may disagree with the information. However, if we become additives is the same. conclusion of GRAS status. One aware of data or information that (Response 38) The comment is correct comment expresses concern that we questions the GRAS status of the use of that a food additive petition would be would take regulatory action to remove a substance that has been the subject of required for an ingredient that is not the substance from the food supply a ‘‘no questions letter,’’ we may send the eligible for classification as GRAS and is rather than discuss our concerns with notifier a subsequent letter advising the not otherwise excepted from the the notifier. notifier of those questions (see statutory definition of a food additive. (Response 35) The comments are § 170.265(c)). Because we would make We agree that indepth review of the correct that a notifier who markets a the subsequent letter readily accessible safety of a substance under the food substance before we issue our letter to the public (see § 170.275(b)(2)), other conditions of its intended use in food by based on our evaluation of the notice stakeholders would have ready access to FDA scientists is necessary when there runs the risk that we may disagree with those questions. is no basis for a conclusion that the the conclusion of GRAS status. (We note (Comment 37) One comment states intended conditions of use have GRAS that a manufacturer who markets a food that GRAS ‘‘determinations’’ must be status. However, see Response 25. Our substance without submitting a GRAS evaluated based on adequate science evaluation of a GRAS notice is a notice runs a similar risk.) However, we and recommends that GRAS substantive evaluation even though we make every effort to evaluate the data ‘‘determinations’’ comply with our respond to a GRAS notice by letter and information submitted on a timely guidance on food additive testing. rather than by establishing a regulation. basis, and in this rule we commit to (Response 37) We agree that safe (Comment 39) One comment asserts responding to a GRAS notice within 180 use(s) of a substance must be supported that we tentatively concluded that the days after filing the notice, with the by adequate science. We do have proposed notification procedure would option to extend an additional 90 days extensive guidance on food additive allow us to direct our resources to the as needed. Because a substance that is testing (Ref. 31 through Ref. 35), and we more significant questions about GRAS GRAS under the conditions of its agree that this guidance on food status, without further explaining what mstockstill on DSK3G9T082PROD with RULES2 intended use is not subject to premarket additive testing can be useful in the these ‘‘more significant questions’’ are. review as a food additive under the evaluation of the safety of a substance This comment further asserts that the FD&C Act, a notifier could decide to when the proponent of the substance obvious conclusion is that we will introduce the substance into the market seeks to demonstrate that the substance simply reduce the Federal layer of without waiting for the letter; we could is GRAS under the conditions of its oversight in the interests of efficiency subsequently determine that the intended use. As discussed in Response and in doing so ignore the history of substance is an unapproved food 128, as resources allow we intend to re- food law, which has repeatedly shown VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00025 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 54984 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations that the public suffers when FDA D. Comments on Certain Terms Used in use the terms ‘‘determine’’ and declines to regulate. the Proposed Regulatory Text ‘‘determination’’ (see the changes to (Response 39) See the actions we §§ 170.3(k), 170.30(c)(1), and 170.30(e) describe in section I.D, on PHOs and 1. Replacing the Terms ‘‘Determine’’ and ‘‘Determination’’ With the Terms in table 29). We are making these caffeinated alcoholic beverages, for conforming changes to clarify that there examples of what we mean by ‘‘more ‘‘Conclude’’ and ‘‘Conclusion’’ would be no distinction between a significant questions.’’ We disagree that In the 2010 notice, we explained our conclusion of GRAS status submitted to directing our resources in such a reasons for tentatively concluding that us as a GRAS notice and a conclusion manner reduces our oversight; on the the terms ‘‘conclude’’ and ‘‘conclusion’’ of GRAS status that remains with its contrary, such actions demonstrate that would be more appropriate in lieu of proponent as an independent we will take appropriate steps to ‘‘determine’’ and ‘‘determination’’ and conclusion (formerly referred to as a address concerns about the safety of requested comment on these terms (see ‘‘self-determination’’) of GRAS status. substances marketed under the GRAS Issue 2, 75 FR 81536 at 81538). provision of the FD&C Act. The (Comment 41) Many comments 2. The Terms ‘‘Exempt,’’ ‘‘Exemption,’’ comment provides no basis for its support replacing the terms and ‘‘Claim’’ assertion that the notification procedure ‘‘determine’’ and ‘‘determination’’ with ignores the history of food law or that the terms ‘‘conclude’’ and ‘‘conclusion.’’ Several provisions in the proposed the public will suffer. One comment disagrees with changing rule would use terms such as ‘‘exempt,’’ (Comment 40) One comment points the terms ‘‘determine’’ and ‘‘exemption,’’ and ‘‘claim.’’ out that our response to a GRAS notice ‘‘determination.’’ This comment asserts (Comment 42) Several comments addresses the question of whether a that the terms ‘‘determine’’ and object to some terms used in the particular use of a notified substance is ‘‘determination’’ are more appropriate proposed procedure for submitting a GRAS, without limiting that question to because a determination is made based GRAS notice. Some comments object to production of that food substance by a on the sum of the total assembled data proposed title for the GRAS notification specific manufacturer (e.g., the notifier and conclusions. This comment also procedure, i.e., ‘‘Notice of a claim for who submitted the GRAS notice). This disagrees with changing the terms exemption based on a GRAS comment asks us to require that any because individuals who already are determination.’’ Most of these other food producer who uses the involved in the GRAS notification comments also object to our substance in food on the basis of a procedure as a result of the Interim Pilot characterization of one of the proposed GRAS conclusion submitted to FDA in program are already familiar with the provisions (proposed § 170.36(c)(1)) as a a GRAS notice meet all requirements terms and meanings of ‘‘determine’’ and ‘‘GRAS exemption claim.’’ In general, and specifications in the submitted ‘‘determination.’’ these comments assert that nothing in GRAS notice, including use of the same One comment observes that the terms the FD&C Act or in the legislative source for the production of the food ‘‘determined’’ and ‘‘determination’’ are history of the FD&C Act supports substance. used in § 170.30 of our regulations designation of GRAS status as an (Response 40) The comment is correct within the context of establishing GRAS ‘‘exemption.’’ In addition, several that our response to a GRAS notice status. This comment asks us to clarify comments object to our use of the term would not limit a food producer other how we would apply the terms ‘‘claim’’ in various proposed provisions than the notifier from relying on the ‘‘determined,’’ ‘‘determination,’’ because our use of this term implies that submitted GRAS notice, and our ‘‘conclude,’’ and ‘‘conclusion’’ and we have legal authority to deny a claim response to that GRAS notice, when that whether we would limit how some or that GRAS status is not operative food producer concludes that a terms apply depending on whether a unless a claim is filed. substance is GRAS under the conditions substance is the subject of a GRAS of its intended use in food. The method notice. This comment expresses concern (Response 42) We have made the of manufacture (including any source that such a distinction in terms could following editorial changes throughout specified for the production of the lead to a misperception that a substance the regulatory text to no longer use notified substance) and specifications that is the subject of a GRAS notice has terms such as ‘‘exempt,’’ ‘‘exemption,’’ identified in a GRAS notice are relevant a more authoritative and/or superior and ‘‘claim.’’ First, we replaced the term to both the identity of the substance and legal standing than a substance that ‘‘exempt’’ with the phrase ‘‘not subject its safety for use in food. We advise any does not. to.’’ Section 201(s) of the FD&C Act food producer who relies on a GRAS (Response 41) We are replacing the provides that a substance that is GRAS notice submitted by another person to term ‘‘determination’’ with under the conditions of its intended use carefully consider whether its ‘‘conclusion,’’ and referring to a is not within the definition of food production process, and/or the intended ‘‘conclusion of GRAS status’’ rather than additive. Whether the statutory GRAS conditions of use of the notified to a ‘‘GRAS determination,’’ throughout provision in section 201(s) is an substance, fall within the parameters, the regulatory text for the GRAS ‘‘exemption,’’ or, is an ‘‘exclusion,’’ is such as method of manufacture notification procedure. We recognize not essential to this rulemaking and, (including a specified source) and that notifiers involved with the GRAS thus, we need not include any specifications, addressed by the notification procedure may be more variations of the term ‘‘exempt’’ in the submitted GRAS notice. We recently familiar with the terms ‘‘determine’’ and final rule. Second, we replaced the term issued guidance to help food producers ‘‘determination.’’ Nevertheless, we ‘‘claim’’ (when used as a noun) with the to do so. See our guidance entitled believe that as notifiers gain more term ‘‘view.’’ In the past, we have used mstockstill on DSK3G9T082PROD with RULES2 ‘‘Assessing the Effects of Significant experience with the GRAS notification the term ‘‘view’’ when describing a Manufacturing Process Changes, procedure set forth in this final rule, statement or assertion that a use of a Including Emerging Technologies, on notifiers will adjust to using substance is GRAS (see, e.g., 62 FR the Safety and Regulatory Status of Food ‘‘concludes’’ and ‘‘conclusion.’’ 36749, July 9, 1997). Finally, we Ingredients and Food Contact We are making conforming changes to simplified the title of the regulatory text Substances, Including Food Ingredients current regulations regarding the use of to ‘‘Generally Recognized as Safe that Are Color Additives’’ (Ref. 6). GRAS substances in food to no longer (GRAS) Notice.’’ VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00026 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 54985 E. Comments on the Use of ‘‘Plain throughout the Federal Government’s procedure, leading to a more effective Language’’ in the Regulatory Text programs and activities as set out in program. ‘‘Improving Electronic Dockets on (Response 43) We have used ‘‘Plain In the 2010 notice, we noted our Regulations.gov and the Federal Docket intent to use ‘‘Plain Language’’ tools Language’’ tools (such as short sections Management System: Best Practices for such as pronouns in the final rule (75 and the use of pronouns) throughout the Federal Agencies’’ (Ref. 22). FR 81536 at 81537). The use of ‘‘Plain (Comment 43) One comment regulatory text of subpart E, which Language’’ tools in government writing, recommends that we use Plain Language establishes the requirements for the now called ‘‘plain writing,’’ is throughout the regulatory text to foster GRAS notification procedure. See table consistent with the government-wide greater understanding about the 4 for the section numbers and titles of initiative to promote transparency, regulatory requirements and the redesignated regulatory text in public participation, and collaboration expectations for the notification subpart E. TABLE 4—REDESIGNATION OF THE GRAS NOTIFICATION PROCEDURE IN SUBPART E Section Title 170.203 ............. Definitions. 170.205 ............. Opportunity to submit a GRAS notice. 170.210 ............. How to send your GRAS notice to FDA. 170.215 ............. Incorporation into a GRAS notice. 170.220 ............. General requirements applicable to a GRAS notice. 170.225 ............. Part 1 of a GRAS notice: Signed statements and certification. 170.230 ............. Part 2 of a GRAS notice: Identity, method of manufacture, specifications, and physical or technical effect. 170.235 ............. Part 3 of a GRAS notice: Dietary exposure. 170.240 ............. Part 4 of a GRAS notice: Self-limiting levels of use. 170.245 ............. Part 5 of a GRAS notice: Experience based on common use in food before 1958. 170.250 ............. Part 6 of a GRAS notice: Narrative. 170.255 ............. Part 7 of a GRAS notice: List of supporting data and information in your GRAS notice. 170.260 ............. Steps you may take before FDA responds to your GRAS notice. 170.265 ............. What FDA will do with a GRAS notice. 170.270 ............. Procedures that apply when the intended conditions of use of a notified substance include use in a product or products sub- ject to regulation by FSIS. 170.275 ............. Public disclosure of a GRAS notice. 170.280 ............. Submission of a supplement. 170.285 ............. Disposition of pending GRAS affirmation petitions. VIII. Definitions Applicable to a GRAS ‘‘GRAS notification’’ appear to be used would think that submitting a GRAS Notice interchangeably in the 2010 notice and notice likewise implies ‘‘exclusivity’’ for asks whether it is our intention to use the substance. The comment notes that A. Definitions We Described in the 2010 ‘‘notice,’’ ‘‘notification,’’ or both terms FDA is not responsible for Notice with regard to the proposed procedure misinterpretations made by industry, In the 2010 notice, we requested for submission of a conclusion of GRAS but asks us to recognize this lack of comment on definitions for the terms status for a use of a food substance. transparency and clarity and remedy it ‘‘amendment,’’ ‘‘notified substance,’’ in a fair and equitable manner. ‘‘notifier,’’ ‘‘qualified expert,’’ and Another comment notes that the proposed rule to establish a GRAS (Response 44) In the proposed rule ‘‘supplement’’ (see Issue 3, 75 FR 81536 notification procedure was followed and in this final rule, we use the term at 81538). We received several soon thereafter by the rulemaking to ‘‘notice’’ as a noun to refer to the comments that generally support adding establish the premarket notification submission that you send to us and we definitions for these terms, and we are program for food contact substances as use the term ‘‘notification’’ as an establishing a section in the regulatory authorized by FDAMA (the FCN adjective, e.g., to modify the noun text of subpart E to define these and program; proposed rule 65 FR 43269, ‘‘procedure.’’ In contrast, the FCN other terms (see § 170.203). July 13, 2000; final rule 67 FR 35724, program uses the term ‘‘notification’’ as B. Definition of ‘‘GRAS Notice’’ May 21, 2002). This comment asserts a noun in addition to using the term as (Comment 44) Some comments that although the proposed GRAS an adjective, consistent with FDAMA’s express concern about the potential for notification procedure and the use of the term as a noun. We continue confusion between the proposed GRAS established FCN program are distinct, to use the term ‘‘notification’’ as an notification procedure and another FDA industry reasonably relied on the close adjective (e.g., GRAS notification ‘‘notification program’’, i.e., the temporal proximity of the 1997 procedure) in this preamble discussion premarket notification program for food proposed rule to establish a GRAS of the requirements for submitting a contact substances (in part 170, subpart ‘‘notification’’ procedure, and the GRAS notice. However, in the D) that we established under FDAMA. rulemaking to establish the FCN regulatory text we only use the term mstockstill on DSK3G9T082PROD with RULES2 These comments assert that this program, as contemporaneous guidance ‘‘notice,’’ and we have added a confusion can lead to uncertainty about for the meaning of the term definition of the term ‘‘GRAS notice’’ to the nature of the proposed GRAS ‘‘notification’’ under FDAMA. Because the regulatory text (see § 170.203). notification procedure, such as with the FCN program provides market The ‘‘exclusivity’’ within the FCN respect to market ‘‘exclusivity’’ for the ‘‘exclusivity’’ for the food contact program is provided by section notified substance. One comment states substance, the comment asserts that it is 409(h)(2)(C) of the FD&C Act. See also that the terms ‘‘GRAS notice’’ and understandable why regulated industry our implementing regulation at VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00027 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 54986 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations § 170.100(a), which provides that a FCN a particular use of a substance is exempt to reference a previously submitted is effective for the food contact from the statutory premarket approval GRAS notice to support a view that an substance manufactured or prepared by requirements based on the notifier’s additional use of the applicable the manufacturer or supplier identified determination that such use is generally substance is GRAS. We also discussed a in the FCN submission. There is no recognized as safe (GRAS) (proposed coordinated evaluation process with similar provision in the FD&C Act or § 170.36(a)). We are establishing this FSIS when the use of a notified our regulations providing exclusivity for statement of an opportunity to submit a substance includes use in products a substance that is used in food based GRAS notice in § 170.205, with the subject to regulation by FSIS. (Note that on a conclusion that the substance is editorial changes described in Response the discussion in the 2010 notice GRAS under the conditions of its 41 and Response 42. referred to a ‘‘coordinated review intended use. X. Comments on Administrative process.’’ As discussed in Response 25, C. Other Terms We Are Defining in the Procedures for Submission of a GRAS we are using the term ‘‘evaluation’’ Rule Notice rather than ‘‘review’’ in connection with We are defining the abbreviation GRAS notices. In addition, in a We proposed that a notice of a ‘‘GRAS Memorandum of Understanding (MOU) ‘‘GRAS’’ to mean ‘‘generally recognized exemption claim’’ be submitted in between FDA and FSIS (Ref. 36), we as safe’’ so that we can use that triplicate to a specified address abbreviation throughout the regulatory specify that we will inform the notifier (proposed § 170.36(b)). We also asked text without defining it in each section in writing that the notice will also be for comment on whether it would be where it appears. To clarify how ‘‘evaluated’’ by FSIS to determine the appropriate to require or recommend pronouns apply in the regulatory text, suitability of the use of the substance in that the submission include an we also are specifying in the definition the production of meat, poultry, or egg electronic copy in addition to the three section that ‘‘you’’ and ‘‘your’’ refer to products. Given the discussion in paper copies (62 FR 18938 at 18946) or, a notifier, and that ‘‘we,’’ ‘‘our,’’ and Response 25 and the terms of the MOU at a minimum, an electronic copy of the ‘‘us’’ refer to FDA. with FSIS, in this document, we use the proposed ‘‘GRAS exemption claim’’ IX. Opportunity To Submit a GRAS (proposed § 170.36(c)(1); final § 170.225 term ‘‘coordinated evaluation’’ rather Notice (part 1 of a GRAS notice). than ‘‘coordinated review.’’) We asked We proposed to provide that any In the 2010 notice, we described for comment relevant to these person may notify FDA of a claim that comments asking us to permit a notifier administrative procedures (see table 5). TABLE 5—ISSUES IN THE 2010 NOTICE RELEVANT TO PROCEDURES FOR ADMINISTERING A GRAS NOTICE Issue Description of our request for comment Reference No. 4 ........ Whether the final rule should include a provision to expressly permit a notifier to incorporate into a 75 FR 81536 at 81538. GRAS notice data and information that were previously submitted by the notifier, or public data and information submitted by another party, when such data and information remain in our files. 13 ...... Whether a notifier who submits a GRAS notice for such a substance should provide an additional 75 FR 81536 at 81541–81542. paper copy or an electronic copy of the GRAS notice that we could send to FSIS. Several comments support the electronic format that is accessible for mailing address and the editorial administrative procedures that we our evaluation or on paper; for paper changes described in Response 42. See proposed or described in the 2010 submissions, a single paper copy of a the regulatory text in § 170.210(a). notice. For example, several comments GRAS notice is sufficient. (Comment 45) One comment asserts support adding a provision to allow a We also are finalizing a provision to that a single GRAS notice to either notifier to incorporate information into allow for incorporation into a GRAS CFSAN or CVM should suffice to inform a GRAS notice, including data and notice of data and information as both Centers of a conclusion of GRAS information previously submitted by the described in the 2010 notice, with status. clarification that the referenced data and (Response 45) We disagree. Our notifier and public data and information information must be specifically regulations directed to human food are submitted by another party, because identified. As discussed in the 2010 established in subchapter B of 21 CFR such a provision would be practical, (i.e., Food For Human Consumption, notice, the provision specifies that promote administrative efficiency, or parts 100–199), whereas our regulations incorporation into a GRAS notice reduce paper. In the following sections, directed to animal food are established applies only when data and information we discuss comments that disagree with in subchapter E of 21 CFR (i.e., Animal remain in our files. We do not retain one or more aspects of the records indefinitely; rather, records may Drugs, Feeds, And Related Products, administrative procedures that we be retired to a Federal Records Center parts 500–599). We have separately proposed or described as potential and subsequently disposed of in established requirements applicable to modifications in the 2010 notice (see, accordance with our Records Control GRAS substances for use in human food e.g., Comment 45); ask us to clarify Schedule. in subchapter B of 21 CFR (e.g., in parts mstockstill on DSK3G9T082PROD with RULES2 these administrative procedures (see, 170, 182, 184, and 186) and e.g., Comment 48 and Comment 49); or A. How To Send a GRAS Notice to FDA requirements applicable to GRAS suggest one or more changes to these We proposed to specify in the substances for use in animal food in administrative procedures (see, e.g., regulatory text the address where you subchapter E of 21 CFR (e.g., in parts Comment 47). After considering these would send a GRAS notice. We are 570, 582, and 584). We also had comments, we are providing that you finalizing this administrative provision separately established requirements for may submit a GRAS notice either in with updates to reflect the current the GRAS affirmation petition process VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00028 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 54987 (which the GRAS notification procedure an electronic copy generated by paper to create an electronic pdf version is replacing) for substances for use in scanning a paper document into of the GRAS notice, and we make the human food in subchapter B of 21 CFR ‘‘Portable Document Format’’ (‘‘pdf’’) electronic pdf document available to all (i.e., in § 170.35(c)) and requirements requires Optical Character Recognition staff who will evaluate the GRAS notice. applicable to the GRAS affirmation before it can be searched electronically. This procedure has reduced the petition process for substances for use Furthermore, the Government resources needed to distribute the GRAS in animal food in subchapter E of 21 Paperwork Elimination Act of 1998 notice to our staff, and we intend to CFR (i.e., in § 570.35(c)). We address (Pub. L. 105–277, Title XVII) requires continue to use this procedure when we food substances separately for human Federal agencies to give persons who receive a GRAS notice on paper. When use and for animal use because the correspond with these agencies the we coordinate our evaluation of a GRAS safety evaluation of a food substance option of doing so electronically when notice with FSIS, we send an electronic relates to the conditions of its intended practicable as a substitute for paper, and copy to FSIS and, thus, an additional use, and the conditions of use of a to use electronic authentication paper copy for use by FSIS is not substance in human food can raise (electronic signature) methods to verify necessary. different safety questions than the the identity of the sender and the (Comment 47) One comment conditions of use of that same substance integrity of the electronic content. We expresses concern about the security of in animal food. For example, a acknowledge that technology may not confidential information in an substance containing copper can be be available to every notifier and, thus, electronic submission. This comment safely used in human food and in food the final rule does not require the asks us to allow a notifier to edit an for many animal species, but even small submission of an electronic copy. electronic copy to remove confidential amounts of copper can be toxic to Instead, the final rule provides that information and present that sheep. As another example, FDA has when you submit your GRAS notice, information only in the paper copy. affirmed that several uses of propylene you may do so either in electronic Another comment asks us to provide the glycol in human food are GRAS format that is accessible for our same protections that would apply to (§ 184.1666), but propylene glycol is evaluation or on paper (see confidential information in written known to be toxic to cats and FDA has § 170.210(b)). Because you have an records to confidential information in prohibited its use in cat food (see option to submit a GRAS notice either electronic records. § 589.1001). Therefore, the final rule electronically or on paper, an electronic (Response 47) We decline the request establishes separate (albeit parallel) copy will essentially replace the need to allow you to edit an electronic copy requirements for submission of a GRAS for a paper copy. In 2010, CFSAN issued of your GRAS notice such that the notice to CFSAN for the use of a draft guidance for how to transmit a electronic copy would differ from the substance in human food and for submission, including a GRAS notice, in paper copy. If you have concerns about submission of a GRAS notice to CVM for electronic format (Ref. 37). the security of confidential information the use of a substance in animal food. We used electronic means to make in an electronic submission, you have submitted GRAS notices accessible to the option to send the GRAS notice on B. Option for Submission of Electronic the public during the Interim Pilot paper (see Response 46). The or Paper Copies of a GRAS Notice program, and intend to continue to do protections applicable to confidential (Comment 46) Most of the comments so under the final rule. However, we information are the same regardless of that responded to our request for decline the request to require that the whether the information is in written or comment on the submission of an submission include an electronic copy electronic form (see part 20, ‘‘Public electronic copy of a GRAS notice solely because we are doing so. We Information’’). In particular, under encourage us to recommend, but not acknowledge that an electronic copy § 20.20(e), ‘‘Policy on disclosure of Food require, submission of an electronic will improve the efficiency with which and Drug Administration records,’’ the copy, explaining that an electronic copy we make GRAS notices available to the term ‘‘record’’ (as well as any other term would make our administration of the public (see the public disclosure used in § 20.20 in reference to notification procedure more efficient. provisions of this rule in § 170.275). information) includes any information However, one comment notes that However, during the Interim Pilot that would be an agency record electronic technology may not be program we made an electronic copy of maintained by the Agency in any universally available. As discussed in a submitted GRAS notice available on format, including an electronic format. Comment 47, another comment the Internet by scanning the paper In addition, the final rule requires you expresses concern about protection for GRAS notice to create an electronic pdf to state in writing your view as to confidential information in an document, and we intend to continue to whether any of the data and information electronic copy. One comment suggests do so when you submit a GRAS notice in your GRAS notice are exempt from that if we use an electronic means to on paper under the final rule. disclosure under FOIA (e.g., as trade make GRAS notices readily accessible to We have decided that a single copy of secret or as commercial or financial the public, then we should require that a GRAS notice that is submitted on information that is privileged or the submission include an electronic paper is acceptable (rather than the confidential) (see § 170.225(c)(8)). The copy. Comments that address Issue 13 three copies that we proposed to final rule also requires that if you view support requiring the notifier to provide require) and have specified that a single any of the data and information in your an additional paper copy that we would paper copy is sufficient in the regulatory GRAS notice as exempt from disclosure send to FSIS as part of this procedure. text (§ 170.210(b)). We proposed to under FOIA, you must identify the (Response 46) We agree that an require three copies of a submitted specific data and information mstockstill on DSK3G9T082PROD with RULES2 electronic copy will make our GRAS notice to make it easier to provide (§ 170.250(d)). Together, these administration of the GRAS notification a paper copy of the GRAS notice to all provisions will give us notice as to procedure more efficient. For example, members of our staff who will evaluate whether we will need to evaluate an electronic copy generated from a the GRAS notice. However, in practice specific data and information under the word processing format generally is during the Interim Pilot program we FOIA and take steps to protect searchable without the need for Optical developed internal procedures in which applicable data and information from Character Recognition techniques, but we scan a GRAS notice submitted on public disclosure. VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00029 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 54988 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations C. Incorporation Into a GRAS Notice on which the notifier relies were provide that a ‘‘food master file’’ be a submitted by another person. confidential repository for proprietary (Comment 48) One comment supports Consistent with the discussion in the data, such as utility and manufacturing adding a provision to allow a notifier to 2010 notice, the provision we are information. incorporate data and information into a adding to allow for incorporation of data (Response 49) We establish a ‘‘food GRAS notice as long as the notifier has and information into a GRAS notice master file’’ for a variety of reasons. For explicit first-hand knowledge of the specifies that data and information example, a person who submits a food referenced files. Other comments submitted by another party must be additive petition may need us to address the limitation, discussed in the ‘‘public.’’ By ‘‘public,’’ we mean data evaluate data and information regarding 2010 notice, that data and information and information that we have provided a substance that the petitioner that are submitted by a person other (or would provide) in response to a purchases from another party for use in than the notifier must be public, noting request under the FOIA, or that are the manufacture of the food additive. that it would be difficult to prevent the otherwise publicly available (e.g., in a The petitioner may ask the use of public information by others or docket). Consistent with the views manufacturer of that substance to that incorporating such data and expressed in the comments, we see no provide the applicable data and information into a GRAS notice would reason to preclude you from referring us information to us, and we then place the be consistent with the criteria for to such public information when we submitted data and information in a general recognition of safety. already have such information in our food master file. Although some or all (Response 48) A notifier must have files, provided that you identify the of the data in such a food master file sufficient knowledge of data and specific data and information and the may be exempt from public disclosure information submitted by another party file(s) containing these data and (e.g., as trade secret information or to be able to identify the specific data information. We would not, for confidential commercial information), a and information that would be example, search our files to look for the determination of whether specific data incorporated into a GRAS notice. To referenced data and information. and information in a food master file is make this clear, the provision we are However, if you intend to incorporate exempt from public disclosure is based adding to the rule to allow for into a GRAS notice data and on the status of the data and information incorporation of data and information information that were submitted by under FOIA rather than on the type of into a GRAS notice requires that such another party, and that you believe to be file in which we place the data and data and information be specifically public information, we recommend that information. We do not limit the type of identified. For example, we expect you you explain the basis for your view that data and information that may be to provide a specific file number (e.g., the data and information are public. If included in a food master file to for a GRAS notice or a food additive we need to evaluate the status of the proprietary data and information. petition) that contains the referenced data and information under the FOIA See also § 170.215 and Response 48. data and information, and to identify (e.g., because the data and information Data and information submitted by a the specific data and information in that have not previously been disclosed to party other than a notifier must be file (rather than to broadly incorporate the public), we may decline to file the public information. If you previously into a GRAS notice the entire file GRAS notice until we have evaluated submitted a food master file to us, and the status of the referenced data and you view the data and information in without explaining which data and information under the FOIA. Doing so your food master file as proprietary, you information to incorporate). Although would be appropriate in light of the must explain in part 6 of your GRAS you may also incorporate into a GRAS perspective of the comments, as notice how GRAS criteria are satisfied notice a ‘‘food master file’’ (provided discussed in the 2010 notice, that the (see § 170.250(e)). that you specifically identify both the file number and the data and process of incorporation would be XI. General Requirements Applicable to information in that file that you are administratively efficient (75 FR 81536 a GRAS Notice at 81538) and the limited time (i.e., 180 asking us to incorporate into a GRAS The final rule specifies two general days) that we have to respond after we notice), the regulatory text does not provisions applicable to a GRAS notice file a submission as a GRAS notice (see include ‘‘food master file’’ as an (see § 170.220). As discussed in § 170.265(b)). A notifier who intends to example of the type of file that you may Response 43, we have redesignated the incorporate data and information that reference because we do not have a single proposed section (i.e., proposed we must evaluate under the FOIA before regulatory definition for ‘‘food master § 170.36) into several distinct, short we determine whether the data and file.’’ See the discussion of ‘‘food master sections of regulatory text in a newly information can be disclosed under the file’’ in Response 49. established subpart E (GRAS Notice). FOIA may find it advantageous to A notifier also must have sufficient request those data and information The first general provision specifies that knowledge of data and information under our public information a GRAS notice has seven parts, refers submitted by another party to be able to procedures (see part 20), and then either the user to the regulatory text for each discuss these data and information in include the data and information we of these parts, and specifies that you the narrative that is required in part 6 disclose in response to that request in must submit the information specified of a GRAS notice (see § 170.250). This the submitted GRAS notice, or refer us in each of these parts on separate pages narrative must explain the basis for the to administrative information or sets of pages (§ 170.220 (a)). notifier’s view that the notified identifying the completed FOIA request Submitting the information on separate substance is safe under the conditions of when asking us to incorporate the data pages or sets of pages is consistent both mstockstill on DSK3G9T082PROD with RULES2 its intended use and that GRAS and information into a GRAS notice. with the guidance we developed for criteria—for both general availability (Comment 49) One comment states its preparation of a GRAS notice in and general acceptance—are satisfied. In presumption that a ‘‘food master file’’ is electronic format (Ref. 37) and with other words, a GRAS notice must not available for public viewing, long-standing requirements for other present the independent conclusions of referring to a ‘‘long-standing center regulatory submissions, such as a food the notifier regarding the basis for GRAS policy’’ that such files are confidential. additive petition (see § 171.1(f)) and a status, even if the data and information This comment asks us to continue to health claim petition (see § 101.70(g)). VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00030 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 54989 The second general provision particular use of a substance is exempt determination are available for our specifies that you must include each of from the premarket approval review and copying at reasonable times the seven parts; if a part is not included, requirements of the FD&C Act because at a specific address set out in the notice you must include an explanation of why the notifier has determined that such or will be sent to us upon request that part does not apply to your GRAS use is GRAS. The proposed ‘‘GRAS (proposed § 170.36(c)(1)). In the 2010 notice (§ 170.220 (b)). We added this exemption claim’’ would include: (1) notice, we requested comment on provision because some parts of a GRAS The name and address of the notifier; (2) several issues relevant to the proposed notice (e.g., Part 4 (self-limiting levels of the common or usual name of the ‘‘GRAS exemption claim’’ (see table 6). use) and Part 5 (experience based on notified substance; (3) the applicable conditions of use of the notified As discussed in Response 42, we have common use in food before 1958)) would not apply to most GRAS notices. substance, including the foods in which made editorial changes throughout the Specifying that Parts 4 and 5 do not the substance is to be used, levels of use rule to replace the term ‘‘exempt’’ with apply to a particular GRAS notice will in such foods, and the purposes for the phrase ‘‘not subject to’’ and to make it clear that a notifier is aware of which the substance is used, including, replace the term ‘‘claim’’ (when used as the requirements of those parts and has when appropriate, a description of the a noun) with the term ‘‘view.’’ In light acknowledged that they do not apply. population expected to consume the of these editorial changes, in the substance; (4) the basis for the GRAS remainder of this section we generally XII. Comments on Part 1 of a GRAS determination (i.e., through scientific use the term ‘‘proposed signed Notice: Signed Statements and procedures or through experience based statements’’ (rather than ‘‘GRAS Certification on common use in food); and (5) a exemption claim’’) when referring to the We proposed that a GRAS notice must statement that the data and information provisions that we had proposed to include a dated and signed claim that a that are the basis for the notifier’s GRAS include in proposed § 170.36(c)(1)). TABLE 6—ISSUES IN THE 2010 NOTICE REGARDING THE PROPOSED SIGNED STATEMENTS IN A GRAS NOTICE Issue Description of our request for comment Reference No. 6a ...... How to best ensure that the identity and authority of the person who is signing the GRAS notice is 75 FR 81536 at 81539. made clear. 6b ...... Whether to require that a notifier submit a statement that to the best of his knowledge, the GRAS 75 FR 81536 at 81539. notice is a representative and balanced submission that includes unfavorable information, as well as favorable information, known to him and pertinent to the evaluation of the safety of the sub- stance. 6b ...... Whether to require a notifier to certify to the statement (described in Issue 6a) regarding the rep- 75 FR 81536 at 81539. resentative and balanced nature of the GRAS notice. 7 ........ Whether to require that the GRAS notice include the name of the notified substance, using an ap- 75 FR 81536 at 81539. propriately descriptive term, instead of the ‘‘common or usual name’’ of the notified substance. 8 ........ Whether to explicitly require that the information submitted in the ‘‘GRAS exemption claim’’ exclude 75 FR 81536 at 81539. non-public information. 9b * .... Whether to require that a notifier who identifies one or more trade secret(s) in the GRAS notice ex- 75 FR 81536 at 81540. plain why it is trade secret information and how qualified experts could conclude that the in- tended use of the notified substance is safe without access to the trade secret(s). 9c * .... Whether to require that a notifier who identifies confidential commercial or financial information in 75 FR 81536 at 81540. the GRAS notice explain why it is confidential commercial or financial information and how quali- fied experts could conclude that the intended use of the notified substance is safe without access to such information. 13 ...... Whether to make our coordinated evaluation process with FSIS explicit in the final rule .................... 75 FR 81536 at 81541–81542. * In the 2010 notice, Issues 9b and 9c asked how qualified experts could conclude that the intended use of the notified substance is ‘‘GRAS’’ rather than ‘‘safe.’’ However, the qualified experts evaluate safety rather than GRAS status; the person who is responsible for the conclusion of GRAS status considers the view of the qualified experts on safety in reaching the conclusion that GRAS criteria are satisfied. In the remainder of this document, we describe Issues 9b and 9c with respect to whether qualified experts could conclude that the intended use of the substance is ‘‘safe’’ rather than ‘‘GRAS.’’ In general, comments directed to the potential modifications (see, e.g., other than the editorial, clarifying, and proposed signed statements agree that Comment 54 and Comment 55); or conforming changes shown in table 29 we should modify the provisions as suggest one or more changes to the and the additional editorial changes discussed in Issues 6a, 6b, 7, 8, 9a, 9b, proposed signed statements and associated with the redesignation of 9c, and 13 in the 2010 notice. In the potential modifications (see, e.g., proposed § 170.36(c)(1) as § 170.225. following sections, we discuss Comment 52, Comment 56, and We did not receive comments comments that address the issues Comment 59). After considering these disagreeing with the proposed discussed in the 2010 notice (see, e.g., comments, we are establishing requirement for a GRAS notice to: (1) Be Comment 50, Comment 51, Comment requirements for Part 1 of a GRAS notice dated and signed by a responsible mstockstill on DSK3G9T082PROD with RULES2 57, Comment 58, and Comment 59); to include certain signed statements and official of your organization, or by your address provisions of the proposed a certification as shown in table 7, with attorney or agent; (2) provide your name signed statements that we did not editorial, clarifying, and conforming and address; and (3) provide the discuss in the 2010 notice (see, e.g., changes as shown in table 29. (See applicable conditions of use of the Comment 53); ask us to clarify how we § 170.225.) Table 7 identifies changes notified substance. Therefore, we are will interpret the provisions of the we made relative to the proposed rule establishing those requirements in the proposed signed statements and or the description in the 2010 notice rule (see § 170.225(c)(1), (2), and (4)). VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00031 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 54990 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations See Comment 42 for our discussion of is not subject to the premarket approval intended use; see Response 42 for the comments on the terms used in final requirements of the FD&C Act based on editorial changes we made in response § 170.225(c)(6), in which you inform us your conclusion that the substance is to those comments. of your view that the notified substance GRAS under the conditions of its TABLE 7—FINAL REQUIREMENTS FOR SIGNED STATEMENTS AND A CERTIFICATION IN PART 1 OF A GRAS NOTICE Proposed Revisions (other than editorial, Final designation in Issue No. designation in the Description. Part 1 of your clarifying, and conforming changes) the regulatory text in the 2010 regulatory text GRAS notice: relative to the proposed rule or the (§ ) notice (§ ) 2010 notice 170.225(a) .............. 170.36(c)(1) ........... N/A Must be dated and signed by a respon- N/A. sible official of your organization, or by your attorney or agent. 170.225(b) .............. N/A ......................... 8 Must not include any information that is Makes an exception for § 170.225(c)(8), trade secret or confidential commer- which requires you to state your view cial information. as to whether any of the data and in- formation in Parts 2 through 7 of your GRAS notice are exempt from disclo- sure under the FOIA. 170.225(c)(1) .......... N/A ......................... N/A Informs us that you are submitting a N/A. GRAS notice in accordance with sub- part E. 170.225(c)(2) .......... 170.36(c)(1)(i) ........ N/A Provides the name and address of your N/A. organization. 170.225(c)(3) .......... 170.36(c)(1)(ii) ....... 7 Provides the name of the notified sub- N/A. stance, using an appropriately de- scriptive term. 170.225(c)(4) .......... 170.36(c)(1)(iii) ...... N/A Describes the intended conditions of Uses the term ‘‘subpopulation’’ rather use of the notified substance, includ- than ‘‘population’’. ing the foods in which the substance will be used, the levels of use in such foods, and the purposes for which the substance will be used, including, when appropriate, a description of a subpopulation expected to consume the substance. 170.225(c)(5) .......... 170.36(c)(1)(iv) ...... N/A Informs us of the statutory basis for • Specifies that a conclusion of GRAS your conclusion of GRAS status (i.e., status through scientific procedures is through scientific procedures or in accordance with both § 170.30(a) through experience based on com- and (b). mon use in food). • Specifies that a conclusion of GRAS status through experience based on common use in food is in accordance with both § 170.30(a) and (c). 170.225(c)(6) .......... 170.36(c)(1) ........... 2 States your view that the notified sub- See Response 42. stance is not subject to the premarket approval requirements of the FD&C Act based on your conclusion that the substance is GRAS under the condi- tions of its intended use. 170.225(c)(7) .......... 170.36(c)(1)(v) ....... N/A States your agreements regarding mak- You agree to a procedure in which we ing data and information available to can access data and information us upon our request. ‘‘during customary business hours’’ rather than ‘‘at reasonable times’’. 170.225(c)(8) .......... N/A ......................... 9 States your view as to whether any of N/A. the data and information in Parts 2 through 7 of your GRAS notice are exempt from disclosure under the FOIA. 170.225(c)(9) .......... 170.36(c)(4) ........... 6b Certifies that, to the best of your knowl- Specifies that your GRAS notice is edge, your GRAS notice is a com- ‘‘complete’’ in addition to ‘‘represent- plete, representative, and balanced ative’’ and ‘‘balanced’’. submission that includes unfavorable information, as well as favorable in- formation, known to you and pertinent mstockstill on DSK3G9T082PROD with RULES2 to the evaluation of the safety and GRAS status of the use of the sub- stance. 170.225(c)(10) ........ 170.36(c)(1) ........... 6a States both the name and position or N/A. title of the person who signs the GRAS notice. VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00032 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 54991 TABLE 7—FINAL REQUIREMENTS FOR SIGNED STATEMENTS AND A CERTIFICATION IN PART 1 OF A GRAS NOTICE— Continued Proposed Revisions (other than editorial, Final designation in Issue No. designation in the Description. Part 1 of your clarifying, and conforming changes) the regulatory text in the 2010 regulatory text GRAS notice: relative to the proposed rule or the (§ ) notice (§ ) 2010 notice 170.225(c)(11) ........ N/A ......................... 13 When applicable, states whether you: We added a statement communicating (1) Authorize us to send any trade how you want us to handle trade se- secrets to FSIS; or (2) ask us to ex- cret information in a copy of a GRAS clude any trade secrets from the copy notice that we send to FSIS. of the GRAS notice that we will send to FSIS. A. Exclusion of Trade Secret and statements for the purpose of informing Response 70. Regarding how we treat Confidential Commercial Information the public about GRAS notices that we non-public information in a GRAS From the Signed Statements are evaluating. However, some notice, see section XXI regarding the (Comment 50) Several comments comments seem to be addressing the provisions of the final rule regarding support a provision specifying that issue of whether other sections of a public disclosure of information in a information submitted in the signed GRAS notice (e.g., Part 2 of a GRAS GRAS notice. Under § 170.275(c), we statements exclude non-public notice (in which a notifier describes the will disclose information that is not information. One of these comments method of manufacture of the notified exempt from public disclosure in states that the information in the signed substance) and Part 6 of a GRAS notice accordance with part 20. statements should be publicly disclosed (in which a notifier discusses the safety B. Name of the Notified Substance, because public disclosure is critical to of the notified substance)) can include Using an Appropriately Descriptive the continued success of the GRAS non-public information. Term program, and that for the use of a Consistent with our request for substance to be ‘‘generally recognized as comment in Issue 8, the final rule (Comment 51) Some comments agree safe’’ the data and research supporting specifies that a notifier must not include that the signed statements should a conclusion of GRAS status must be any information that is trade secret or identify the name of the notified available for public view. Other confidential commercial information in substance using an ‘‘appropriately comments disagree that non-public Part 1 of a GRAS notice, except in the descriptive term’’ instead of the information should be excluded from statement in § 170.225(c)(8) (see ‘‘common or usual name,’’ and also the signed statements and assert that the § 170.225(b) and the discussion of agree with our statement in the 2010 final rule should allow for the § 170.225(c)(8) in Response 57). This notice that the ‘‘appropriately submission of limited amounts of non- provision does not preclude a notifier descriptive term’’ may be the same as public information at the discretion of from including non-public information the common or usual name of the the notifier or when necessary to clarify in other parts of a GRAS notice. substance in some circumstances (75 FR the safety of the notified substance for However, if a notifier views any 81536 at 81539). One comment the purposes of our evaluation. These submitted data and information as disagrees and asks us to continue to comments emphasize we should take exempt from disclosure under the FOIA specify that the signed statements in a care to remove such non-public then that notifier must identify the GRAS notice identify the name of the information from any public disclosure specific data and information, and notified substance using the common or or, or at a minimum, discuss or clear our explain how there could be a basis for usual name of the notified substance. intent to disclose non-public a conclusion of GRAS status if qualified This comment recommends that a information with the notifier before experts generally do not have access to notifier work with us to establish the disclosing it. those data and information (see common or usual name of the notified (Response 50) Some of these § 170.250(d) and (e)). Section 170.250(d) substance if the common or usual name comments appear to misinterpret the and (e) is consistent with the criteria for is not known or well defined. This reach of our request for comment in eligibility for classification as GRAS, comment also asks us to include the Issue 8 in the 2010 notice. We narrowly because: (1) The criteria provide that common or usual name of the notified directed Issue 8 to the signed statements general recognition of safety may be substance in any ‘‘no questions letter’’ that would provide the name and corroborated by unpublished from us to make the common our usual address of the notifier; the name of the information; and (2) the notifier has a name clear to the public. A few notified substance; the applicable burden to explain how GRAS criteria comments support requiring that the conditions of use of the notified are satisfied given that certain data and signed statements include both the substance; the statutory basis for the information in the GRAS notice are common or usual name of the notified conclusion of GRAS status; and trade secret or confidential commercial substance, as well as an appropriately agreement to make the data and information. descriptive term for the notified information that are the basis for the See section XIII.B for a discussion of substance. One comment asks us to mstockstill on DSK3G9T082PROD with RULES2 notifier’s conclusion of GRAS status comments regarding including non- continue the practice, described in the available for our review and copying. public information in part 2 of a GRAS 2010 notice (75 FR 81536 at 81539), of The signed statements provide notice (particularly with respect to the reminding notifiers that our response to administrative information rather than method of manufacture). Regarding a GRAS notice should not be considered safety information and, as discussed in whether we would ‘‘clear our intent’’ to an endorsement for any given term for the 2010 notice, we extract notice- disclose non-public information with the purpose of complying with the specific information from the signed the notifier before disclosing it, see labeling provisions of the FD&C Act. VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00033 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 54992 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations (Response 51) The final rule requires statutory basis for a conclusion of GRAS support a conclusion of GRAS status. that you provide the name of the status may be through scientific Some of the data and information that notified substance, using an procedures, through experience based we may ask to see during our evaluation appropriately descriptive term, in Part 1 on common use in food, or through both of a GRAS notice may be ‘‘public’’ data of your GRAS notice (§ 170.225(c)(3)). scientific procedures and experience and information in that it would be data The appropriately descriptive term may based on common use in food. These and information that we would provide be the same as the common or usual comments assert that many conclusions in response to a request under the FOIA name of the substance under our of GRAS status are based on both (see Response 48), even though it may labeling regulations (see 21 CFR 102.5). statutory criteria. not have been disseminated to the We decline the request to use resources (Response 52) We disagree that this public (e.g., in the scientific literature or that we are directing to the evaluation modification is needed. The final rule on the Internet (e.g., when a science- of the safety and regulatory status of does not prevent you from basing your based organization uses the Internet to food substances under sections 201 and conclusion of GRAS status on both disseminate scientific or technical 409 of the FD&C Act to also address the statutory criteria. Importantly, if you information or recommendations)). If we labeling requirements of the FD&C Act assert that your conclusion of GRAS receive data and information that are given the limited time (i.e., 180 days) status is based on both statutory criteria, non-public, such data and information that we have to respond (see you must fully support each conclusion would be protected from public § 170.265(b)). You may consult with our and address all requirements of the rule disclosure in accordance with part 20. staff in operating divisions that address regarding each conclusion; partial (Comment 54) One comment states the labeling requirements of the FD&C support for each of the two statutory that the phrase ‘‘at reasonable times’’ Act, currently CFSAN’s Office of criteria for a conclusion of GRAS status refers not only to hours of a day, but Nutrition and Food Labeling (for human is not adequate. You could not, for also to a reasonable amount of time food); however, doing so would be a example, assert that a substance is following the submission of a GRAS separate process from the GRAS GRAS under the conditions of its notice. This comment recommends that notification procedure. (See section intended use through scientific ‘‘several years (for example, five years)’’ XXV.C for contact information for procedures, but ‘‘fill in data gaps’’ by after submission of a GRAS notice CVM.) also asserting that the substance was would be a reasonable time for notifiers commonly used in food before 1958. to retain such data and information in C. Intended Conditions of Use of the Likewise, you could not assert that a Notified Substance their active files. substance is GRAS under the conditions We did not receive comments (Response 54) By ‘‘at reasonable of its intended use through experience disagreeing with the proposed times,’’ we meant the time of day that based on common use in food if you requirement for the signed statements in we would have access to data and cannot provide evidence of a substantial a GRAS notice to include the applicable information you retained but did not history of consumption of the notified conditions of use of the notified include in your GRAS notice. To clarify substance for food use by a significant substance, including the foods in which that the requirement relates to the time number of consumers prior to January 1, the substance is to be used, levels of use of day rather than to the timeframe for 1958. in such foods, and the purposes for These comments highlight the retaining the data and information, the which the substance is used, including, importance of fully supporting a final rule specifies that you agree to a when appropriate, a description of the conclusion of GRAS status through each procedure in which we can access data population expected to consume the of the statutory criteria. Because the and information ‘‘during customary substance, and we are establishing this general criteria in § 170.30(a), as well as business hours’’ rather than ‘‘at requirement in the final rule (see the specific criteria in § 170.30(b) or (c), reasonable times.’’ § 170.225(c)(4)). As noted in table 29, must be satisfied to support a As previously discussed (62 FR 18938 the final rule refers to the ‘‘intended conclusion of GRAS status, the final at 18951), we may, at some point after conditions of use’’ rather than the rule specifies that a conclusion of GRAS our response to a GRAS notice, receive ‘‘applicable conditions of use’’ for status through scientific procedures is additional information about a notified consistency with other provisions in the in accordance with both § 170.30(a) and substance that raises questions about the rule. The final rule also uses the term (b) and that a conclusion of GRAS status safety of that substance. To address this ‘‘subpopulation’’ rather than through experience based on common possibility, the rule specifies that we ‘‘population’’ to provide more context use in food is in accordance with both will send you a subsequent letter about about when it would be appropriate to § 170.30(a) and (c). your GRAS notice if circumstances specify the expected consumers of a warrant (see § 170.265(c)). Although the food. Most foods are broadly available to E. Agreement To Make Data and rule does not specify any timeframe to all consumers; a few are more Information Available Upon Request retain the data and information that specifically targeted to particular (Comment 53) Some comments support your conclusion of GRAS subpopulations, such as persons with recommend that there be a means for us status, preservation of the data and specific dietary needs (such as persons to request non-public information if we information that are the basis for the on liquid diets or persons with deem it necessary for our evaluation of conclusion of GRAS status represents conditions like phenylketonuria), the intended conditions of use of the prudent practice for those who claim an infants consuming infant formula, and notified substance, provided that the exclusion from a statutory requirement persons seeking alternatives to information can be considered as regardless of whether the person mstockstill on DSK3G9T082PROD with RULES2 commonly used food ingredients (such confidential and protected from subsequently notifies us (62 FR 18938 at as persons on a gluten-free diet). disclosure. 18947). (Response 53) These comments (Comment 55) One comment asks us D. Statutory Basis for the Conclusion of appear to misinterpret the reach of the to clarify that electronic records are GRAS Status proposed requirement to agree to acceptable for documenting the data and (Comment 52) Some comments ask us provide us access to data and information that support a conclusion of to modify the rule to provide that the information that a notifier relies on to GRAS status. VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00034 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 54993 (Response 55) Electronic records are to include certain elements of a GRAS and/or the definition of ‘‘scientific acceptable for documenting the data and notice in a standard format. The form, procedures’’ (§ 170.3(h)); and the criteria information that support a conclusion of and elements that would be prepared as for general recognition of safety (see GRAS status. If we ask you to send us attachments to the form, may be § 170.30)). such data and information for a notified submitted in electronic format via the Electronic Submissions Gateway, as F. Statements and Any Applicable substance that would be used in human electronic files on physical media, or in Explanation Regarding Data and food, we recommend that you do so by paper format. At this time, we cannot Information That a Notifier Views as following the instructions in CFSAN’s accept media such as thumb drives, Exempt From Disclosure Under FOIA guidance entitled ‘‘Guidance for Industry: Providing Regulatory which can present a security risk. (Comment 56) One comment asks us In Issue 9 in the 2010 notice (75 FR Submissions in Electronic or Paper 81536 at 81539–81540), we discussed to develop criteria for the required Format to the Office of Food Additive three issues regarding confidential data documentation underlying industry Safety’’ (Ref. 37), which includes conclusions of GRAS status. and information that are included in a instructions for making an electronic (Response 56) We are not establishing GRAS notice. See table 8. Most of the submission through our Electronic criteria in the rule for the comments that address Issue 9 address Submission Gateway, as well as on documentation a notifier would have Issue 9a, particularly with respect to media that we can access on our regarding a conclusion of GRAS status. how we would protect trade secret or network computers. CFSAN’s Regardless of whether a person who confidential commercial information procedures for making an electronic concludes that a use of a food substance from public disclosure. See sections submission through our Electronic is GRAS notifies us, the applicable XIII.B and XXI.C for a discussion of Submission Gateway use a form that documentation would address the safety those comments, and our response to CFSAN developed for a GRAS notice of the substance as described in the those comments. In the following when a substance would be used in definition of ‘‘safe’’ or ‘‘safety’’ (see paragraphs, we discuss comments on human food (i.e., Form FDA 3667) (Ref. § 170.3(i)); as applicable, the definition Issues 9b and 9c, and respond to those 38). Form FDA 3667 prompts a notifier of ‘‘common use in food’’ (see § 170.3(f) comments. TABLE 8—ISSUES IN THE 2010 NOTICE REGARDING CONFIDENTIAL DATA AND INFORMATION IN A GRAS NOTICE Issue Description of our request for comment Reference No. 9a ...... Whether the final rule should stipulate that the method of manufacture exclude any trade secrets, 75 FR 81536 at 81539–81540. as we proposed. 9b ...... Whether to require that a notifier who identifies one or more trade secret(s), as defined in 75 FR 81536 at 81539–81540. § 20.61(a), in the GRAS notice explain why it is trade secret information and how qualified ex- perts could conclude that the intended use of the notified substance is safe without access to the trade secret(s). 9c ...... Whether to require that a notifier who identifies confidential commercial or financial information, as 75 FR 81536 at 81539–81540. defined in § 20.61(b), in the GRAS notice explain why it is confidential commercial or financial in- formation and how qualified experts could conclude that the intended use of the notified sub- stance is safe without access to such information. (Comment 57) One comment supports financial information that is privileged containing personal privacy information the recommendation we made in the or confidential) (§ 170.225(c)(8)). that we needed to redact before we proposed rule for a notifier who Requiring this statement in Part 1 of a could make the GRAS notice available considers that certain information in a GRAS notice will give us notice as to to the public. The rule does not require submission should not be available for whether we will need to evaluate that a notifier submit such information, public disclosure to identify as specific data and information under the and redaction of unnecessary privacy confidential the relevant portions of the FOIA and take steps to protect information takes resources that we submission for our consideration (62 FR applicable data and information from would otherwise use to evaluate the 18938 at 18952). Those comments that public disclosure. See also § 170.250(d), GRAS notice. We ask that notifiers address Issues 9b and 9c agree with the which requires that Part 6 of a GRAS exclude personal privacy information outcome of our discussion, in the 2010 notice (a narrative) identify specific data from a GRAS notice whenever possible. notice, that we should require that a and information that a notifier views as If a notifier does include such notifier who identifies a trade secret or exempt from disclosure under the FOIA. information, in Part 1 of a GRAS notice confidential commercial information Whereas Part 1 of a GRAS notice only the notifier should state his view that explain why it is a trade secret or requires that the signed statements in a the GRAS notice contains personal confidential commercial information GRAS notice state the notifier’s view as privacy information. In Part 6 of a GRAS and how qualified experts can conclude to whether any of the data and notice, the notifier should identify the that the use of a substance is safe information in Parts 2 through 7 of a personal privacy information. without access to the trade secret or GRAS notice are exempt from disclosure mstockstill on DSK3G9T082PROD with RULES2 G. Certification Statement confidential commercial information. under the FOIA, in Part 6 of a GRAS (Response 57) The final rule requires notice the notifier would specifically (Comment 58) Several comments a notifier to state his view as to whether identify the applicable data and support a requirement for a GRAS any of the data and information in Parts information. notice to include a certification 2 through 7 of a GRAS notice are During the Interim Pilot program, we statement similar to the certification exempt from disclosure under the FOIA sometimes received a curriculum vitae statement that had been required in a (e.g., as trade secret or as commercial or (e.g., of a GRAS panel member) GRAS affirmation petition. One VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00035 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 54994 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations comment agrees that the notifier should discussion in Response 69 and notifier who submits a GRAS notice that submit a statement that the notice is a Response 78. we would send to FSIS to include in representative and balanced submission, (Comment 59) One comment asks us part 1 of the GRAS notice a statement but does not agree that the notifier to specify that the statement include the as to whether the notifier: (1) Authorizes needs to certify the statement. date the statement was certified. us to send any trade secrets to FSIS; or (Response 58) The final rule requires (Response 59) The rule requires that (2) asks us to exclude any trade secrets a certification statement as described in Part 1 of a GRAS notice be dated and from the copy of the GRAS notice that the 2010 notice, with one modification signed by a responsible official of your we will send to FSIS (see (see § 170.225(c)(9)). We added that the organization, or by your attorney or § 170.225(c)(11)). Under the provisions statement certify that the GRAS notices agent (see § 170.225(a)). The that make the coordinated evaluation of is ‘‘complete’’ in addition to certification statement is included in a GRAS notice with FSIS explicit, we ‘‘representative’’ and ‘‘balanced,’’ to Part 1 of the GRAS notice; it is not will exclude any trade secrets unless emphasize your responsibility to necessary to date each statement you have authorized us to send trade identify, discuss, and place in context, included in Part 1. secret information to FSIS (see data and information that are, or may H. Person Signing Part 1 of the GRAS § 170.270). These provisions will enable appear to be, inconsistent with a us, with your authorization, to share a Notice conclusion of GRAS status, regardless of GRAS notice that includes trade secret whether those data and information are (Comment 60) Several comments information with FSIS without first generally available (see the support a provision to require a GRAS redacting the GRAS notice to remove requirements of the narrative in Part 6 notice to clearly identify the person the trade secret information and, thus, of a GRAS notice (§ 170.250, in signing the GRAS notice, such as by will reduce the time it takes for us to particular § 170.250(c))). The printing or stating the name and the title provide FSIS with a copy of the GRAS certification is appropriate and of the person signing the GRAS notice. notice. These provisions also will clarify necessary to underscore your legal (Response 60) The final rule requires your expectations regarding whether we responsibility for the conclusion of you to state both the name and position should share trade secret information GRAS status. As discussed in the 2010 or title of the person who signs the with FSIS and, thus, require us to redact notice, the specific text of the GRAS notice (see § 170.225(c)(10)). the trade secret information from the certification statement that you must I. Authorization for FDA To Send Trade copy we send to FSIS when consistent include in a GRAS notice is consistent Secret Information to FSIS with your express wishes. with the specific text of the certification Note that our rule establishing the statement in the GRAS affirmation In the 2010 notice, we described some requirements of the GRAS notification petition process that the notification of the terms of a MOU, between FDA procedure does not specify the data and procedure is replacing. The use of and USDA’s FSIS, that provides for a information that FSIS will need to certification statements has become coordinated evaluation process with evaluate whether the intended use of routine in other submissions to FDA for FSIS when the intended conditions of the notified substance complies with food programs (see, e.g., the certification use of a notified substance include use applicable statutes and regulations, or, if statement in Part V of Form FDA 3480 in a product or products subject to not, whether the use of the substance (for a food contact notification regulation by USDA under statutes that would be permitted in products under submission) (Ref. 39); and the it administers (75 FR 81536 at 81541– FSIS jurisdiction under specified certification statement in Section 13 of 81542); in 2015 we amended that MOU conditions or restrictions. We Form FDA 3537 (for registration of a to include more details about the recommend that you contact the food facility) (Ref. 40)). procedures FDA and FSIS will follow to appropriate staff at FSIS regarding the By ‘‘complete,’’ we also mean that do so (Ref. 36). We also asked for data and information that FSIS will your GRAS notice identifies, and places comment on whether to make our need you to provide. FSIS provides in context, unpublished data and coordinated evaluation process with contact information for its programs on information that you believe corroborate FSIS explicit in the final rule (see Issue its Web site (Ref. 41). GRAS status. For example, if you 13, 75 FR 81536 at 81541–81542). conduct six toxicology studies, but only In accordance with our public XIII. Comments on Part 2 of a GRAS publish three of the studies, it may be information regulations in § 20.85 Notice: Identity, Method of that you consider the remaining three (Disclosure to other Federal government Manufacture, Specifications, and studies to be corroborative of safety. As departments and agencies), we can Physical or Technical Effect an example, it may be that you were share confidential commercial We proposed to require that a GRAS dissatisfied with the study design of one information with another Federal notice include detailed information study, repeated that study with an agency pursuant to a written agreement about the identity of the notified improved study design, and published that the record will not be further substance, including, as applicable, its the study with the improved study disclosed. The amended MOU between chemical name, Chemical Abstracts design. If you consider that the findings FDA and USDA’s FSIS now provides for Service (CAS) Registry Number, Enzyme of the unpublished studies corroborate FDA to share with FSIS confidential Commission number, empirical formula, safety, even if they do not establish it, commercial information in a submission structural formula, quantitative a ‘‘complete, representative, and such as a GRAS notice (Ref. 36). We composition, method of manufacture balanced’’ submission would briefly generally cannot share trade secret (excluding any trade secrets and describe the unpublished studies. In information with other Federal agencies including, for a substance of natural mstockstill on DSK3G9T082PROD with RULES2 addition, we expect that you would under section 301(j) of the FD&C Act (21 biological origin, source information describe, and place in context, U.S.C. 331(j)), and therefore we would such as genus and species), unpublished data and information if need your authorization to share this characteristic properties, any content of you consider that the findings of the information with FSIS. For efficiency in potential human toxicants, and unpublished data and information administering the coordinated specifications for food-grade material warrant sharing with any ‘‘GRAS panel’’ evaluation of a GRAS notice with FSIS, (proposed § 170.36(c)(2)). In the 2010 that you convene. See also the we have added a requirement for a notice, we requested comment on VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00036 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 54995 several issues relevant to the proposed about the identity of the notified requirements for detailed information substance (see table 9). TABLE 9—ISSUES IN THE 2010 NOTICE REGARDING THE PROPOSED REQUIREMENTS FOR DETAILED INFORMATION ABOUT THE IDENTITY OF THE NOTIFIED SUBSTANCE Issue Description of our request for comment Reference No. 9a ...... Whether the final rule should continue to stipulate that the method of manufacture exclude any 75 FR 81536 at 81539–81540. trade secrets, as proposed. 10a .... What scientific information would be sufficient to identify the biological source ................................... 75 FR 81536 at 81540. 10b .... Whether to require that information about the identity of the notified substance specify any known 75 FR 81536 at 81540. toxicants that could be in the source. 10c .... Whether the final rule should address, as part of identity, particle size and other chemical and 75 FR 81536 at 81540. physical properties that may be used to characterize engineered materials. Some comments support the proposed requiring that this information specify physical or technical effect of the requirements, with the potential toxicants that could be in the source. notified substance as shown in table 10, modifications described in the 2010 Most of the comments regarding our with editorial, clarifying, and notice, without change. For example, proposal to require that a GRAS notice conforming changes as shown in table most of the comments that address the include detailed information about the 29. (See § 170.230). Table 10 identifies issue of scientific information sufficient identity of the notified substance changes we made relative to the to identify a biological source support address the issues discussed in 2010 proposed rule or the description in the requiring both taxonomic information notice. In the following sections, we 2010 notice other than the editorial, discuss these and other comments. After and the part of any animal or plant used clarifying, and conforming changes considering these comments, we are as a source. As another example, several shown in table 29 and the additional establishing requirements for Part 2 of a comments that address the issue of GRAS notice to include information editorial changes associated with the scientific information sufficient to about the identity, method of redesignation of proposed § 170.36(c)(2) identify a biological source support manufacture, specifications, and as § 170.230. TABLE 10—FINAL REQUIREMENTS FOR DETAILED INFORMATION IN PART 2 OF A GRAS NOTICE ABOUT THE IDENTITY OF A NOTIFIED SUBSTANCE Proposed Revisions (other than editorial, Final designation in Issue No. designation in the Description. Part 2 of your clarifying, and conforming changes) the regulatory text in the 2010 regulatory text GRAS notice: relative to the proposed rule (§ ) notice (§ ) or the 2010 notice 170.230(a)(1) ......... 170.36(c)(2) ........... N/A Must include scientific data and infor- N/A. mation that identifies the notified sub- stance. 170.230(a)(1) ......... 170.36(c)(2) ........... 10a Must include data and information suffi- • Must provide taxonomic information cient to identify a biological source of at the sub-species level (e.g., variety, a notified substance. strain) in addition to genus and spe- cies. • Must specify the part of any plant or animal used as the source. 170.230(a)(2) ......... 170.36(c)(2) ........... 10b Must include data and information suffi- N/A. cient to identify any known toxicants that could be in the source. 170.230(b) .............. 170.36(c)(2) ........... 9a Must include the method of manufac- • No longer requires that the method of ture of the notified substance in suffi- manufacture exclude any trade se- cient detail to evaluate the safety of crets. the notified substance as manufac- • Requires ‘‘sufficient detail to evaluate tured. the safety of the notified substance as manufactured’’ rather than ‘‘de- tailed information.’’ 170.230(c) .............. 170.36(c)(2) ........... N/A Must include specifications for food- N/A. grade material. 170.230(d) .............. N/A ......................... N/A When necessary to demonstrate safety, New requirement based on comments must include relevant data and infor- that addressed experience during mation bearing on the physical or CVM’s Interim Pilot program (see other technical effect the notified sub- section XXV.E). mstockstill on DSK3G9T082PROD with RULES2 stance is intended to produce, includ- ing the quantity of the notified sub- stance required to produce such ef- fect. VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00037 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 54996 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations A. Scientific Information About the disagree that we should use guidance, descriptor necessary to sufficiently Identity of a Notified Substance rather than the regulatory text of this identify that animal or plant source. rule, to describe the types of data and Therefore, although breed may be an 1. Scientific Information Sufficient To information that are necessary to appropriate taxonomic descriptor in Identify a Biological Source sufficiently identify the biological some circumstances, the circumstances (Comment 61) One comment asserts source because the types of information are rare enough that we have not seen that the scientific information, beyond we are specifying are necessary—rather it as necessary information in more than the standard taxonomic information, than merely recommended— 15 years. Therefore, we are not that is sufficient to identify a biological information. For example, data and specifying it as an example of applicable source for a notified substance should information at the sub-species level taxonomic information in the rule. In a be determined on a case-by-case basis (e.g., variety, strain) is necessary for specific circumstance where breed is consistent with established practice and source microorganisms because so many necessary to adequately identify a publicly available guidance. Another microorganisms (e.g., Escherichia coli particular animal or plant source, and comment asserts that identifying the and Saccharomyces cerevisiae) have you do not specify the breed, we intend source organism by the genus and multiple strains, and although some to ask you to amend your GRAS notice species (without additional information strains are both non-toxigenic and non- to identify the breed. such as strain or variety) is sufficient pathogenic, others are not. For example, (Comment 63) One comment asks us when the notified substance is an there are several pathogenic strains of to address substances produced from enzyme preparation produced by a Saccharomyces cerevisiae, even though microorganisms, particularly microorganism. However, this comment nonpathogenic strains are commonly bioengineered microorganisms. This also asserts that if safety concerns for a used in food and in the production of comment explains that the development specific genus and species have been enzyme preparations. As another of a production microorganism through addressed (i.e., by genetic modification example, both Aspergillus oryzae and bioengineering is, for the most part, to remove a characteristic of concern) Aspergillus niger naturally produce highly confidential and cannot be for a specific strain within that species mycotoxins, but strains that do not disclosed publicly. In addition, the then information about the strain would produce mycotoxins have been production microorganism often is be appropriate. This comment developed and are used for production modified on an ongoing basis, e.g., to emphasizes that the description of the of enzyme preparations. In addition, for improve yield. This comment asks us to source of a biological material should be phage production some host strains specify the point at which subsequent based on the safety of that source and have been pathogens (e.g., Listeria modification of a production consider all relevant information related monocytogenes) and produce toxins. microorganism would trigger to safety. Likewise, data and information about submission of a new GRAS notice and (Response 61) The information, the part of a plant used as a source is notes that in some cases subsequent beyond the standard taxonomic necessary because some plants that have modification of a production organism information, that we discussed in the edible parts also secrete toxins in non- could be incorporated into the original 2010 notice is consistent with edible parts. For example, the leaf stalks GRAS notice by ‘‘amendment’’ or by established practice (see section III.J.1 of (petioles) of rhubarb (Rheum reference. This comment also asserts CFSAN’s 2010 experience document rhaponticum) are edible, but the leaves that submission of a new GRAS notice (Ref. 18)) and the final rule specifies contain notable quantities of oxalic acid. should not be needed in the case of safe that when the source of a notified As another example, the leaves and strain lineage as described in the substance is a biological material, your stems of tomato (Solanum scientific literature (Ref. 42). GRAS notice must include both lycopersicum) contain solanine. Another comment asks us to specify taxonomic information (e.g., genus, We agree that the description of a that information identifying a substance species), including as applicable data biological source should be based on the derived from a biological source must and information at the sub-species level safety of that source and consider all specify whether the plant or animal is (e.g., variety, strain) and the part of any relevant information related to safety. genetically engineered or cloned. plant or animal used as the source (see The regulatory text requires taxonomic (Response 63) We recommend that § 170.230(a)(2)). We agree that the information beyond genus and species, notifiers consult our guidance entitled specific scientific information, beyond such as variety or strain, ‘‘when ‘‘Assessing the Effects of Significant the standard taxonomic information, applicable’’ for a source microorganism Manufacturing Process Changes, that is sufficient to identify a biological such as those used to produce enzyme Including Emerging Technologies, on source is determined on a case-by-case preparations. Examples of when the Safety and Regulatory Status of Food basis, and section III.J.1 of CFSAN’s information such as variety or strain Ingredients and Food Contact 2010 experience document would be applicable are those microbial Substances, Including Food Ingredients demonstrates that the specific scientific sources, such as some fungi, for which that Are Color Additives’’ (Ref. 6). That information included in a GRAS notice there are multiple strains or subspecies guidance lists a change in the source to describe a biological source varied on that have different properties with microorganism (including a change in a case-by-case basis. For example, when respect to the ability to produce toxins, strain) used for a food substance derived the notified substance was derived from antibiotics, or other substances that are from fermentation of a microorganism as a microorganism, the notifier specified a not suitable for use in food. an example of a significant particular strain or subspecies or stated (Comment 62) One comment asks us manufacturing process change. the strain was a nontoxigenic and to specify that information identifying a Whenever there has been a significant mstockstill on DSK3G9T082PROD with RULES2 nonpathogenic strain; when the notified substance derived from a biological manufacturing process change for a food substance was derived from a plant, the source must include the breed of animal substance that is the subject of a notifier identified the specific part(s) of or plant. previous conclusion of GRAS status, the the plant used as the starting material, (Response 62) During the Interim Pilot guidance recommends that the such as fruit, seeds or seed husks, program we did not evaluate any GRAS manufacturer consider whether the expressed oil, flowers, roots, leaves, notices in which the breed of an animal GRAS status of the use of the food pulp, wood, or bark. However, we or plant source was a taxonomic substance would be affected; consult VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00038 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 54997 with us regarding the conclusions about information (whether included in a notice, of how the method of the impact of the significant GRAS notice, or provided privately to a manufacture and specifications for the manufacturing change on the safety and GRAS panel) is corroborative of safety, notified substance lead you to conclude regulatory status of the use of the food rather than necessary to demonstrate that the notified substance as substance; and make an appropriate safety, if, for example, the method of manufactured is safe and that the regulatory submission to us as manufacture included in a GRAS notice criteria for general recognition are circumstances warrant. In the specific meets the requirements of the rule to satisfied. circumstance of a production provide sufficient detail to evaluate the (Comment 65) One comment refers to microorganism that is modified on an safety of the notified substance as a statement we made, in the 2010 ongoing basis, a modification that manufactured. Alternatively, the notifier notice, that we have found that results in a new strain would no longer could describe the development of the information about substances known to fall within the description of the source, production microorganism in sufficient be toxicants is relevant regardless of the which must include information at the detail to address any safety issues state of the science regarding the sub-species level (see § 170.230(a)(2)(i)). associated with use of that production specific toxicity of the substance to If a notifier concludes that a microorganism. For enzyme humans (75 FR 81536 at 81540). This modification that results in a new strain preparations that would be used in comment asserts that specifying that the has no impact on the conclusion of human food, we recommend that identity of the notified substance GRAS status, one approach could be to notifiers consult our guidance entitled include any known toxicants that could submit a supplement to the GRAS ‘‘Guidance for Industry: Enzyme be in the source does not fully address notice. Doing so would be consistent Preparations: Recommendations for whether the toxicants cause a safety with CFSAN’s 2010 experience during Submission of Chemical and concern. Another comment states that the Interim Pilot program. See section Technological Data for Food Additive the ‘‘GRAS process’’ should contain a IV.J of CFSAN’s 2010 experience Petitions and GRAS Notices’’ (Ref. 33), safety/risk assessment for known document (Ref. 18), in which CFSAN and ‘‘Food-Processing Enzymes From toxicants, not just identify the toxicants. discusses a GRAS notice in which a Recombinant Microorganisms—A (Response 65) We agree that a GRAS notifier consulted with CFSAN about Review’’ (Ref. 43), for details about our notice must address the safety concerns mechanisms to inform CFSAN about its recommendations for safety information associated with toxicants known to be conclusion that additional uses of the regarding enzyme preparations derived in a biological source, not just identify notified substance are also GRAS. The from bioengineered microorganisms. the toxicants. See the requirements for notifier supplemented its original GRAS a GRAS notice to include the method of 2. Potential Toxicants in the Source of manufacture of the notified substance notice with a letter informing CFSAN of the Notified Substance (§ 170.230(b)), specifications for food- the additional conclusion of GRAS status and CFSAN issued a second ‘‘no (Comment 64) One comment agrees grade material (§ 170.230(c)), and a questions letter’’ to the notifier as that a review of known toxicants that narrative explaining why the data and additional correspondence. could be produced by the biological information in a GRAS notice provide a We decline the request to require that source of a notified substance should be basis for the notifier’s view that the information identifying a substance part of the safety review, but notified substance is safe under the derived from a biological source specify recommends that the depth of the conditions of its intended use whether the plant or animal is review be addressed on a case-by-case (§ 170.250). ‘‘genetically engineered’’ or ‘‘cloned.’’ basis and be tailored to the substance (Comment 66) One comment We consider that the more general and the source of the substance. This recommends using our guidance requirement to identify a biological comment asserts that it would be entitled ‘‘Recommendations for source at the sub-species level is difficult and impractical to define a Submission of Chemical and adequate to identify the source. In method for this review or to define the Technological Data for Direct Food practice during the Interim Pilot specific toxicants that are required to be Additive Petitions’’ (Ref. 31) as a more program, notifiers routinely informed us reviewed for each particular substance. ‘‘holistic’’ approach to addressing about the use of such techniques in (Response 64) We agree that the safety potential safety concerns regarding describing production microorganisms, review should be tailored to the known toxicants in a biological source, particularly for GRAS notices about the substance and its source because of the because the guidance describes how to intended conditions of use of enzyme diversity of toxicants that could be in use the manufacturing process to preparations. (See, e.g., the list of the biological source. It is your control, reduce, or concentrate toxicant enzyme preparations in section IV.N of responsibility to determine how to levels and explains the importance of CFSAN’s 2010 experience document conduct the safety review; the rule does establishing limits for any known (Ref. 18).) The source microorganisms not prescribe any method for this review natural toxicants in or on food additives for several of the listed enzyme or any specific toxicants that must be derived from a natural source. The preparations were developed using reviewed for a particular substance or comment asserts that this guidance bioengineering techniques. source. In some cases (e.g., when it is should apply to GRAS substances as When confidential data and well established in the scientific well as food additives because general information about the development of a community that a source is non- recognition of safety through scientific production microorganism through toxigenic), citations to publicly procedures requires the same quantity bioengineering are necessary to provide available information about a biological and quality of evidence as is required to evidence that a notified substance source may be sufficient to address the establish a food additive regulation for mstockstill on DSK3G9T082PROD with RULES2 produced from that production safety of the notified substance with the use of the substance, and therefore organism is safe under the conditions of respect to potential toxicants in the the information about the identity of the its intended use, the use of the notified source. In other cases (e.g., when a substance should be consistent with the substance would not satisfy GRAS source is known to be toxigenic), the requirements for food additives. This criteria. See the discussion in Response information about the toxigenic source comment notes that section III.A of 69, where we explain that it may be would lead you to a discussion, in the ‘‘Recommendations for Submission of possible to explain that confidential narrative required in Part 6 of a GRAS Chemical and Technological Data for VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00039 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 54998 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations Direct Food Additive Petitions’’ clearly Environmental Protection Agency (EPA) of any substance—including an outlines the information needed for has already made case-by-case rulings engineered nanomaterial—satisfy GRAS ‘‘allowing the unequivocal on the safety of certain nanoparticles. criteria is a case-by-case conclusion that identification and characterization of Several comments assert that any depends on whether the generally the food additive’’ and that the requirement for a GRAS notice to available data and information support principles in specific sections in section address particle size and other chemical a conclusion that the substance is III.A of the guidance apply to GRAS or physical properties should apply generally recognized, among qualified substances even though they are written only to engineered nanomaterials, and experts, to be safe under the conditions to specifically address food additives. that it is not typically necessary to of its intended use. Section 201(s) of the (Response 66) We agree that many of address such properties for non- FD&C Act does not limit the eligibility the recommendations in our guidance engineered materials. One comment of a substance for classification as GRAS entitled ‘‘Recommendations for asserts that engineered nanomaterials based on factors such as its Submission of Chemical and could never be eligible for classification characteristic properties. Technological Data for Direct Food as GRAS because they either are new Additive Petitions’’ (Ref. 31) could be materials with unfamiliar properties or 4. Other Comments About the Identity useful to a person who assesses whether represent a significant new use of a of the Notified Substance a substance is GRAS under the material. (Comment 68) One comment asserts conditions of its intended use. As the (Response 67) The final rule requires that the criteria used to conclude that a comment points out, the guidance that a GRAS notice include scientific particular substance is GRAS, including currently is structured to address the information that identifies the notified details regarding biological source, specific requirements in § 171.1 substance, and includes ‘‘characteristic known toxicants, particle size, etc., (particularly § 171.1(c)) for food additive properties’’ in a list of examples of should be based on what qualified petitions. Consistent with available appropriate information that a notifier experts determine to be necessary. resources, we will consider revising that would include. We agree that data and (Response 68) We disagree that the guidance to clarify how its information about particle size, and any role of qualified experts in a conclusion recommendations apply to an chemical and physical properties of GRAS status means that the evaluation of whether a substance is attributable to small particle size, are requirements for a GRAS notice should GRAS under the conditions of its appropriate for engineered be silent on the types of data and intended use. nanomaterials; a GRAS notice about an information that generally apply to any engineered nanomaterial likely would conclusion of GRAS status—in this case, 3. Particle Size not provide an adequate basis for a data and information regarding the In the 2010 notice, we noted that conclusion of GRAS status without such identity of the substance. In the substances that have a small particle information. We also agree that data and narrative required by part 6 of a GRAS size often have chemical, physical, or information about particle size may not notice, a notifier must explain why the biological properties that are different be relevant for non-engineered materials data and information in the notice from those of their larger counterparts and, thus, we are including the broad provide a basis for the notifier’s view (75 FR 81536 at 81540). We requested example of ‘‘characteristic properties’’ that the notified substance is safe under comment on whether the final rule in the final rule without adding the the conditions of its intended use should address, as part of identity, narrow example of ‘‘particle size’’ (see (§ 170.250(a)(1)); identify what specific particle size and other chemical and § 170.230(a)(1)). data and information that the notifier physical properties that may be used to We note that we have several discusses to support his view that the characterize engineered materials (see guidances applicable to significant notified substance is safe under the table 9). manufacturing changes in food, conditions of its intended use are (Comment 67) Some comments including nanotechnology (Ref. 6; Ref. generally available, and what specific recommend that a GRAS notice discuss 8; and Ref. 44). Our guidance entitled data and information that the notifier particle size only if it is relevant to the ‘‘Guidance for Industry: Assessing the discusses are not generally available safety or effectiveness of the notified Effects of Significant Manufacturing (§ 170.250(a)(2)); and explain how the substance. One comment recommends Process Changes, Including Emerging generally available data and information that the rule not address particle size, at Technologies, on the Safety and that a notifier relies on to establish least until this area is better understood. Regulatory Status of Food Ingredients safety provide a basis for the notifier’s Another comment asks us to clarify and Food Contact Substances, Including conclusion that the notified substance is what we mean by the term ‘‘small Food Ingredients that are Color generally recognized, among qualified particle size’’ if we include that term in Additives’’ (Ref. 6) states: ‘‘At present, experts, to be safe under the conditions the rule. for nanotechnology applications in food of its intended use (§ 170.250(b)). The One comment asks us to require substances, there are questions related narrative is the appropriate mechanism information about particle size and to the technical evidence of safety as for a notifier to explain how the view of other physical/chemical properties that well as the general recognition of that qualified experts supports his view that may be used to characterize engineered safety, that are likely to be sufficient to the notified substance is GRAS under materials. This comment asserts that warrant formal premarket review and the conditions of its intended use. nanoparticles are not simply smaller approval by FDA, rather than to satisfy versions of materials; instead criteria for GRAS status.’’ However, that B. Method of Manufacture nanoparticles are specifically guidance reflects the generally available (Comment 69) Several comments mstockstill on DSK3G9T082PROD with RULES2 engineered to create new properties and data and information at present, and we address Issue 9a, i.e., whether the final behaviors that give products certain disagree that data and information rule should continue to stipulate that attributes and highly reactive supporting the safety of engineered the method of manufacture exclude any nanoparticles can exhibit a toxic nanomaterials could never satisfy GRAS trade secrets, as proposed. Some of reaction with their environments, criteria. Whether the generally available these comments support stipulating that including the cells of living organisms. data and information supporting the the method of manufacture exclude any This comment also notes that the U.S. safety of the intended conditions of use trade secrets. The stated reasons varied. VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00040 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 54999 For example, some comments state that for FDA to protect trade secrets or other See also Comment 57. in the past experience of notifiers, it is confidential information in a GRAS (Response 69) See table 11, and the generally possible to include sufficient notice from public disclosure, just as we regulatory text in §§ 170.230(b), information on the manufacturing would in the case of submissions such 170.225(c)(8), 170.250(d), and process without disclosing trade secrets. as food additive petitions. To promote 170.250(e), for a series of changes we One comment states that transparency, clarity and transparency, some of these made to the rule to address these by both FDA and industry, and the use comments recommend revising the rule comments about the method of of publicly available information is to require that a notifier who includes manufacture included in a GRAS notice, critical to the continued success of the trade secret information explain why including comments about trade secret GRAS notification procedure. One the information is trade secret and why information associated with the method comment states that the common the trade secret information has a of manufacture. Although the changes knowledge element of the GRAS corroborative role in the safety in Parts 1 and 6 of a GRAS notice standard inherently limits the assessment. Some comments emphasize submission of confidential information that a notifier who submits trade secret broadly apply to any non-public and/or trade secrets by the notifier to information must mark the information information, in this response we focus substantiate a conclusion of GRAS as non-public. Other comments assert on how these provisions apply to trade status. that information identified as trade secret information that you may include Other comments point to the secret or confidential information in the description of the method of proposed requirement that a GRAS should only be allowed if the manufacture. Collectively, these notice include ‘‘detailed information information is not critical to a changes: (1) Emphasize that the about the . . . method of manufacture conclusion of GRAS status. description of the method of (excluding any trade secrets . . .)’’ and One comment suggests that a notifier manufacture must be in sufficient detail question whether a method of could provide trade secret information to evaluate the safety of the notified manufacture that excludes trade secrets to a GRAS panel for review on a substance as manufactured, without can be sufficiently detailed to meet the confidential basis because deliberations stipulating that the method of requirements of a GRAS notice. One of the panel would not necessarily be manufacture exclude any trade secrets comment recommends that we clarify subject to public disclosure. One (§ 170.230(b)); (2) require the notifier to the rule by requiring that the notice comment notes that supporting include a signed statement with his include appropriate information on the information can be valuable to a GRAS view as to whether the method of method of manufacture, sufficient to panel and allowing submission of manufacture includes trade secret conduct an adequate safety review, so confidential information in a GRAS information (§ 170.225(c)(8)); (3) require that confidential information would not notice could inform FDA of the full the notifier to identify any trade secret be submitted when a very general and range of information taken into information in the method of non-confidential description suffices. consideration by a GRAS panel. manufacture (§ 170.250(d)); and (4) Several comments acknowledge that Some comments cite our regulations require the notifier to explain how there there may be situations where trade for new drugs, premarket notification could be a basis for a conclusion of secret information is necessary to for medical devices, and premarket GRAS status if qualified experts do not complete the description of the method approval of medical devices as evidence have access to trade secret information of manufacture and recommend that the that our regulations implementing FOIA that the notifier considered in final rule provide flexibility for a specifically regard methods of concluding that the substance is safe notifier to provide trade secret manufacture as confidential and urge us under the conditions of its intended use information when appropriate (e.g., to to adopt a similar approach for GRAS (§ 170.250(e)). See also Response 57, help us evaluate the GRAS notice), and notices. Response 78, and section XVII. TABLE 11—REQUIREMENTS THAT APPLY WHEN A NOTIFIER INCLUDES TRADE SECRET OR OTHER NON-PUBLIC INFORMATION IN A GRAS NOTICE Final designation in the Proposed designation regulatory text in the regulatory text Description Revision (§ ) (§ ) 170.230(b) ................... 170.36(c)(2) ................ In Part 2 of your GRAS notice, you must in- • We replaced ‘‘detailed’’ with ‘‘sufficient de- clude a description of the method of manu- tail to evaluate the safety of the notified facture in sufficient detail to evaluate the substance as manufactured’’. safety of the notified substance as manu- • We no longer stipulate that the description factured. of the method of manufacture must exclude trade secret information. 170.225(c)(8) ............... N/A ............................. In Part 1 of your GRAS notice, you must Requires a notifier who includes information state your view as to whether any of the that the notifier views as non-public infor- data and information in Parts 2 through 7 mation to make FDA aware of that view. of your GRAS notice are exempt from dis- See Response 57. closure under the FOIA (e.g., as trade se- cret or as commercial or financial informa- mstockstill on DSK3G9T082PROD with RULES2 tion that is privileged or confidential). 170.250(d) ................... N/A ............................. In Part 6 of your GRAS notice (the narrative), Requires a notifier who includes information if you view any of the data and information that the notifier views as non-public infor- in your notice as exempt from disclosure mation to identify the non-public informa- under the FOIA, you must identify the spe- tion. See section XVII. cific data and information. VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00041 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 55000 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations TABLE 11—REQUIREMENTS THAT APPLY WHEN A NOTIFIER INCLUDES TRADE SECRET OR OTHER NON-PUBLIC INFORMATION IN A GRAS NOTICE—Continued Final designation in the Proposed designation regulatory text in the regulatory text Description Revision (§ ) (§ ) 170.250(e) ................... In Part 6 of your GRAS notice (the narrative), Requires a notifier to place non-public infor- you must explain how there could be a mation in the context of a conclusion of basis for a conclusion of GRAS status if GRAS status. See section XVII. qualified experts generally do not have ac- cess to non-public, safety-related data and information. 170.275(c) ................... 170.36(f)(1) ................. We will disclose all remaining data and infor- Uses active voice to emphasize that we will mation that are not exempt from public dis- apply the protections from public disclosure closure in accordance with part 20. under the FOIA to non-public information included in a GRAS notice. This rule establishes requirements for range of information taken into the notifier has a basis to conclude that the information that a notifier submits consideration by the GRAS panel, the notified substance is GRAS under to FDA in a GRAS notice. GRAS criteria consistent with the signed statement the conditions of its intended use. The require that any conclusion of GRAS that the GRAS notice is a complete, use of the substance would be a food status be based on common knowledge representative, and balanced submission additive use and, if the notifier submits (see § 170.30(a)) and, thus, there could (see Response 58 and § 170.225(c)(9)). a food additive petition for that use, our be no basis for a conclusion of GRAS The notifier could do so either by regulations governing a food additive status if trade secret information (or including in his GRAS notice a non- petition would protect the information other non-public information) is confidential description of the trade from public disclosure, as do our necessary for qualified experts to reach secret information that was shared, or regulations for new drugs, premarket a conclusion that the notified substance by providing the trade secret notification for medical devices, and is safe under the conditions of its information shared with a GRAS panel. premarket approval of medical devices. intended use. In the particular case of a Importantly, the notifier would be (Comment 70) Several comments conclusion of GRAS status through required to explain how there could be express concern about the possibility scientific procedures, GRAS criteria a basis for a conclusion of GRAS status that we would determine that require that the conclusion of GRAS if qualified experts generally do not information a notifier identifies as a status be based on data, information, have access to non-public, safety related trade secret or as confidential and methods that are generally available data and information (see Response 78 commercial information is available for (see § 170.30(b)). Non-public and § 170.250(e)). If the public public disclosure. One comment asserts information may be used to corroborate description of the method of that if we choose to allow the safety but cannot be used to establish manufacture that a notifier includes in submission of confidential information safety; as discussed in Response 9, a GRAS notice cannot provide sufficient in a GRAS notice, we should not be the qualified experts must be able to detail to evaluate the safety of the party who determines whether conclude that the substance is not notified substance as manufactured, information should be publicly harmful under the conditions of its there could be no basis to support a disclosed. Another comment asks us to intended use without access to conclusion of GRAS status. However, if provide an opportunity for a notifier to ‘‘corroborative’’ information (see that public description meets the make a ‘‘cease to evaluate’’ request § 170.30(a)). requirements of the rule to provide before we disclose confidential sufficient detail to evaluate the safety of information. We believe that it will be rare for a One comment asks us to allow the GRAS notice to include trade secret the notified substance as manufactured submission of limited confidential information. Likewise, we expect it will (see § 170.230(b)), it may be possible to information to supplement (or be rare that trade secret information explain that trade secret information corroborate) the publicly available would warrant sharing with members of that a GRAS panel evaluated is information in a GRAS notice, such as a GRAS panel, because a notifier must corroborative of safety rather than by providing sufficient information in a write a non-confidential description of necessary to demonstrate safety. GRAS notice to support a conclusion of the method of manufacture to include in Under § 20.61, trade secrets and GRAS status but also including the GRAS notice and could share this commercial or financial information additional, corroborating information in non-confidential description, rather which is privileged or confidential are a food master file. The comment than trade secret information, with the exempt from public disclosure. Under explains that the public GRAS notice GRAS panel. If the GRAS panel had §§ 20.100(c)(7) and 171.1(h)(2)(i), would be complete and sufficient to questions about that description of the manufacturing methods or processes, form a conclusion of GRAS status, but method of manufacture, we expect that including quality control procedures, we would have access to additional, the notifier would revise the description are exempt from public disclosure confidential information that would mstockstill on DSK3G9T082PROD with RULES2 to address those questions rather than unless they have been previously ensure that we are informed of new provide the GRAS panel with trade disclosed to the public (as defined in manufacturing or technological secret information to address those § 20.81) or they relate to a product or developments. This comment points out questions. If, however, a notifier does ingredient that has been abandoned. If that we have for many years employed provide the GRAS panel with trade a notifier believes that all information food, drug, and medical device master secret information, we agree that the about the method of manufacture files for the submission of confidential notifier should inform us of the full should be non-public, it is unlikely that information. VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00042 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 55001 (Response 70) We disagree that we GRAS status in two separate files, and or other technical effect the notified should not be the party who determines we may decide to decline to file a GRAS substance is intended to produce, whether information should be publicly notice that is accompanied by a separate including the quantity of the notified disclosed. Under our public information file containing data and information that substance required to produce such regulations in part 20, we have the you view as non-public. effect, when necessary to demonstrate responsibility to determine whether (Comment 71) Some comments assert safety (see § 170.230(d) and Response information should be publicly that many manufacturers will choose 144). Data and information bearing on disclosed, regardless of whether a not to notify us of a conclusion of GRAS the physical or other technical effect the person who submits the information has status because they expect that we will notified substance is intended to marked it as non-public. Marking determine that all information produce are only necessary when they records submitted to us as confidential, submitted in a GRAS notice is available bear on safety. This relationship to or with any other similar term, raises no for public disclosure in most safety is consistent with the obligation by FDA to regard such circumstances. requirements of the FD&C Act for a records as confidential, to return them (Response 71) Our experience during petition to establish the safety of a food to the person who has submitted them, the Interim Pilot program does not additive (see section 409(b)(2)(C) of the to withhold them from disclosure to the support the assertions in these FD&C Act). An example of when such public, or to advise the person comments. As noted in Response 24 and data and information would be relevant submitting them when a request for Response 26, CFSAN has filed more to safety is when the intended use of the their public disclosure is received or than 600 GRAS notices between 1998 notified substance is as an antimicrobial when they are in fact disclosed (see and 2015, for an average of agent. For example, an antimicrobial § 20.27). We also disagree that providing approximately 34 GRAS notices per agent may change the microbiological an opportunity for a notifier to ask us year. profile of food such that it suppresses to cease to evaluate a GRAS notice (Comment 72) One comment states one group of pathogenic would impact the public disclosure of that commercial and financial microorganisms while allowing others data and information that do not satisfy information are not relevant to the to proliferate, thereby creating a the criteria in part 20 for exemption determination of safety of a notified potential health problem (Ref. 32). from disclosure; under § 20.29 a GRAS substance. (Response 72) Confidential XIV. Comments on Part 3 of a GRAS notice is available for public disclosure commercial information may on Notice: Dietary Exposure in accordance with part 20. occasion be used to corroborate safety. Data and information submitted to us One example is an article that has been We proposed that a notice regarding are available for public disclosure based accepted for publication, but has not yet a conclusion of GRAS status through on the nature of the data and been published. This article would scientific procedures include a information, not the name of the file likely be considered confidential until it comprehensive discussion of, and where we store the data and is published, but it could be used to citations to, generally available and information. Thus, asking us to store corroborate other published accepted scientific data, information, data and information that you view as information. methods, or principles that the notifier confidential in a specific type of file, relies on to establish safety, including a such as a ‘‘food master file,’’ would not C. Specifications for the Notified consideration of the probable automatically protect the information Substance consumption of the substance and the from public disclosure. Furthermore, in We received no comments that probable consumption of any substance Part 6 of your GRAS notice you would disagreed with our proposed formed in or on food because of its use be required to explain how there could requirement for a GRAS notice to and the cumulative effect of the be a basis for a conclusion of GRAS include specifications for food-grade substance in the diet, taking into status if qualified experts generally do material and we are finalizing it as account any chemically or not have access to the confidential data proposed for a substance used in human pharmacologically related substances in and information in the separate file. We food. See table 29 for an editorial such diet (proposed § 170.36(c)(4)(i)(A)). also would expect that you provide a change we made to the regulatory text In the 2010 notice, we requested statement in Part 1 of your GRAS notice for specifications for a substance used in comment on several issues relevant to with your view that the additional data animal food. the proposed requirements for a and information in the separate file are comprehensive discussion that exempt from disclosure under the FOIA D. Data and Information Bearing on the considers the probable consumption of (see § 170.225(c)(8)). Because part 20 Physical or Other Technical Effect of the the substance and the probable already provides protection of non- Notified Substance consumption of any substance formed public information from disclosure, and As discussed in section XXV.E, in or on food because of its use and the because your GRAS notice would need several comments discuss their cumulative effect of the substance in the to both acknowledge the data and experience with CVM’s practice, during diet, and noted that the simple term information in the separate file and the Interim Pilot program, of asking a ‘‘dietary exposure’’ could be used in explain how there could be a basis for notifier to provide data or information place of the statutory language (i.e., a conclusion of GRAS status if qualified demonstrating the effectiveness, or derived from section 409(c)(5) of the experts generally do not have access to utility, of the notified substance. After FD&C Act) we used in the proposed rule these data and information, we consider considering these comments, we have (see table 12). See table 27 for issues in mstockstill on DSK3G9T082PROD with RULES2 it administratively inefficient to added a requirement for Part 2 of a the 2010 notice regarding dietary maintain the data and information GRAS notice to include relevant data exposure when a notified substance submitted in support of a conclusion of and information bearing on the physical would be added to animal food. VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00043 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 55002 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations TABLE 12—ISSUES IN THE 2010 NOTICE REGARDING DIETARY EXPOSURE WHEN A NOTIFIED SUBSTANCE WOULD BE ADDED TO HUMAN FOOD Issue Description of our request for comment Reference No. 11a ..... Whether the final rule should continue to restate the statutory language of section 409(c)(5) 75 FR 81536 at 81540–81541. of the FD&C Act or whether this provision should be stated more clearly, for example, by requiring information about dietary exposure (i.e., the amount of the notified substance that consumers are likely to eat or drink as part of a total diet). 11b ..... Whether a GRAS notice should be required to include information about dietary exposure to 75 FR 81536 at 81540–81541. contemporary consumers regardless of whether the determination of GRAS status is through scientific procedures or through experience based on common use in food. In the following sections, we discuss as shown in table 13, with editorial, conforming changes shown in table 29 comments on the proposed clarifying, and conforming changes as and the additional editorial changes requirements applicable to dietary shown in table 29. (See § 170.235). associated with the redesignation of exposure and the issues discussed in the Table 13 identifies changes we made some of the regulatory text of proposed 2010 notice. After considering these relative to the proposed rule or the § 170.36(c)(4)(i)(A) as § 170.235. comments, we are establishing description in the 2010 notice other requirements for Part 3 of a GRAS notice than the editorial, clarifying, and TABLE 13—FINAL REQUIREMENTS FOR DATA AND INFORMATION ABOUT DIETARY EXPOSURE IN PART 3 OF A GRAS NOTICE Proposed Revisions (other than editorial, Final designation in Issue No. designation in the clarifying, and conforming changes) the regulatory text in the 2010 Description regulatory text relative to the proposed rule or the (§ ) notice (§ ) 2010 notice 170.235 .................. 170.36(c)(4)(i)(A) ... 11a In Part 3 of your GRAS Notice, you • Uses the term ‘‘dietary exposure’’ and 11b must provide data and information describes it as meaning ‘‘the amount about dietary exposure (i.e., the of relevant substances that con- amount of relevant substances that sumers are likely to eat or drink as consumers are likely to eat or drink part of a total diet.’’ as part of a total diet), regardless of • Requires data and information about whether your conclusion of GRAS dietary exposure regardless of wheth- status is through scientific procedures er your conclusion of GRAS status is or through experience based on com- through scientific procedures or mon use in food. through experience based on com- mon use in food. 170.235(a) .............. 170.36(c)(4)(i)(A) ... 11a In Part 3 of your GRAS Notice, you Uses the term ‘‘dietary exposure.’’ must provide data and information about dietary exposure to the notified substance that includes exposure from its intended use and all sources in the diet. 170.235(b) .............. 170.36(c)(4)(i)(A) ... 11a When applicable, in Part 3 of your • Uses the term ‘‘dietary exposure.’’ GRAS Notice you must provide data • Gives examples of substances that and information about dietary expo- could be formed in or on food be- sure to any other substance that is cause of the use of the notified sub- expected to be formed in or on food stance. because of the use of the notified substance (e.g., hydrolytic products or reaction products). 170.235(c) .............. 170.36(c)(4)(i)(A), 11a When applicable, in Part 3 of your Requires an estimate of dietary expo- 170.36(c)(2). GRAS Notice you must provide data sure to substances such as contami- and information about dietary expo- nants and by-products as a means to sure to any other substance that is establish specifications for applicable present with the notified substance ei- contaminants and by-products. ther naturally or due to its manufac- ture (e.g., contaminants or by-prod- ucts). 170.235(d) .............. 170.36(c)(4)(i)(A) ... 11a In Part 3 of your GRAS notice, you Specifies a necessary aspect of the must describe the source of any food proposed ‘‘comprehensive discus- mstockstill on DSK3G9T082PROD with RULES2 consumption data that you use to es- sion’’ of scientific data, information, timate dietary exposure. and methods. 170.235(e) .............. 170.36(c)(4)(i)(A) ... 11a In Part 3 of your GRAS notice, you Specifies a necessary aspect of the must explain any assumptions you proposed ‘‘comprehensive discus- made to estimate dietary exposure. sion’’ of scientific data, information, and methods. VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00044 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 55003 TABLE 13—FINAL REQUIREMENTS FOR DATA AND INFORMATION ABOUT DIETARY EXPOSURE IN PART 3 OF A GRAS NOTICE—Continued Proposed Revisions (other than editorial, Final designation in Issue No. designation in the clarifying, and conforming changes) the regulatory text in the 2010 Description regulatory text relative to the proposed rule or the (§ ) notice (§ ) 2010 notice 170.250(a)(1) ......... 170.36(c)(4)(i)(A) ... N/A In Part 6 of your GRAS notice, you N/A. must explain why the data and infor- mation in your notice provide a basis for your view that the notified sub- stance is safe under the conditions of its intended use, considering all die- tary sources and taking into account any chemically or pharmacologically related substances in such diet. See section XXV.F for a discussion of notifier provide data and information is reasonable (see § 170.235(d) and (e) comments on the issues listed in table about dietary exposure to any other and table 13). Our guidance entitled 27 regarding dietary exposure when a substance that is expected to be formed ‘‘Estimating Dietary Intake of notified substance would be added to in or on food because of the use of the Substances in Food’’ provides general animal food and for changes we made notified substance (e.g., hydrolytic recommendations for calculating and to the regulatory text regarding dietary products or reaction products) submitting estimates of dietary intake to exposure when a notified substance (§ 170.235(b)). Example of such support the documentation of the safety would be added to animal food. substances are benzoates (which react of substances introduced into food (Comment 73) Some comments with ascorbic acid (such as in beverages) either intentionally to accomplish a support retaining the statutory language to form benzene) and sulfur dioxide technical effect, adventitiously as a derived from section 409(c)(5) of the (which reacts irreversibly with component of an added substance, or FD&C Act when stating the requirement thiamine, such that we have prescribed inadvertently through contamination for a comprehensive discussion in a limitations on the use of sulfur dioxide resulting from processing (Ref. 25). GRAS notice that considers dietary in some food products (see § 182.3862)). (Comment 75) One comment exposure. One of these comments states The rule also requires, when applicable, emphasizes that the requirement for that the proposed statutory language that a notifier provide data and consideration of dietary exposure must regarding dietary exposure is consistent information about dietary exposure to discuss the potential cumulative effect with the criteria for general recognition any other substance that is present with of the notified substance. of safety through scientific procedures, the notified substance either naturally (Response 75) We agree. We are which requires the same quantity and or due to its manufacture (e.g., specifying that the narrative included in quality of scientific evidence necessary contaminants or by-products). An Part 6 of a GRAS notice must address for a food additive petition. Other estimate of dietary exposure to the safety of the notified substance, comments support revising the substances such as contaminants and considering all dietary sources and proposed requirement as a means of by-products is necessary to establish taking into account any chemically or clarifying that the comprehensive specifications for applicable pharmacologically related substances in discussion in a GRAS notice must contaminants and by-products (see such diet (see § 170.250(a)(1)). consider dietary exposure. § 170.230(c), which requires that a (Comment 76) Some comments (Response 73) We agree that: (1) The GRAS notice include specifications for support requiring that a GRAS notice requirements of the rule regarding what food-grade material). See also Response include information about dietary a notifier must include in a GRAS notice 75. exposure to contemporary consumers regarding dietary exposure must be (Comment 74) One comment asks us when the conclusion of GRAS status is clear; and (2) the statutory language of to allow for a reasonable methodology through experience based on common section 409(c)(5)(A) of the FD&C Act is that does not overestimate dietary use in food prior to 1958, e.g., because consistent with the criteria for general exposure in the extreme. dietary exposure to contemporary recognition of safety through scientific (Response 74) The rule neither consumers serves as a baseline for procedures, which requires the same prescribes the methodology you would future studies/assessment. Other quantity and quality of scientific use to estimate dietary exposure nor comments do not support such a evidence necessary for a food additive requires that you overestimate dietary requirement and assert that it is not petition. To meet both of these goals, the exposure. Consistent with the proposed critical to update the exposure data if final rule requires information about requirement for the consideration of consumption of the GRAS substance dietary exposure (i.e., the amount of dietary exposure to be a was already widespread before 1958, or relevant substances that consumers are ‘‘comprehensive discussion,’’ the rule that information about dietary exposure likely to eat or drink as part of a total requires you to describe the source of to contemporary consumers would only diet), as we suggested in the 2010 any food consumption data that you use be necessary if the exposure has mstockstill on DSK3G9T082PROD with RULES2 notice, but also retains the detailed to estimate dietary exposure and any significantly changed since 1958. statutory direction as proposed (see assumptions you made to estimate One comment questions the value of § 170.235(a) through (c), § 170.250(a)(1), dietary exposure; such information is requiring information about and table 13). In addition to requiring an necessary for the estimates of dietary contemporary dietary intake of an estimate of dietary exposure to the exposure to be scientifically sound and ingredient that is GRAS through notified substance (§ 170.235(a)), the provides an opportunity for you to experience based on common use in rule requires, when applicable, that a explain why the methodology you used foods. This comment asserts that the VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00045 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 55004 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations FD&C Act deems an ingredient to be conditions of its intended use. Under disagreeing with this proposed GRAS if it was commonly used in foods both the FD&C Act and the definition of requirement. Therefore, we are prior to January 1, 1958, and that FDA ‘‘safe’’ in our regulations, relevant establishing a requirement for you to has long recognized that a conclusion of factors must be considered, including include in Part 4 of your GRAS notice GRAS status through experience based the ‘‘probable consumption of the data and information on self-limiting on common use in food may be made substance and of any substance formed levels of use in circumstances where the without the quantity or quality of in or on food because of its use’’ (see amount of the notified substance that scientific procedures required for section 409(c)(5)(A) of the FD&C Act can be added to food is limited because establishment of a food additive and § 170.3(i)(1)). We recognize that a food containing levels of the notified regulation. This comment asserts that conclusion of GRAS status through substance above a particular level there is no requirement for a GRAS experience based on common use in would become unpalatable or ingredient to be consumed at the same food does not require the same quantity technologically impractical (see use level as in 1958 and that imposition or quality of scientific information § 170.240). We included an explanation of such a new requirement may be required for establishment of a food of the circumstances in which the level impracticable, e.g., because there may additive regulation; however, this of use is self-limiting for clarity. not be any databases that would allow means that a conclusion of GRAS status XVI. Comments on Part 5 of a GRAS for the calculation of dietary exposures through experience based on common Notice: Common Use in Food Before prior to 1958. This comment also asserts use in food is not necessarily supported 1958 that in many instances there may be by the same testing data as would be insufficient information to establish an required to support establishment of a We proposed that a GRAS notice acceptable daily intake (ADI) for the food additive regulation. See, for include a comprehensive discussion of, ingredient because studies that can be example, the 1976 final rule establishing and citations to, generally available data used to calculate ADIs may not be GRAS criteria, which provides, ‘‘for and information that the notifier relies available for many of these ingredients, those substances that were widely used on to establish safety, including and that without information about the before 1958, under the terms of the evidence of a substantial history of ADI it would be difficult to imagine the statute FDA must consider available consumption of the substance by a relevance of the estimated daily intake, data and may not prohibit use of a significant number of consumers, for a which would be calculated through substance merely because tests that conclusion of GRAS status through dietary exposure. would be required for new food experience based on common use in Another comment asserts that additives have not been performed.’’ (41 food (proposed § 170.36(c)(4)(ii)(A)). §§ 170.30(c) and 170.3(f) clearly provide FR 53600, December 7, 1976). Like a During the Interim Pilot program, we that for a substance to be GRAS through conclusion of GRAS status based on received fewer than a dozen GRAS experience based on common use in scientific procedures, a conclusion of notices where the statutory basis was food there must be a substantial history GRAS status through experience based through experience based on common of consumption of the substance in food on common use in food requires that the use in food (Ref. 45). by a significant number of people prior substance be ‘‘safe,’’ as defined in 21 We did not receive comments to 1958 and that the requirements for CFR 170.3(i), under the conditions of its disagreeing with this proposed information about consumption data in intended use. requirement and we are establishing a a GRAS notice should be consistent The rule requires that a notifier requirement for you to include in Part with those regulatory provisions. This provide evidence of substantial history 5 of your GRAS notice evidence of a comment also asserts that requiring of consumption of the substance for substantial history of consumption of information about dietary exposure to food use by a significant number of the notified substance for food use by a contemporary consumers would consumers prior to January 1, 1958, but significant number of consumers prior represent an additional regulatory does not require an estimate of dietary to January 1, 1958 if the statutory basis burden that would not impact the exposure prior to 1958 (see § 170.245). for your conclusion of GRAS status is original conclusion of GRAS status The rule requires that the narrative in through experience based on common through experience based on common Part 6 of a GRAS notice explain why the use in food (see § 170.245). See table 29 use in food if there are no safety data and information in the notice for conforming changes for a substance concerns when the notified substance is provide a basis for the notifier’s view used in animal food. used in accordance with the intended that the notified substance is safe under XVII. Comments on Parts 6 and 7 of a conditions of use. the conditions of its intended use, GRAS Notice: Narrative and List of (Response 76) We are requiring that a considering all dietary sources and Supporting Data and Information notifier provide data and information taking into account any chemically or about dietary exposure, regardless of pharmacologically related substances in We proposed that a GRAS notice must whether the conclusion of GRAS status such diet (§ 170.250(a)); to do so, the include a detailed summary of the basis is through scientific procedures or notifier must consider the estimated for the notifier’s determination that a through experience based on common dietary exposure (which this comment particular use of the notified substance use in food (see § 170.235). The FD&C refers to as ‘‘estimated daily intake’’). is exempt from the premarket approval Act and our regulations do not provide However, the rule does not specify that requirements of the FD&C Act because that a substance is necessarily GRAS a notifier must determine an such use is GRAS (proposed under the conditions of its intended use ‘‘acceptable daily intake’’ as part of the § 170.36(c)(4)). Regardless of whether merely because it was commonly used narrative. the conclusion of GRAS status was mstockstill on DSK3G9T082PROD with RULES2 in food prior to 1958. Rather, the FD&C based on scientific procedures or Act provides that such a substance must XV. Comments on Part 4 of a GRAS through experience based on common be generally recognized, among experts Notice: Self-Limiting Levels of Use use in food, we proposed to require: (1) qualified by scientific training and We proposed that a GRAS notice must A comprehensive discussion of, and experience to evaluate its safety, include information on any self-limiting citations to, generally available and through experience based on common levels of use (proposed § 170.36(c)(3)). accepted scientific data and information use in food, to be safe under the We did not receive comments that the notifier relies on to establish VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00046 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 55005 safety (proposed § 170.36(c)(4)(i)(A) and reasonable certainty that the substance consumption of any substance formed 170.36(c)(4)(ii)(A)); (2) a comprehensive is not harmful under the intended in or on food because of its use and the discussion of any reports of conditions of use (proposed cumulative effect of the substance in the investigations or other information that § 170.36(c)(4)(i)(C) and (c)(4)(ii)(C)). diet, taking into account any chemically may appear to be inconsistent with the When the conclusion of GRAS status is or pharmacologically related substances GRAS determination (proposed based on scientific procedures, we also in such diet (proposed § 170.36(c)(4)(i)(B) and (c)(4)(ii)(B)); and proposed that the discussion of § 170.36(c)(4)(i)(A)). (3) the basis for concluding, in light of generally available and accepted In the 2010 notice, we requested the data and information in the GRAS information that the notifier relies on to comment on issues relevant to the notice, that there is consensus among establish safety include methods and applicability of confidential data and experts qualified by scientific training principles, and include a consideration information to a conclusion that a and experience to evaluate the safety of of the probable consumption of the substance is GRAS under the conditions substances added to food that there is substance and the probable of its intended use (see table 14). TABLE 14—ISSUES IN THE 2010 NOTICE REGARDING THE APPLICABILITY OF CONFIDENTIAL DATA AND INFORMATION TO A CONCLUSION OF GRAS STATUS Issue Description of our request for comment Reference No. 9b ...... Whether to require that a notifier who identifies one or more trade secret(s), as defined in 75 FR 81536 at 81539–81540. § 20.61(a), in the GRAS notice explain why it is trade secret information and how qualified ex- perts could conclude that the intended use of the notified substance is safe without access to the trade secret(s). 9c ...... Whether to require that a notifier who identifies confidential commercial or financial information, as 75 FR 81536 at 81539–81540. defined in § 20.61(b), in the GRAS notice explain why it is confidential commercial or financial in- formation and how qualified experts could conclude that the intended use of the notified sub- stance is safe without access to such information. In the following paragraphs, we as shown in table 15, and for Part 7 of or the description in the 2010 notice discuss comments on the proposed a GRAS notice to include a list of other than the editorial, clarifying, and requirements applicable to a detailed supporting data and information as conforming changes shown in table 29 summary of the basis for the notifier’s shown in table 16, with editorial, and the additional editorial changes conclusion of GRAS status and the clarifying, and conforming changes as associated with the redesignation of issues discussed in the 2010 notice. shown in table 29. (See §§ 170.250 and proposed § 170.36(c)(4) as §§ 170.250 After considering these comments, we 170.255.) and 170.255. are establishing requirements for Part 6 Table 15 and table 16 identify changes of a GRAS notice to include a narrative we made relative to the proposed rule TABLE 15—FINAL REQUIREMENTS FOR A NARRATIVE IN PART 6 OF A GRAS NOTICE Proposed Revisions (other than editorial, Final designation in Issue No. in designation in the Description. Part 6 of your clarifying, and conforming changes) the regulatory text the 2010 regulatory text GRAS notice: relative to the proposed rule or the (§ ) notice (§ ) 2010 notice 170.250 .................. 170.36(c)(4) ........... N/A You must include a narrative that pro- N/A. vides the basis for your conclusion of GRAS status. 170.250(a)(1) ......... 170.36(c)(4) ........... N/A You must explain why the data and in- N/A. formation in your notice provide a basis for your view that the notified substance is safe under the condi- tions of its intended use, considering all dietary sources and taking into ac- count any chemically or pharma- cologically related substances in such diet. 170.250(a)(2) ......... 170.36(c)(4) ........... 9a, 9b, and 9c You must identify what specific data Requires that your narrative clarify the and information are generally avail- status of all data and information that able, and what specific data and in- you rely on to establish safety. formation are not generally available, by providing citations to the list of data and information that you include mstockstill on DSK3G9T082PROD with RULES2 in Part 7 of your GRAS notice. VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00047 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 55006 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations TABLE 15—FINAL REQUIREMENTS FOR A NARRATIVE IN PART 6 OF A GRAS NOTICE—Continued Proposed Revisions (other than editorial, Final designation in Issue No. in designation in the Description. Part 6 of your clarifying, and conforming changes) the regulatory text the 2010 regulatory text GRAS notice: relative to the proposed rule or the (§ ) notice (§ ) 2010 notice 170.250(b) .............. 170.36(c)(4) ........... N/A You must explain how the generally Uses the term ‘‘generally recognized’’ available data and information that rather than the term ‘‘consensus.’’ you rely on to establish safety provide a basis for your conclusion that the notified substance is generally recog- nized, among qualified experts, to be safe under the conditions of its in- tended use. 170.250(c) .............. 170.36(c)(4) ........... 6b You must either: (1) Identify, discuss, When applicable, requires an affirmative and place in context, data and infor- statement that you have reviewed the mation that are, or may appear to be, available data and information and inconsistent with your conclusion of are not aware of any data and infor- GRAS status, regardless of whether mation that are, or may appear to be, those data and information are gen- inconsistent with your conclusion of erally available; or GRAS status. (2) State that you have reviewed the available data and information and are not aware of any data and infor- mation that are, or may appear to be, inconsistent with your conclusion of GRAS status.. 170.250(d) .............. N/A ......................... 9b and 9c In Part 6 of your GRAS notice (the nar- N/A. rative), if you view any of the data and information in your notice as ex- empt from disclosure under the FOIA, you must identify the specific data and information. 170.250(e) .............. N/A ......................... 9b and 9c In Part 6 of your GRAS notice (the nar- Your explanation must address all non- rative), you must explain how there public safety-related data and infor- could be a basis for a conclusion of mation, not just confidential data and GRAS status if qualified experts gen- information included in your GRAS erally do not have access non-public, notice. safety-related data and information. TABLE 16—FINAL REQUIREMENTS FOR A LIST OF SUPPORTING DATA AND INFORMATION IN PART 7 OF A GRAS NOTICE Proposed Revisions (other than editorial, Final designation in Issue No. in designation in the Description. Part 7 of your clarifying, and conforming changes) the regulatory text the 2010 regulatory text GRAS notice: relative to the proposed rule or the (§ ) notice (§ ) 2010 notice 170.255(a) .............. • 170.36(c)(4)(i)(A) 9a, 9b, and 9c You must include a list of all of the data Clarifies that the list includes all data • 170.36(c)(4)(ii)(A) and information that you discuss in and information, not just generally part 6 of your GRAS notice to provide available data and information. a basis for your view that the notified substance is safe under the condi- tions of its intended use. 170.255(b) .............. • 170.36(c)(4)(i)(A) 9a, 9b, and 9c The data and information that you list Requires that you characterize each • 170.36(c)(4)(ii)(A) must specify which data and informa- item in your list as to whether it is tion are generally available, and generally available. which data and information are not generally available. In the requirements for Parts 6 and 7 proposed requirements for a detailed information that are not generally of the final rule, we made changes to summary and comprehensive available (see § 170.230(b) (which no require that the narrative in Part 6 of discussion for consistency with: (1) The longer stipulates that the method of your GRAS notice, and the criteria for eligibility for classification as manufacture must exclude trade secret), accompanying list of supporting data GRAS through scientific procedures § 170.225(c)(8), Response 57 and mstockstill on DSK3G9T082PROD with RULES2 and information in Part 7 of your GRAS (which provide that a conclusion of Response 69). notice, clarify the status of all data and GRAS status may be corroborated by the In the requirements for Part 6 of a information that you rely on to establish application of unpublished scientific GRAS notice, we also made a change to safety as to whether it is generally data, information, or methods (see require that your narrative either: (1) available (see §§ 170.250(a)(2) and § 170.30(b), Response 8, and Response Identify, discuss, and place in context, 170.255, table 15, and table 16). We 12)); and (2) the provisions of the rule data and information that are, or may made these changes relative to the that allow you to include data and appear to be, inconsistent with your VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00048 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 55007 conclusion of GRAS status, regardless of information warrant sharing with any term ‘‘consensus’’ because the revised whether those data and information are ‘‘GRAS panel’’ that you convene). GRAS criteria that we are establishing in generally available; or (2) state that you (Comment 77) One comment asserts § 170.30 continue to use the statutory have reviewed the available data and that the proposed requirement for a language rather than the consensus information and are not aware of any GRAS notice to include the basis for standard applied by the courts in data and information that are, or may concluding that there is consensus applying the statutory language to appear to be, inconsistent with your among qualified experts about the safety specific situations. Using the statutory conclusion of GRAS status. See of the substance misstates the statutory language in both the GRAS criteria and § 170.250(c) and table 15. We made this standard for general recognition in the requirement for the submission of a change relative to the proposed section 201(s) of the FD&C Act. This narrative in a GRAS notice will requirement for a comprehensive comment asserts that the term emphasize your burden to explain how discussion of any reports of ‘‘consensus’’ denotes complete or near the data and information in the notice investigations or other information that unanimity, whereas the standard of regarding the safety of the notified general recognition requires that substance under the conditions of its may appear to be inconsistent with a qualified experts predominantly, but not intended use satisfy the GRAS criteria. conclusion of GRAS status to emphasize unanimously, accept the safety of the See also Response 128, in which we your responsibility to seek out such substance. Although the comment respond to comments recommending reports and information, as we do acknowledges that the proposed rule that we clarify that the same standards during our evaluation of a GRAS notice. stated that the term ‘‘consensus’’ does apply to a conclusion of GRAS status See also § 170.225(c)(9) and Response not imply unanimity (62 FR 18938 at regardless of whether the conclusion is 58, in which we discuss the 18941), the comment argues that the submitted to us as a GRAS notice or is requirements for a statement certifying example used in our explanation, about not submitted to us. As noted in that the GRAS notice is ‘‘complete’’ in whether a single published report Response 128, we believe that the addition to ‘‘representative’’ and questioning the safety of use of a provisions of the GRAS notification ‘‘balanced,’’ to emphasize your substance in food would preclude procedure will be a useful resource to responsibility to identify, discuss, and general recognition, wrongly implied any person who intends to use a place in context, data and information that general recognition requires near substance in food based on a conclusion that are, or may appear to be, unanimity (62 FR 18938 at 18941). The of GRAS status, regardless of whether inconsistent with a conclusion of GRAS comment asks us to revise the rule by the conclusion of GRAS status is status. Under §§ 170.225(c)(9) and replacing the term ‘‘consensus,’’ which submitted to us in a GRAS notice. In 170.250(c), we expect you to describe does not appear in the statute, with the developing any recommendations (e.g., unpublished reports of investigations or phrase ‘‘general recognition,’’ which in guidance) that would broadly apply other information that may appear to be derives from the statute itself. to any conclusion of GRAS status, it is inconsistent with a conclusion of GRAS (Response 77) As discussed in the simpler to consistently use the same status, not just published reports. If we proposed rule (62 FR 18938 at 18939), regulatory text in both the GRAS criteria identify relevant information that was our interpretation that general and the submission requirements for a not discussed in the GRAS notice, we recognition requires consensus is GRAS notice. may question the credibility of the consistent with the case law on the (Comment 78) One comment notes certification statements in the GRAS general recognition standard. See that industry has various options for notice and respond with an United States v. Western Serum Co., handling confidential information. For ‘‘insufficient basis letter.’’ As noted in Inc., 666 F.2d 335, 338 (9th Cir. 1982); example, confidential agreements are Response 58, the use of certification United States v. Articles of commonly used instruments to help statements has become routine in other Drug...Promise Toothpaste, 624 F.Supp. maintain the confidentiality of submissions to FDA for food programs, 776, 778 (N.D. Ill. 1985), aff’d 826 F.2d proprietary trade secret information, and the certification statements in Form 564 (7th Cir. 1987); United States v. and therefore qualified experts on GRAS FDA 3480 (for a food contact Articles of Drug...Hormonin, 498 panels can have access to such notification submission) (Ref. 39) and in F.Supp.2d 424, 435 (D.N.J. 1980). See information if it is necessary for a Form FDA 3537 (for registration of a also the discussion of the consensus conclusion of GRAS status. The food facility) (Ref. 40) remind the standard in Response 20. comment asks us to require that submitter of criminal penalties under 18 We proposed to provide our notifiers indicate whether qualified U.S.C. 1001 for a materially false, interpretation of section 201(s) of the experts (such as on the notifier’s GRAS FD&C Act in the requirement for Part 6 panel) had access to trade secrets when fictitious, or fraudulent statement to the of a GRAS notice to provide more they concluded that the substance is U.S. Government. Now that certification context to notifiers than merely safe under the conditions of its intended statements will be required in a GRAS repeating the statutory language. We use. notice, we intend to modify the form disagree with the comment’s assertion (Response 78) The rule establishes no that we make available for the that the example we described in the requirements specific to a GRAS panel. submission of a GRAS notice (i.e., Form However, we agree that it is appropriate proposed rule requires ‘‘near FDA 3667 (Ref. 38)) to likewise remind for a notifier to indicate whether unanimity’’; CFSAN’s experience during any person who submits a GRAS notice qualified experts (such as on the the Interim Pilot program demonstrates of the applicability of criminal penalties notifier’s GRAS panel) who reviewed that CFSAN’s ‘‘insufficient basis letters’’ for a materially false, fictitious, or the data and information supporting did not apply a standard of ‘‘near mstockstill on DSK3G9T082PROD with RULES2 fraudulent statement to the U.S. unanimity’’ when evaluating the safety had access to safety-related trade Government. notifier’s basis for a conclusion of GRAS secrets in reaching a conclusion that the See also Response 78. We also expect status (see section III.A.3 of CFSAN’s notified substance is safe under the you to describe unpublished data and 2010 experience document (Ref. 18)). conditions of its intended use. information that you consider to be However, we have decided to use the Therefore, we are requiring that a corroborative of safety (e.g., if you statutory language (i.e., ‘‘generally notifier explain how there could be a consider that the unpublished data and recognized’’) rather than the proposed basis for a conclusion of GRAS status if VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00049 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 55008 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations qualified experts generally do not have questions letter,’’ and later determine inconsistent with the GRAS provision in access to non-public safety-related data that the GRAS notice was not section 201(s) of the FD&C Act, which and information (see § 170.250(e)). This ‘‘complete’’ (e.g., because it did not requires general recognition among requirement applies to all non-public describe unpublished reports of qualified experts. See also the safety-related data and information, not investigations that are, or may appear to discussion in Response 70, in which we just trade secret information, and is not be, inconsistent with the conclusion of explain our reasons for why we may limited to non-public safety-related data GRAS status), we may send the notifier decide to decline to file a GRAS notice and information that are included in the a subsequent letter regarding the that is accompanied by a separate file notice. As requested by the comment, omission; such a letter would be readily containing data and information that this requirement would apply if the accessible to the public (§§ 170.265(c) you view as non-public. notifier provided non-public safety- and 170.275(b)(2)). XVIII. Comments on Steps a Notifier related information to outside experts (Comment 79) One comment suggests May Take Before We Respond to a (such as on a GRAS panel). As already that if the qualified experts are FDA GRAS Notice discussed, if a GRAS panel considers reviewers, an option might be for the non-public safety-related information notifier to submit a ‘‘sanitized’’ version In the 2010 notice, we described that a notifier does not include in a of the GRAS notice, excluding non- comments regarding steps you may take GRAS notice, we also expect the notifier public information, together with a before we respond to your GRAS notice to inform us that the GRAS panel had separate appendix to the GRAS notice (see table 17). As noted in section access to such information, consistent where the notifier would include VIII.A, we are establishing a definition with the notifier’s signed statement that relevant trade secrets or confidential for ‘‘amendment’’ in the rule (see the GRAS notice is a complete, information needed to support the § 170.203). In the following paragraphs, representative, and balanced submission conclusion of GRAS status. we discuss additional comments (see § 170.225(c)(9)) (see Response 58 Alternatively, we could require that a regarding the issues in table 17. Some of and Response 69). notifier submit two versions of the these comments agree that the rule See also table 11 and table 15. The submission: (1) A sanitized version that should have such a provision. Other rule also requires that a notifier state his excludes non-public information; and comments ask us to clarify how such a view as to whether any of the data and (2) a more detailed version including provision would operate in practice information in Parts 2 through 7 of a the confidential information. The (see, e.g., Comment 82) or suggest one GRAS notice are exempt from disclosure comment states that these options or more changes to the provision as we under the FOIA (see § 170.225(c)(8)) and would both allow our reviewers access described it in the 2010 notice (see, e.g., identify what specific data and to the information and facilitate the Comment 80, Comment 81, and information in the notice are generally process of promptly making GRAS Comment 83). After considering these available, and what specific data and notices available for public disclosure. comments, we are establishing two information in the notice are not (Response 79) In enacting the GRAS provisions regarding steps you may take generally available (see § 170.250(a)(2) provision, Congress clearly before we complete our evaluation of a and (d)). Collectively, the requirements contemplated a process of concluding GRAS notice. The first provision in §§ 170.225(c)(8) and (9) and that a food substance is GRAS under the specifies that you may submit a timely 170.250(a)(2), (d), and (e) address the conditions of its intended use as an amendment to your filed GRAS notice, underlying issue in the comment’s alternative to submission of a food to update your GRAS notice or in request, i.e., that there must be a basis additive petition to FDA and response to a question from us, before for a conclusion of GRAS status if some establishment of a regulation we respond to your notice by letter (see safety-related data and information that prescribing the conditions under which the regulatory text of § 170.260(a)). The a notifier assesses in his deliberations the substance may be safely used. It second provision specifies that you may are non-public (e.g., trade secret follows that the qualified experts who ask us to cease to evaluate your GRAS information or otherwise are evaluate the basis for a conclusion that notice as described in the 2010 notice, confidential information), regardless of the notified substance is safe under the with clarifications as a result of whether the notifier shares such conditions of its intended use must not comments (see the regulatory text of information with a GRAS panel. If a exclusively be ‘‘FDA’s experts’’ (such as § 170.260(b)). One clarification is that GRAS notice does not provide a basis our scientific staff who evaluate GRAS such a request does not preclude you for a conclusion that the notified notices). The suggestion of this from submitting a future GRAS notice substance is safe under the conditions of comment that a notifier could rely with respect to the notified substance. A its intended use without access to such exclusively on evaluation by FDA second clarification is that we will send information, we would respond to the experts to support his view that there is you a letter informing you of our notice with an ‘‘insufficient basis a basis for concluding that there is decision regarding your request (see the letter.’’ If we respond with a ‘‘no consensus among ‘‘qualified experts’’ is regulatory text of § 170.265(b)(3)). TABLE 17—ISSUES IN THE 2010 NOTICE REGARDING STEPS YOU MAY TAKE BEFORE WE RESPOND TO YOUR GRAS NOTICE Issue Description of our request for comment Reference No. mstockstill on DSK3G9T082PROD with RULES2 3a ...... Whether to define ‘‘amendment’’ to mean any data or other information that you submit regarding a 75 FR 81536 at 81538. filed GRAS notice before we respond to the notice. 5 ........ Whether the final rule should explicitly provide that you may request in writing that we cease to 75 FR 81536 at 81538–81539. evaluate your GRAS notice at any time during our evaluation of that GRAS notice. VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00050 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 55009 See section XXV.I for a discussion of document (Ref. 18)). Although we already immersed in the substantive comments regarding steps you may take expect to contact you when we have evaluation of the notice, rather than to before we respond to your GRAS notice questions, whether we intend to provide issue an ‘‘insufficient basis letter’’ and for a substance used in animal food, and you with an opportunity to submit an begin the evaluation process anew when for our response to those comments. amendment to a GRAS notice before the notifier addresses the questions in a responding to the notice has been, and new GRAS notice. See section XVIII.B A. Communicating With a Notifier will continue to be, a matter committed for a discussion of what we mean by a Before We Respond to a GRAS Notice to our discretion. ‘‘timely’’ amendment. (Comment 80) Several comments note In the following paragraphs, we If we file your submission as a GRAS that the proposed rule did not say that discuss some key factors we intend to notice and our evaluation of the we would contact a notifier, before we consider regarding the purpose of our available data and information identifies issue our publicly available response, to contact with you regarding your GRAS a safety concern, the purpose of our provide preliminary feedback regarding notice, particularly with respect to contact with you would depend on our evaluation of a GRAS notice. One of whether we intend to provide you with whether the safety concern could be these comments asks us to include a an opportunity to submit an amendment addressed by a timely, clarifying provision specifying that we may to a GRAS notice. These factors are: (1) amendment. For example, in some cases communicate with the notifier about Whether our questions can be addressed the available data and information may any aspect of a notice while the notice by a timely, clarifying amendment; (2) support safety only under modified is pending. Some comments express whether our evaluation identifies a conditions of use relative to the concern that a letter listing answerable safety concern; and (3) whether we conditions of use described in your and nonsubstantive questions about a question whether GRAS criteria are GRAS notice, and our contact with you GRAS notice could cause confusion and satisfied, even if our evaluation does not would focus on your opportunity to misunderstanding in the marketplace, identify a safety concern. See also the address the safety concern through a particularly if additional information, discussion in Response 85 regarding timely amendment specifying modified clarification, or amendment would factors that could lead us to decline to conditions of use. However, if we address our concerns. file a submission as a GRAS notice, believe that the safety concern could not (Response 80) We decline the request rather than to file it for our evaluation be addressed through a timely, to include a provision specifying that of your view that the notified substance clarifying amendment or by re- we may communicate with you about is GRAS under the conditions of its submission of a new GRAS notice (e.g., any aspect of a notice while your notice intended use and issue an ‘‘insufficient after studies are conducted to address is pending. As discussed in section basis letter.’’ the safety concern), we likely would III.C.1 of CFSAN’s 2010 experience We agree that an ‘‘insufficient basis contact you to make you aware of our document (Ref. 18), during the Interim letter’’ listing answerable questions concerns and then issue an ‘‘insufficient Pilot program CFSAN contacted several about a GRAS notice could cause basis letter’’ that clearly and fully notifiers to request clarification about confusion and misunderstanding in the articulates our reasons for that safety data and information in the notice marketplace, particularly if additional concern, including the full context of under the framework of existing information, clarification, or the risk to human or animal health. regulations governing meetings and amendment would address our If we file your submission as a GRAS correspondence (§ 10.65(g)). It is not concerns. Section III.C.1 of CFSAN’s notice and find that your narrative does necessary to duplicate the existing 2010 experience document provides not support a conclusion of GRAS procedures in § 10.65(g) in the examples of circumstances where status, even if the available data and requirements for the GRAS notification CFSAN contacted a notifier and information support your view that the procedure. expected that the information notified substance is safe under the We infer that this comment is exchanged between CFSAN and the conditions of its intended use (e.g., specifically asking us to require that we notifier would clarify, rather than because data and information that are contact you to provide preliminary substantively amend, the original necessary to establish safety are not feedback before we respond to your notice. We intend to continue generally available), the purpose of our GRAS notice with an ‘‘insufficient basis contacting notifiers in such contact with you would focus on your letter.’’ As discussed in section III.C.1 of circumstances. By ‘‘clarify, rather than opportunity to address the regulatory CFSAN’s 2010 experience document substantively amend,’’ we mean that the status of the notified substance. For (Ref. 18), our experience during the amendment would add or modify example, it may be possible for you to Interim Pilot program demonstrates that specific sections in the notice, not that submit a new GRAS notice after we are willing to engage in a dialog with the clarifying information would publishing applicable data and a notifier to clarify particular aspects of necessarily be nonsubstantive in nature. information and allowing sufficient time a GRAS notice. As discussed in section For example, as discussed in Response to allow the expert scientific community IV.H.4 of CFSAN’s 2010 experience 96 during the Interim Pilot program we to access the published information. document (Ref. 18), our experience contacted notifiers when the notice Alternatively, it may be more during the Interim Pilot program also contained insufficient information about appropriate for you to consider the demonstrates that we do not issue an dietary exposure and when the notice notified substance as a food additive ‘‘insufficient basis letter’’ with contained insufficient information to under the conditions of its intended use, ‘‘nonsubstantive questions.’’ Although adequately identify the substance. We and to make a premarket submission we have issued ‘‘insufficient basis did so because it is efficient, for us as such as a food additive petition. For mstockstill on DSK3G9T082PROD with RULES2 letters’’ due to an overall poor quality of well as the notifier, to bring a GRAS examples of circumstances leading to a submission, to conserve resources our notice to closure with a ‘‘no questions the options for addressing questions practices have evolved so that we letter’’ when it is likely that a timely, about the regulatory status of the generally do not file such submissions clarifying amendment would resolve substance when we have not identified as GRAS notices (see section XIX.A our questions. For example, it is more a safety concern, see section III.A.4 of regarding filing decisions and section efficient for us to bring a GRAS notice CFSAN’s 2010 experience document III.K of CFSAN’s 2010 experience to closure while our reviewers are (Ref. 18). Any letter we issue would VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00051 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 55010 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations include our view of the regulatory status an amendment is to clarify questions Given the public nature of a GRAS of the substance at the time that we that we have about your conclusion of notice, it is appropriate for the reasons issued the letter, based on the generally GRAS status rather than to substantively leading to a ‘‘cease to evaluate letter’’ to available data and information at that amend the GRAS notice. also be public. Therefore, as of October time. 17, 2016, we intend to change this C. Notifier’s Request That We Cease To practice and increase transparency by B. Submitting an Amendment Evaluate a GRAS Notice describing the reasons leading to any Comments support adding a provision (Comment 81) Some comments ask us ‘‘cease to evaluate letter.’’ to clarify that you may submit an to make public the reason for a notifier’s Table 1 in CFSAN’s 2010 experience amendment to your GRAS notice and, request that we cease to evaluate a document (Ref. 18) shows that thus, we are establishing a provision notice. One comment asks that any new approximately 16 percent of GRAS specifying that you may submit a timely information, or questions about the notices that CFSAN responded to during amendment to your filed GRAS notice scientific consensus about whether a the 12-year period spanning 1998 (§ 170.260(a)). In some cases, you would substance is safe, be made clear to the through 2009 came to closure when the submit such an amendment after we public as well as FDA. Another notifier asked us to cease to evaluate a contact you to discuss our questions comment expresses concern that GRAS notice. Table 1 in CFSAN’s 2010 about your GRAS notice. (See the companies ask FDA to cease evaluations experience document also shows that discussion in Response 80 regarding of their GRAS notices with ‘‘alarming CFSAN issued equal numbers of ‘‘cease contacting a notifier.) In other cases, you frequency.’’ to evaluate letters’’ and ‘‘insufficient may conclude that it is appropriate to (Response 81) We are establishing a basis letters’’ during the years 1998 submit an amendment to update your provision specifying that a notifier may through 2002 (i.e., 16 ‘‘cease to evaluate GRAS notice on your own initiative, ask us to cease to evaluate his GRAS letters’’ and 16 ‘‘insufficient basis e.g., if new data and information about notice (see § 170.260(b)). As a letters’’). However, during the years the notified substance under the companion provision, we are specifying 2003 through 2009 CFSAN issued 31 conditions of its intended use become that if a notifier asks us to cease to ‘‘cease to evaluate letters,’’ but no available after we file your submission evaluate a GRAS notice, we will send ‘‘insufficient basis letters.’’ In addition, as a GRAS notice. Depending on the the notifier a letter informing the table 1 in CFSAN’s 2016 experience circumstances, you could then decide to notifier of our decision regarding that document (Ref. 19) shows that during explain your view that the new data and request (see § 170.265(b)(3)). As the years 2010 through 2015 CFSAN information do not alter the basis for discussed in section III.E of CFSAN’s issued 48 ‘‘cease to evaluate letters’’ but your conclusion of GRAS status; 2010 experience document (Ref. 18), only one ‘‘insufficient basis letter.’’ We alternatively, you could decide to ask us during the Interim Pilot program acknowledge that there has been a to cease to evaluate your GRAS notice CFSAN’s ‘‘cease to evaluate letters’’ distinct shift between the ratio of the while you evaluate the impact of the generally repeated any reason specified number of ‘‘cease to evaluate letters’’ new data and information on the GRAS in a request letter, but may not have compared to the number of ‘‘insufficient status of the notified substance under otherwise described the reasons basis letters’’ issued during the years the conditions of its intended use (see underlying the request. If a notified 1998 through 2002 and the § 170.260(b)). substance is marketed even though we corresponding ratio for letters issued By timely, we mean that you submit issue a ‘‘cease to evaluate letter,’’ there during the years 2003 through 2015. We your amendment in a timeframe that could be confusion about the GRAS consider that the data in the experience provides us with sufficient time to status of the notified substance even document demonstrate an evolving evaluate it before we respond to your when the conditions of use in the practice in which CFSAN has declined GRAS notice. Given that the rule marketplace differ from the notified use to file some submissions as GRAS requires us to end our evaluation and that was the subject of the ‘‘cease to notices when the notice lacks much of respond to your GRAS notice within evaluate letter.’’ For example, a notifier the required data and information 180 days, with an extension of up to an could ask us to cease to evaluate a necessary for us to evaluate a notifier’s additional 90 days on an as needed GRAS notice because we identified a view that the notified substance is basis § 170.265(b)(1)), we reserve the safety concern about the specified use GRAS under the conditions of its right to not consider your amendment if level of the notified substance in food intended use (see Response 85). In you submit it so late in our evaluation products, and then decide to market the addition, such a frequency demonstrates that it would impact our ability to substance at a lower use level than the that CFSAN has been willing to contact respond within our established level specified in the GRAS notice, notifiers with questions about a timeframes. Therefore, as a companion where we would no longer have that conclusion that the notified substance is provision, the rule also provides that we concern. In addition, as discussed in the GRAS under the conditions of its will consider any timely amendment proposed rule we proposed to make all intended use. As discussed in Response that you submit to a filed GRAS notice, response letters readily accessible to the 80, when our questions cannot be to update your GRAS notice or in public because such a system will addressed by a timely amendment, response to a question from us, before properly underscore a notifier’s contacting the notifier provides the we respond to you by letter based on acceptance of responsibility for the notifier an opportunity to re-submit a our evaluation of your notice if we deem conclusion of GRAS status, and a GRAS new GRAS notice or other regulatory that doing so is feasible within the notice that is submitted to us is a public submission (such as a food additive established timeframes (see notice (62 FR 18938 at 18953). A ‘‘cease petition) that addresses our questions. mstockstill on DSK3G9T082PROD with RULES2 § 170.265(a)(4)). If we deem that to evaluate letter’’ signals that a As discussed in section III.E of considering your amendment is not submitted GRAS notice does not CFSAN’s 2010 experience document feasible within the established provide an adequate basis for a (Ref. 18), in many cases a notifier who timeframes, we will inform you that we conclusion that the notified substance is received a ‘‘cease to evaluate letter’’ are not considering your amendment. GRAS under the conditions of its resubmitted a new GRAS notice, and See also the discussion in Response intended use, even though we do not CFSAN responded with a ‘‘no questions 101, which emphasizes that the role of issue an ‘‘insufficient basis letter.’’ letter.’’ For many GRAS notices, the VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00052 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 55011 questions we raised and discussed with that the safety concern could not be (75 FR 81536 at 81538–81539), our the notifier clearly addressed issues addressed through a timely, clarifying current regulations regarding public other than a fundamental safety amendment, by re-submitting a new information stipulate that no person concern. For example, some of the GRAS notice, or by submitting another may withdraw records submitted to letters that CFSAN lists in section III.E premarket submission (such as a food FDA (see § 20.29), and those regulations of its 2010 experience document additive petition), we likely would issue will apply to any GRAS notice that we provide reasons such as preparing a new an ‘‘insufficient basis letter’’ even receive. To make this clear, the notice that will not contain any though we would have contacted the provision we are establishing in the confidential business information and notifier to discuss our concerns. final rule provides an opportunity for that will clarify that the statutory basis Asking us to cease to evaluate a GRAS you to ask us to ‘‘cease to evaluate’’ a for the conclusion of GRAS status is notice does not guarantee that we will GRAS notice rather than ‘‘withdraw’’ a through scientific procedures; needing honor that request. Depending on the GRAS notice. to revise an estimate of dietary circumstances, we may decide to (Comment 84) Some comments ask us exposure; and clarifying and providing decline the request and instead respond to specify that if a notifier requests that additional information for a new notice. with an ‘‘insufficient basis letter’’; we cease to evaluate a submitted GRAS However, CFSAN only made these depending on the time remaining notice, such notices will remain in our reasons transparent to the public between when we receive the request files and will be available for public because the notifier chose to provide and the timeframes by which we must disclosure. these reasons in his request that we respond to the GRAS notice, we may cease to evaluate the GRAS notice. In either send the notifier a separate letter (Response 84) See § 20.29 and the other circumstances, the public had no declining the request, or note in the discussion of Issue 5 in the 2010 notice way to know what the issue was until ‘‘insufficient basis letter’’ that we had (75 FR 81536 at 81538–81539). If a we responded to the resubmitted notice. declined the request. See the discussion notifier asks us to cease to evaluate a We intend to continue to contact a in section III.C.1 of CFSAN’s 2010 submitted GRAS notice, the notice will notifier to discuss our questions, and experience document (Ref. 18) for an remain in our files and will be available provide an opportunity for the notifier example of a situation in which CFSAN for public disclosure in accordance with to ask us to cease to evaluate the GRAS responded with an ‘‘insufficient basis part 20. It is not necessary to repeat the notice (e.g., so that the notifier can letter’’ after a notifier asked CFSAN to provisions of § 20.29 in the GRAS submit a new GRAS notice that cease to evaluate its GRAS notice, notification procedure. addresses the issues). However, we also submitted a new GRAS notice, and XIX. Comments on What We Will Do intend to briefly describe these issues in asked CFSAN to cease to evaluate the With a GRAS Notice a ‘‘cease to evaluate letter’’ that follows second submitted GRAS notice. that contact. As CFSAN did during the (Comment 82) One comment asks us We proposed that: (1) We would Interim Pilot program, we intend to to clarify that a notifier’s request that we acknowledge receipt of a notice, within consider any reasons a notifier provides cease to evaluate a GRAS notice would 30 days of receipt, by informing the for the request, and to include those be without prejudice for future notifier in writing of the date on which reasons in our ‘‘cease to evaluate letter.’’ submissions. the notice was received (proposed If, however, we conclude that a (Response 82) The final provision § 170.36(d)); (2) we would respond to notifier’s explanation does not specifies that your request that we cease the notifier in writing within 90 days of adequately describe the reasons leading to evaluate a GRAS notice does not receipt of the notice (proposed to a ‘‘cease to evaluate’’ request, we preclude you from submitting a future § 170.36(e)); and (3) a copy of any intend to explain the reasons for ceasing GRAS notice with respect to the notified subsequent letter that we issued to evaluate the notice from our point of substance. regarding a GRAS notice would be view. Doing so will both ensure clear (Comment 83) One comment asks us readily accessible for public review and communication about the reasons and to specify that, if feasible, the files could copying (proposed § 170.36(f)(2)(iii)). In make the reasons transparent to the be returned to the notifier at the the 2010 notice, we asked for comment public. notifier’s expense. on issues relating to what we will do As discussed in Response 80, if we (Response 83) We decline this with a GRAS notice as shown in table identify a safety concern and believe request. As discussed in the 2010 notice 18. TABLE 18—ISSUES IN THE 2010 NOTICE REGARDING WHAT WE WILL DO WITH A GRAS NOTICE Issue Description of our request for comment Reference No. 12 ...... Whether we should make explicit the process by which we make a filing decision, including the fac- 75 FR 81536 at 81541. tors we would use to determine whether to file a submission as a GRAS notice. 14 ...... Whether we should retain a set timeframe for us to respond to a GRAS notice, and, if so, whether it 75 FR 81536 at 81542. should be 90 days or another timeframe. In the following sections, we discuss editorial, clarifying, and conforming editorial changes associated with the mstockstill on DSK3G9T082PROD with RULES2 comments on what we will do when we changes as shown in table 29. Table 19 redesignation of proposed § 170.36(d), receive a GRAS notice. After identifies changes we made relative to (e), and (f)(2)(iii) as § 170.265. See considering these comments, we are the proposed rule or the description in section XXV.I for a discussion of establishing requirements in § 170.265 the 2010 notice other than the editorial, comments specific to a filing decision for what we will do when we receive a clarifying, and conforming changes for a substance used in animal food. GRAS notice as shown in table 19, with shown in table 29 and the additional VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00053 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 55012 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations TABLE 19—FINAL REQUIREMENTS FOR WHAT FDA WILL DO WITH A GRAS NOTICE Proposed Revisions (other than editorial, Final designation in Issue No. in designation in the clarifying, and conforming changes) the regulatory text the Description regulatory text relative to the proposed rule or the (§ ) 2010 notice (§ ) 2010 notice 170.265(a)(1) ......... N/A ......................... 12 We will conduct an initial evaluation of N/A. your submission to determine wheth- er to file it as a GRAS notice for eval- uation of your view that the notified substance is GRAS under the condi- tions of its intended use. 170.265(a)(2) ......... 170.36(d) ............... 12 If we file your submission as a GRAS N/A. notice, we will send you a letter that informs you of the date of filing. 170.265(a)(3) ......... N/A ......................... 12 If we do not file your submission as a Clarifies that we would inform you by GRAS notice, we will send you a let- letter if we do not file your submission ter that informs you of that fact and as a GRAS notice. provides our reasons. 170.265(a)(4) ......... N/A ......................... 3a We will consider any timely amendment Clarifies that we will only consider an that you submit to a filed GRAS no- amendment if we deem that doing so tice, to update your GRAS notice or is feasible within the established time- in response to a question from us, frames. before we respond to you by letter based on our evaluation of your no- tice if we deem that doing so is fea- sible within the established time- frames. If we deem that considering your amendment is not feasible within the established timeframes, or if we have granted your request to cease to evaluate your notice, we will inform you that we are not considering your amendment. 170.265(b)(1) ......... 170.36(e) ............... 14 Within 180 days of filing, we will re- • Specifies that the timeframe for our spond to you by letter based on our response is 180 days, rather than 90 evaluation of your notice. We may ex- days. tend the 180 day timeframe by 90 • Provides for an extension of our eval- days on an as needed basis. uation by 90 days on an as needed basis. 170.265(b)(2) ......... N/A ......................... 14 If we extend the timeframe, we will in- Provides that we will inform you if we form you of the change in writing as extend the timeframe for our re- soon as practicable but no later than sponse. within 180 days of filing. 170.265(b)(3) ......... N/A ......................... 5 If you ask us to cease to evaluate your Companion change in light of new regu- GRAS notice, we will send you a let- latory text (in § 170.260(b)) expressly ter informing you of our decision re- providing that you may ask us to garding your request. cease to evaluate your GRAS notice. 170.265(c) .............. 170.36(f)(2)(iii) ....... N/A If circumstances warrant, we will send Clarifies that we may send a subse- you a subsequent letter about the no- quent letter, in addition to specifying tice. under the public disclosure provisions of the rule that such a letter would be readily available to the public (see § 170.275(b)(2)). A. Filing Decision though it would be beneficial to the decline to file a submission as a GRAS notifier. notice would both discourage voluntary (Comment 85) One comment asks for submissions of GRAS conclusions from greater refinement, clarity, and Another comment asks us to specify the criteria that we use to decide to industry and conflict with GAO’s transparency when we decline to file a recommendations (in their 2010 report) provide verbal feedback to a notifier GRAS notice. Some comments ask us to that we should take steps to increase our (e.g., by telephone) rather than send the communicate any questions or concerns awareness of independent conclusions notifier a letter informing the notifier that could be quickly addressed upon of GRAS status. that we have declined to file a submission of a GRAS notice. Another (Response 85) These comments raise submission as a GRAS notice. This mstockstill on DSK3G9T082PROD with RULES2 comment asks us to use specific criteria comment expresses concern that our a number of issues regarding the for a ‘‘decline to file’’ determination refusal to explain the problem in a letter importance of a written communication when format and general categories are could be interpreted to mean that we from us to a notifier when we decline adequate. Another comment states that have safety concerns. This comment to file a submission as a GRAS notice, an explicit process for how we will asserts that a process in which we including transparency and the make a filing decision need not be neither provide specific guidance, nor potential that lack of a written detailed ‘‘in the public domain’’ even provide written feedback, when we explanation for why we declined to file VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00054 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 55013 a submission as a GRAS notice could (Comment 86) In the 2010 notice, we notified substance are not eligible for lead to suppositions, such as whether explained that we may decide to classification as GRAS because, for we have safety concerns. To address respond to a submission as general example, the intended conditions of use these issues, the final rule provides that correspondence, rather than file it as a are excepted from the definition of if we do not file a submission as a GRAS GRAS notice, if the subject of the ‘‘food additive’’ in section 201(s) of the notice, we will send the notifier a letter submission is: (1) Already authorized FD&C Act (and thus, from the GRAS that informs the notifier of that fact and for use under our regulations; or (2) a provision included in that definition of provides our reasons for not filing the mixture of substances that are already ‘‘food additive’’). See, for example, the submission as a GRAS notice (see authorized for use under our exception for a color additive in section § 170.265(a)(3)). We would not place regulations. One comment asks us to 201(s)(3) of the FD&C Act, for a dietary that letter ‘‘in the public domain’’ by clarify how we would determine that ingredient intended for use in a dietary including it in our publicly available the use of a substance is authorized for supplement in section 201(s)(6) of the Inventory of GRAS Notices, because the use under our regulations, with respect FD&C Act, and for a new animal drug submission had not been filed as a to the similarity of factors such as: (1) in section 201(s)(5) of the FD&C Act. GRAS notice and, thus, there would be The substance; (2) the intended (Comment 88) Some comments ask us no entry where we would place the conditions of use of the substance, to contact the notifier when our initial letter. However, whether the letter including food categories and use levels; evaluation of a GRAS notice raises would be releasable in response to a and (3) the manufacturing process. questions, and provide the notifier with FOIA request would be a case-by-case (Response 86) We decline this request an opportunity to withdraw the notice determination based on the contents of because it is overly broad. We do not without prejudice before we begin a the letter and the provisions of part 20. have a ‘‘formula’’ that would apply in substantive evaluation of the notice. all circumstances. Just as the factors that (Response 88) We agree that our We are not specifying in the decision to not file a submission as a apply to a particular GRAS notice may regulatory text the factors that could GRAS notice would be without be very specific to that notice, the lead us to decline to file a submission prejudice to a future submission of a factors that would apply in determining as a GRAS notice, because the factors GRAS notice for the notified substance. whether the intended conditions of use that apply to a particular GRAS notice However, see Response 70, Response of a notified substance are already may be very specific to that notice. 112, and the discussion in the 2010 authorized by our regulations may be Importantly, a GRAS notice presents an very specific to that substance. notice at 75 FR 81536 at 81539. Just as opportunity for a notifier to inform us However, with regard to similarities in a filed GRAS notice is available for about a conclusion of GRAS status the manufacturing process, we likely public disclosure subject to the rather than an opportunity for a notifier would apply the same factors that we procedures established in part 20, a to test a hypothesis that there is a have advised industry to apply when submission that you send to us is a sufficient basis to reach a conclusion of assessing the effects of significant record that is available for public GRAS status. If our initial evaluation of manufacturing process changes on the disclosure subject to the procedures a submission demonstrates that it lacks safety and regulatory status of food established in part 20, regardless of much of the required data and ingredients (Ref. 6). whether we file that submission as a information necessary for us to evaluate We note that we also may decide to GRAS notice. Thus, you cannot the notifier’s view that the notified respond to a submission as general ‘‘withdraw’’ a submission from our files substance is GRAS under the conditions correspondence, after communicating after you send it to us. of its intended use, our current practice with the submitter as appropriate, rather (Comment 89) One comment asks is to decline to file it as a GRAS notice than file it for evaluation as a GRAS whether ‘‘substantial equivalence’’ (see § 170.265(a)(3)). By declining to file notice, if the subject of the submission considerations are linked to ‘‘decline to a submission as a GRAS notice, we is: (1) Already the subject of a GRAS file’’ decisions or play a dominant role would both conserve our own resources notice, and we have responded to that in ‘‘decline to file’’ decisions. This and provide the notifier an opportunity GRAS notice with a ‘‘no questions comment also asks us to issue a letter to to submit a new GRAS notice, that letter’’; or (2) a mixture of substances the notifier explaining the basis for a contains appropriate data and that already are the subject of GRAS ‘‘decline to file’’ decision if ‘‘substantial information and an adequate narrative, notices, and we have responded to those equivalence’’ is the reason. rather than move forward knowing that GRAS notices with ‘‘no questions (Response 89) As discussed in section an amendment necessary for us to letters.’’ In contrast to the statutory IV.N of CFSAN’s 2010 experience evaluate the notifier’s view that the provisions for the FCN program (section document (Ref. 18), several GRAS notified substance is GRAS under the 409(h) of the FD&C Act), there is no notices filed during the Interim Pilot conditions of its intended use would be provision in the FD&C Act providing program relied, in part, on the concept so substantive as to make the original exclusivity for a notifier for the use of of ‘‘substantial equivalence’’; in each of submission largely irrelevant. For a substance on the basis that it is GRAS the listed examples CFSAN had no additional examples of factors we have under the conditions of its intended use. questions about the notifier’s conclusion considered in determining whether to (Comment 87) One comment asks us of GRAS status. As discussed in file a submission as a GRAS notice, see to conduct a preliminary evaluation of Response 21, whether, and to what the examples we provided in the 2010 a GRAS notice to determine whether the extent, similarity between two notice (75 FR 81536 at 81541), the notice appears to be inadequate because substances could support a conclusion discussion of filing decisions in section the intended conditions of use of the of GRAS status depends on many mstockstill on DSK3G9T082PROD with RULES2 III.K of CFSAN’s 2010 experience notified substance raise ‘‘general situation-specific variables. Thus, it document (Ref. 18), Response 48, and policy’’ issues. would be the complete evaluation Response 70. As discussed in Response (Response 87) It is not clear what the process, rather than the initial 152, CVM intends to consider the same comment means by ‘‘general policy’’ evaluation that we conduct as part of a factors that CFSAN considers regarding issues. However, we note that we would filing decision, that would determine whether to file a submission as a GRAS not file a submission as a GRAS notice whether a GRAS notice that relies on notice. if the intended conditions of use of the the concept of ‘‘substantial equivalence’’ VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00055 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 55014 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations provides a basis for a conclusion of to include in the final rule the specific generally known and accepted by GRAS status. As discussed in Response language for the response letter, qualified experts.’’ 85, the final rule provides that if we do particularly when we do not raise any • ‘‘The notice provides a sufficient not file a submission as a GRAS notice, questions about the notifier’s conclusion basis for the notifier’s determination we will send the notifier a letter that of GRAS status. Some comments assert that the substance is GRAS for its informs the notifier of that fact and that a notifier who invests resources in intended use.’’ provide our reasons for not filing the a GRAS notice deserves a response that (Response 92) See table 1 for the submission as a GRAS notice (see is standardized and predictable and will typical text of a ‘‘no questions letter’’ § 170.265(a)(3)); if problems with a not change as personnel changes occur. that we issued during the Interim Pilot notifier’s use of the concept of (Response 91) See table 1. During the program. At this time, we intend to ‘‘substantial equivalence’’ play a role in Interim Pilot program we developed continue including such text in our ‘‘no our decision to not file a submission as three categories of response letter: (1) questions letters.’’ We agree that the a GRAS notice, we intend to say so. ‘‘No questions letter’’; (2) ‘‘insufficient regulatory significance of a ‘‘no basis letter’’; and (3) ‘‘cease to evaluate questions letter’’ should be clear. As B. Our Response to a GRAS Notice shown in table 1, during the Interim letter.’’ As discussed in sections IV.H.1 1. Administrative Content of Our through IV.H.7 of CFSAN’s 2010 Pilot program a typical ‘‘no questions Response to a GRAS Notice experience document (Ref. 18), these letter’’ made clear that: (1) It is the letters include some standard information that is provided by the (Comment 90) Several comments notifier that forms the basis for our address the administrative content of a information that is consistent across those letters, such as opening and response, and that the notifier (rather letter that responds to a GRAS notice. In than FDA) is responsible for the general, these comments ask us to closing paragraphs using a standard format, and administrative information conclusion of GRAS status; and (2) our include the following items in the response must be considered in context response letter: (1) Name and address of (e.g., the date of our receipt of the GRAS notice). They also include unique based on the knowledge and the notifier; (2) the date of our receipt information available to us at a point in of the notice; (3) the common or usual features that depend upon the circumstances, such as labeling issues time, because scientific knowledge and name of the notified substance; and (4) information about a particular the applicable conditions of use of the and whether the use of the substance ingredient can evolve and sometimes notified substance. One comment states could require a color additive listing. change over time. that use of a standard format and The content of the three categories of The typical text of a ‘‘no questions language in our letters would be response letter has evolved over time, letter’’ issued during the Interim Pilot administratively efficient. and may continue to evolve. In addition, program is similar to the specific (Response 90) We agree that a it is possible that in the future a suggestion of one comment (i.e., FDA at standard format and language in our response to a GRAS notice may not fit this time does not question your letters would be administratively squarely within one of the current determination that the notified use of efficient and that the administrative categories of response letter. Therefore, this substance is GRAS), except that features suggested by these comments the final rule continues to specify that under the final rule we will use the term are appropriate to include in our we will respond to a GRAS notice but ‘‘conclusion’’ rather than response letter. During the Interim Pilot does not specify any detail about the ‘‘determination.’’ We disagree that a ‘‘no program, we both developed a standard nature of the response. questions letter’’ should state that we format and language for our response (Comment 92) Several comments ‘‘find’’ that there is substantial evidence letters and included the administrative address the content of a ‘‘no questions supporting both the safety of the features suggested by these comments letter.’’ These comments ask that a ‘‘no intended conditions of use of the (see section III.H.1 of CFSAN’s 2010 questions letter’’ be clear and definitive, notified substance and the fact that this experience document (Ref. 18)). We provide clear assurance that we safety is generally known and accepted intend to continue incorporating these recognize the GRAS status of the by qualified experts; a GRAS notice features in letters issued under the final substance under the conditions of its reflects the conclusion of the notifier, rule. However, as discussed in Response intended use, have some regulatory not a finding by FDA. Likewise, we 51, the final rule requires that you significance, and be as affirmative as disagree that a ‘‘no questions letter’’ provide the name of the notified possible. Some of these comments note should state that a notice ‘‘provides a substance, using an appropriately that our statements in the proposed rule sufficient basis’’ for the notifier’s descriptive term, rather than the (62 FR 18938 at 18950) indicated that conclusion that the notified substance is ‘‘common or usual name’’ of the notified we would evaluate a GRAS notice to GRAS under the conditions of its substance (see § 170.225(c)(3)). determine whether there is a sufficient intended use; the phrase ‘‘providing a Therefore, CFSAN’s response letters basis for the notifier’s conclusion of sufficient basis’’ would imply that we will include an appropriately GRAS status and suggest that our are taking responsibility for the descriptive term for the notified response to a GRAS notice could reflect notifier’s conclusion of GRAS status. substance provided in a GRAS notice those statements. Comments also As discussed in Response 41, we are submitted to CFSAN. See section XXV.C suggest the following specific replacing the term ‘‘determination’’ with regarding the name of the notified statements that could be included in a ‘‘conclusion,’’ and referring to a substance provided in a GRAS notice ‘‘no questions letter’’: ‘‘conclusion of GRAS status’’ rather than submitted to CVM. • ‘‘FDA at this time does not question to a ‘‘GRAS determination,’’ throughout mstockstill on DSK3G9T082PROD with RULES2 your determination that the notified the regulatory text for the GRAS 2. Substantive Content of Our Response use(s) of this substance is (are) notification procedure. We intend to to a GRAS Notice Generally Recognized as Safe.’’ modify the typical text of our response (Comment 91) Several comments note • ‘‘The Agency finds that there is letters to refer to the ‘‘notifier’s that the proposed rule did not specify substantial evidence supporting both conclusion’’ (rather than the ‘‘notifier’s what we would say in a letter the safety of the intended uses of the determination’’) in letters issued under responding to a GRAS notice and ask us substance and the fact that this safety is the final rule (see table 20). We also VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00056 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 55015 intend to specify that we have not section II.B, we intend to adapt our current scientific information, our affirmed the GRAS status of the notified practices, consistent with the provisions available resources, and the scientific substance under the conditions of its of this rule, as circumstances warrant and regulatory issues raised by specific intended use, rather than to specify that and as necessary to administer the GRAS notices. Thus, the text shown in we have not made our own GRAS notification program consistent table 20 is for illustrative purposes only determination. However, as noted in with appropriate public health policy, and could evolve over time. TABLE 20—CATEGORIES OF LETTERS RESPONDING TO A GRAS NOTICE UNDER THE FINAL RULE Category of response letter Typical text of for a response as modified to incorporate terms used in the rule ‘‘No questions letter’’ ....................... Based on the information provided by the notifier, as well as other information available to FDA, the Agen- cy has no questions at this time regarding the notifier’s conclusion that the notified substance is GRAS under the conditions of its intended use. By this letter, however, the Agency has not affirmed the GRAS status of the notified substance under the conditions of its intended use in accordance with 21 CFR 170.35. As always, it is the continuing responsibility of the notifier to ensure that food ingredients that the firm markets are safe, and are otherwise in compliance with all applicable legal and regulatory re- quirements. ‘‘Insufficient basis letter’’ ................. FDA has evaluated the data and information in the GRAS notice as well as other available information. The notice does not provide a sufficient basis for a conclusion that the notified substance is GRAS under the conditions of its intended use. ‘‘Cease to evaluate letter’’ .............. In correspondence dated [month, day, year], you asked that we cease to evaluate your GRAS notice. We ceased to evaluate your GRAS notice, effective the date we received your correspondence. (Comment 93) One comment suggests conditions of use of the notified ‘‘insufficient basis letter’’ and ask us to that a written response need not assess substance are safe and the criteria for be specific about any deficiencies that the quality of the submission but rather GRAS status are satisfied. In addition, as we identify in the notice. Some could acknowledge whether the notice circumstances warrant, we evaluate comments assert that an ‘‘insufficient was complete in addressing all key information that is not included in the basis letter’’ must clearly distinguish issues. notice but is otherwise available to us between deficiencies that relate to safety (Response 93) We disagree that we (see section IV.G of CFSAN’s 2010 and those that relate to a technical could acknowledge whether a notice is experience document (Ref. 18)). matter, such as the level of the ‘‘complete’’ without assessing the (Comment 95) Some comments ask substance that is needed to accomplish quality of the submission. Providing a that a ‘‘no questions letter’’ include a the intended technical effect. One basis for whether the data and positive statement that we have not comment asks us to include in the final information regarding the safety of a identified a problem with the notice rule guidelines that articulate clear substance under the conditions of its because finished food producers have standards for issues that are of sufficient intended use satisfy GRAS criteria is not been reluctant to use a substance magnitude to result in an ‘‘insufficient a matter of whether there is ‘‘something without such documentation. These basis letter.’’ behind each tab.’’ It would not be comments both assert that the only (Response 96) We agree that we appropriate, for example, for us to alternative available to manufacturers should be specific about identified acknowledge that a GRAS notice is whose customers require such a positive problems and distinguish between ‘‘complete’’ because it included the statement would be to seek food circumstances that lead to an narrative required by Part 6 of a GRAS additive approval for an ingredient and insufficient basis letter. Our experience notice without assessing the adequacy maintain that such approval is during the Interim Pilot program of the narrative. Whether a notice is unnecessary from a legal perspective. demonstrates that we have done so, and ‘‘complete’’ in addressing all key issues (Response 95) Consistent with the we intend to continue this practice depends on the nature and quality of the request of these comments, we intend to under the final rule. For example, as submitted data and information. continue including a statement that we discussed in sections IV.H.4 and IV.H.7 (Comment 94) Some comments ask ‘‘have no questions at this time’’ (see of CFSAN’s 2010 experience document that a ‘‘no questions letter’’ qualify that table 1 and table 20). Whether a (Ref. 18), we have issued an insufficient we have not affirmed that the intended manufacturer’s customer requires a basis letter in cases where health effects conditions of use of the notified regulation prescribing the conditions seen in toxicological or clinical studies substance are GRAS. Other comments under which a substance may be safely were not adequately explained or ask that a ‘‘no questions letter’’ qualify used in food, when there is a basis for because the notice did not describe that we have not conducted a concluding that the substance is GRAS adequate toxicological studies; when the substantive review. under the conditions of its intended use, notice contained insufficient (Response 94) We agree that a ‘‘no is a business matter between the information about dietary exposure; questions letter’’ should be clear that we manufacturer and the customer. If the when the notice contained insufficient have not affirmed that the substance is manufacturer submits a food additive information to adequately identify the GRAS under the conditions of its petition and we find, based on the data substance; when the notice contained intended use. See table 20. and information submitted in the insufficient information to satisfy the mstockstill on DSK3G9T082PROD with RULES2 However, we disagree that a ‘‘no petition, that the intended conditions of standard for demonstration of GRAS questions letter’’ should state that we use of the substance are safe, we would status through experience based on did not conduct a substantive review of issue a regulation prescribing the common use in food; and as a result of the GRAS notice. See Response 25. Our conditions under which the food the regulatory framework associated evaluation of a GRAS notice is a additive may be safely used. with the substance. To date, we have substantive evaluation of the notifier’s (Comment 96) Several comments not issued an insufficient basis letter basis for concluding that the intended address the specific content of an solely as a result of insufficient VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00057 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 55016 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations evidence regarding the level of the of its intended use (see table 1), and we to submit a GRAS notice. One comment substance that is needed to accomplish intend to continue including such text asserts that we should be held the intended technical effect. However, in letters issued under the final rule, accountable to the proposed 90-day CVM’s experience document modified to refer to a ‘‘conclusion’’ of timeframe, whereas another comment demonstrates that CVM has included GRAS status rather than a suggests that the proposed 90-day lack of information regarding the ‘‘determination’’ of GRAS status (see timeframe provide a benchmark at intended technical effect as one of table 20). This typical text addresses the which we should make the notifier several reasons leading to an adequacy of the notice rather than the aware of the current status of our insufficient basis letter (Ref. 20). Some regulatory status of the substance; evaluation of the notice even if we have ‘‘no questions letters’’ issued by CFSAN consistent with the request of these not had sufficient time to completely have discussed the level of the comments, this text does not specify review the safety of the notified substance that is needed to accomplish that we have concluded that the substance. the intended technical effect, e.g., when intended conditions of use of the One comment that asks us to retain CFSAN informed a notifier who notified substance are ‘‘not GRAS.’’ In the proposed 90-day timeframe stresses received a ‘‘no questions letter’’ that several cases during the Interim Pilot that we should have flexibility to take FSIS needed information regarding the program, a notifier who received an additional time as needed. Another lowest level necessary for the substance ‘‘insufficient basis letter’’ submitted a comment agrees that it would be to achieve its intended effect in meat, second GRAS notice and received a ‘‘no appropriate for us to extend the meat food product, or poultry product questions letter’’ in response to the evaluation period, provided we do so (see section III.L of CFSAN’s 2010 second GRAS notice (see sections III.D only in limited instances. experience document (Ref. 18)). and IV.K of the experience document One comment asserts that the Our experience during the Interim (Ref. 18)). In these examples, CFSAN’s requirements of the GRAS notification Pilot program demonstrates that response to the notifier’s first GRAS procedure are similar to the whether a notice provides a sufficient notice made clear that the submitted requirements of the GRAS affirmation basis for a conclusion of GRAS status is notice did not provide a basis for a petition process and questions whether a case-by-case evaluation and that the conclusion of GRAS status, but CFSAN we could respond to a GRAS notice circumstances vary. Therefore, we had no questions about the basis for within 90 days because we did not decline the request to specify standards GRAS status provided by the second respond to a GRAS petition in such a for issues that are of sufficient notice. short timeframe. One comment that magnitude to result in an ‘‘insufficient stresses the importance of retaining a set basis letter.’’ See sections IV.H.4 and 3. Our Consideration of a Timely evaluation timeframe suggests that the IV.H.7 of CFSAN’s 2010 experience Amendment timeframe be 90–180 days based on document (Ref. 18) for information on As discussed in section XVIII.B, the CFSAN’s experience during the Interim specific GRAS notices that received an rule provides that you may submit a Pilot program, and opposes a timeframe ‘‘insufficient basis letter’’ from CFSAN, timely amendment to your filed GRAS greater than 180 days. Other comments and table 1 in CVM’s experience notice to update your GRAS notice or in support a 180-day timeframe because it document (Ref. 20) for information on response to a question from us would be realistic and reasonable, GRAS notices that received an (§ 170.260(a)). As a companion would be sufficient to resolve all of the ‘‘insufficient basis letter’’ from CVM. provision, the rule also provides that we issues raised by a GRAS notice with Our letters responding to each of these will consider any timely amendment procedural fairness, and could be GRAS notices describe the problems in that you submit to a filed GRAS notice, consistent and fair across both CFSAN more detail and are available on to update your GRAS notice or in and CVM. CFSAN’s Web site (Ref. 46) and CVM’s response to a question from us, before (Response 98) We are establishing a Web site (Ref. 47). we respond to your notice based on our timeframe of 180 days from the date of (Comment 97) Some comments ask evaluation of your notice if we deem filing for our response to a GRAS notice. that an ‘‘insufficient basis letter’’ that doing so is feasible within the We also are providing that we may include a qualifying statement that we established timeframes (see extend the 180-day response timeframe have not conducted a substantive § 170.265(a)(4)). If we deem that by 90 days on an as needed basis; if we review and have not concluded that the considering your amendment is not do so, we will inform you of the intended conditions of use of the feasible within the established extension in writing as soon as notified substance are not GRAS. These timeframes, we will inform you that we practicable but no later than within 180 comments assert that a response that are not considering your amendment days of filing. (See the regulatory text of does not include such a statement could (see § 170.265(a)(4)). We also will § 170.265(b)(1) and (2)). We agree that have the practical effect of challenging inform you that we are not considering the 180-day timeframe is realistic and the use of a substance in the absence of your amendment if we have granted reasonable, would be sufficient to a threshold determination that the your request to cease to evaluate your resolve all of the issues raised by a notified use is not GRAS. notice (i.e., if we send you a ‘‘cease to GRAS notice with procedural fairness in (Response 97) We disagree that an evaluate letter’’). See § 170.265(b)) and most cases, and could be consistent and ‘‘insufficient basis letter’’ should state Response 98 for the timeframe fair across both CFSAN and CVM. that we did not conduct a substantive established in this rule for our response We disagree that we should establish review of the GRAS notice. See to your GRAS notice. a 90-day timeframe merely because we Response 25 and Response 94. Our had proposed this timeframe before we mstockstill on DSK3G9T082PROD with RULES2 evaluation of a GRAS notice is a 4. Timeframe for Our Response to a gained experience with evaluating substantive evaluation. GRAS Notice GRAS notices. As shown in section The typical text of an ‘‘insufficient (Comment 98) Several comments III.M of CFSAN’s 2010 experience basis letter’’ specified that ‘‘the notice support retaining the proposed 90-day document, less than 12 percent of the does not provide a sufficient basis’’ for timeframe. According to these response letters CFSAN issued as of a determination that the notified comments, a 90-day timeframe would December 31, 2009, were sent within substance is GRAS under the conditions provide an incentive for a manufacturer the proposed 90-day timeframe (Ref. VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00058 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 55017 18). Importantly, section III.M of determination of an appropriate respond within an established CFSAN’s 2010 experience document timeframe for our response to a GRAS timeframe. Rather than a process in also shows that in many cases a dialog notice. which we stop and start a review clock between FDA and a notifier about (Comment 99) One comment on a particular GRAS notice, we have scientific issues associated with a GRAS expresses concern that a 90-day provided that you may ask us to cease notice, with an ensuing amendment timeframe would be unrealistic unless to evaluate a GRAS notice when your from the notifier, played a role in the we allocate additional resources to the preparation of an amendment would timeframe for CFSAN’s response to a program. This comment asks us to impact our ability to respond within 180 GRAS notice. As discussed in the 2010 consider a process similar to the process days. notice, several comments ask us to for the FCN program, where there is a fixed review period during which we 5. Responding to a GRAS Notice in All allow a notifier to address questions we can ‘‘object to’’ a submitted notification. Circumstances have about a GRAS notice by submitting an amendment to the notice (see Issue If we do not object within the review In the proposed rule, we noted that 3a, 75 FR 81536 at 81538), and the final period or do not request an extension to the GRAS notification procedure could rule expressly provides that you may the review period, a notification be structured so that we respond only submit an amendment to a filed GRAS submitted to the FCN program is when we question the GRAS status of notice before we respond to the notice considered effective. the intended use of the substance and (see § 170.260(a)). Although we are (Response 99) We decline this requested comment on whether we including flexibility to take additional request. We disagree that the GRAS should, in all cases, provide a notifier time as needed, our goal is to do so in notification procedure should be with a letter at the conclusion of our only limited instances, such as when modeled after the FCN program. Unlike evaluation of a notice (62 FR 18938 at the intended conditions of use of the the GRAS notification procedure, the 18951). notified substance raise complex FCN program is a mandatory process for (Comment 102) Several comments scientific issues. food contact substances under section agree with our discussion in the We have no basis to judge whether a 409(h) of the FD&C Act. Furthermore, proposed rule that a written response 90-day timeframe, but not a 180-day the statute provides that the FCN from us would give manufacturers an timeframe, would provide an incentive program shall not operate unless it has incentive to notify us of their to a manufacturer to submit a GRAS certain appropriated funds. See section conclusions of GRAS status; these notice. However, as noted in Response 409(h)(5)(A)(i) of the FD&C Act and comments recommend that we respond 24 CFSAN filed more than 600 GRAS § 170.104(c)(3). There are no similar in writing in all circumstances. Other notices during the time period 1998 statutory requirements applicable to our comments suggest that we limit our through 2015, including 69 GRAS evaluation of the basis for a conclusion response to circumstances in which we notices filed during 2014 and 51 GRAS of GRAS status. identify a problem with a notice because notices filed during 2015, even though (Comment 100) One comment asserts such a limitation would make it easier CFSAN rarely responded to a GRAS that we should respond to a GRAS for us to respond within the proposed notice within 90 days. We believe that notice within 90 days unless we identify 90-day timeframe. One comment the ongoing submission of GRAS notices a problem that warrants dialog with the expresses concern that a written is evidence that the 180-day timeframe notifier and an ensuing amendment. response could create a misperception that is consistent with our experience (Response 100) We disagree. The that we had undertaken an independent during the Interim Pilot program is not suggestion of this comment could lead review of the data described in the a disincentive to a manufacturer. to the unintended consequence of GRAS notice; to prevent this We note that the procedural seeking unnecessary amendments misperception, this comment suggests requirements of the GRAS notification merely to stay within an established that we respond in writing only if we procedure are very different from the timeframe. We believe it is more find a problem with the notice. procedural requirements of the GRAS appropriate to establish a single (Response 102) We acknowledge that affirmation petition process in that we timeframe that would broadly apply to limiting our response to circumstances respond to a GRAS notice by letter all GRAS notices, with the potential to in which we identify a problem with a whereas we respond to a GRAS extend the timeframe on an as needed notice would reduce the number of affirmation petition through rulemaking. basis. letters that we write. However, we As previously discussed (62 FR 18938 at (Comment 101) One comment asks us believe that it is important to publicly 18941), the resource-intensive to stop the ‘‘review clock’’ when we document our evaluation of the GRAS rulemaking process includes: (1) inform a notifier that we have questions notice in light of all the comments Publishing a filing notice in the Federal about a notice and then restart the submitted to this rulemaking. (See, e.g., Register; (2) requesting comment on the ‘‘review clock’’ upon receipt of an Comment 25 and the comments we petitioned request; (3) conducting a amendment that answers our questions. discuss in section VII.C). In addition, in comprehensive review of the petition’s (Response 101) We decline this our experience it is the process of data and information and comments request. We acknowledge that there evaluating a submission and reaching a received to the filing notice to could be an advantage to such a process, decision about whether the notice determine whether the evidence because stopping the review clock provides a basis for a conclusion of establishes that the petitioned use of the would reduce the time pressures on our GRAS status, rather than the process of substance is GRAS; (4) drafting a staff. However, the role of an drafting and issuing a letter, that detailed explanation of why the use is amendment is to clarify questions that requires the most time. mstockstill on DSK3G9T082PROD with RULES2 GRAS (as opposed to simply being safe); we have about your conclusion of GRAS We acknowledge the potential that a and (5) publishing that explanation in status rather than to substantively ‘‘no questions letter’’ could be the Federal Register. Therefore, we amend the GRAS notice. A process in misinterpreted, e.g., to mean that FDA, disagree with the perspective of one which we stop and start a review clock rather than the notifier, had reached a comment that our experience in implies that the timeframe for you to conclusion of GRAS status. To mitigate responding to a GRAS affirmation submit an amendment could be so long the potential for such misinterpretation, petition should have any bearing on the as to significantly impact our ability to the typical text of our response letters VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00059 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 55018 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations issued during the Interim Pilot program to inform us about your conclusion of used to refer to the notified substance referred to the notifier’s determination GRAS status rather than an opportunity for the purpose of the letter should not and stated that we have not made our for you to test a hypothesis that there is be considered an endorsement of that own determination regarding the GRAS a sufficient basis to reach a conclusion term for the purpose of declaring the status of the subject use of the notified of GRAS status. substance in the ingredient statement of substance (see table 1). We intend to (Comment 105) One comment food products; (3) clarified FSIS’ continue including such typical text in suggests that we issue a written position regarding the use of the letters issued under the final rule, response only when we have reached a notified substance in meat, meat food modified as shown in table 20. conclusion regarding safety. product or poultry product; and (4) (Comment 103) One comment (Response 105) This comment may corrected a mistake in the original suggests that we respond in writing only have misunderstood the proposed response. CFSAN also sent a subsequent at the notifier’s request. notification procedure. Under the letter as an administratively efficient (Response 103) We decline this notification procedure, you analyze the mechanism of responding to a notifier suggestion, which is contrary to available data and information and who provided CFSAN with information emphasis that the rule places on the reach a conclusion about whether the supporting a conclusion that an notifier’s acceptance of responsibility notified substance is safe under the additional use of the notified substance for a conclusion of GRAS status (see the conditions of its intended use and satisfied GRAS criteria. discussion at 62 FR 18938 at 18953). whether there is a basis to conclude that In addition, CFSAN has issued a (Comment 104) One comment asserts the criteria for GRAS status are satisfied. subsequent letter when CFSAN’s first that a letter acknowledging receipt of a We evaluate your conclusions regarding letter was an ‘‘insufficient basis letter’’ GRAS notice would constitute a form of the available data and information. rather than a ‘‘no questions letter.’’ For response. Another comment suggests During the Interim Pilot program, the example, CFSAN did so when a notifier that a letter acknowledging receipt of a typical text of a ‘‘no questions letter’’ who received an ‘‘insufficient basis GRAS notice state whether the notice stated that we had not reached our own letter’’ submitted a new GRAS notice meets the listed requirements for a determination regarding the GRAS that did not address the questions GRAS notice, eliminating the need for a status of the notified substance under CFSAN raised in the ‘‘insufficient basis second letter responding to the notice the conditions of its intended use (see letter.’’ CFSAN also did so when a when we complete our evaluation. This table 1). notifier who received an ‘‘insufficient comment asserts that a second letter To the extent that the comment is basis letter’’ submitted a supplement to would be unnecessary for two reasons. suggesting that we issue an ‘‘insufficient its original GRAS notice rather than First, the notifier has accepted full basis letter’’ when the problem with the submit a new GRAS notice. See section responsibility for the conclusion of notice relates to safety, but not to IV.J of CFSAN’s 2010 experience GRAS status and does not require general recognition, we disagree. It document (Ref. 18). premarket approval from us. Second, would be inconsistent with the legal under the terms of the rule a notifier basis of the GRAS standard for us to D. Procedures if a Notifier Disagrees must agree to make all data and only focus on safety, and we did not do With Our Response information available to us. so during the Interim Pilot program. In the proposed rule, we explained (Response 104) The final rule (See section III.A.3 of CFSAN’s 2010 that there are existing processes that we provides that we will inform you of the experience document (Ref. 18), where considered would be appropriate for a date on which we filed your notice CFSAN identifies ‘‘insufficient basis notifier to use to engage us if the notifier rather than the date on which we letters’’ in which CFSAN had questions disagreed with our response (see 62 FR received it, as we had proposed. We about whether there was general 18938 at 18952 and table 21). We also disagree that a letter informing you of recognition of safety.) noted that any person with concerns the date of filing in any way responds about our response to a GRAS notice to a GRAS notice or should state C. Additional Correspondence as may contact our Office of the Chief whether the notice meets the listed Circumstances Warrant Mediator and Ombudsman; that office requirements for a GRAS notice. As (Comment 106) One comment works on resolving issues and conflicts discussed in Response 93, we cannot expresses the view that a ‘‘no questions that arise in any FDA component. acknowledge whether a notice ‘‘meets letter’’ should not affect our ability to the listed requirements’’ without change our position if additional TABLE 21—EXISTING PROCEDURES IN assessing the quality of the submission, information indicates that the use of the OUR REGULATIONS THAT CAN which we do during the evaluation that substance raises any safety concerns. APPLY IF A NOTIFIER DISAGREES follows filing the submission as a GRAS (Response 106) We agree, and the WITH OUR RESPONSE TO A GRAS notice. final rule expressly provides that we We acknowledge that submitting a will send the notifier a subsequent letter NOTICE GRAS notice means that a notifier has about the notice if circumstances Regulatory accepted full responsibility for the warrant (see § 170.265(c)). The section Description conclusion of GRAS status. We also circumstances may not relate to safety. (§ ) acknowledge that the use of a GRAS As discussed in section IV.J of CFSAN’s substance is not subject to our 2010 experience document (Ref. 18), as 10.25 ........ Initiation of administrative pro- premarket review. However, we disagree of December 31, 2009, none of the ceedings. 10.33 ........ Administrative reconsideration of that a relevant factor in determining subsequent letters CFSAN issued during mstockstill on DSK3G9T082PROD with RULES2 action. whether we should respond to a notifier the Interim Pilot program reflected a 10.65 ........ Meetings and correspondence. is the notifier’s agreement to make all change in CFSAN’s position and several 10.75 ........ Internal agency review of deci- data and information available to us if addressed issues other than the safety of sions. we question whether the notice the use of the substance. For example, provides an adequate basis for a CFSAN issued subsequent letters that: (Comment 107) Several comments conclusion of GRAS status. A GRAS (1) Clarified the intended conditions of express concern that the processes notice presents an opportunity for you use; (2) clarified that the term CFSAN discussed in the proposed rule would be VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00060 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 55019 available only after we sent, and made importance of timeframes for decisions XX. Coordinating Our Evaluation of a readily accessible to the public, an by our officials. GRAS Notice With FSIS ‘‘insufficient basis letter.’’ Other (Response 108) We decline the In the 2010 notice, we described some comments express concern about the request to include in the final rule an of the terms of a MOU, between FDA practical effect of an ‘‘insufficient basis and USDA’s FSIS, that provides for a appeals process that would be specific letter’’ on the notifier’s ability to market coordinated evaluation process with to the GRAS notification procedure. We a notified substance while the notifier is FSIS when the intended conditions of seeking review of our evaluation. Some agree that the process to contact us about a response to a GRAS notice use of a notified substance include use comments ask that our letter be in a product or products subject to ‘‘stayed’’ until any problems that we should be clear. However, we disagree that the existing procedures are unclear, regulation by USDA under statutes that identified in our response to the notice because our regulations fully describe it administers (75 FR 81536 at 81541– are resolved under such a process. (Response 107) We acknowledge the these procedures (§§ 10.25, 10.33, 10.65, 81542). We also asked for comment on concerns expressed in these comments and 10.75). We acknowledge that the whether to make our coordinated but are making no changes to the rule listed procedures do not provide a clear evaluation process with FSIS explicit in to address these concerns. One of the the final rule (see Issue 13, 75 FR 81536 timeline and that some of the listed underpinnings of the GRAS notification at 81541–81542). In 2015, we amended procedures (e.g., §§ 10.25 and 10.33) are procedure is that making our response that MOU to include more details about more cumbersome than others (such as the procedures FDA and FSIS will readily accessible to the public will requesting a meeting under § 10.65 or properly underscore your responsibility follow to do so (Ref. 36). requesting internal Agency review of a (Comment 109) Comments support for the conclusion of GRAS status (62 decision under § 10.75). In practice FR 18938 at 18953). As discussed in coordinating our evaluation of GRAS during the Interim Pilot program, notices with FSIS and including the Response 104, a GRAS notice presents several notifiers who received an an opportunity for you to inform us procedure for this coordination in the ‘‘insufficient basis letter’’ took steps to final rule. Comments also support about your conclusion of GRAS status resolve our questions and subsequently requiring the notifier to provide an rather than for you to test a hypothesis that there is a sufficient basis to reach submitted a new GRAS notice or a food additional paper copy that we would a conclusion of GRAS status. If we send additive petition (see the discussion in send to FSIS as part of this procedure. you an ‘‘insufficient basis letter,’’ we section III.K of CFSAN’s 2010 (Response 109) The final rule advise you to carefully consider experience document (Ref. 18)). Given includes procedures for coordinating whether marketing the notified the variety of circumstances that could our evaluation of a GRAS notice with substance would be lawful. ‘‘Staying’’ lead to an ‘‘insufficient basis letter,’’ we FSIS when the use of the notified an ‘‘insufficient basis letter’’ informing believe that taking steps to resolve our substance includes use in a product or you that there may not be a legal basis questions, and submitting a new GRAS products subject to regulation by FSIS to market the notified substance, e.g., so notice or a food additive petition, can be under statutes that it administers. (See that you could market the substance an efficient mechanism for you to use in § 170.270). If you send your GRAS while you are working to resolve the lieu of the procedures we discussed in notice on paper, a single paper copy is issues that led us to send you an the proposed rule. Doing so would be sufficient; we would send FSIS an ‘‘insufficient basis letter’’, would not electronic copy. (See § 170.210(b) and consistent with the suggestion of some change the legal status of the notified Response 46). Under § 170.270(d), we comments that an appeals mechanism substance. will inform you of the advice we receive specific to the GRAS notification (Comment 108) Several comments from FSIS in the letter we send you in procedure could include submission of accordance with § 170.265(b)(1), as assert that the processes we had additional data and information for our identified in the proposed rule are appropriate. By ‘‘as appropriate,’’ we evaluation, except that the data and mean that in most circumstances we do cumbersome and do not provide manufacturers with a clear framework information would be submitted in a not intend to provide advice from FSIS or timeline for responding to our new GRAS notice rather than be an about the use of the notified substance questions or concerns. In general, these ‘‘appeal’’ to the GRAS notice that when we respond with an ‘‘insufficient comments ask us to include in the final received an ‘‘insufficient basis letter.’’ basis letter,’’ because doing so has the rule a prompt, fair, and effective process We do not have an FDA-certified potential to create confusion about the that would be specific to the GRAS third-party review organization that regulatory status of a use of the notified notification procedure. A few comments could review the matter and issue an substance in products subject to suggest that such an appeal mechanism opinion. We disagree that convening an regulation by FSIS. Likewise, we do not also apply to subsequent independent advisory committee would intend to provide advice from FSIS correspondence from us about a GRAS be appropriate as an additional, routine about the use of the notified substance notice. mechanism to appeal an ‘‘insufficient when we respond with a ‘‘cease to Some comments provide specific evaluate letter’’ and, thus, the procedure basis letter.’’ Under our regulations in suggestions for how an appeals described in § 170.270(d) does not part 14 governing advisory committees, mechanism specific to the GRAS specify that we will inform you of the notification procedure could work, e.g., it would be FDA—not a notifier—who advice we receive from FSIS in a letter by specifying that a notifier may submit decided to convene a meeting of our we send you in accordance with additional data and information for our Food Advisory Committee about the use § 170.265(b)(3). mstockstill on DSK3G9T082PROD with RULES2 evaluation, or by providing for an of a substance in food. We would have As we noted in section XII.I, this rule independent advisory committee or an little basis to convene a meeting of our does not specify the data and FDA-certified third-party review Food Advisory Committee as part of an information that FSIS will need to organization to review the matter and appeal to an ‘‘insufficient basis letter’’ evaluate whether the intended use of issue an opinion. Some comments unless the notifier had first used one or the notified substance complies with suggest that an appeals mechanism more of the procedures listed in table applicable statutes and regulations, or, if specify appeal steps and stressed the 21. not, whether the use of the substance VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00061 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 55020 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations would be permitted in products under for use in animal food and, thus, the In the final rule, you include the FSIS jurisdiction under specified process would not apply to a GRAS signed statements that we proposed be conditions or restrictions. We notice received by CVM. See also in a ‘‘GRAS exemption claim’’ in Part 1 recommend that you contact the Response 45. of your GRAS notice, and we no longer appropriate staff at FSIS regarding the use the term ‘‘GRAS exemption claim’’ XXI. Comments on Public Disclosure of data and information that FSIS will (see Response 42). As discussed in a GRAS Notice need you to provide. FSIS provides Response 50, the final rule stipulates contact information for its programs on We proposed that a ‘‘GRAS exemption that you must not include any its Web site (Ref. 41). claim’’ would be immediately available for public disclosure on the date the information that is trade secret or (Comment 110) One comment agrees notice is received. All remaining data confidential commercial information in that the evaluation of a GRAS notice should be coordinated between FDA and information in the notice would be Part 1 of your GRAS notice (see and FSIS when ‘‘animal products’’ are available for public disclosure, in § 170.225(b)). involved. This comment notes that FSIS accordance with part 20, on the date the In the following sections, we discuss does not currently review the use of a notice is received (proposed comments on the proposed substance intended for use in animal § 170.36(f)(1)). We also proposed that requirements for public disclosure of a food and recommends that CVM be the following information would be GRAS notice. After considering these involved in the safety review process of readily accessible for public review and comments, we are establishing the notice if the notice involves a copying: (1) A copy of the ‘‘GRAS requirements applicable to the public substance to be used in animal food. exemption claim’’ (proposed disclosure of a GRAS notice as shown (Response 110) This comment appears § 170.36(f)(2)(i)); (2) a copy of our in table 22, with editorial, clarifying, to have misunderstood the purpose of response letter (proposed and conforming changes as shown in the coordinated evaluation process that § 170.36(f)(2)(ii)); and (3) a copy of any table 29. (See § 170.275.) Table 22 we discussed in the 2010 notice. That subsequent letter we issued regarding identifies changes we made relative to process applies to the use of a substance the notice (proposed § 170.36(f)(2)(iii)). in human food products, such as meat In the 2010 notice, we noted that the proposed rule or the description in and poultry products, that are subject to although the decision to submit a GRAS the 2010 notice other than the editorial, regulation by USDA and would be notice would be voluntary, the clarifying, and conforming changes evaluated by CFSAN; it does not apply provisions governing the GRAS shown in table 29 and the additional to the use of a substance in animal food. notification procedure, including the editorial changes associated with the FSIS, under the statutes it administers, information to be submitted, would be redesignation of proposed § 170.36(f) as does not evaluate a substance intended mandatory (75 FR 81536 at 81540). § 170.275. TABLE 22—FINAL REQUIREMENTS APPLICABLE TO PUBLIC DISCLOSURE OF A GRAS NOTICE Proposed Revisions (other than editorial, Final designation in Issue No. in designation in the clarifying, and conforming changes) the regulatory text the 2010 Description regulatory text relative to the proposed rule or the (§ ) notice (§ ) 2010 notice 170.275(a)(1) ......... N/A ......................... N/A The data and information in a GRAS Clarify that a notice is considered a notice (including data and information mandatory, rather than voluntary, submitted in any amendment or sup- submission for purposes of their sta- plement to your GRAS notice or in- tus under the FOIA and part 20. corporated into your GRAS notice) are considered a mandatory, rather than voluntary, submission for pur- poses of its status under the FOIA and part 20. 170.275(a)(2) ......... 170.36(f)(1) ............ N/A The data and information in a GRAS Clarify that part 20 applies to amend- notice (including data and information ments and supplements as well as to submitted in any amendment or sup- the GRAS notice as originally sub- plement to your GRAS notice or in- mitted. corporated into your GRAS notice) are available for public disclosure in accordance with part 20 as of the date that we receive your GRAS no- tice. 170.275(b)(1) ......... 170.36(f)(2)(i) ......... N/A We will make readily accessible to the Clarifies that the list of submissions that public a list of filed GRAS notices, in- we make publicly available are those cluding the information described in that we have ‘‘filed’’ as GRAS no- the signed statements you include in tices. § 170.225(c)(2) through (c)(5). 170.275(b)(2) ......... 170.36(f)(2)(ii) ........ N/A We will make readily accessible to the N/A. public the text of any letter that we mstockstill on DSK3G9T082PROD with RULES2 issue under § 170.265(b)(1) or (3) (e.g., a ‘‘no questions letter’’ or an ‘‘insufficient basis letter’’); or under § 170.265(c) (a ‘‘subsequent letter’’). 170.275(b)(3) ......... 170.36(f)(2)(ii) ........ N/A We will make readily accessible to the Clarify that the provisions in which we public the text of any letter that we make certain letters readily acces- issue under § 170.265(b)(3) (e.g., a sible to the public apply to a ‘‘cease ‘‘cease to evaluate letter’’). to evaluate letter’’. VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00062 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 55021 TABLE 22—FINAL REQUIREMENTS APPLICABLE TO PUBLIC DISCLOSURE OF A GRAS NOTICE—Continued Proposed Revisions (other than editorial, Final designation in Issue No. in designation in the clarifying, and conforming changes) the regulatory text the 2010 Description regulatory text relative to the proposed rule or the (§ ) notice (§ ) 2010 notice 170.275(c) .............. 170.36(f)(2)(iii) ....... N/A We will disclose public information in N/A. accordance with part 20. A. Data and Information in a GRAS whether any of the data and information GRAS affirmation petition is disclosed Notice Are Available for Public in Parts 2 through 7 of your GRAS only after the petition has been accepted Disclosure on the Date That We Receive notice are exempt from disclosure under for filing (former § 170.35(c)(2)); and (2) It the FOIA. the health claim petition process, in (Comment 111) One comment asserts (Comment 112) Several comments which a health claim petition becomes that the releasability of the contents of assert that a GRAS notice should not be available for public disclosure only after a GRAS notice should be governed by publicly available until after we have it is filed and a health claim petition § 20.111 (data and information completed our evaluation. These that is denied without filing is not submitted voluntarily to us) because the comments also assert that a delay in available for disclosure (21 CFR FD&C Act does not require submission disclosure, coupled with an opportunity 101.70(j)). of a GRAS notice. The comment asserts for a notifier to amend the notice, (Response 113) The final rule that § 20.111 would affect the would: (1) Avoid the release of continues to specify that the data and releasability of the content of a GRAS information that we deemed to be information in a GRAS notice are notice in three ways. First, while a inadequate or incomplete; and (2) avoid available for public disclosure as of the GRAS notice is pending, § 20.111 would release of a notice that was withdrawn date of receipt (see § 170.275(a)(2)). The protect from disclosure safety data or if coupled with an opportunity for a former GRAS affirmation petition information about an ingredient under notifier to withdraw a notice. process did not specify when a development. Second, § 20.111 would (Response 112) We disagree that we submitted GRAS affirmation petition permanently protect from disclosure should refrain from disclosing the would be available for public any data or information relating to existence of a GRAS notice, or the disclosure. Instead, the former GRAS manufacturing, production or sales, or contents of a GRAS notice, until after affirmation petition process merely formulas. Third, § 20.111 would we have completed our evaluation. As specified that we would place the establish that a notifier has the right to previously discussed, immediate petition on public file in the office of request that we evaluate the notifier’s disclosure of a GRAS notice underscores the Division of Dockets Management position that specific data or a notifier’s responsibility for a and publish a notice of filing in the information in a GRAS notice are conclusion of GRAS status (62 FR 18938 Federal Register within 30 days after protected from disclosure because these at 18953). As discussed in Response 2, the date of filing. In addition, we data or information fall within the immediate disclosure of a GRAS notice disagree that the public disclosure exemption in § 20.61 for trade secrets also provides an opportunity for outside provisions in § 101.70(j) applicable to and commercial or financial parties to make us aware of dissenting the health claim petition process should information, which is privileged or views about whether the available data apply to the GRAS notification confidential. and information support a conclusion procedure. Those provisions derive (Response 111) We disagree that the that the notified substance is safe under directly from the statutory provisions provisions of § 20.111 apply to a GRAS the conditions of its intended use, and that direct the health claim program notice. Although your decision to we did receive information from outside (section 403(r)(4)(A)(i) of the FD&C Act submit a GRAS notice is voluntary, the parties during the Interim Pilot program. (21 U.S.C. 343(r)(4)(A)(i))). information included in your GRAS Continuing to provide an opportunity Under § 20.103, with few exceptions notice is required. To make that clear, for public participation is consistent all correspondence from members of the the final rule stipulates that the data and with our substitution of the GRAS public, organization or company information in a GRAS notice (including notification procedure for the former officials, or other persons, is available data and information submitted in any GRAS affirmation petition process, in for public disclosure at the time that we amendment or supplement to your which there was a public comment receive it unless a different time for GRAS notice or incorporated into your period. such disclosure is specified in other GRAS notice) are considered a As discussed in Response 83, our rules established or cross-referenced in mandatory, rather than voluntary, current regulations regarding public part 20. As noted in Comment 86 and submission for purposes of its status information stipulate that no person Response 86, we may decide to file and under the FOIA and part 20 (see may withdraw records submitted to respond to a submission as general § 170.275(a)(1)). FDA (see § 20.29), and those regulations correspondence, rather than as a GRAS We agree that a notifier has a right to will apply to a GRAS notice that you to notice, in certain circumstances; if we request that we evaluate the notifier’s ask us to ‘‘cease to evaluate.’’ do so, the data and information in the position that specific data or (Comment 113) One comment asks us submission would be available as of the mstockstill on DSK3G9T082PROD with RULES2 information in a GRAS notice are to make a GRAS notice available for date of receipt. Retaining date of receipt protected from disclosure because these public disclosure only after we accept as the timeframe for when a submission data or information fall within the the submission for review. Some you transmit as a GRAS notice is exemption in § 20.61 for trade secrets comments contrast our proposal for available for public disclosure is both and confidential commercial immediate disclosure of a GRAS notice consistent with § 20.103 and a practical information. See § 170.225(c)(8), which with the provisions of: (1) The GRAS approach to a situation in which we requires that you state your view as to affirmation petition process, in which a receive a FOIA request for a GRAS VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00063 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 55022 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations submission before we have determined the notice), § 170.265(b)(3) (a letter if we Dockets Management, because all new whether to file the submission as a grant a request that we cease to evaluate information sent to the Division of GRAS notice. As a practical matter, we a GRAS notice), or § 170.265(c) (a Dockets Management is maintained believe that such situations will be rare, subsequent letter that we send about a electronically; paper submissions are and that in most cases a GRAS GRAS notice). (See § 170.275(b).) We are scanned to electronic form. submission will be disclosed after we not specifying that the mechanism for (Comment 117) One comment that have determined whether to file it and us to do so is through an ‘‘Inventory’’ addresses the discussion in the 2010 evaluate it as a GRAS notice, or to file because the procedure we used to make notice about the reasons that may lead it and respond to it as general this information readily accessible to us to decline to file a submission as a correspondence. the public evolved over time during the GRAS notice, such as when the use is (Comment 114) Some comments Interim Pilot program, and may covered by an existing regulation, asks disagree with the assumption we stated continue to evolve (see section III.I.1 in us to include those submissions in the in the proposed rule (62 FR 18938 at CFSAN’s 2010 experience document GRAS inventory so there will be no 18952) that submission of a GRAS (Ref. 18)). confusion as to the status of the notice would not reflect the notifier’s (Comment 116) In the proposed rule, ingredient. plans about the timing or the use of the we stated our intention to initially (Response 117) We decline this substance in a marketed product, maintain a paper version of an request. The purpose of the inventory of because a GRAS substance may be inventory at our Dockets Management GRAS notices is to provide a list of all marketed without prior approval. Branch (now Division of Dockets the GRAS notices that we have filed and (Response 114) We acknowledge that Management) and asked for comment on evaluated, not to interpret the uses immediate disclosure of a GRAS notice making an inventory available through listed in our regulations or, as discussed could, in certain circumstances, provide electronic means such as the Internet in Response 86, covered by an existing information about the timing of market (62 FR 18938 at 18953). Comments GRAS notice. entry. However, when the data and support maintaining an inventory in (Comment 118) A few comments information regarding the safety of the paper format, electronic format, or both suggest that a publicly available substance under the conditions of its formats so that all members of the inventory of GRAS notices could suffice intended use satisfy GRAS criteria, public could have ready access to such to document that certain notices raised neither the law nor this rulemaking information regarding GRAS notices. no significant issues. would prevent you from marketing a Some comments point out that (Response 118) We agree that a substance before submitting a GRAS electronic access would be particularly publicly available inventory of GRAS notice or during our evaluation of that important to the international food notices can document which notices notice. industry. Some comments support the result in a ‘‘no questions letter, e.g., by Division of Dockets Management as the prominently listing the category of our B. We Will Make a List of Filed GRAS response. The Inventory of GRAS Notices and Our Responses to GRAS best location for an inventory maintained in paper format. Notices developed during the Interim Notices Readily Accessible Pilot program prominently classifies (Response 116) As discussed in (Comment 115) Several comments section III.I.1 in CFSAN’s 2010 each response letter as ‘‘no questions,’’ address our stated intention to maintain experience document (Ref. 18), the ‘‘insufficient basis,’’ and ‘‘cease to an inventory of GRAS notices that we procedure we used to make this evaluate’’ (Ref. 46). However, we receive, our response, and any information readily accessible to the disagree that merely displaying the subsequent relevant correspondence. public evolved over time during the category of our response, without (See the discussion at 68 FR 18938 at Interim Pilot program. It began as a providing the full text of a letter that 18953.) Some of these comments agree paper file (first maintained at the places that category of response in with the discussion in the proposed rule Division of Dockets Management, and context, is appropriate, regardless of that an inventory of GRAS notices then maintained in the public reading whether the response to the GRAS should be an adjunct to the proposed room of our Freedom of Information notice is ‘‘no questions,’’ ‘‘insufficient rule rather than be included in the Staff), and evolved into its current basis,’’ or ‘‘cease to evaluate.’’ For regulatory text. Other comments electronic format on our Internet site example, even when we answer ‘‘FDA disagree and ask us to include the (Ref. 46). We intend to continue using has no questions,’’ our response letter creation and availability of the the Internet as the principal means to highlights key safety considerations, inventory in the regulatory text. These make the inventory readily accessible such as the importance of ensuring that comments assert that a provision that because doing so is an efficient and the method of manufacture removes merely states that the inventory exists effective mechanism to disseminate potential contaminants. and is available for public review would information to anyone who has access to (Comment 119) One comment asks us address the concern that we identified the Internet. The inventory on the to provide ‘‘public notice’’ of all GRAS in the proposed rule about the need to Internet can be accessed and printed notices and the information provided maintain flexibility regarding our from computers in the public reading therein. Another comment asks us to administration of the inventory. room at Division of Dockets make the ‘‘GRAS exemption claim’’ (Response 115) The final rule Management, as well as from computers readily accessible to the public by specifies that we will make the located at businesses, at homes, and at publishing information that would be in following readily accessible to the public locations such as libraries and the publicly accessible file in the public: (1) A list of filed GRAS notices, Internet cafes. If a person either does not Federal Register in addition to placing mstockstill on DSK3G9T082PROD with RULES2 including the information described in have access to the Internet or chooses the ‘‘GRAS exemption claim’’ in a certain of the signed statements that are not to access the inventory through the readily accessible file. This comment included in Part 1 of a GRAS notice (i.e., Internet, that person can request each states that doing so would provide the § 170.225(c)(2) through (c)(5)); and (2) GRAS notice, and each letter listed in public with access to as much The text of any letter that we issue § 170.265(b)(1) or (3) or (c), under the information as possible about what under § 170.265(b)(1) (our response to a FOIA. It is no longer practical for us to substances would be used in food on the GRAS notice based on our evaluation of maintain a paper file at the Division of basis of the GRAS provision if FDA is VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00064 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 55023 going to ‘‘forgo its role’’ in the Register, that is the official repository of comment, the rule provides that those evaluation of the safety of GRAS our regulations listing authorized uses data and information are available for substances. This comment also asks us of food substances. public disclosure upon receipt (see to publish the receipt of the notice and We disagree that we are forgoing our § 170.275(a)(2)). See also Response 50. all of our subsequent responses to the role in the evaluation of the safety of (Comment 122) Some comments ask notice in the Federal Register. substances used in food on the basis of us to alert the notifier, and grant the Another comment asks us to publish the GRAS provision. See Response 25. notifier an option to withdraw the semi-annually, either in a Federal (Comment 120) One comment asks us notice, in order to protect information Register notice or by regulation, a list of to place the entire GRAS notice, rather designated as confidential from GRAS notices that receive a ‘‘no than only the proposed ‘‘GRAS disclosure. questions letter’’ in addition to posting exemption claim,’’ in a readily (Response 122) We decline this the Inventory of GRAS notices on our accessible paper file, e.g., at the Division request. A person who submits a record Web site. This comment explains that of Dockets Management. In the to us may not withdraw that record from questions are sometimes raised— comment’s view, a simple provision that our files (§ 20.29). Rather, the especially from outside the United a notifier submit one additional paper procedures that govern the release of States—about the regulatory status of a copy would mitigate our concerns about information that a notifier identifies as substance used in food on the basis of the administrative inefficiency of confidential in a GRAS notice are the GRAS provision unless that use of maintaining duplicate files at both the established in §§ 20.61 and 20.27. Under the substance is either incorporated into center and Agency levels. Another § 20.61(d), a person who submits the CFR or otherwise officially comment asks us to make the entire records to us may designate part or all published. This comment asserts that notice readily accessible in electronic of the information in such records as periodic publications in the Federal form. exempt from disclosure under Register would assist in addressing this (Response 120) We currently make a exemption 4 of FOIA. However, under concern. hyperlink to an electronic copy of each § 20.27 marking records submitted to us (Response 119) By specifying that we GRAS notice accessible from within the as confidential, or with any other will make a list of filed GRAS notices entry for that GRAS notice in the similar term, raises no obligation by readily accessible (currently, through inventory, after appropriate redaction FDA to regard such records as the inventory on the Internet), the rule (e.g., of privacy information, confidential, to return them to the requires us to actively disclose those copyrighted material, and any data and person who has submitted them, to GRAS notices. There is a gap between information that are exempt from public withhold them from disclosure to the the date on which we receive a GRAS disclosure) (Ref. 18, footnote 3). As a public, or to advise the person notice and the date on which we add it practical matter, placing paper files on submitting them when a request for to the inventory, e.g., CFSAN currently public display requires space, which is their public disclosure is received or updates its inventory on an finite, and our Division of Dockets when they are in fact disclosed. approximately monthly basis. However, Management scans paper submissions in practice during the Interim Pilot into electronic format. XXII. Submission of a Supplement program there was ample public notice The rule provides that you may C. Public Disclosure of a GRAS Notice submit a supplement to a GRAS notice of the receipt of the GRAS notice before Is in Accordance With Our Public after we respond to your notice based on CFSAN responded to it (see the Information Regulations in Part 20 our evaluation of your notice or cease to discussion of the timeframe for CFSAN’s response in section III.M of (Comment 121) One comment agrees evaluate your notice (§ 170.280). CFSAN’s 2010 experience document that information submitted under the However, if our response to your GRAS (Ref. 18)). In addition, the rule provides proposed ‘‘GRAS exemption claim’’ notice raises questions about your that we may send a subsequent letter should exclude from public disclosure conclusion that the notified substance is about the GRAS notice if circumstances the non-public confidential information GRAS under the conditions of its warrant; such circumstances could with the exception of safety data. intended use, the appropriate include data and information, received (Response 121) This comment appears mechanism for you to address those from a member of the public, after we to have misinterpreted the proposed questions would be to submit a new responded to the GRAS notice. provisions regarding submission of non- GRAS notice or other regulatory We decline the requests to provide public information and how the public submission (such as a food additive public notice through an announcement disclosure provisions of this rule apply petition) rather than to submit a in the Federal Register. Publishing an to non-public information. The supplement. See section III.C.2 of announcement in the Federal Register proposed ‘‘GRAS exemption claim’’ is CFSAN’s 2010 experience document for requires an expenditure of our resources the precursor of Part 1 of a GRAS notice examples of supplements that CFSAN (including time and cost of publication) (which we are establishing in received during the Interim Pilot that would be inconsistent with our goal § 170.225). The rule specifies that you program (Ref. 18). of using our resources efficiently and must not include any information that is effectively. Even if we conserved trade secret or confidential commercial XXIII. Comments on the Administrative resources by publishing such a notice information in Part 1 of your GRAS Process for Pending GRAS Affirmation only on a semi-annual basis, we notice, except in the statement of your Petitions disagree that ‘‘officially publishing’’ a view as to whether any of the data and We proposed that any pending list of GRAS notices that receive a ‘‘no information in Parts 2 through 7 of your petitions would be presumptively mstockstill on DSK3G9T082PROD with RULES2 questions letter’’ in the Federal Register GRAS notice are exempt from disclosure converted to a GRAS notice on the date would address concerns, in the under the FOIA. Part 1 of a GRAS notice the final rule becomes effective domestic or international community, includes signed statements and a (proposed § 170.36(g)(1)). An affected about the regulatory status of the use of certification, not ‘‘safety data.’’ The petitioner would have an opportunity to a substance when that use is not listed ‘‘safety data’’ would be included in amend the converted petition to meet in our regulations. It is the Code of Parts 2 through 7 of the GRAS notice. the requirements of the GRAS Federal Regulations, not the Federal Consistent with the view of this notification procedure by submitting a VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00065 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 55024 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations ‘‘GRAS exemption claim’’ (proposed date of receipt of the notice (proposed In the 2010 notice, we requested § 170.36(g)(2)). A GRAS affirmation § 170.36(g)(3)(i)). After 90 days from the comments on three issues related to the petition that is converted to a notice and date of publication of the final rule, we pending petitions as shown in table 23. that the affected petitioner amends would inform any affected petitioner Although the 2010 notice classified all would be reviewed and administered who had not amended an applicable of these issues as ‘‘Issue 17,’’ for according to the provisions of the GRAS petition that the converted petition is presentation purposes in this document notification procedure; the date of inadequate as a GRAS notice. we classify the three issues as 17a, 17b, receipt of the amendment would be the and 17c. TABLE 23—ISSUES IN THE 2010 NOTICE REGARDING PENDING GRAS AFFIRMATION PETITIONS Issue Description of our request for comment Reference No. 17a .... How to reduce the impact on affected petitioners while retaining the principle that we will not devote 75 FR 81536 at 81542–81543. resources to pending petitions. 17b .... Whether an outcome of ‘‘withdrawal without prejudice’’ instead of ‘‘insufficient basis’’ would be more 75 FR 81536 at 81542–81543. appropriate when an affected petitioner simply chooses not to have the pending petition consid- ered under the GRAS notification procedure. 17c .... Whether an affected petitioner could request that we incorporate into a GRAS notice a withdrawn 75 FR 81536 at 81542–81543. GRAS affirmation petition into a GRAS notice, and if so, if any requirements of the GRAS notifi- cation procedure should be waived. In the following paragraphs, we provisions for the pending petitions as description in the 2010 notice other discuss comments regarding the shown in table 24, with editorial, than the editorial, clarifying, and disposition of pending petitions in light clarifying, and conforming changes as conforming changes shown in table 29 of the deletion of the GRAS affirmation shown in table 29. (See § 170.285.) and the additional editorial changes petition process. After considering these Table 24 identifies changes we made associated with the redesignation of comments, we are establishing relative to the proposed rule or the proposed § 170.36(g) as § 170.285. TABLE 24—FINAL REQUIREMENTS FOR DISPOSITION OF PENDING GRAS AFFIRMATION PETITIONS Proposed Revisions (other than editorial, Final designation in Issue No. in designation in the clarifying, and conforming changes) the regulatory text the 2010 Description regulatory text relative to the proposed rule or the (§ ) notice (§ ) 2010 notice 170.285(a) .............. 170.36(g)(1) ........... 17a and 17b On the effective date of the rule, we will We administratively close the docket for close the docket for any GRAS affir- the GRAS affirmation petition rule- mation petition that is still pending as making rather than convert the pend- of that date. ing petition to a GRAS notice. 170.285(b) .............. 170.36(g)(2) ........... 17c Any person who submitted a GRAS af- The affected petitioner submits a GRAS firmation petition that is pending as of notice rather than an amendment to a the date of the final rule may submit ‘‘converted petition’’. a GRAS notice and request that we incorporate the GRAS affirmation pe- tition. N/A ......................... 170.36(g)(3)(i) ........ N/A N/A ......................................................... No longer specifies the procedures for FDA’s evaluation of a former pending petition. N/A ......................... 170.36(g)(3)(ii) ....... 17a and 17b N/A ......................................................... No longer treats a pending petition that is not evaluated as a GRAS notice as having an insufficient basis to support GRAS status. (Comment 123) Some comments to these comments state that, in most the converted petition to satisfy the the proposed rule support our proposal cases, FDA also had dedicated requirements of the GRAS notification to convert pending GRAS affirmation significant resources to the review of procedure. One of these comments petitions to GRAS notices on the these petitions and, in some cases, had argues that there need not be any effective date of the rule. However, as even arranged for an additional third urgency in closing the applicable files discussed in the 2010 notice, many party to review the substance that was because many of these petitions had comments to the proposed rule object to the subject of the petition. These been pending for years, and the subjects our proposal for administering the comments suggest options such as of the petitions had been marketed mstockstill on DSK3G9T082PROD with RULES2 pending petitions as being ‘‘grandfathering’’ pending petitions, i.e., during those years. fundamentally unfair, because an completing the rulemaking process for Some comments to the proposed rule affected petitioner had invested them, particularly if we had completed assert that more resources would be considerable time and resources in the our scientific review with no needed to review a petition that is petition process and should not be outstanding questions. Some comments converted to a GRAS notice than would penalized by our adoption of a new ask us to provide an affected petitioner be needed to complete the review of GRAS notification procedure. Some of 180 days, rather than 90 days, to amend each pending petition and issue a VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00066 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 55025 regulation. One comment suggests that We received no comments asking us comments that objected to the proposal it would be simpler and more efficient to waive any of the requirements of the to convert a pending petition to a GRAS administratively to allow an affected notification procedure. notice assert that the substances that are petitioner an option to update a GRAS (Response 123) We have revised the the subject of the pending petitions have affirmation petition to include proposed provisions regarding the been marketed for years; clearly, these additional conditions of use or new disposition of pending petitions in light affected petitioners are able to market specifications than to require separate of the concern of the comments that the the substance without a listing in our GRAS notices for such changes. proposed process was unfair to affected regulations. Other comments ask us to clarify the petitioners. The final rule provides that We agree that it is appropriate to procedures we would use to convert a on the effective date of the rule, we will extend the timeframe for an affected GRAS affirmation petition to a GRAS close the docket for any GRAS petitioner to take action with respect to notice as well as procedures for affirmation petition that is still pending a pending petition. Under final amending a petition that was converted as of that date (§ 170.285(a)). Any § 170.285(b), there is no limit on the to a GRAS notice through an additional person who submitted a GRAS timeframe for an affected petitioner to submission. Some comments assert that affirmation petition that is pending as of submit a GRAS notice that incorporates we should not require an affected the date of the final rule may submit a a GRAS affirmation petition. petitioner to submit such an amendment GRAS notice and request that we We decline the request to because all of the pertinent information incorporate the GRAS affirmation ‘‘grandfather’’ any pending petitions. would already be included in the petition (§ 170.285(b)). We are closing We simply do not have sufficient petition and argue that technical the docket for the petition by operation resources to devote to the rulemaking adherence to the format of a GRAS of law because the process that would process that is required for GRAS notice should not take precedence over be necessary to bring a petition to affirmation, regardless of whether we administrative efficiency and common closure (i.e., § 170.35(c)) no longer already have completed our scientific sense. Other comments express concern exists. We decided to close the docket review. For example, even if we have that it was not clear that the proposed for the petition, rather than classify the completed our scientific review, the additional submission (proposed petition as withdrawn without Administrative Procedures Act (5 U.S.C. § 170.36(g)(2)) was in fact a skeleton prejudice, for two reasons. First, closing 553) requires that we consider relevant notice that primarily would cross- the docket is an administrative option data, views, or arguments submitted to reference the original GRAS affirmation that is open to us, whereas in our us by interested persons and that we petition. petition processes withdrawing a publish a concise general statement of Some comments to the 2010 notice petition is an option that falls to the the basis and purpose of the regulation. suggest that a pending petition could be petitioner (see, e.g., § 171.1(j) for In addition, Executive Order 12866 ‘‘withdrawn without prejudice’’ or withdrawal of a food additive petition requires that we assess the costs and ‘‘suspended’’ so that it would no longer without prejudice). Second, benefits of available regulatory require FDA resources to review it. ‘‘withdrawal without prejudice’’ alternatives when we conduct Other comments to the 2010 notice generally means ‘‘without prejudice to a rulemaking, and the Regulatory express the view that a simple letter of future filing,’’ and ‘‘future filing’’ refers Flexibility Act (5 U.S.C. 601–612) conversion should be adequate, but that to the same type of filing; however, we requires that we consider alternatives if an affected petitioner chose not do so have eliminated the GRAS affirmation that would minimize the economic then the outcome of the converted petition process and, thus, an affected impact of our regulations on small petition would more appropriately be petitioner could not submit another entities. Thus, to complete the described as ‘‘withdrawn without GRAS affirmation petition. rulemaking associated with the GRAS prejudice’’ rather than ‘‘insufficient’’ as Closing the docket is neutral with affirmation petition process, we require a GRAS notice. Other comments to the respect to a conclusion by an affected significant resources beyond those 2010 notice continue to express the petitioner that the petitioned substance associated with scientific review. Even view that we should ‘‘grandfather’’ a is GRAS under the conditions of its if we did ‘‘grandfather’’ a pending pending petition. One of these intended use, because closing the petition, it is highly unlikely that we comments asserts that failure to docket does not result in a publicly would be able to devote resources to grandfather those affirmation petitions available ‘‘insufficient basis letter.’’ To this voluntary process in light of where FDA had completed its review clarify that closing the petition is competing programs that are required by and no outstanding scientific issues without prejudice to eligibility for statute. For example, the resources that exist would be unfair because the GRAS classification of the use of the substance could be directed to the GRAS notification procedure results in a lower as GRAS, the final rule specifically affirmation petition process must be level of authoritativeness than the GRAS provides that an affected petitioner may considered together with the resources affirmation petition process, and the incorporate the former GRAS that are required to administer the food affected petitioners had invested affirmation petition into a GRAS notice. and color additive petition processes considerable time and resources in the Given the passage of time since the and the premarket notification process petition process. This comment also pending petitions were submitted, it is for food contact substances, which are notes that after we published the likely that some of the data and required programs under sections 409 proposed rule we continued to review information in the petition would need and 721 of the FD&C Act. GRAS affirmation petitions and to be updated. In addition, the affected For the reasons discussed in the completed the process for six GRAS petitioner would need to follow all previous paragraph, we disagree that we mstockstill on DSK3G9T082PROD with RULES2 affirmation petitions before format requirements for a GRAS notice, would have needed more resources to discontinuing further activity in 1999. including the narrative required in Part review a petition that is converted to a Comments that address Issue 17c 6 of a GRAS notice. GRAS notice than to complete the recommend that an affected petitioner We acknowledge that our response to review of each pending petition and be allowed to incorporate information a GRAS notice does not have the same issue a regulation. We also disagree that from a ‘‘withdrawn’’ GRAS affirmation level of ‘‘authoritativeness’’ as a listing it would be simpler and more efficient petition into a GRAS notice. in our regulations. However, some of the administratively to allow an affected VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00067 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 55026 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations petitioner an option to update a GRAS statement that the lack of an affirmation We also have placed a list of the affirmation petition. As discussed in regulation does not indicate that FDA pending petitions that we are closing in CFSAN’s 2016 experience document disagrees with the affected petitioner’s the docket for this rule (Ref. 48). (Ref. 19), during the 10-year period GRAS determination. XXIV. Other Comments extending from 1990 through 1999, (Response 124) We decline this CFSAN completed the rulemaking A. GRAS Panels and Conflict of Interest request. Our regulations in part 184 process for 24 GRAS affirmation In the 2010 notice, we explained that represent our own conclusions petitions, with an average elapsed time the GAO report noted that we have not of approximately 7.9 years (median regarding the GRAS status of a listed substance under the conditions of its issued any conflict of interest guidance elapsed time approximately 6.9 years). that companies can use to help ensure In contrast, under the final rule we will intended use. It is inappropriate for our regulations to become a catalog of that the members of their expert panels respond to a GRAS notice in 180 days, are independent (75 FR 81536 at 81542). with an option to extend the timeframe circumstances where we have not reached our own conclusion regarding The GAO report recommended that we by an additional 90 days (see Response develop a strategy to minimize the 98). GRAS status. potential for conflicts of interest, As of August 17, 2016 there are 45 However, under final § 170.275(b), we including taking steps such as issuing pending GRAS affirmation petitions. We will make a list of filed GRAS notices guidance for companies on conflict of intend to contact each affected readily accessible to the public. The interest and requiring information in petitioner to inform the petitioner that: inventory of GRAS notices that GRAS notices regarding expert (1) We are closing the affected docket as currently makes this list available panelists’ independence. In the 2010 of October 17, 2016; and (2) the includes a link to information about notice, we requested comments on three petitioner may submit a GRAS notice each listed GRAS notice. When the issues related to GAO’s that incorporates the former GRAS GRAS notice was originally submitted recommendation regarding conflict of affirmation petition. as a GRAS affirmation petition, we have interest as shown in table 25. Although (Comment 124) One comment asks us included the petition number. We the 2010 notice classified all of these to issue a regulation, to be included in intend to continue this practice under issues as ‘‘Issue 15,’’ for presentation part 184, that lists the pending petitions. the final rule. purposes in this document we classify The comment also asks us to include a the three issues as 15a, 15b, and 15c. TABLE 25—ISSUES IN THE 2010 NOTICE REGARDING GUIDANCE ON CONFLICT OF INTEREST Issue Description of our request for comment Reference No. 15a .... Whether companies would find it useful to have guidance on potential conflicts of interest of GRAS 75 FR 81536 at 81542. expert panelists. 15b .... If guidance on potential conflicts of interest of GRAS expert panelists would be useful, what compa- 75 FR 81536 at 81542. nies currently do to mitigate such a conflict. 15c .... Whether to require that GRAS notices include information regarding expert panelists’ independence 75 FR 81536 at 81542. (Comment 125) Most of the comments § 10.115(c) and (g)). Under that of disclosing and addressing potential that addressed Issues 15a and 15b ask us framework, we prepare a draft of Level conflicts of interest. However, we to provide guidance regarding potential 1 guidance and then: (1) Publish a disagree that this awareness means that conflicts of interest of GRAS panel notice in the Federal Register we should not issue a guidance members. One of these comments announcing that the draft guidance regarding conflict of interest. A provided an example of a draft guidance document is available; (2) post the draft guidance from us on conflict of interest for our consideration. Other comments guidance document on the Internet and could promote consistency in provide criteria that they ask us to make it available in hard copy; and (3) addressing conflict of interest by consider in the guidance. One comment invite public comment on the draft different companies. asks us to provide an opportunity for guidance document. After providing an (Comment 126) One comment notes industry, academia, and the public to opportunity for public comment on a that an external GRAS panel is not comment on our proposed course of Level 1 guidance document, FDA will: required for a conclusion of GRAS action for the topic of conflict of (1) Review any comments received and status when the conclusion is supported interest. prepare the final version of the guidance by peer-reviewed literature or a ‘‘long One comment asserts that there is no document that incorporates suggested history of safe use.’’ (By ‘‘long history of need for guidance regarding potential changes, when appropriate; (2) publish safe use,’’ we assume that the comment conflicts of interest of GRAS panel a notice in the Federal Register is referring to the provision that GRAS members because industry is aware of announcing that the guidance document criteria may be satisfied through the importance of disclosing and is available; (3) post the guidance experience based on common use in addressing potential conflicts of interest document on the Internet and make it food prior to January 1, 1958. See and often has Standard Operating available in hard copy; and (4) § 170.30(a) and (c)). mstockstill on DSK3G9T082PROD with RULES2 Procedures delineating rules for implement the guidance document. We (Response 126) We agree that an disclosure. will consider the recommendations and external GRAS panel is not required for (Response 125) We have decided to draft guidance submitted in the a conclusion of GRAS status. As we issue guidance regarding conflict of comments to this rule in developing our previously noted, convening a GRAS interest. We will do so as Level 1 draft guidance for public comment. panel has historically been a way to guidance within the framework of our We acknowledge that some members provide evidence that generally good guidance practices regulation (see of industry are aware of the importance available data and information are VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00068 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 55027 generally accepted by the expert requirements applicable to a GRAS guidance in the preamble to the scientific community, but convening a panel. Therefore, we are addressing proposed rule and in our guidance for GRAS panel is not the only way to issues regarding a GRAS panel in industry entitled ‘‘Frequently Asked provide such evidence (62 FR 18938 at guidance rather than in the regulation. Questions About GRAS’’ (Ref. 49). We 18943). See also Comment 14 and Response 14. requested comments on two issues (Comment 127) Some comments related to guidance on documenting a address Issue 15c and recommend that B. Guidance on Documenting Conclusions of GRAS Status conclusion of GRAS status as shown in a notifier include information on table 26. Although the 2010 notice independence of the panel members in In the 2010 notice, we explained that classified both of these issues as ‘‘Issue a submitted GRAS notice. the GAO report recommended that we (Response 127) The rule neither issue guidance on how to document a 16,’’ for presentation purposes in this requires that a notifier convene a GRAS conclusion of GRAS status (75 FR 81536 document we classify the two issues as panel nor establishes any other at 81542). We noted that there is 16a and 16b. TABLE 26—ISSUES IN THE 2010 NOTICE REGARDING GUIDANCE ON DOCUMENTING GRAS CONCLUSIONS Issue Description of our request for comment Reference No. 16a .... Whether there is a need to clarify that our guidance applying to GRAS submissions also applies to 75 FR 81536 at 81542. a GRAS conclusion that is not submitted to us in the form of a GRAS notice. 16b .... Whether there is a need for us to develop further guidance on documenting a GRAS conclusion 75 FR 81536 at 81542. when the GRAS conclusion is not submitted to us as a GRAS notice. (Comment 128) Most of the comments own initiative, to emphasize that point an independent GRAS conclusion that that addressed Issue 16a recommend (see the changes to §§ 170.3(i) and (k), is not submitted to us. For example, the that we clarify that the same standards 170.30(c), 170.30(e), and 170.35(a) and requirements in Part 3 of a GRAS notice apply to a conclusion of GRAS status (b) in table 29). As already noted in make clear that a conclusion of GRAS regardless of whether the conclusion is section I.E of this document, we advise status requires consideration of dietary submitted to us as a GRAS notice or is any company that intends to market a exposure. Likewise, the requirements in not submitted to us. food substance on the basis of an Part 6 of a GRAS notice demonstrate the (Response 128) To reach a conclusion independent conclusion of GRAS status importance of a complete and balanced of GRAS status, the proponent of GRAS to carefully consider whether this use evaluation of all applicable data and status must: (1) Establish that the fully satisfies the criteria for eligibility information, including data and substance is safe under the conditions of for classification as GRAS and to information that are, or may appear to its intended use within the meaning of carefully review the discussions in this be, inconsistent with a conclusion of section 409(c)(5) of the FD&C Act and document relevant to those criteria, GRAS status. Therefore, we recommend our implementing regulation in such as the discussion in Response 9 that any person who intends to use a § 170.3(i); and (2) establish that the regarding the role of corroborative data substance in food based on a conclusion safety of the substance under the and information, the discussions in of GRAS status, but does not intend to conditions of its intended use is Response 10 and Response 11 regarding submit a GRAS notice to us, use the generally recognized within the the limitations of a published report of provisions of part 170, subpart E as meaning of section 201(s) of the FD&C a GRAS panel, and the discussion in guidance. We also recommend that such Act and our regulations in § 170.30 Response 69 regarding the ramifications persons organize the data and governing the eligibility for of providing trade secret information (or information that support an classification as GRAS. See the other non-public information) to a independent conclusion of GRAS status discussion in section I.C of the proposed GRAS panel. according to the organization presented rule of the elements of the GRAS Our 2004 guidance entitled by Parts 1 through 7 of a GRAS notice. standard, where we described the ‘‘Frequently Asked Questions About Doing so would facilitate our evaluation evaluation of safety as the ‘‘technical GRAS’’ generally applies to a of that independent conclusion of GRAS element’’ of the GRAS standard and the conclusion of GRAS status regardless of status if circumstances warrant, e.g., if evaluation of general recognition as the whether that conclusion of GRAS status we have cause to question the ‘‘common knowledge element’’ of the is submitted to us as a GRAS notice. independent conclusion of GRAS status. GRAS standard. In considering whether Exceptions include current questions Because we make information about GRAS criteria are satisfied because the specific to the notification procedure as GRAS notices readily accessible to the available data and information it operated during the Interim Pilot public, we also recommend that you demonstrate that the use of a substance program, such as ‘‘Where do I send my make the basis for your independent is safe and the safety is generally GRAS notice? ’’ We are modifying that GRAS conclusion publicly available recognized, we do not distinguish guidance to update it in light of the (e.g., by making publicly available a between a conclusion of GRAS status publication of this rule. document analogous to the narrative of submitted to us as a GRAS notice and We believe that the provisions of the a GRAS notice, a report of a GRAS panel mstockstill on DSK3G9T082PROD with RULES2 an independent conclusion of GRAS GRAS notification procedure in part (if you convene a GRAS panel), or both status that remains with the proponent. 170, subpart E will be a useful resource a narrative and a report of a GRAS As discussed in Response 41, in this to any person who intends to use a panel). rulemaking we made conforming substance in food based on a conclusion General recognition of safety based changes to current regulations regarding of GRAS status, regardless of whether upon scientific procedures requires the the use of GRAS substances in food, and the conclusion of GRAS status is same quantity and quality of scientific our affirmation of GRAS status on our submitted to us in a GRAS notice or is evidence as is required to obtain VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00069 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 55028 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations approval of a food additive regulation us. One comment agrees with the the comments maintain we should for the ingredient (§ 170.30(b)). We recommendation in the GAO report that consider, on a case-by-case basis, address scientific issues associated with we take steps to ensure that companies whether a particular GRAS notice is demonstrating the safety of a food maintain proper documentation to sufficient to comply with the substance in a series of guidance support a conclusion of GRAS status. requirements of the applicable program documents on our Internet (Ref. 6, Ref. (Response 129) We agree that rather than categorically disallow a 25, and Ref. 32 through Ref. 35). companies should maintain proper GRAS notice as a means for satisfying Currently, some of these scientific documentation to support a conclusion the requirements of the applicable guidance documents are expressly of GRAS status. As we discussed in the program. directed to evaluation of the safety of proposed rule (62 FR 18938 at 18947), (Response 130) We are not including food additives. For example, in any person who concludes that a this proposed provision in the final rule Response 66 we noted that our guidance substance is GRAS under the conditions because it is not necessary to do so. Any entitled ‘‘Recommendations for of its intended use should have person who submits a health claim Submission of Chemical and assembled and evaluated the evidence petition, or who submits a new infant Technological Data for Direct Food that forms the basis of that conclusion, formula submission, must comply in Additive Petitions’’ (Ref. 31) currently is regardless of whether the person full with the requirements of the structured to address the specific subsequently notifies us. Preserving the applicable program whether this rule requirements of a food additive petition, applicable data and information says so or not. An FDA office that even though many of the represents prudent practice for those evaluates a health claim petition or a recommendations in that guidance who assert that the statutory premarket new infant formula submission will take could nonetheless be useful to any review requirements do not apply to the into account our response to a GRAS person who evaluates whether a use of a substance in food. notice when evaluating the health claim substance is GRAS under the conditions To emphasize the importance of petition or new infant formula of its intended use. As resources allow, maintaining the data and information submission. In practice during the we intend to re-visit these scientific that support an independent conclusion Interim Pilot program, an FDA office guidance documents to determine of GRAS status, we are issuing a evaluated a health claim petition or a whether and how to modify them to guidance directed to any person who new infant formula submission for clarify that our guidance on evaluating evaluates whether the available data and several substances that were the subject the safety of a food substance generally information regarding the safety of a of a previously submitted GRAS notice. applies regardless of whether the substance under the conditions of its In each case, FDA’s evaluation of the substance would be used in food as a intended use satisfy GRAS criteria. The health claim petition or new infant food additive or as a GRAS substance. purpose of the guidance is to: (1) formula submission had an outcome Regardless of any implication, in the Remind such persons of their that was consistent with our response to title or text of these guidance responsibilities under the FD&C Act that GRAS notice (see section IV.A of documents, that the subject of the regarding a conclusion of GRAS status, CFSAN’s 2010 experience document document applies to a food additive, we regardless of whether the conclusion of (Ref. 18)). recommend that you consider that the GRAS status is submitted to us as a GRAS notice; and (2) refer such persons D. Impact on Other Federal Agencies scientific recommendations in these guidance documents may also apply to to key resources, such as those In our discussion in the proposed rule substances that would be used in food discussed in Response 128, for of the proposed procedures for making on the basis of a GRAS conclusion. evaluating the safety of the substance information about GRAS notices readily Some scientific guidance documents under the conditions of its intended use accessible to the public, we stated our already do make clear that they apply and for evaluating whether the available belief that there would be considerable regardless of the regulatory status of a data and information regarding safety interest, from a broad segment of the substance (e.g., as a food additive, color satisfy the criteria for eligibility for public, including other Federal additive, food contact substance, or classification as GRAS in § 170.30. We agencies, in notices received under the GRAS substance) (Ref. 6). In addition, as believe that such guidance is proposed notification procedure (62 FR discussed in Response 37, we recently appropriate in light of the 18938 at 18952). We also stated our issued a notice announcing a public recommendations of the GAO report. expectation that such groups will likely meeting, and requesting comments, on want to know whether we are aware that C. Compliance With Other FDA a substance is being used in food on the our intent to update our guidance Regulations basis of the GRAS provision and entitled ‘‘Guidance for Industry and Other Stakeholders: Toxicological We proposed that a GRAS notice whether we have advised a notifier that Principles for the Safety Assessment of would not constitute compliance with we have identified a problem with the Food Ingredients’’ (79 FR 64603), and the requirements for a health claim notice. reiterated that general recognition of petition in § 101.14(b)(3)(ii) or for a new (Comment 131) The Bureau of safety based upon scientific procedures infant formula submission in Alcohol, Tobacco and Firearms (BATF) requires the same quantity and quality § 106.120(b)(6)(ii). We specified that any (in the U.S. Department of the Treasury of evidence as is required to approve a person who submits a health claim (now TTB) submitted a comment stating food additive. petition, or who submits a new infant that it has no major problem with our (Comment 129) Some comments formula submission, must comply in proposal to replace the GRAS support issuing additional guidance on full with the requirements of the affirmation petition process with a mstockstill on DSK3G9T082PROD with RULES2 documenting a conclusion of GRAS applicable program (proposed notification procedure, but that there are status, particularly for a GRAS § 170.36(a)(2)). two ways in which the proposed rule conclusion that is not submitted to us. (Comment 130) Several comments would impact TTB. First, TTB’s wine One comment asserts that there is no object to the perceived implication that regulations in 27 CFR 24.250 need for us to develop additional a GRAS notice could never be used to (Application for use of new treating guidance on documenting a conclusion support a health claim petition or a new material or process) require that a of GRAS status that is not submitted to infant formula submission. In general, proprietor who wishes to use a new VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00070 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 55029 wine treating material submit to TTB an agency must be able to accept our procedures CFSAN will use when application that includes documentary response to a GRAS notice in lieu of a coordinating its evaluation of a GRAS evidence of FDA’s approval of the regulation affirming GRAS status. One notice with FSIS (see § 170.270). material under the conditions of its comment notes that the proposed rule EPA. CFSAN has discussed the intended use. If we issue a final rule to did not explicitly address the impact of concerns raised by these comments with establish a GRAS notification the proposed rule on other Federal representatives from EPA (Ref. 50). The procedure, TTB would need to amend agencies and urges us to consult with representatives from EPA deferred to this requirement to state that TTB needs the cited Federal agencies prior to CFSAN regarding the appropriate either evidence of FDA approval or issuing the final rule. process for voluntary interaction evidence that FDA has been notified of (Response 132) None of the Federal between us and the regulated industry a conclusion of GRAS status and has no agencies cited by these comments have with respect to GRAS substances. questions about that conclusion. advised us that the absence of a E. Impact on International Trade Second, certain alcoholic beverage regulation affirming GRAS status for the products require formula approval by use of a food substance would preclude In the proposed rule, we requested TTB due to the ingredients (such as the applicable Agency from carrying out comment on whether the proposed colors, flavors, herbs, and spices) in the its statutory responsibilities. As substitution of a GRAS notification products. Currently, TTB requires that discussed in the following paragraphs, procedure for the GRAS affirmation these ingredients be approved by FDA we have interacted with each of these petition process would have any impact before TTB approves the formula. If we agencies as requested. on international trade (62 FR 18938 at issue a final rule to establish a GRAS TTB. As discussed in section IV.B of 18955). notification procedure, TTB would still CFSAN’s 2010 experience document (Comment 133) Comments that check the ingredients in these formulas (Ref. 18), during the Interim Pilot responded to this request for comment before approving the formula, but could program CFSAN received and filed express the view that whether the accept evidence that FDA has been several GRAS notices for substances proposed substitution of a GRAS notified of a conclusion of GRAS status intended for use in alcoholic beverage notification procedure for the GRAS and has no questions about that products. These notices demonstrate affirmation petition process would have conclusion. that manufacturers of alcoholic beverage a positive, neutral, or negative impact TTB asks us to include the conditions products are aware of the GRAS on international trade would depend on of use in our response to a GRAS notice notification procedure and are using the nature of our response to a GRAS so that TTB would know the parameters GRAS notices as a means to satisfy notice, particularly when we do not that FDA evaluated in considering the TTB’s regulations. As also discussed in question the notifier’s basis for a GRAS notice (i.e., the foods and section IV.B of CFSAN’s 2010 conclusion of GRAS status. The beverages and the amounts in those experience document (Ref. 18), on comments explain that the proposed foods and beverages). TTB also asks us September 29, 2005, representatives of rule could have a positive or neutral to publish and update a list of GRAS TTB met with representatives of CFSAN impact on international trade if our notices on a frequent basis, and to in the offices of CFSAN’s Office of Food response is clear and definitive, include the conditions of use that FDA Additive Safety. At that meeting, provides regulatory significance, and is evaluated in this list. representatives of CFSAN described the as affirmative as possible, but could (Response 131) The provisions of this GRAS notification procedure that was have a negative impact on international rule are consistent with TTB’s requests. operating under the framework of the trade if our response is neutral or vague. The rule specifies that we will make a proposed rule. CFSAN provided a copy One comment expresses the opinion list of filed GRAS notices, including the of TTB’s comments to these that any impact on international trade information described in § 170.225(c)(2) representatives, and none of TTB’s would be minimal because JECFA through (c)(5), readily accessible to the representatives expressed any concern frequently assesses uses of a food public (see § 170.275(b)(1)). The about the operation of the program. ingredient, and foreign regulatory information the rule specifies will be FSIS. As discussed in section III.L of agencies frequently reach a decision to readily accessible includes the intended CFSAN’s 2010 experience document allow uses of a food ingredient, before conditions of use of the notified (Ref. 18), during the period 1998 we complete our rulemaking under the substance, including the foods in which through 2009 more than 25 percent of GRAS affirmation petition process. the substance will be used, the levels of GRAS notices filed by CFSAN described (Response 133) The ‘‘no questions use in such foods, and the purpose(s) for use of the notified substance in meat, letters’’ we issued during the Interim which the substance will be used (see meat food products, or poultry products. Pilot program make clear that the § 170.225(c)(4)). The response letters During CFSAN’s review of these GRAS notifier (rather than FDA) is responsible that we issued during the Interim Pilot notices, CFSAN consulted with FSIS for the conclusion of GRAS status, and program described the conditions of use regarding the use of the applicable place our statement that we have no of the notified substance, and we intend substance. FSIS provided feedback to questions about the notifier’s conclusion to continue describing the conditions of CFSAN about the use of the notified of GRAS status in the contexts of both use of the notified substance in letters substance in products regulated by FSIS time and the available data and issued under the final rule. and requested that CFSAN provide this information (see table 1). These features (Comment 132) Some comments feedback to the notifier. In 2000, FDA of the ‘‘no questions letters’’ make the assert that our affirmation of GRAS and FSIS formalized this process of letters clear and definitive and provide status established a clear standard that inter-agency consultation in a MOU (65 regulatory significance (i.e., regulatory mstockstill on DSK3G9T082PROD with RULES2 was needed by other Federal agencies to FR 33330, May 23, 2000). Subsequently, status), and we intend to retain these carry out their own regulatory FDA and FSIS have amended the MOU features in letters we issue under the responsibilities. The comments cite to include simultaneous evaluation of final rule. Moreover, the fact that many BATF (now TTB), FSIS (in USDA), and substances subject to regulation by GRAS notices were submitted by foreign EPA as examples of such Federal USDA under the Egg Products firms demonstrates that foreign firms agencies. In general, these comments Inspection Act (21 U.S.C. 1033(a)(2)) see value in submitting GRAS notices to maintain that the applicable Federal (Ref. 36). The final rule includes the us (Ref. 51). VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00071 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 55030 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations Under the final rule, we will respond affirmation petition if we audit the data circumstances where our evaluation of to a GRAS notice within 180 days after supporting a GRAS notice. an environmental assessment, which is we file a submission as a GRAS notice, (Response 135) As discussed in required for a food additive petition, with an option to extend the timeframe Response 24 and Response 123, we have precludes timely action by us on a by an additional 90 days as needed (see eliminated the former GRAS affirmation petition. § 170.265(b)(1)). As discussed in petition process. Therefore, the (Response 138) We advise potential Response 123, during the ten year administrative process requested by notifiers that the lack of a requirement period extending from 1990 through these comments is no longer operative. to submit an environmental component 1999, we completed the rulemaking (Comment 136) One comment asks us (e.g., an environmental assessment) with process for 24 GRAS affirmation to incorporate two procedures to avoid a GRAS notice does not eliminate a petitions, with an average elapsed time any uncertainty regarding the results of notifier’s responsibility to comply with of approximately 7.9 years (median the audit. First, the comment asks us to applicable Federal, State, tribal, and elapsed time approximately 6.9 years). provide the notifier with a letter local law or requirements regarding Thus, we believe that the GRAS confirming that the audit is completed protection of the environment. notification procedure will come to and we have no basis to question the conclusion of GRAS status if that is the H. Substances Affirmed as GRAS With closure more quickly than the GRAS Specific Limitations affirmation petition process. outcome of our audit. Second, the comment asks us to apply any appeal (Comment 139) One comment asks us F. Audits mechanism specified by the rule to to ‘‘modernize the standard’’ in In the proposed rule, we stated that it circumstances in which we question a § 184.1(b)(2) to allow expedited review would be prudent for us monitor conclusion of GRAS status based on an under the notification program of new compliance with the essence of the audit. uses of substances affirmed as GRAS (Response 136) We decline these under § 184.1(b)(2). (Section 184.1(b)(2) statutory requirements for GRAS status requests. If we have no questions about specifies that if an ingredient is affirmed (i.e., that there is common knowledge the notifier’s conclusion of GRAS status, as GRAS with specific limitation(s), it among qualified experts that there is we would respond with a ‘‘no questions shall be used in food only within such reasonable certainty that the substance letter’’ based on our evaluation of the limitation(s), including the category of is not harmful under the conditions of entire GRAS notice, not based solely on food(s), the functional use(s) of the its intended use) and announced that the results of an audit of the data and ingredient, and the level(s) of use, and we intended to conduct random audits information maintained by the notifier any use of such an ingredient not in full of data and information maintained by to support the notifier’s GRAS notice. compliance with each such established the notifier (62 FR 18938 at 18947). In As discussed in Response 108, the rule limitation shall require a food additive addition, because the proposed does not include an appeals process that regulation.) substitution of a GRAS notification (Response 139) We decline the procedure for the GRAS affirmation would be specific to the GRAS notification procedure. request to amend § 184.1(b) beyond the petition process would allow us to editorial, clarifying, and conforming (Comment 137) One comment direct our resources to priority changes listed in table 29. The comment suggests that our audit examine the questions about GRAS status, we might provides no basis for us to do so. As same ‘‘quantum of evidence’’ as we conduct an audit on a broad issue or discussed during the rulemaking to would review to affirm GRAS status, class of products if the issue or use of establish § 184.1(b)(2) (41 CFR 53600 at and asserts that a strong statement of a class of products raises important 53601, December 7, 1976), that confidence, if not outright affirmation, public health issues. regulation does not require that a would be appropriate after successful (Comment 134) One comment asks us completion of this type of an indepth subsequent use be covered by a food to renew our commitment to random review. additive regulation even though it may auditing to ensure that companies (Response 137) The purpose of the be GRAS. As an alternative to a food maintain proper recordkeeping audit would be to verify that a notifier additive regulation, the regulation practices. maintains the data and information affirming a substance as GRAS with (Response 134) As discussed in specified in the notice, not to conduct specific limitations on the conditions of section IV.C of CFSAN’s 2010 a full scientific evaluation of those data use may be amended to cover additional experience document (Ref. 18), during and information (62 FR 18938 at 18947). uses that have become GRAS. the Interim Pilot program, CFSAN did Therefore, we decline the request to Importantly, both mechanisms (i.e., food not conduct any random audits of data examine the same ‘‘quantum of additive regulation and GRAS and information maintained by the evidence’’ as we would review to affirm affirmation regulation) require notifier. However, CFSAN did not GRAS status. Because the purpose of an rulemaking, and the appropriate hesitate to ask a notifier to provide audit would be to verify compliance mechanism for a manufacturer to certain data or information as an with the statutory requirements for lawfully use a substance outside the amendment to a GRAS notice. (See also GRAS criteria, we disagree our response limitations established in a regulation the discussion in section III.C.1 of to a GRAS notice following a favorable affirming specific uses of the substance CFSAN’s 2010 experience document audit should result in a ‘‘strong as GRAS with specific limitations is to regarding amendments to GRAS statement of confidence’’ rather than a submit a petition to us. A manufacturer notices.) In essence, CFSAN used its ‘‘no questions letter.’’ However, we may submit a food additive petition resources to seek access to data and intend that our response letter would asking us to conduct rulemaking that mstockstill on DSK3G9T082PROD with RULES2 information on a priority, rather than a mention any audit that we conduct results in a food additive regulation; random, basis. At this time, we intend before responding to a GRAS notice. alternatively, now that the GRAS to continue directing our resources on a affirmation petition process is no longer priority basis under the final rule. G. Lack of an Environmental operative, the manufacturer may submit (Comment 135) One comment asks us Assessment a citizen petition in accordance with to provide a notifier with the option of (Comment 138) One comment § 10.30 asking us to conduct rulemaking converting a GRAS notice to a GRAS suggests that a GRAS notice is ideal in that amends the regulation affirming a VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00072 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 55031 substance as GRAS with specific advise that we are denying the request provisions of the rule (see, e.g., limitations on the conditions of use. to initiate rulemaking to amend the §§ 570.30, 570.225(c)(4), 570.235, (See also Ref. 4.58 to CFSAN’s 2010 GRAS affirmation regulation, but note 570.245, and 570.250). In the following experience document). that we could accommodate the request sections, we discuss how comments on See section III.N.2 of CFSAN’s 2010 to conduct rulemaking through the food these issues, and associated conforming experience document (Ref. 18) for a additive petition process. changes, lead to specific revisions to the discussion of a GRAS affirmation XXV. Comments on Substances regulatory text. See table 28 for the petition to amend a specific regulation Intended for Use in Animal Food principal changes specific to the that affirmed a substance as GRAS with proposed animal food rule other than specific limitations on the conditions of A. Issues in the 2010 Notice Specific to the editorial, clarifying, and conforming use; we converted that GRAS Animal Food changes shown in table 29 and the affirmation petition to a food additive In the 2010 notice, we discussed additional editorial changes associated petition and authorized the additional several issues associated with the with the redesignation of the proposed conditions of use in a food additive requirements for a GRAS notice for an notification procedure (proposed regulation. We advise persons who wish intended use in animal food to consider § 570.36) as part 570, subpart E. Table to petition us to provide for additional dietary exposure (see table 27). 28 does not include those changes that uses of substances that have been Although we discussed these issues in we made to the proposed requirements affirmed as GRAS with specific a section entitled ‘‘Dietary exposure,’’ when we made an analogous change to limitations that under § 10.30(e) we may these issues broadly applied to several the human food regulations in part 170. TABLE 27—ISSUES IN THE 2010 NOTICE SPECIFIC TO ANIMAL FOOD Issue Description of our request for comment Reference No. 11c .... Whether it is necessary to clarify that the GRAS notification procedure is applicable to substances 75 FR 81536 at 81541. used in both food and drinking water of animals and, if so, whether it would be necessary to clar- ify this in the provisions of the proposed notification procedure. 11d .... Whether it is necessary to clarify proposed § 570.36(c)(1)(iii) to explicitly require submission of in- 75 FR 81536 at 81541. formation about the animal species expected to consume the substance. 11e .... Whether it is necessary to clarify applicable sections of the proposed rule to explicitly require, for 75 FR 81536 at 81541. substances intended for use in the food of an animal used to produce human food, the submis- sion of information about both target animal and human safety. TABLE 28—SUMMARY OF PRINCIPAL CHANGES SPECIFIC TO THE PROPOSED ANIMAL FOOD RULE Regulatory section in the final rule Change § 570.30(a), (b), and (c) .................. Specify that general recognition of safety is based on data and information that addresses safety for both the target animal and for humans consuming human food derived from food-producing animals. § 570.225(c)(4) ................................ Requires you to describe the intended conditions of use of a notified substance in animal food by speci- fying the levels of use in foods or drinking water. § 570.235 ......................................... In part 3 of your GRAS notice, you must provide data and information about exposure to the target animal and to humans consuming human food derived from food-producing animals. § 570.250(a) and (b) ....................... You must explain how the generally available data and information in your notice provide a basis for your view that the notified substance is generally recognized as safe, among qualified experts, under the con- ditions of its intended use for both the target animal and for humans consuming human food derived from food-producing animals. B. Criteria for Eligibility for animal and for humans consuming food regulations, include specific Classification as GRAS for a Substance human food derived from food- criteria for eligibility for classification as Intended for Use in Animal Food producing animals (see §§ 570.225(c)(4), GRAS through experience based on (§ 570.30) 570.235, 570.245, and 570.250). To common use in food prior to 1958 when clarify that the submission requirements that use occurred exclusively or (Comment 140) Comments that reflect the GRAS criteria for the use of primarily outside the United States (see address Issue 11e agree that data and a substance in animal food, we also § 170.30(c)(2)). This comment asks us to information in a GRAS notice must be have modified § 570.30(a), (b), and (c) to maintain parallel criteria for eligibility sufficient to address safety for both the specify that general recognition of safety for classification as GRAS through target animal and for humans is based on data and information that experience based on common use in consuming human food derived from addresses safety for both the target food in the human food regulations and food-producing animals (see Comment animal and for humans consuming the animal food regulations by 150 and Comment 151). human food derived from food- amending § 570.30(c) of the animal food mstockstill on DSK3G9T082PROD with RULES2 (Response 140) We have modified producing animals. See the regulatory regulations to include a provision several provisions of the GRAS text of § 570.30. See also Response 141 analogous to § 170.30(c)(2). notification procedure to specify how regarding the definition of common use (Response 141) We are amending the notifier must provide data and in food in § 570.3(f). § 570.30(c) to include a provision information to address the safety of the (Comment 141) One comment notes analogous to § 170.30(c)(2). See the notified substance under the conditions that the proposed human food regulatory text of § 570.30(c)(1) and (2). of its intended use for both the target regulations, but not the proposed animal For consistency with the clarifying VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00073 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 55032 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations amendment to the general criteria in constituting the common or usual name mean by ‘‘subpopulation.’’ The § 570.30(a), we also are revising for animal food ingredients, including physical, physiologic, and absorption/ § 570.30(c) to clarify that general pet food (Ref. 52). distribution/metabolism/elimination recognition of safety through experience characteristics of a given animal species D. Part 1 of a GRAS Notice for a based on common use in food shall may vary based on life stages within the Substance Intended for Use in Animal address safety for both the target animal same animal species. A substance that is Food: Intended Conditions of Use and for humans consuming human food safe for use in an animal species at one (§ 570.225(c)(4)) derived from food-producing animals. stage of life may not be safe for use in For consistency with the clarifying (Comment 142) One comment asks us the same animal species at a different amendment to the general criteria in to require that a notifier specify whether stage of life. See also Response 51. § 570.30(a), we also are revising the the intended use of the notified substance is in food or in drinking E. Part 2 of a GRAS Notice for a definition of common use in food to water. Another comment asks CVM to Substance Intended for Use in Animal mean a substantial history of accept the anticipated consumption Food: Data and Information Bearing on consumption of a substance by a levels by animals that are based upon the Physical or Other Technical Effect of significant number of animals of the general formulation principles that the Notified Substance (§ 570.230(d)) species to which the substance is intended to be fed (and, for food- consider the availability of (Comment 144) Several comments producing animals fed with such contemporary feedstuffs. discuss CVM’s practice, during the substance, also means a substantial (Response 142) The final Interim Pilot program, of asking a history of consumption by humans requirements for Part 1 of a GRAS notice notifier to provide data or information consuming human foods derived from require you to describe the intended demonstrating the effectiveness, or those food-producing animals), prior to conditions of use of a notified substance utility, of the substance. Some January 1, 1958 (see § 570.3(f) and table in animal food by stating whether the comments ask us to limit the 29). substance will be added to food notification procedure to the (including drinking water) for animals information necessary to conduct an C. Part 1 of a GRAS Notice for a in which the substance will be used, appropriate safety assessment, without Substance Intended for Use in Animal and by identifying the foods to which it submission of additional data and Food: Name of the Notified Substance will be added and the levels of use in information to demonstrate the (§ 570.225(c)(3)) such foods (see § 570.225(c)(4)). In technical effect of the substance within As shown in table 6, in the 2010 describing the levels of use of the animal food in cases where the notice we asked for comment on notified substance, you may base the technical effect has no impact on safety. whether to require that the GRAS notice levels of use upon general formulation Some comments agree that the intended include the name of the notified principles that consider the availability conditions of use of the notified substance, using an appropriately of contemporary feedstuffs. See also substance in animal food must be descriptive term, instead of the Response 148 regarding the calculation described and supported in the notice, ‘‘common or usual name’’ of the notified of target animal exposure. but assert that the need for utility data substance (Issue 7). The final rule (Comment 143) Some comments ask generated from target animal feeding requires that Part 1 of a GRAS notice for us to specifically require submission of studies is inappropriate and an intended use of a notified substance information about the animal species unnecessary because the pivotal issue is in animal food include the name of the expected to consume the substance. One whether the ingredient is safe to feed to notified substance, using an comment states that specifying the animals. appropriately descriptive term target animal is as important as (Response 144) We have added a (§ 570.225(c)(3)). The appropriately specifying whether the substance would requirement for Part 2 of a GRAS notice descriptive term may be the same as the be consumed by humans in human food to include relevant data and information common or usual name of the derived from the animal. Another bearing on the physical or other substance. You may consult with CVM’s comment suggests that requiring technical effect the notified substance is staff in operating divisions that address submission of information about the intended to produce, including the the labeling requirements of the FD&C animal that would consume the quantity of the notified substance Act, currently CVM’s Division of substance would avoid the unnecessary required to produce such effect, when Animal Feeds, regarding any common delays associated with CVM’s questions necessary to demonstrate safety (see or usual name for a substance used in that result in an amendment to the § 570.230(d)). We agree that data and animal food. In addition, for substances notice with information about the information bearing on the physical or used in animal food, the Association of animal species expected to consume the other technical effect the notified American Feed Control Officials substance. substance is intended to produce are (AAFCO) annually publishes its Official (Response 143) The final only necessary when they bear on Publication, a handbook which requirements for Part 1 of a GRAS notice safety. This relationship to safety is contains, among other things, Official require you to describe the intended consistent with the requirements of the Feed Terms, which define many of the conditions of use of a notified substance FD&C Act for a petition to establish the terms commonly used in the animal in animal food, including the animal safety of a food additive (see section food manufacturing industry. It also species for which the foods are 409(b)(2)(C) of the FD&C Act). contains Official and Tentative intended. In addition, the final The physical or other technical effects Definitions of Feed Ingredients, a set of requirements for Part 1 of a GRAS notice of substances added to animal food fall mstockstill on DSK3G9T082PROD with RULES2 definitions for ingredients commonly specify that in describing the intended into two main categories: (1) Substances used in animal food. Under CVM’s conditions of use of a notified substance fed for a nutritive effect in the animal Compliance Policy Guide CPG 665.100 in animal food, you must, when (e.g., providing one or more nutrients or (Common or Usual Names for Animal appropriate, describe any other nutritive effect); and (2) Feed Ingredients), the definitions, as ‘‘subpopulation’’ expected to consume substances that have technical effects in they appear in the AAFCO Official the notified substance; the life stage of the food (e.g., anti-caking agents, Publication, are generally regarded as an animal is an example of what we binders, emulsifiers, enzymes, mixing VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00074 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 55033 aids, preservatives, processing aids, study conducted in one animal species ingredient) would not provide evidence stabilizers, and substances added for (or in one stage of life of an animal that the mineral is in a form that is aroma, flavor, or other technical effects) species) can be used to support safety in available to the animal. However, for an rather than nutritive effects in the another animal species (or in a different ingredient that is intended to provide an animal. As discussed in the following stage of life in the same animal species). essential amino acid, the need for an paragraphs, a substance added for either See Response 145 for a discussion of animal feeding study can depend on the a nutritive effect or for a technical effect when data and information that are form and composition of the ingredient. in animal food can have an impact on obtained from an animal study and bear For example, it can be possible to rely safety for the target animal. on the nutritive effect of a substance on published literature to establish that Nutritive effect in the animal. Data could be extrapolated from one animal a crystalline amino acid will be and information bearing on the nutritive species to another animal species, or to bioavailable to an animal (and, thus, effect of a substance may be necessary a different stage of life of the same functional). However, if a complex to demonstrate safety because animals animal species. In the following matrix, such as a biomass composed of (e.g., food-producing animals, paragraphs, we provide examples of microbial cells or a processed oilseed companion animals) typically are fed when data and information bearing on meal, is intended to be a source of the same diet formula for long periods the nutritive effect of a substance amino acids, an animal feeding study of their life. These diets are formulated intended for use in animal food could generally would be needed to provide to supply all of the animal’s daily be established through the use of evidence that the bioavailability of the nutrient needs for a specific life stage generally available and accepted data amino acids has not been adversely (e.g., growth, reproduction, adult and information, or likely would need impacted by the other substances maintenance). The diet must provide to be established through an animal present in the complex matrix. appropriate amounts of all nutrients the feeding study that specifically supports Technical effect in the food (rather animal requires in a form that the the nutritive effect of the substance than nutritive effect in the animal). As animal can use and consume daily; under the conditions of its intended use. with a substance intended to provide a otherwise, a nutrient deficiency or For some types of substances, nutritive effect in the animal, data and toxicity can result, causing adverse generally available and accepted data information bearing on a substance’s effects to animal health, including poor and information about the function of a technical effect in the food (e.g., growth, excessive weight loss, organ substance may be adequate to support substances such as anti-caking agents, system failures, and death. Under these the nutritive effect of the substance constraints of how animals are fed, a without also relying on an animal binders, emulsifiers, enzymes, mixing substance intended to provide one or feeding study. For example, generally aids, preservatives, processing aids, more nutrients becomes unsafe if the available and accepted data and stabilizers, and substances added for nutrients are, in fact, not provided in a information about the function of fat aroma, flavor or other technical effects) form usable by the animals consuming and carbohydrates as sources of dietary may be necessary to demonstrate safety the diet. energy often can be used for substances because of the physical form and The typical approach to support the providing fat intended as a source of properties of animal diets. Although nutritive effect of a substance intended dietary energy (rather than as a source generally available and accepted data for use in animal food is to combine of essential fatty acids) and for and information can provide evidence generally available and accepted data substances providing carbohydrates of a technical effect in the food, it is and information about the general intended as a source of dietary energy. common for studies to be conducted function of the substance with animal Likewise, generally available and with the animal food to demonstrate the feeding studies demonstrating that the accepted data and information about the intended technical effect. Depending on substance acts as intended. When an nutritive content of human food can the intended technical effect, an animal appropriate animal feeding study (i.e., provide support for the nutritive effect feeding study (whether previously an animal feeding study that is relevant, of unsalable human food products (such published or newly conducted) may be properly designed, and well-controlled) as bruised produce) being collected for also needed to demonstrate the intended is already generally available (e.g., in animal food use for their nutritional technical effect of the substance. In the the peer-reviewed scientific literature), content rather than entering landfills or following paragraphs, we provide it can be possible to support the being incinerated. examples of when animal feeding nutritive effect of a substance without For other types of substances, an studies may be needed to support the conducting a new study. If an animal feeding study (whether intended technical effect of the appropriate animal feeding study is not previously published or newly substance. We also provide examples of already generally available, an animal conducted) is the norm to support the when an intended technical effect in feeding study specifically conducted to nutritive effect of the substance. For animal food could be established support the nutritive effect would example, for an ingredient that is through the use of generally available ordinarily be published and, as intended to supply an essential mineral and accepted data and information discussed in Response 19, there would (such as phosphorus or zinc), generally about the technical effect and the be a time gap between the publication available data and information can studies conducted with the intended of the study and the use of the provide support that the mineral is an animal food matrix. As with a substance published study to support a conclusion essential nutrient for the animal, but the intended to provide a nutritive effect in of GRAS status. (As discussed in bioavailability of the mineral in the the animal, when an appropriate study, Response 9, unpublished studies can be ingredient that would be added to which may be an animal feeding study, mstockstill on DSK3G9T082PROD with RULES2 used to corroboratively support the animal food generally needs to be is already generally available (e.g., in intended nutritive effect of the determined in an animal feeding study the peer-reviewed scientific literature), substance under the conditions of its conducted with that specific ingredient, it can be possible to support the intended use.) In addition, for any because data regarding the amount of technical effect of a substance in the animal feeding study a factor to be the mineral that is added to the feed in food without conducting a new study. If considered is whether data and the ingredient (or that can be detected an appropriate study is not already information obtained from a feeding analytically in the feed or in the generally available, a study conducted VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00075 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 55034 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations to support the technical effect in the Flavors are added to animal food for effects of a substance intended for use food would ordinarily be published and, certain species, generally for specific in animal food, the potential to as discussed in Response 19, there life stages of that species. For example, extrapolate from the conclusions of a would be a time gap between the flavors can be added to animal food feeding study conducted in one animal publication of the study and the use of intended for consumption by piglets species to another animal species the published study to support a being transitioned from a milk-based depends on the similarities of their conclusion of GRAS status. diet to a commercial growth diet to digestive systems, physiology, and diets. Enzymes are often added to animal increase consumption of the commercial For example, when a bioavailability food to alter the bioavailability of growth diet. Flavors also are added to study for selenium present in selenium nutrients already in the food. For commercial animal food intended for yeast is conducted in cattle (which have example, it is well known that the aquaculture to attract newly hatched a fermentative digestive tract), it can be enzyme phytase increases the fish (fish fry) to the commercial food possible to extrapolate the conclusions bioavailability to animals of the when the commercial food does not of that bioavailability study to other phosphorus present in grain (Ref. 53), resemble the food that fish fry would animal species that have fermentative and substances that provide phytase consume in nature. If the fish fry are not digestive tracts. However, when a activity are often added to diets for attracted to the commercial food, the bioavailability study for copper is poultry and swine. Poultry and swine fish fry can starve to death. Animal conducted in a ruminant animal diets are typically formulated with the feeding studies are the norm to support species, it may not be appropriate to minimal amount of phosphorus. If the the function of the substance as a flavor extrapolate the conclusions of that phytase enzyme does not carry out the when added to animal food. bioavailability study to sheep, even effect of improving phosphorus Substances such as emulsifiers and though sheep are ruminants, because availability to the animal as intended, stabilizers are added to animal food to sheep physiology is such that sheep are the consequence will be a diet that is ensure that an animal consumes all of much more sensitive to copper toxicity deficient in phosphorus and therefore the ingredients in the correct than other ruminant species. In results in adverse impacts on animal proportions in order to meet its addition, when a bioavailability study health in the form of decreased growth, nutritional needs. Inconsistent nutrient for a nutrient is conducted in animals increased orthopedic disease (e.g., content and delivery of a diet to the other than fish, it may not be possible rickets), and suffering animals (Ref. 54). animal can cause either nutrient to extrapolate the conclusions of that As another example, protease enzymes deficiency diseases, or toxicities. For bioavailability study to aquaculture-fed can be added to an animal food to affect example, liquid cattle foods are often fish, because aquaculture diets that are the digestibility of proteins in the food available to the animal at all times and consumed in the water present special (Ref. 55). Both animal feeding studies cattle simply lick the feeding device to challenges, particularly for slow-feeding and stability studies (to assess the obtain the food. If the minerals present or bottom-feeding aquaculture species, stability of the enzyme in the food and, in the liquid fall out of suspension and where the diet pellet must retain its thus, its ability to perform its intended settle to the bottom, the first animals to form and nutrient content until the technical effect) are the norm when access the feeder will consume lower pellet is consumed. For example, it is enzymes are added to animal food. nutrient levels than expected, while possible for nutrients that are soluble in However, when the function of an those animals that access the feeder water to dissolve out of the pellet before enzyme in animal food is well known, later and consume the bottommost consumption, preventing the it is also common to use generally material may be at risk of toxicity due aquaculture animal from accessing all available and accepted data and to higher nutrient levels. For dry the required nutrients. information about the function of the ingredients, the ingredients in the See Response 144 for a discussion of enzyme in combination with animal formulated diet must be uniformly circumstances where generally available feeding studies and stability studies to dispersed and mixed, remain mixed and accepted data and information can support the function of the enzyme (see during handling, and be physically be used to provide evidence bearing on section IV in CVM’s experience stable as a formulated animal diet is the nutritive effects of a substance document (Ref. 20)). moved through augers and conveyors, intended for use in animal food (e.g., for Substances such as binders, and transported in bulk in trucks, which substances providing fat intended as a lubricants, and pelleting agents are can result in the loss of nutrients source of dietary energy, for substances added to animal food that will be fed as through sifting or ‘‘unmixing.’’ These providing carbohydrates intended as a pellets. In some cases, such substances effects are assessed on the diet itself source of dietary energy, for unsalable are added to ensure that the pellet through appropriate studies. human food products, and when a retains its desired form and that the (Comment 145) One comment asks us crystalline amino acid is added to individual ingredients remain to accept reasonable arguments as to the animal food). See also Response 150 for agglomerated, making it more difficult worst-case exposures (inclusion levels) additional discussion of limitations on for an animal to select only those if the substance or class of substances the use of generally available and ingredients it prefers. In aquaculture has well-established use patterns rather accepted data and information, such as foods, such substances are added to than require utility data to support the a weight of evidence approach, for the prevent the pellet from dissolving or intended nutritional effect. This extrapolation of available data and prevent the nutrients from leaching out comment also asks us to be flexible information from an animal species of the pellet. Depending on the when utility data are warranted to other than the target animal. circumstances, either technical effect support an entirely new use in animal Regardless of whether the intended mstockstill on DSK3G9T082PROD with RULES2 studies conducted with the animal food, feeds when utility data from one use of the notified substance is to or generally available and accepted data representative species would be provide nutritive value or technical and information about the function of sufficient to address utility in the target effect, any person who concludes that the substance, can be used to support animal. the available data and information the intended technical effect, such as (Response 145) When animal feeding regarding the safety of a notified that of a binder, lubricant, or pelleting studies are necessary to provide data substance under the conditions of its agent, etc., when added to animal food. and information bearing on the nutritive intended use satisfy GRAS criteria must VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00076 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 55035 have a basis for the conclusion of GRAS journals directed to food safety would applicable to substances used in both status, irrespective of whether that be willing to publish data and food and drinking water of animals. person notifies us of that conclusion in information bearing on the physical or (Response 147) The final a GRAS notice. If you submit your other technical effect the notified requirements for Part 3 of a GRAS notice conclusion of GRAS status to FDA, you substance is intended to produce when specify that ‘‘animal food’’ includes must explain how the data and those data and information are ‘‘drinking water.’’ See also Response information in your GRAS notice necessary to demonstrate safety (see 142. provide the basis for your conclusion, section III.A.1 of CFSAN’s 2010 2. Data and Information About the e.g., in Part 2 of the GRAS notice (where experience document (Ref. 18)). Dietary Exposure for the Target Animal you would describe the applicable data See also Response 144 for a and information), in the narrative in (Comment 148) One comment states discussion of circumstances where that exposure information can usually Part 6 of your GRAS notice, or in both generally available and accepted data Parts 2 and 6 of your GRAS notice. We be obtained from published data sources and information can be used to provide and that if a worst-case exposure cannot would then evaluate whether the data, evidence bearing on the nutritive effects information, and narrative in your be established without new data, then of a substance intended for use in data for one representative animal GRAS notice support your conclusion. animal food. There may be situations When data and information bearing on species are sufficient, especially if the where sufficient generally available and selected species represents a worst-case the physical or other technical effect of accepted data and information on the notified substance are necessary to scenario. As an example, the comment exposure to the substance or class of suggests that data from one support safety, we could conclude that substances can satisfy GRAS criteria representative poultry species would be a GRAS notice that does not discuss without publication of specific data and sufficient to address the conditions of such data and information is information bearing on the physical or use of a notified substance intended for incomplete, and either contact a notifier other technical effect the notified poultry. As noted in Comment 142, to request an amendment discussing substance is intended to produce. For another comment asks CVM to accept such data and information, or issue an example, as discussed in section IV of the anticipated consumption levels by insufficient basis letter. (Comment 146) One comment asserts CVM’s experience document during the animals that are based upon general that a requirement for proof of utility, Interim Pilot program CVM responded formulation principles that consider the with subsequent publication of utility with a ‘‘no questions letter’’ when the availability of contemporary feedstuffs. data, is unnecessary, and that a use of published information for (Response 148) See the regulatory text requirement for utility data to be technical effects such as nutrient, of § 570.235(a) for the requirements for documented by means of a peer- enzyme, and component of a defoamer what you must provide in Part 3 of a reviewed publication would burden the was used, in whole or in part, to support GRAS notice regarding exposure to the industry with additional cost, not only such technical effects (Ref. 20). As target animal. The regulatory text to conduct the studies but also to discussed in Response 12, GRAS status addressing the types of exposure to the prepare the manuscript and have it may be corroborated by unpublished target animal parallels the regulatory accepted for publication. This comment scientific data, information, or methods, text for dietary exposure to a notified also asserts that finding a journal and there may be some unpublished substance in the human food regulations willing to publish such germane studies scientific data, information, or methods (see § 170.235). As noted in Response may be challenging because the regarding the safety of a use of a food 142, you may base the levels of use manuscript may be viewed as serving substance. As discussed in Response 8, upon general formulation principles the manufacturer’s interest rather than the criteria for GRAS status through that consider the availability of providing any new scientific scientific procedures provide for the contemporary feedstuffs. We agree that information. As alternatives to application of ‘‘generally available and exposure information may be available publication of a target animal feeding accepted’’ scientific data, information, from published data sources. If exposure study, this comment suggests means or methods, which ‘‘ordinarily’’ are cannot be established without new data, such as documenting the chemical published and, thus, provide flexibility then data for one representative animal nature of the substance in relation to for supporting a conclusion of GRAS species may be sufficient if the selected same (or similar) substance with ample status through the application of species represents a worst-case scenario. public information, and placing scientific data, information, or methods (Comment 149) One comment asks unpublished studies conducted by the that are generally available through a that any restatement of the regulatory notifier in the context of published mechanism other than publication in a text regarding dietary exposure consider literature about the use of the substance peer-reviewed scientific journal. how to use the word ‘‘consumer,’’ or related substances. This comment See the discussion in Response 150 because ‘‘consumers’’ are humans for also asserts that CVM and industry regarding the evaluation of safety the purpose of part 170 but are resources could be better utilized to studies, including the applicability of ‘‘animals’’ for the purpose of part 570. demonstrate the safety of the intended worst-case exposure on a case-by-case (Response 149) To reduce the use of the substance with a focus on basis. potential for confusion, the final establishing the worst-case exposure requirements for part 3 of a GRAS notice and relating it to available safety F. Part 3 of a GRAS Notice for a for a substance intended for use in information to establish a margin of Substance Intended for Use in Animal animal food do not use the term safety. Food: Target Animal and Human ‘‘consumer.’’ mstockstill on DSK3G9T082PROD with RULES2 (Response 146) See Response 15, in Exposures (§ 570.235) which we respond to comments G. Data and Information in a GRAS 1. Substances Intended for Use in Food Notice About Safety for the Target asserting it can be difficult to publish or Drinking Water for Animals data and information that do not raise Animal (§ 570.250) an issue of concern. Consistent with (Comment 147) Comments that (Comment 150) Comments that CFSAN’s experience during the Interim address Issue 11c support clarifying that address Issue 11e agree that data and Pilot program, we believe that some the GRAS notification procedure is information in a GRAS notice must be VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00077 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 55036 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations sufficient to address safety for the target target animal safety were conducted explain how you extrapolated available animal. However, most of these only on broiler chickens (Ref. 20). In data and information from an animal comments express concern about the such cases, you would explain the species other than the target animal, or standard for demonstrating safety to the relevance of the available data to the how you extrapolated available data and target animal, specifically whether target species in the narrative required information from the same animal safety must be established through in Part 6 of a GRAS notice rather than species to a different life stage of that feeding studies specific to the target describe species-specific data and animal species. animal or could be extrapolated from information. Any person who concludes that the data and information regarding species However, extrapolating data from one available data and information regarding other than the target animal. Although animal species to another is not always one comment asserts that a notifier must the safety of a notified substance under appropriate because a substance that is the conditions of its intended use satisfy submit evidence that the substance is safe for use in one animal species may safe for all the species in question if a GRAS criteria must have a basis for the not be safe for use in another species or conclusion of GRAS status, regardless of substance is expected to be consumed in the same species at a different stage by different animal species, other whether that person notifies us of that of life. For example, a substance that is conclusion in a GRAS notice. A comments emphasize that safety could safe for use in a species that is a be established through either feeding resource that may help determine when ruminant animal (e.g., cattle) may not be it could be appropriate to extrapolate studies in the target animal or through safe for use in a species considered a extrapolation of data obtained from species-specific data and information monogastric animal (e.g., swine) from one animal species to another species other than the target animal. because of the difference in their Some comments suggest that the rule animal species is our guidance entitled digestive systems and different nutrient require a clear and concise written ‘‘Guidance for Industry: requirements. For example, in ruminant explanation of how studies in non-target Recommendations for Preparation and animals, non-protein nitrogen species relate to the target animal rather Submission of Animal Food Additive compounds (e.g., urea and biuret) than require safety data in the target Petitions’’ (# 221) (June 2015) (Ref. 56). release ammonia, which is then animal species. metabolized by rumen microorganisms Section G.2 of that guidance (on target One comment disagrees that the animal safety) recommends that target into microbial proteins. These microbial GRAS notification procedure should animal safety studies be conducted proteins are a useful source of protein establish any absolute requirement for using the life stage and animal species data addressing safety for the target to ruminant animals. However, in monogastric animals, the liberated for which the food additive will be species. This comment asserts that CVM marketed. In cases where the food should not require species-specific data ammonia from non-protein nitrogen compounds is absorbed directly by the additive is intended for multiple animal for all substances and species covered species or life stages, the food additive by the intended use of the notified animal, resulting in adverse toxicological events, and possibly death. should be tested in the most sensitive substance because recognized scientific life stage and/or species. The guidance procedures, such as a weight of Even within the same species of animal, or for different species in the same class recommends using current scientific evidence approach, allow for the literature to identify the most sensitive extrapolation of data and that these of animals (e.g., chicken, duck, turkey), extrapolating safety data may not be life stage and/or species. As with types of scientific procedures can be appropriate. For example, a substance guidance documents prepared by applied to notified substances. This that is safe for laying hens may not be CFSAN, CVM’s scientific comment also asserts that a CVM safe for use in broilers because of the recommendations in a guidance requirement for safety data in the target animal, rather than a written different nutrient requirements, such as directed to food additives can be explanation of how studies in non-target the higher calcium level in a laying hen applied to the evaluation of whether a species relate to the target animal, diet (which is intended to meet the substance is GRAS under the conditions cannot be scientifically justified and nutrient demand for egg production). If of its intended use (see Response 66). will put the animal feed industry at a that high level of calcium is consumed Another resource is a book entitled disadvantage for obtaining recognition by broiler chickens, the potential ‘‘Safety of Dietary Supplements for of new GRAS substances, and that the calcification of soft tissue such as that Horses, Dogs, and Cats’’ by the National additional cost and time will stifle of kidneys could become detrimental to Research Council (Ref. 57), which innovation and reduce growth in the the broiler chickens. Likewise, a identifies five factors to consider when U.S. feed industry and animal substance that is safe for chickens may selecting appropriate surrogates for agriculture. not be safe for ducks or turkeys because horses, dogs and cats. In addition, it (Response 150) Whether species- the nutrient requirements for different advises considering nutritional, specific data and information (such as species of poultry vary widely. Feeding metabolic, pharmacokinetic, and natural feeding studies) are necessary to satisfy a diet intended for one species of dietary patterns when selecting GRAS criteria depends on the intended poultry to another species could cause appropriate animal model species. use of the notified substance. We nutrient imbalances, deficiencies, or Although the material is directed to recognize that there may be situations excesses, which could have adverse only three target animals, some aspects where scientific procedures, such as a consequences ranging from loss of of its approach can be generalized. weight of evidence approach, allow for production to damages to tissues and the extrapolation of available data and organs and even to death. When If you submit your conclusion of mstockstill on DSK3G9T082PROD with RULES2 information from an animal species extrapolating data and information from GRAS status to FDA, you must explain other than the target animal. For another animal species is not how the data and information in your example, CVM had no questions appropriate, in Part 6 of your GRAS GRAS notice provide the basis for your regarding an enzyme preparation notice you would discuss data and conclusion; we would then evaluate intended for use in food for turkeys, information developed specifically for whether the data, information, and broiler chickens, and laying hens, when the target animal, or for the stage of life narrative in your GRAS notice support the feeding studies used to support in the same animal species, rather than your conclusion. VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00078 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 55037 H. Data and Information in a GRAS any residues that humans may be GRAS notices during the Interim Pilot Notice About the Safety for Humans exposed to in edible animal tissues; and program. Some comments describe Consuming Human Food Derived From (2) the data and information you rely on CFSAN’s practice of using conference a Food-Producing Animal (§§ 570.235 to establish the potential quantities of calls to obtain a clarification or and 570.250) such residues (see § 570.235(b)). These additional information, with a (Comment 151) Some comments requirements parallel the requirements reasonable period of time for the notifier support clarifying the rule to explicitly for target animal exposure, but are to provide the clarification or additional require the submission of information directed to the quantity of potential information. These comments assert that about safety for both the target animal residues of the notified substance, and CVM’s practice is different from of any other substance that is expected CFSAN’s practice because CVM does and for humans consuming human food to be formed in or on the animal food not contact a notifier to discuss CVM’s derived from food-producing animals. because of the use of the notified questions after a submission has been One comment states that the safety and substance, and those residues from any accepted for filing. One comment asserts wholesomeness of food given to animals other substances present with the that CVM has informally indicated that that eventually end up in human food notified substance, whether naturally, once a GRAS notice is accepted for must be held to the same standard as for due to its manufacture (e.g., filing, there will be no further a substance intended for use in human contaminants or by-products), or communication with the notifier and food. Another comment asks us to produced as a metabolite in edible the GRAS notice will be judged solely specify that the submission of data and animal tissues when the notified on what was accepted for filing. This information about both target animal substance is consumed by a food- and human safety is required when such comment further asserts that such a producing animal. It is well established process is unreasonable because the data and information are developed for that substances consumed by food- food-producing animals. error or omission may be trivial and/or producing animals, and substances such easily remedied. This comment also One comment states that it is the as metabolites produced by a food- responsibility of the notifier to asserts that allowing informal contacts producing animal, can accumulate in (including telephone, email, and fax) to determine the extent of the safety edible animal tissues and have an assessment of a substance intended for address minor issues would be adverse impact on public health. For consistent with how FDA has handled use in the food of a food-producing example, aflatoxin M1 is a metabolite of animal. This comment asserts that there a wide range of submissions that require aflatoxin B1 that is produced during review. Another comment asserts that is no need to set explicit standards for normal biological processes of animals addressing both target animal and CVM’s practice of not contacting the ingesting the toxin (e.g., from food notifier is a major concern for the human food safety in applicable contaminated with aflatoxin B1) and has sections of the rule, because whether industry and that CVM’s reviewers may been shown to cause liver cancer in have questions that could be easily new data, such as tissue residue data, certain animals (Ref. 58). As another would be warranted would be answered by the notifier, if contacted. example, there can be human food Some comments ask CVM to engage determined through application of safety concerns about the level of general scientific principles from the in the same informal practice as CFSAN, selenium in animal tissues when food- fields of animal nutrition and with respect to contacting the notifier producing animals consume large metabolism. and allowing remedial action, if such amounts of a substance that contains Another comment asserts that neither action may be completed in a reasonable selenium in their diets. human feeding studies nor tissue We agree that the specific data and period of time. Some comments ask the residue accumulation data should be information that are necessary to Centers to establish a uniform system of required when available scientific determine the safety for humans contact and communication after a information can be used to draw consuming human food derived from a submission (and/or agreeing to evaluate conclusions using a weight of the food-producing animal would be an amendment to a GRAS notice) to evidence approach, as CFSAN does for determined through the application of prevent delays or other inefficiencies human food substances. This comment general scientific principles from the over issues that could easily be clarified asserts that CVM must clarify what data fields of animal nutrition and and resolved. Some comments note that need to be provided regarding safety for metabolism and that it is the notifier’s uniformity between CFSAN and CVM in humans consuming human food derived responsibility to determine what those the submission and handling of requests from food-producing animals before specific data and information are. to cease to evaluate a GRAS notice is of industry could agree to the requirement. Therefore, we have modified the great importance in maintaining (Response 151) We are clarifying the requirements for the narrative in Part 6 transparency and efficiency in the requirement to address safety for of a GRAS notice to clarify that the GRAS notification procedure. humans consuming human food derived narrative must address the safety for (Response 152) The regulatory text from food-producing animals in Parts 3 both the target animal and for humans governing what CVM will do with a and 6 of a GRAS notice. consuming human food derived from GRAS notice (§ 570.265) is the same as In the requirements for Part 3 of a food-producing animals (see the regulatory text governing what GRAS notice for a substance intended § 570.250(a)(1) and (b)). CFSAN will do with a GRAS notice for use in animal food, we have (§ 170.265). In addition, the regulatory modified the title of the regulatory text I. Filing Decision, Opportunity for a text that provides for a notifier who to specify that Part 3 addresses Notifier To Submit an Amendment, and submits a GRAS notice to CVM to mstockstill on DSK3G9T082PROD with RULES2 exposures to both the target animal and Asking Us To Cease To Evaluate a submit a timely amendment to a filed to humans consuming human food GRAS Notice for a Substance Intended GRAS notice, and to ask us to cease to derived from food-producing animals for Use in Animal Food (§§ 570.260 and evaluate a GRAS notice (§ 570.260), is (see § 570.235). When the intended use 570.265) the same as the regulatory text that of the notified substance is in food for (Comment 152) Some comments provides for a notifier who submits a food-producing animals, you must express concern about differences in GRAS notice to CFSAN to submit a provide: (1) The potential quantities of how CFSAN and CVM administered timely amendment to a filed GRAS VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00079 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 55038 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations notice, and to ask us to cease to evaluate could be) timely, the final rule does, as notice by letter or cease to evaluate your a GRAS notice (§ 170.260). requested by the comments, consider notice (§ 570.280). As discussed in We disagree that CVM did not contact whether an amendment could be section VI of CVM’s experience notifiers during the Interim Pilot prepared and submitted in a reasonable document (Ref. 20), as of December 31, program. As shown in table 1 in CVM’s period of time. Importantly, as 2015, CVM had not received any experience document (Ref. 20), CVM discussed in Response 101, the role of supplements to a GRAS notice. contacted the notifier regarding 9 of 18 an amendment is to clarify questions that we have about your conclusion of K. GRAS Affirmation Petitions for GRAS notices during its evaluation Substances Used in Animal Food process. CVM issued ‘‘no questions GRAS status, rather than to letters’’ to seven of these nine notices substantively amend the notice. CVM has no pending GRAS after the notifiers provided clarifying Whether we will evaluate an affirmation petitions and, thus, the final amendments. amendment to a GRAS notice before animal food regulations do not include responding to the notice is a matter that provisions for the disposition of Moving forward under the final rule, we will consider on a case-by-case basis. CVM intends to consider the same pending GRAS affirmation petitions for factors that CFSAN considers regarding J. Opportunity for a Notifier To Submit substances used in animal food. whether to file a submission as a GRAS a Supplement to a GRAS Notice for a XXVI. Editorial, Clarifying, and notice (see Response 85), the purpose of Substance Intended for Use in Animal Conforming Amendments contacting a notifier (including whether Food (§ 570.280) to provide an opportunity for a notifier (Comment 153) One comment asks The revised regulatory text includes to ask us to cease to evaluate a GRAS CVM to adopt CFSAN’s approach of several changes that we have made to notice) (see Response 80), and the allowing a notifier to submit make the requirements more clear and transparency of the reasons for a ‘‘cease information to a GRAS notice after FDA improve readability. The revised to evaluate letter’’ (see Response 81). responds to the notice. regulatory text also includes several Because our factors regarding the (Response 153) The rule provides conforming changes that we have made purpose of contacting a notifier, and the that, if circumstances warrant, a notifier when a change to one provision affects provisions that provide an opportunity who submits a GRAS notice to CVM other provisions. We summarize the for a notifier to submit an amendment, may submit a supplement to a filed principal editorial and conforming consider whether an amendment is (or GRAS notice after we respond to your changes in table 29. TABLE 29—PRINCIPAL EDITORIAL, CLARIFYING, AND CONFORMING CHANGES Designation in the regulatory text Revision Explanation (§ ) § 20.100(c)(46) ..................... Add new paragraph (c)(46) to clarify applicability of Conforming change in light of the new GRAS notifica- § 20.100 (the handling of FDA records upon a re- tion procedures established in §§ 170.36 and 570.36. quest for public disclosure) to GRAS notices in §§ 170.36(h) and 570.36(h). § 25.20(k) ............................. • Replace ‘‘Affirmation of a food substance as GRAS • Conforming change in light of the deletion of the for humans or animals, on FDA’s initiative or in re- GRAS affirmation petition process. sponse to a petition, under parts 182, 184, 186, or • Correct the list of applicable categorical exclusions 582 of this chapter’’ with ‘‘Establishment or amend- that apply to include the categorical exclusions listed ment of a regulation for a food substance as GRAS in § 25.32(i) and (j). under the conditions of its intended use for humans or animals under parts 182, 184, 186, 582, or 584 of this chapter’’. • Replace ‘‘unless categorically excluded in § 25.32(f), (k), or (r)’’ with ‘‘unless categorically excluded in § 25.32(f), (i), (j), (k), or (r)’’. § 25.32(f) .............................. Replace ‘‘Affirmation of a food substance as GRAS for • Clarify that GRAS affirmation applies to the intended humans or animals on FDA’s initiative or in response conditions of use of a substance, not the substance to a petition, under parts 182, 184, 186, or 582 of itself. this chapter’’ with ‘‘Establishment or amendment of a • Conforming change in light of the deletion of the regulation for a food substance as GRAS under the GRAS affirmation petition process. conditions of its intended use for humans or animals under parts 182, 184, 186, 582, or 584 of this chap- ter’’. § 25.32 (i), (j), (k), and (r) .... Replace ‘‘or GRAS affirmation petition’’ with ‘‘establish- • Clarify that GRAS affirmation applies to the intended ment or amendment of a regulation for a food sub- conditions of use of a substance, not the substance stance as GRAS under the conditions of its intended itself. use for humans or animals under parts 182, 184, • Conforming change in light of the deletion of the 186, 582, or 584 of this chapter’’. GRAS affirmation petition process. § 170.3(h), § 570.3(h) ........... • Specify ‘‘data from human, animal, analytical, or • Clarify that the four listed types of studies (human, mstockstill on DSK3G9T082PROD with RULES2 other scientific studies’’ rather than ‘‘data from animal, analytical, and other) do not necessarily human, animal, analytical, and other scientific stud- apply in all circumstances. ies’’. • Replace ‘‘appropriate to establish the safety of a sub- • Include statutory language from section 201(s) of the stance’’ with ‘‘appropriate to establish the safety of a FD&C Act to clarify that GRAS status applies to the substance under the conditions of its intended use’’. intended conditions of use of a substance, not the substance itself. VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00080 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 55039 TABLE 29—PRINCIPAL EDITORIAL, CLARIFYING, AND CONFORMING CHANGES—Continued Designation in the regulatory text Revision Explanation (§ ) 170.3(i) ................................. In the definition of ‘‘safe’’ or ‘‘safety,’’ replace ‘‘under Conforming change to consistently use the exact statu- the intended conditions of use’’ with ‘‘under the con- tory language in section 201(s) ‘‘under the conditions ditions of its intended use’’. of its intended use’’ rather than variations (such as under the intended conditions of use). § 170.3(k) ............................. Replace ‘‘General recognition of safety shall be deter- Conforming change. See Response 41. mined in accordance with 170.30’’ with ‘‘General rec- ognition of safety shall be in accordance with § 170.30’’. Throughout § 170.30 ............ Replace ‘‘§ 186.1’’ with ‘‘part 186’’ .................................. Correction to clarify that the provision applies to all of part 186, not just § 186.1. § 170.30(a) ........................... Replace the proposed regulatory text ‘‘there is reason- Conforming change to consistently use the exact statu- able certainty that the substance is not harmful under tory language in section 201(s) ‘‘under the conditions the intended conditions of use’’ with ‘‘there is reason- of its intended use’’ rather than variations (such as able certainty that the substance is not harmful under under the intended conditions of use). the conditions of its intended use’’. § 170.30(b), § 570.30(b) ....... Replace ‘‘General recognition of safety based upon sci- • Clarify that FDA approves a food additive, not a entific procedures shall require the same quantity ‘‘food additive regulation’’. and quality of scientific evidence as is required to ob- • Clarify that the same quantity and quality of scientific tain approval of a food additive regulation for the in- evidence is required regardless of whether the sub- gredient’’ with ‘‘General recognition of safety based stance is intended for use as an ‘‘ingredient’’. upon scientific procedures shall require the same quantity and quality of scientific evidence as is re- quired to obtain approval of a food additive’’. § 170.30(c)(1), § 570.30(c)(1) Replace ‘‘General recognition of safety through experi- • Conforming change. See Response 41. ence based on common use in food prior to January • Clarify that FDA approves a food additive, not a 1, 1958, may be determined without the quantity or ‘‘food additive regulation’’. quality of scientific procedures required for approval of a food additive regulation’’ with ‘‘General recogni- tion of safety through experience based on common use in food prior to January 1, 1958, may be achieved without the quantity or quality of scientific procedures required for approval of a food additive’’. § 170.30(c)(2) ....................... • Replace ‘‘if the information about the experience es- • Conforming change to consistently use the exact tablishes that the use of the substance is safe within statutory language in section 201(s) ‘‘under the con- the meaning of the act (see § 170.3(i))’’ with ‘‘if the ditions of its intended use’’ rather than variations information about the experience establishes that the (such as ‘‘the use of the substance’’). substance is safe under the conditions of its intended • Clarify that the applicable section of the FD&C Act is use within the meaning of section 201(u) of the Fed- section 201(u). Section 170.3(i) is in our regulations, eral Food, Drug, and Cosmetic Act (see also not in the FD&C Act. § 170.3(i))’’. • Editorial change to include the full name of the stat- • Replace ‘‘in this country’’ with ‘‘in the United States’’ ute. • Editorial change to be specific that ‘‘this country’’ means ‘‘the United States’’. 170.30(c)(2), 170.38(a), Replace ‘‘the act’’ with ‘‘the Federal Food, Drug, and Editorial. It is now our practice to include the full name 570.38(a). Cosmetic Act’’ in any provision that we otherwise re- of this statute when we refer to it. vised. § 170.30(e) ........................... • Replace ‘‘Beginning in 1969, the Food and Drug Ad- • See Response 41. ministration has undertaken a systematic review of • Include statutory language from section 201(s) of the the status of all ingredients used in food on the de- FD&C Act to clarify that GRAS status applies to the termination that they are GRAS or subject to a prior intended conditions of use of a substance, not the sanction’’ with ‘‘Beginning in 1969, the Food and substance itself. Drug Administration has undertaken a systematic re- • Clarify that GRAS status pursuant to parts 184 and view of the status of all ingredients used in food 186 is affirmed by FDA. based on the view that they are GRAS under the conditions of their intended use or subject to a prior sanction’’. • Replace ‘‘All determinations of GRAS status or food additive status or prior sanction status pursuant to this review shall be handled pursuant to §§ 170.35, 170.38, and 180.1 of this chapter. Affirmation of GRAS status shall be announced in part 184 or mstockstill on DSK3G9T082PROD with RULES2 § 186.1 of this chapter’’ with ‘‘All affirmations of GRAS status or determinations of food additive sta- tus or prior sanction status pursuant to this review shall be handled pursuant to §§ 170.35, 170.38, and 180.1 of this chapter. Affirmation of GRAS status shall be announced in part 184 or part 186 of this chapter’’. VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00081 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 55040 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations TABLE 29—PRINCIPAL EDITORIAL, CLARIFYING, AND CONFORMING CHANGES—Continued Designation in the regulatory text Revision Explanation (§ ) § 170.30(l) ............................ Replace ‘‘Any change in part 182, part 184, or § 186.1 Clarify the applicability of the requirement. of this chapter shall be accomplished pursuant to § 170.38’’ with ‘‘Any change to the GRAS status of a food ingredient in part 182, part 184, or part 186 of this chapter shall be accomplished pursuant to § 170.38’’. § 170.35(a), § 570.35(a) ....... Replace ‘‘may affirm the GRAS status of substances’’ • Editorial change to use the singular. with ‘‘may affirm that a substance that directly or indi- • Include statutory language from section 201(s) of the rectly becomes a component of food is GRAS under FD&C Act to clarify that GRAS affirmation applies to the conditions of its intended use’’. the intended conditions of use of a substance, not the substance itself. § 170.35(b)(1), Replace ‘‘If the Commissioner proposes on his own ini- Include statutory language from section 201(s) of the § 570.35(b)(1). tiative that a substance is entitled to affirmation as FD&C Act to clarify that GRAS affirmation applies to GRAS’’ with ‘‘If the Commissioner proposes on his the intended conditions of use of a substance, not own initiative that a substance is entitled to affirma- the substance itself. tion as GRAS under the conditions of its intended use’’. § 170.35(b)(3), • Replace ‘‘convincing evidence that the substance is • Include statutory language from section 201(s) of the § 570.35(b)(3). GRAS’’ with ‘‘convincing evidence that the substance FD&C Act to clarify that GRAS affirmation applies to is GRAS under the conditions of its intended use’’. the intended conditions of use of a substance, not • Replace ‘‘listing the substance as GRAS in part 182, the substance itself. part 184, or part 186 of this chapter’’ with ‘‘listing the • Deleted reference to parts 182 and 582. If FDA af- GRAS conditions of use of the substance in part 184 firms GRAS status, the affirmation regulation would or part 186 of this chapter’’. appear in part 184 or 186. § 170.35(b)(4), Replace ‘‘there is a lack of convincing evidence that the Include statutory language from section 201(s) of the § 570.35(b)(4). substance is GRAS’’ with ‘‘there is a lack of con- FD&C Act to clarify that GRAS affirmation applies to vincing evidence that the substance is GRAS under the intended conditions of use of a substance, not the conditions of its intended use’’. the substance itself. § 170.38(a), § 570.38(a) ....... • Replace ‘‘may, in accordance with § 170.35(b)(4) or • See Response 41. (c)(5), publish a notice in the Federal Register deter- • Conforming change in light of the deletion of the mining that a substance is not GRAS’’ with ‘‘may, in GRAS affirmation petition process. accordance with § 170.35(b)(4), publish a notice in • Include statutory language from section 201(s) of the the Federal Register determining that a substance is FD&C Act to clarify that GRAS affirmation applies to not GRAS under the conditions of its intended use’’. the intended conditions of use of a substance, not the substance itself. • Replace ‘‘may, in accordance with § 570.35(b)(4) or (c)(5), publish a notice in the Federal Register deter- mining that a substance is not GRAS’’ with ‘‘may, in accordance with § 570.35(b)(4), publish a notice in the Federal Register determining that a substance is not GRAS under the conditions of its intended use’’. • Throughout part 170, sub- Replace variations of ‘‘data or other information’’ with Editorial change. Although data is a type of ‘‘informa- part E. ‘‘data and information’’. tion,’’ it is simpler and clearer to say ‘‘data and infor- • Throughout part 570, sub- mation.’’ part E. • Throughout part 170, sub- Replace variations of ‘‘determine’’ and ‘‘determination’’ See Response 41. part E. with ‘‘conclude’’ and ‘‘conclusion’’. • Throughout part 570, sub- part E. • Throughout part 170, sub- • Replace ‘‘exempt’’ with ‘‘not subject to: ................... See Response 42. part E. • Replace ‘‘claim’’ with ‘‘view’’ ........................................ • Throughout part 570, sub- part E. § 170.203, § 570.203 ............ In the definition of ‘‘notifier,’’ add a parenthetical with Clarification by including text from the definition of examples of what we mean by ‘‘person’’ (e.g., an in- ‘‘person’’ in § 10.3. dividual, partnership, corporation, association, or other legal entity). § 170.225(c)(4) ..................... Replace the proposed phrase ‘‘applicable conditions of Clarifying change to use the statutory term ‘‘intended’’ use’’ with ‘‘intended conditions of use’’. in place of ‘‘applicable’’. § 184.1(a) ............................. Replace ‘‘The direct human food ingredients listed in Clarify that the GRAS status of the uses of substances this part have been reviewed by the Food and Drug listed in part 184 has been affirmed by FDA, either mstockstill on DSK3G9T082PROD with RULES2 Administration and determined to be generally recog- on FDA’s initiative or in response to a GRAS affirma- nized as safe (GRAS) for the purposes and condi- tion petition. tions prescribed’’ with ‘‘The direct human food ingre- dients listed in this part have been reviewed by the Food and Drug Administration and affirmed to be generally recognized as safe (GRAS) for the pur- poses and under the conditions prescribed’’. VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00082 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 55041 TABLE 29—PRINCIPAL EDITORIAL, CLARIFYING, AND CONFORMING CHANGES—Continued Designation in the regulatory text Revision Explanation (§ ) § 184.1(b)(1) ......................... • Replace ‘‘shall independently establish’’ with ‘‘shall • Conforming change to reflect ‘‘conclusions’’ of GRAS have a basis to conclude’’. status. • Remove the last sentence, i.e., ‘‘Persons seeking • Conforming change in light of the deletion of the FDA approval of an independent determination that a GRAS affirmation petition process. use of an ingredient is GRAS may submit a GRAS petition in accordance with 170.35 of this chapter.’’. § 186.1(a) ............................. Replace ‘‘The indirect human food ingredients listed in Clarify that the GRAS status of the uses of substances this part have been reviewed by the Food and Drug listed in part 186 has been affirmed by FDA, either Administration and determined to be generally recog- on FDA’s initiative or in response to a GRAS affirma- nized as safe (GRAS)’’ with ‘‘The indirect human tion petition. food ingredients listed in this part have been re- viewed by the Food and Drug Administration and af- firmed to be generally recognized as safe (GRAS)’’. § 186.1(b)(1) ......................... • Replace ‘‘shall independently establish’’ with ‘‘shall Conforming change in light of the deletion of the GRAS have a basis to conclude’’. affirmation petition process. • Remove the last sentence, i.e., ‘‘Persons seeking FDA approval of an independent determination that a use of an ingredient is GRAS may submit a GRAS petition in accordance with 170.35 of this chapter.’’. § 570.3(f) .............................. • Add ‘‘of the species to which the substance is in- Changes to tended to be fed’’ in describing the animals con- • Conform with revisions to § 570.30(a) and (c) suming the substance. • Conform with the corresponding definition for human • Delete ‘‘in the United States’’ ...................................... food in § 170.3(f), which does not specify ‘‘in the • Add ‘‘(and, for food-producing animals fed with such United States.’’ substance, also means a substantial history of con- • Clarify that substantial history of consumption should sumption by humans consuming human foods de- be demonstrated by the same animal species as the rived from those food-producing animals) prior to species intended to be fed to conform with the sub- January 1, 1958. mission requirements in part 5 of a GRAS notice when the basis for the conclusion of GRAS status is through experience based on common use in food (§ 570.245). • Clarify that substantial history of consumption for food-producing animals also should be demonstrated by a substantial history of consumption by humans consuming human foods derived from those food- producing animals prior to January 1, 1958 to con- form with the submission requirements in part 5 of a GRAS notice. § 570.3(k) ............................. Replace ‘‘General recognition of safety shall be deter- Conforming change. The GRAS notification procedure mined in accordance with § 570.30’’ with ‘‘General does not use the term ‘‘determine.’’ recognition of safety shall be in accordance with § 570.30’’. § 570.3 ................................. Define ‘‘food-producing animal’’ to mean an animal Clarify the meaning of this term for the purpose of part used to produce human food. 570, subpart E in light of provisions that address the safety of a substance for humans consuming human food derived from an animal used to produce human food. § 570.30(c) ........................... Replace ‘‘General recognition of safety through experi- • Conforming change. The GRAS notification proce- ence based on common use in food prior to January dure does not use the term ‘‘determine.’’ 1, 1958, may be determined without the quantity or • Clarify that FDA approves a food additive, not a quality of scientific procedures required for approval ‘‘food additive regulation’’. of a food additive regulation’’ with ‘‘General recogni- tion of safety through experience based on common use in food prior to January 1, 1958, may be achieved without the quantity or quality of scientific procedures required for approval of a food additive’’. § 570.30(d) ........................... • Replace ‘‘ingredients listed as GRAS in part 582 of Clarify that the provisions apply regardless of whether this chapter’’ with ‘‘ingredients listed as GRAS in part an ingredient is listed as GRAS in part 582 or af- 582 of this chapter or affirmed as GRAS in part 584 firmed as GRAS in part 584. of this chapter’’. • Replace ‘‘without specific inclusion in part 582 of this mstockstill on DSK3G9T082PROD with RULES2 chapter’’ with ‘‘without specific inclusion in part 582 or part 584 of this chapter’’. § 570.30(i) ............................ Replace ‘‘Any use of such and ingredient’’ with ‘‘Any Editorial correction of ‘‘and’’ to ‘‘an’’. use of such an ingredient’’. 570.225(c)(4), 570.225(c)(5), Replace ‘‘food’’ with ‘‘animal food’’ ................................. Clarification for part 570. 570.230(c), 570.235, 570.240, 570.245. VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00083 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 55042 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations XXVII. Economic Analysis of Impacts their conclusion with their notices. The Economic Analysis of Impacts of We have examined the impacts of the Although uncertain, we estimate that the final rule performed in accordance final rule under Executive Order 12866, notifiers will spend between 5 more with Executive Order 12866, Executive Executive Order 13563, the Regulatory hours and 20 more hours to prepare and Order 13563, the Regulatory Flexibility Flexibility Act (5 U.S.C. 601–612), and submit each notice. We estimate that Act, and the Unfunded Mandates the Unfunded Mandates Reform Act of this will cost notifiers less than $0.1 Reform Act (Ref. 51) is available at 1995 (Pub. L. 104–4). Executive Orders million each year. http://www.regulations.gov under the 12866 and 13563 direct us to assess all For all affected notifiers, we expect docket number for this final rule and at costs and benefits of available regulatory that they will spend time reading and http://www.fda.gov/AboutFDA/ understanding the requirements of the ReportsManualsForms/Reports/ alternatives and, when regulation is final rule and revising standard EconomicAnalyses/default.htm. necessary, to select regulatory approaches that maximize net benefits operating procedures for preparing and XXVIII. Analysis of Environmental (including potential economic, submitting GRAS notices. We estimate Impact environmental, public health and safety, that it will take from 20 hours to 80 hours for notifiers to perform this We have carefully considered the and other advantages; distributive potential environmental effects of this impacts; and equity). We have action. Firms with outstanding GRAS affirmation petitions may choose to action. We have concluded under 21 developed a comprehensive Economic CFR 25.30(h) that this action is of a type Analysis of Impacts that assesses the submit GRAS notices and incorporate the information included in their that does not individually or impacts of the final rule. We believe that cumulatively have a significant effect on this final rule is not a significant petition. To account for the additional effort by these firms, we include the the human environment. Therefore, regulatory action as defined by neither an environmental assessment Executive Order 12866. one-time cost to prepare and submit a nor an environmental impact statement The Regulatory Flexibility Act GRAS notice for all outstanding is required. requires us to analyze regulatory options petitions. We estimate that notifiers will that would minimize any significant spend between 170 and 190 hours to XXIX. Paperwork Reduction Act of impact of a rule on small entities. The submit GRAS notices for each 1995 final rule replaces the voluntary GRAS outstanding petition. The total one-time This final rule contains information affirmation petition process with a costs of the final rule range from $0.8 collection provisions that are subject to voluntary GRAS notification procedure. million to $2.7 million. review by OMB under the PRA (44 Similar to the petition process, we We estimate that over 10 years with U.S.C. 3501–3520). The title, expect that profit-maximizing firms will a 7 percent discount rate, the present description, and respondent description only submit the GRAS notice when the value of the total costs of the final rule of the information collection provisions private benefits equal or exceed the range from $0.9 million to $3.3 million; are shown in the following paragraphs costs of the GRAS notice, regardless of with a 3 percent discount rate, the with an estimate of the one-time and the size of the firm. Because small firms present value of the total costs range annual reporting burdens. Included in face the same voluntary business from $0.9 million to $3.4 million. The the estimate is the time for reviewing decision as large firms, we certify that annualized costs of the rule range from instructions, searching existing data the final rule will not have a significant $0.1 million to $0.4 million with a 7 sources, gathering and maintaining the economic impact on a substantial percent discount rate and range from data needed, and completing and number of small entities. $0.1 million to $0.5 million with a 3 reviewing each collection of The Unfunded Mandates Reform Act percent discount rate. information. of 1995 (section 202(a)) requires us to We do not quantify the benefits of the Title: Substances Generally prepare a written statement, which final rule. However, based on the Recognized as Safe Notification includes an assessment of anticipated differences in review time between the Procedure (21 CFR parts 170 and 570) costs and benefits, before issuing ‘‘any GRAS petition process and the GRAS (OMB Control No. 0910–0342)— rule that includes any Federal mandate notification procedure, we anticipate Revision. that may result in the expenditure by that industry will benefit from the more Description: The FD&C Act requires State, local, and tribal governments, in speedy notification procedure. For that all food additives (as defined by the aggregate, or by the private sector, of example, we have filed more than 600 section 201(s)) be approved by FDA $100,000,000 or more (adjusted GRAS notices for human food before they are marketed (sections annually for inflation) in any one year.’’ substances since 1998. During this time, 402(a)(2)(C) and 409 of the FD&C Act). The current threshold after adjustment it took an average of 200 days for us to Section 201(s) of the FD&C Act excludes for inflation is $146 million, using the respond to 588 GRAS notices; it took an from the definition of a food additive a most current (2015) Implicit Price average of 7.9 years to complete 24 substance ‘‘generally recognized, among Deflator for the Gross Domestic Product. previous GRAS affirmation petitions. experts qualified by scientific training This final rule will not result in an We began to accept GRAS notices for and experience to evaluate its safety, as expenditure in any year that meets or animal food substances in 2010 and we having been adequately shown through exceeds this amount. have filed 18 GRAS notices for animal scientific procedures (or, in the case of The final rule will eliminate the food substances since that time. It took a substance used in food prior to petition process to affirm a substance is an average of 294 days for us to respond January 1, 1958, through either GRAS and replace the petition process to 12 GRAS notices with a ‘‘no scientific procedures or experience mstockstill on DSK3G9T082PROD with RULES2 with a GRAS notification procedure. questions letter’’ or ‘‘insufficient basis based on common use in food) to be safe The level of effort required by a firm to letter’’; it took an average of 4.9 years to under the conditions of its intended reach a conclusion that a substance is respond to the three previous GRAS use.’’ This final rule amends our GRAS for its intended use remains affirmation petitions. With the GRAS regulations in parts 170 and 570 and unchanged by the final rule. However, notification procedure, we can complete revises the information collection the rule will require that firms submit our evaluation within the timelines provisions regarding the notification some additional information to support specified in the final rule. procedures for GRAS substances. The VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00084 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 55043 regulations implement the GRAS As discussed in section II.B of the through XVIII. While none of the provision of section 201(s) of the FD&C preamble to this final rule, previously comments suggested we modify the Act in part 170 and part 570 for human manufacturers were invited to submit estimated annual burden associated food and animal food, respectively. notices of their independent GRAS with the information collection, we Description of Respondents: determinations for review under the have revised the underlying notification Respondents to the collection of framework of the proposed rule during procedures and, consequently, have information are manufacturers of the period between issuance of the revised the underlying information substances used in human food and proposed rule and any final rule based collection provisions consistent with animal food. We estimate there are 480 on the proposed rule. The proposed the final rule. such respondents. As estimated in the regulations provided a standard format Specifically the final rule establishes Final Regulatory Impact Analysis (Ref. 51), approximately 340 to 460 notifiers for the voluntary submission of a notice. a voluntary administrative procedure for (for human food) and approximately 10 To date, the GRAS program has been notifying FDA about a conclusion that a to 20 notifiers (for animal food) will be administered under these proposed substance is GRAS under the conditions affected by the final rule. The Final procedures. Comments regarding the of its intended use in human food or Regulatory Impact Analysis reflects an information collection topics solicited animal food. The final rule explains that overall increase in respondents to the in the proposed rule and subsequent a GRAS notice must include the program and we have therefore adjusted 2010 notice are discussed in the following seven parts: our respondent numbers accordingly. preamble in sections IV, VII, and X TABLE 30—INFORMATION TO BE INCLUDED IN EACH PART OF A GRAS NOTICE Part No. Information to be included Part 1 .............................................. Signed statements and a certification. Part 2 .............................................. The identity, method of manufacture, specifications, and physical or technical effect of the notified sub- stance. Part 3 .............................................. Dietary exposure to the notified substance. Part 4 .............................................. Self-limiting levels of use in circumstances where the amount of the notified substance that can be added to human food or animal food is limited because the food containing levels of the notified substance above a particular level would become unpalatable or technologically impractical. Part 5 .............................................. The history of consumption of the substance for food use by a significant number of consumers (or ani- mals in the case of animal food) prior to January 1, 1958, if a conclusion of GRAS status is based on common use of the substance in food prior to 1958. Part 6 .............................................. A narrative that provides the basis for the notifier’s conclusion of GRAS status, including why the scientific data, information, methods, and principles described in the notice provide a basis for the conclusion that the notified substance is generally recognized, among qualified experts, to be safe under the conditions of its intended use. Part 7 .............................................. A list of the generally available data, information, and methods the notifier cites in the GRAS notice. The information submitted to us in a operating procedures for preparing and (Ref. 51), up to 45 petitions (for human GRAS notice is necessary to allow us to submitting GRAS notices. As noted, we food) will be submitted as GRAS notices administer efficiently the FD&C Act’s estimate that approximately 340 to 460 and incorporated. We use the upper- various provisions that apply to the use notifiers (for human food) and bound estimate of 45 as shown in row of substances added to food, specifically approximately 10 to 20 notifiers (for 3. To account for the additional effort by with regard to whether a substance is animal food) will be affected by the final these firms, we include the one-time GRAS under the conditions of its rule. We use the upper-bound estimates burden to prepare and submit a GRAS intended use or is a food additive of 460 and 20 respondents as shown in notice for all outstanding petitions. subject to premarket review. We will rows 1 and 2. We estimate that it will Because there are no outstanding GRAS use the information collected through take from 20 to 80 hours for respondents petitions regarding substances intended the GRAS notification procedure to to perform this action. We use the for use in animal food, we do not complete our evaluation within the upper-bound estimate of 80 hours as account for any burden for the timelines specified in the final rule. shown in rows 1 and 2. Of the 480 submission of a GRAS notice that One-Time Reporting Burden affected respondents, some will have incorporates a GRAS petition regarding Table 31 shows the estimated one- outstanding GRAS petitions. Firms with a substance intended for use in animal time reporting burden associated with outstanding GRAS petitions regarding food. We estimate that respondents will the final rule. We expect that all substances intended for use in human spend between 170 and 190 hours to respondents to the information food may choose to submit GRAS submit GRAS notices for each collection will spend time reading and notices and incorporate the information outstanding petition and have used, understanding the requirements of the included in their petition. As estimated therefore, an average estimate of 185 final rule and revising standard in the Final Regulatory Impact Analysis hours as shown in row 3. mstockstill on DSK3G9T082PROD with RULES2 VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00085 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 55044 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations TABLE 31—ESTIMATED ONE-TIME REPORTING BURDEN 1 Number of Average Number of Total annual Activity/21 CFR section responses per burden per Total hours respondents responses respondent response Notifier’s review of final rule and revision of procedures for preparing and submitting GRAS notices for human food, 170.210 through 170.270. ................................................ 460 1 460 80 36,800 Notifier’s review of final rule and revision of procedures for preparing and submitting GRAS notices for animal food, 570.210 through 570.270 ................................................. 20 1 20 80 1,600 Prepare and submit GRAS notice for an outstanding GRAS petition, 170.285 ................................................... 45 1 45 185 8,325 Total .............................................................................. ........................ ........................ ........................ ........................ 46,725 1 There are no capital costs or operating and maintenance costs associated with this collection of information. Recurring Reporting Burden additional information to support the authorization to us to share any trade conclusions found within their notices. secrets with FSIS (§ 170.270). Because Table 32 shows the estimated The additional information might the amount of additional information recurring annual reporting burden include an amendment (§§ 170.260 and may vary, we estimate that respondents associated with the final rule. As 570.260); a supplement (§§ 170.280 and will spend between 155 and 170 hours previously discussed, the final rule 570.280); a request for FDA to cease to to prepare and submit each notice. replaces the petition process with a evaluate a GRAS notice (§§ 170.260 and Using the upper-bound figure of 170 GRAS notification procedure. The level 570.260); an incorporation into a GRAS hours, we therefore estimate that the 50 of effort required by a firm to reach a notice (§§ 170.215 and 570.215); and, notifiers for human food and 25 conclusion that a substance is GRAS for information required when the intended notifiers for animal food will expend its intended use remains unchanged by conditions of use of a notified substance 12,750 hours annually as shown, the final rule. However, the final rule includes use in a product subject to respectively, in rows 1 and 2. requires that firms submit some regulation by FSIS, including TABLE 32—ESTIMATED ANNUAL REPORTING BURDEN 1 Number of Average Number of Total annual Activity/21 CFR section responses per burden per Total hours respondents responses respondent response GRAS notification procedure for human food, 170.210 through 170.270 ............................................................... 50 1 50 170 8,500 GRAS notification procedure for animal food, 570.210 through 570.270 ............................................................... 25 1 25 170 4,250 Total .............................................................................. ........................ ........................ ........................ ........................ 12,750 1 There are no capital costs or operating and maintenance costs associated with this collection of information. Recordkeeping 10.33 are approved under OMB control direct effects on the States, on the number 0910–0191. relationship between the National The final rule does not contain The information collection provisions Government and the States, or on the recordkeeping requirements. We believe of this final rule have been submitted to distribution of power and that documentation used by OMB for review as required by section responsibilities among the various respondents in support of a conclusion 3507(d) of the PRA. Before the effective levels of government. Accordingly, we of GRAS status is information that is date of this final rule, FDA will publish have concluded that the rule does not collected and retained as a part of usual a notice in the Federal Register contain policies that have federalism and customary business practices for a announcing OMB’s decision to approve, implications as defined in the Executive firm engaged in the manufacture of modify, or disapprove the information order and, consequently, a federalism substances used in human food and collection provisions in this final rule. summary impact statement is not animal food. We have, therefore, not An Agency may not conduct or sponsor, required. provided an estimate for these activities and a person is not required to respond (5 CFR 1320.3(b)(2)). XXXI. References to, a collection of information unless it This final rule also refers to other displays a currently valid OMB control The following references are on currently approved collections of number. display in the Division of Dockets mstockstill on DSK3G9T082PROD with RULES2 information found in our regulations. Management (HFA–305), Food and Drug XXX. Federalism Administration, 5630 Fishers Lane, Rm. These collections of information are subject to review by OMB under the We have analyzed this final rule in 1061, Rockville, MD 20852, and are PRA. The collections of information in accordance with the principles set forth available for viewing by interested 21 CFR 25.32(i) are approved under in Executive Order 13132. FDA has persons between 9 a.m. and 4 p.m., OMB control number 0910–0541. The determined that the rule does not Monday through Friday; they also are collections of information in 21 CFR contain policies that have substantial available electronically at http:// VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00086 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 55045 www.regulations.gov. FDA has verified ucm233990.htm). Accessed and printed and the Federal Docket Management the Web site addresses, as of the date on January 31, 2016. System: Best Practices for Federal this document publishes in the Federal 11. Letter dated November 17, 2010, from Agencies,’’ (http://www.regulations.gov/ Joann M. Givens of FDA to Rhonda docs/FactSheet_eRulemaking_Best_ Register, but Web sites are subject to Practices.pdf), 2010. Accessed and Kallman of New Century Brewing change over time. Company, (http://www.fda.gov/iceci/ printed on January 15, 2016. 1. House Report No. 2284, July 28, 1958. See enforcementactions/warningletters/2010/ 23. Dictionary.com. Dictionary.com Reference 1 to the proposed rule. ucm234028.htm). Accessed and printed Unabridged. Random House, Inc. (http:// 2. Price, J.M., C.G. Biava, B.L. Oser, et al., on January 31, 2016. dictionary.reference.com/browse/ ‘‘Bladder Tumors in Rats Fed 12. Letter dated November 17, 2010, from corroborate), 2016. Accessed and printed Cyclohexylamine or High Doses of a Joann M. Givens of FDA to Jaisen on February 23, 2016. Mixture of Cyclamate and Saccharin,’’ Freeman, Chris Hunter, and Jeff Wright 24. Food and Agriculture Organization of the Science, 167:1131–1132, 1970. See of Phusion Projects, (http://www.fda.gov/ United Nations and the World Health Reference 2 to the proposed rule. iceci/enforcementactions/warningletters/ Organization, ‘‘Chapter 6, Dietary 3. New York Times, p. 22, October 31, 1969. 2010/ucm234023.htm). Accessed and Exposure Assessment of Chemicals in See Reference 3 to the proposed rule. printed on January 31, 2016. Food’’ in Environmental Health Criteria 4. United States Government Accountability 13. Letter dated November 17, 2010, from 240. Principles and Methods for the Risk Office, ‘‘Report to Congressional Joann M. Givens of FDA to Michael Assessment of Chemicals in Food, Requestors on Food Safety: FDA Should Michail of United Brands Company, (http://apps.who.int/iris/bitstream/ Strengthen Its Oversight of Food (http://www.fda.gov/iceci/enforcement 10665/44065/9/WHO_EHC_240_9_eng_ Ingredients Determined to Be Generally actions/warningletters/2010/ Chapter6.pdf), 2009. Accessed and Recognized as Safe (GRAS),’’ Report No. ucm234002.htm). Accessed and printed printed on February 13, 2006. GAO–10–246, (http://www.gao.gov/ on January 31, 2016. 25. FDA, ‘‘Guidance for Industry: Estimating new.items/d10246.pdf), February 2010. 14. TTB, Industry Circular 2010–8, (http:// Dietary Intake of Substances in Food,’’ Accessed and printed on May 3, 2010. www.ttb.gov/industry_circulars/archives/ (http://www.fda.gov/Food/Guidance See Reference 2 to the 2010 notice. 2010/10–08.html), 2010. Accessed and Regulation/GuidanceDocuments 5. FDA, ‘‘Draft Guidance for Industry: printed on January 21, 2016. RegulatoryInformation/ucm074725.htm), Assessing the Effects of Significant 15. The National Academies of Sciences, 2006. Accessed and printed on January Manufacturing Process Changes, Health and Medicine Division, ‘‘Caffeine 15, 2016. Including Emerging Technologies, on the in Food and Dietary Supplements: 26. Renwick, A.G., ‘‘The Use of a Sweetener Safety and Regulatory Status of Food Examining Safety—Workshop Substitution Method to Predict Dietary Ingredients and Food Contact Summary,’’ (http://www.national Exposures for the Intense Sweetener Substances, Including Food Ingredients academies.org/hmd/Reports/2014/ Rebaudioside A.,’’ Food and Chemical that Are Color Additives,’’ (http:// Caffeine-in-Food-and-Dietary- Toxicology, 46:S61–S69, 2008. www.regulations.gov in Docket No. Supplements-Examining-Safety.aspx), 27. Mitchell, D.C., C.A. Knight, J. FDA–2011–D–0490), 2012. Accessed and 2014. Accessed and printed on May 27, Hockenberry, et al., ‘‘Beverage Caffeine printed on February 19, 2016. 2016. Intakes in the U.S.,’’ Food and Chemical 6. FDA, ‘‘Guidance for Industry: Assessing 16. Memorandum of Meeting Held on Toxicology, 63:136–142, 2014. the Effects of Significant Manufacturing December 11, 2014, between 28. Fulgoni, V.L., D.R. Keast, and H.R. Process Changes, Including Emerging Representatives of FDA and Lieberman, ‘‘Trends in Intake and Technologies, on the Safety and Representatives of the Caffeine Technical Sources of Caffeine in the Diets of US Regulatory Status of Food Ingredients Working Group on the American Adults: 2001–2010,’’ The American and Food Contact Substances, Including Beverage Association (ABA) Caffeine Journal of Clinical Nutrition, 101:1081– Food Ingredients that Are Color Technical Working Group (CTWG) 1087, 2015. Additives,’’ (http://www.fda.gov/Food/ Research Plans. 29. Branum, A.M., L.M. Rossen, and K.C. GuidanceRegulation/Guidance 17. International Life Sciences Institute (ILSI Schoendorf, ‘‘Trends in Caffeine Intake DocumentsRegulatoryInformation/ North America), ‘‘Caffeine Working Among U.S. Children and Adolescents,’’ ucm300661.htm), 2014. Accessed and Group,’’ (http://ilsina.org/our-work/food- Pediatrics, 133(3):386–393, 2014. printed on January 15, 2016. safety/caffeine/), 2015. Accessed and 30. Food and Agriculture Organization and 7. FDA, ‘‘Draft Guidance for Industry: printed on June 8, 2016. World Health Organization, ‘‘Joint FAO/ Considering Whether an FDA-Regulated 18. Experience With GRAS Notices Under the WHO Expert Consultation on Product Involves the Application of 1997 Proposed Rule, Memorandum Biotechnology and Food Safety,’’ (ftp:// Nanotechnology,’’ (http:// Dated November 4, 2010, from Linda S. ftp.fao.org/es/esn/food/ www.regulations.gov in Docket No. Kahl of FDA to Docket No. FDA–1997– biotechnology.pdf), 1996. See Reference FDA–2010–D–0530), 2011. Accessed and N–0020. See Reference 1 to the 2010 6 to the proposed rule. printed on February 19, 2016. notice. 31. FDA, ‘‘Guidance for Industry: 8. FDA, ‘‘Guidance for Industry: Considering 19. ‘‘Substances that Are Generally Recommendations for Submission of Whether an FDA-Regulated Product Recognized as Safe (GRAS); Updated Chemical and Technological Data for Involves the Application of Experience With GRAS Notices,’’ Direct Food Additive Petitions,’’ (http:// Nanotechnology,’’ (http://www.fda.gov/ Memorandum Dated June 1, 2016, from www.fda.gov/Food/GuidanceRegulation/ RegulatoryInformation/Guidances/ Paulette M. Gaynor of FDA to Docket No. GuidanceDocumentsRegulatory ucm257698.htm), 2014. Accessed and FDA–1997–N–0020. Information/ucm124917.htm), 2009. printed on January 15, 2016. 20. ‘‘Experience With GRAS Notices Under Accessed and printed on January 15, 9. The Pew Charitable Trusts, ‘‘Fixing the CVM’s Interim Pilot Program,’’ 2016. Oversight of Chemicals Added to Our Memorandum Dated June 10, 2016, from 32. FDA, ‘‘Guidance for Industry: Food,’’ (http://www.pewtrusts.org/∼/ David Edwards of FDA to Docket No. Microbiological Considerations for media/legacy/uploadedfiles/phg/ FDA–1997–N–0020. Antimicrobial Food Additive content_level_pages/reports/food 21. Memorandum for the Heads of Executive Submissions,’’ (http://www.fda.gov/ mstockstill on DSK3G9T082PROD with RULES2 additivescapstonereportpdf.pdf), 2013. Departments and Agencies, Dated June 1, Food/GuidanceRegulation/Guidance Accessed and printed on February 19, 1998, Signed by President William J. DocumentsRegulatoryInformation/ 2016. Clinton, (http://www.plainlanguage.gov/ ucm230417.htm), 2008. Accessed and 10. Letter dated November 17, 2010, from whatisPL/govmandates/memo.cfm). printed on January 15, 2016. Joann M. Givens of FDA to Mr. Tim Accessed and printed on July 14, 2008. 33. FDA, ‘‘Guidance for Industry: Enzyme Baggs, Charge Beverages Corporation, See Reference 3 to the 2010 notice. Preparations: Recommendations for (http://www.fda.gov/iceci/enforcement 22. eRulemaking Program, ‘‘Improving Submission of Chemical and actions/warningletters/2010/ Electronic Dockets on Regulations.gov Technological Data for Food Additive VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00087 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 55046 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations Petitions and GRAS Notices,’’ (http:// Enzymes From Recombinant Accessed and printed on January 15, www.fda.gov/Food/GuidanceRegulation/ Microorganisms—A Review,’’ Regulatory 2016. GuidanceDocumentsRegulatory Toxicology and Pharmacology, 57. National Research Council, ‘‘General Information/IngredientsAdditives 45(2):144–158, 2006. 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Accessed and printed on January 46. GRAS Notice Inventory, (http:// compliancepolicyguidancemanual/ 15, 2016. www.fda.gov/Food/IngredientsPackaging ucm074482.htm), 2005. Accessed and 35. FDA, ‘‘Guidance for Industry and Other Labeling/GRAS/NoticeInventory/ printed on January 15, 2016. Stakeholders: Toxicological Principles default.htm), 2016. Accessed and printed for the Safety Assessment of Food on January 15, 2016. Ingredients. Redbook 2000,’’ (http:// List of Subjects 47. Current Animal Food GRAS Notices www.fda.gov/Food/GuidanceRegulation/ Inventory, (http://www.fda.gov/Animal 21 CFR Part 20 GuidanceDocumentsRegulatory Veterinary/Products/AnimalFoodFeeds/ Information/IngredientsAdditives GenerallyRecognizedasSafeGRAS Confidential business information, GRASPackaging/ucm2006826.htm), Notifications/ucm243845.htm), 2016. Courts, Freedom of information, 2007. Accessed and printed on January Accessed and printed on February 23, Government employees. 15, 2016. 2016. 36. 225–00–2000 ‘‘Amendment 1: 48. FDA, List of Pending GRAS Affirmation 21 CFR Part 25 Memorandum of Understanding Between Petitions as of December 31, 2015. the United States Department of 49. FDA, ‘‘Guidance for Industry: Frequently Environmental impact statements, Agriculture Food Safety Inspection Asked Questions About GRAS,’’ (http:// Foreign relations, Reporting and Service and the United States www.fda.gov/Food/GuidanceRegulation/ recordkeeping requirements. Department of Health and Human GuidanceDocumentsRegulatory Services Food and Drug Administration, 21 CFR Part 170 Information/IngredientsAdditivesGRAS (http://www.fda.gov/AboutFDA/ Packaging/ucm061846.htm), 2004. Administrative practice and PartnershipsCollaborations/ Accessed and printed on October 13, procedure, Food additives, Reporting MemorandaofUnderstandingMOUs/ 2010. See Reference 6 to the 2010 notice. 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FDA, ‘‘Compliance Policy Guide CPG additives. 38. Form FDA 3667. ‘‘Generally Recognized Sec. 665.100 Common or Usual Names for Animal Feed Ingredients,’’ (http:// Therefore, under the Federal Food, As Safe (GRAS) Notice,’’ (http:// Drug, and Cosmetic Act and under www.fda.gov/downloads/AboutFDA/ www.fda.gov/iceci/compliancemanuals/ ReportsManualsForms/Forms/ compliancepolicyguidancemanual/ authority delegated to the Commissioner UCM350015.pdf), 2016. Accessed and ucm074687.htm), 1995. Accessed and of Food and Drugs, 21 CFR chapter I is printed on June 1, 2016. printed on January 7, 2016. amended as follows: 39. Form FDA 3480. ‘‘Food Contact 53. Selle, P.H. and V. Ravindran, ‘‘Microbial Substance: Notification for New Use, Phytase in Poultry Nutrition,’’ Animal PART 20—PUBLIC INFORMATION Pre-Notification Consultation, Food Feed Science and Technology, 135:1–41, Master File’’, (http://www.fda.gov/ 2007. ■ 1. The authority citation for part 20 downloads/AboutFDA/ReportsManuals 54. Hatten., L.F., D.R. Ingram., and S.T. continues to read as follows: Forms/Forms/UCM076880.pdf), 2016. Pittman, ‘‘Effect of Phytase on Accessed and printed on June 1, 2016. Production Parameters and Nutrient Authority: 5 U.S.C. 552; 18 U.S.C. 1905; 40. Form FDA 3537. ‘‘DHHS/FDA Food Availability in Broilers and Laying Hens: 19 U.S.C. 2531–2582; 21 U.S.C. 321–393, Facility Registration,’’ (http:// A Review,’’ The Journal of Applied 1401–1403; 42 U.S.C. 241, 242, 242a, 242l, www.fda.gov/downloads/aboutfda/ Poultry Research, 10(3):274–278, 2001. 242n, 243, 262, 263, 263b–263n, 264, 265, reportsmanualsforms/forms/ 55. Angel, C.R., W. Saylor, S.L. Vieira, and 300u–300u–5, 300aa–1. ucm071977.pdf), 2014. Accessed and N. Ward, ‘‘Effects of a Monocomponent printed on January 15, 2016. Protease on Performance and Protein ■ 2. In § 20.100, add paragraph (c)(46) to 41. FSIS, ‘‘Contact Us,’’ (http:// Utilization in 7- to 22-Day-Old Broiler read as follows: www.fsis.usda.gov/wps/portal/ Chickens,’’ Poultry Science, 90:2281– mstockstill on DSK3G9T082PROD with RULES2 informational/contactus). Accessed and 2286, 2011. § 20.100 Applicability; cross-reference to printed on January 28, 2016. 56. FDA, ‘‘Guidance for Industry: other regulations. 42. Pariza, M.W. and M. Cook, ‘‘Determining Recommendations for Preparation and * * * * * the Safety of Enzymes Used in Animal Submission of Animal Food Additive (c) * * * Feed,’’ Regulatory Toxicology and Petitions (# 221),’’ (http://www.fda.gov/ Pharmacology, 56:332–342, 2010. downloads/AnimalVeterinary/Guidance (46) Generally recognized as safe 43. Olempska-Beer Z.S., R.I Merker, M.D. ComplianceEnforcement/Guidancefor (GRAS) notices, in part 170, subpart E Ditto, and M.J. DiNovi, ‘‘Food-Processing Industry/UCM367746.pdf), 2015. and part 570, subpart E of this chapter. VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00088 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 55047 PART 25—ENVIRONMENTAL IMPACT (j) Approval of a food additive safety of a substance under the CONSIDERATIONS petition, establishment or amendment of conditions of its intended use. a regulation for a food substance as (i) Safe or safety means that there is ■ 3. The authority citation for part 25 GRAS under the conditions of its a reasonable certainty in the minds of continues to read as follows: intended use for humans or animals competent scientists that the substance Authority: 21 U.S.C. 321–393; 42 U.S.C. under parts 182, 184, 186, 582, or 584 is not harmful under the conditions of 262, 263b–264; 42 U.S.C. 4321, 4332; 40 CFR of this chapter, the granting of a request its intended use. * * * parts 1500–1508; E.O. 11514, 35 FR 4247, 3 for exemption from regulation as a food * * * * * CFR, 1971 Comp., p. 531–533 as amended by additive under § 170.39 of this chapter, (k) General recognition of safety shall E.O. 11991, 42 FR 26967, 3 CFR, 1978 Comp., or allowing a notification submitted be in accordance with § 170.30. p. 123–124 and E.O. 12114, 44 FR 1957, 3 under 21 U.S.C. 348(h) to become CFR, 1980 Comp., p. 356–360. * * * * * effective, when the substance is to be ■ 8. Amend § 170.30 as follows: ■ 4. In § 25.20, revise paragraph (k) to used as a component of a food-contact ■ a. Revise the last sentence of read as follows: surface of permanent or semipermanent equipment or of another food-contact paragraph (a); § 25.20 Actions requiring preparation of an ■ b. Revise paragraph (b). article intended for repeated use. environmental assessment. ■ c. Revise the the first sentence of (k) Approval of a food additive paragraph (c)(1) and revise paragraph * * * * * petition or color additive petition, (k) Establishment or amendment of a (c)(2); establishment or amendment of a ■ d. Remove ‘‘§ 186.1’’ and add in its regulation for a food substance as GRAS regulation for a food substance as GRAS under the conditions of its intended use place ‘‘part 186’’ wherever it appears in under the conditions of its intended use paragraph (d); for humans or animals under parts 182, for humans or animals under parts 182, ■ e. Revise paragraph (e); 184, 186, 582, or 584 of this chapter, or 184, 186, 582, or 584 of this chapter, or ■ f. Remove and reserve paragraph (f); establishment or amendment of a allowing a notification submitted under ■ g. Remove ‘‘§ 186.1’’ and add in its regulation for a prior-sanctioned food 21 U.S.C. 348(h) to become effective, for ingredient, as defined in §§ 170.3(l) and place ‘‘part 186’’ in paragraphs (h) substances added directly to food that introductory text, (h)(1), (i), (j), and (k); 181.5(a) of this chapter, unless are intended to remain in food through categorically excluded in § 25.32(f), (i), and ingestion by consumers and that are not ■ h. Revise the last sentence of (j), (k), or (r). intended to replace macronutrients in paragraph (l). * * * * * food. The revisions read as follows: ■ 5. In § 25.32, revise paragraphs (f), (i), * * * * * (j), (k), and (r) to read as follows: § 170.30 Eligibility for classification as (r) Approval of a food additive generally recognized as safe (GRAS). § 25.32 Foods, food additives, and color petition or color additive petition, establishment or amendment of a (a) * * * General recognition of safety additives. requires common knowledge throughout regulation for a food substance as GRAS * * * * * the scientific community knowledgeable under the conditions of its intended use (f) Establishment or amendment of a about the safety of substances directly or for humans or animals under parts 182, regulation for a food substance as GRAS indirectly added to food that there is 184, 186, 582, or 584 of this chapter, or under the conditions of its intended use reasonable certainty that the substance allowing a notification submitted under for humans or animals under parts 182, is not harmful under the conditions of 21 U.S.C. 348(h) to become effective for 184, 186, 582, or 584 of this chapter, its intended use (see § 170.3(i)). a substance that occurs naturally in the and establishment or amendment of a (b) General recognition of safety based environment, when the action does not regulation for a prior-sanctioned food upon scientific procedures shall require alter significantly the concentration or ingredient, as defined in §§ 170.3(l) and the same quantity and quality of distribution of the substance, its 181.5(a) of this chapter, if the substance scientific evidence as is required to metabolites, or degradation products in or food ingredient is already marketed obtain approval of a food additive. the environment. in the United States for the proposed General recognition of safety through use. PART 170—FOOD ADDITIVES scientific procedures shall be based * * * * * upon the application of generally (i) Approval of a food additive ■ 6. The authority citation for part 170 available and accepted scientific data, petition, establishment or amendment of continues to read as follows: information, or methods, which a regulation for a food substance as Authority: 21 U.S.C. 321, 341, 342, 346a, ordinarily are published, as well as the GRAS under the conditions of its 348, 371. application of scientific principles, and intended use for humans or animals may be corroborated by the application under parts 182, 184, 186, 582, or 584 ■ 7. In § 170.3, revise paragraph (h), the of unpublished scientific data, of this chapter, the granting of a request first sentence of paragraph (i), and information, or methods. for exemption from regulation as a food paragraph (k), to read as follows: (c)(1) General recognition of safety additive under § 170.39 of this chapter, through experience based on common or allowing a notification submitted § 170.3 Definitions. use in food prior to January 1, 1958, under 21 U.S.C. 348(h) to become * * * * * may be achieved without the quantity or effective, when the substance is present (h) Scientific procedures include the quality of scientific procedures required mstockstill on DSK3G9T082PROD with RULES2 in finished food-packaging material at application of scientific data (including, for approval of a food additive. * * * not greater than 5 percent-by-weight and as appropriate, data from human, (2) A substance used in food prior to is expected to remain with finished animal, analytical, or other scientific January 1, 1958, may be generally food-packaging material through use by studies), information, and methods, recognized as safe through experience consumers or when the substance is a whether published or unpublished, as based on its common use in food when component of a coating of a finished well as the application of scientific that use occurred exclusively or food-packaging material. principles, appropriate to establish the primarily outside of the United States if VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00089 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 55048 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations the information about the experience the conditions of its intended use, he 170.245 Part 5 of a GRAS notice: establishes that the substance is safe will place all of the data and Experience based on common use in under the conditions of its intended use information on which he relies on food before 1958. within the meaning of section 201(u) of public file in the office of the Division 170.250 Part 6 of a GRAS notice: Narrative. 170.255 Part 7 of a GRAS notice: List of the Federal Food, Drug, and Cosmetic of Dockets Management and will supporting data and information in your Act (see also § 170.3(i)). Common use in publish in the Federal Register a notice GRAS notice. food prior to January 1, 1958, that giving the name of the substance, its 170.260 Steps you may take before FDA occurred outside of the United States proposed uses, and any limitations responds to your GRAS notice. shall be documented by published or proposed for purposes other than safety. 170.265 What FDA will do with a GRAS other information and shall be * * * * * notice. corroborated by information from a (3) The Commissioner will evaluate 170.270 Procedures that apply when the second, independent source that intended conditions of use of a notified all comments received. If he concludes substance include use in a product or confirms the history and circumstances that there is convincing evidence that products subject to regulation by the of use of the substance. The information the substance is GRAS under the Food Safety and Inspection Service used to document and to corroborate the conditions of its intended use as (FSIS) of the United States Department of history and circumstances of use of the described in § 170.30, he will publish a Agriculture. substance must be generally available; notice in the Federal Register listing the 170.275 Public disclosure of a GRAS that is, it must be widely available in GRAS conditions of use of the substance notice. the country in which the history of use in part 184 or part 186 of this chapter, 170.280 Submission of a supplement. has occurred and readily available to as appropriate. 170.285 Disposition of pending GRAS interested qualified experts in the affirmation petitions. (4) If, after evaluation of the United States. A person who concludes comments, the Commissioner concludes Subpart E—Generally Recognized as that a use of a substance is GRAS that there is a lack of convincing Safe (GRAS) Notice through experience based on its evidence that a substance is GRAS common use in food outside of the under the conditions of its intended use § 170.203 Definitions. United States should notify FDA of that and that it should be considered a food The definitions and interpretations of view in accordance with subpart E of additive subject to section 409 of the terms in § 170.3 apply to such terms this part. Federal Food, Drug, and Cosmetic Act, when used in this subpart. The * * * * * he shall publish a notice thereof in the following definitions also apply: (e) Food ingredients were listed as Federal Register in accordance with Amendment means any data and GRAS in part 182 of this chapter during § 170.38. information that you submit regarding a 1958–1962 without a detailed scientific ■ 10. In § 170.38, revise paragraph (a) to filed GRAS notice before we respond to review of all available data and read as follows: your notice by letter in accordance with information relating to their safety. § 170.265(b)(1) or cease to evaluate your Beginning in 1969, the Food and Drug § 170.38 Determination of food additive notice in accordance with Administration has undertaken a status. § 170.265(b)(3). systematic review of the status of all (a) The Commissioner may, in GRAS means generally recognized as ingredients used in food based on the accordance with § 170.35(b)(4), publish safe. view that they are GRAS under the a notice in the Federal Register GRAS notice means a submission that conditions of their intended use or determining that a substance is not informs us of your view that a substance subject to a prior sanction. All GRAS under the conditions of its is not subject to the premarket approval affirmations of GRAS status or intended use and is a food additive requirements of the Federal Food, Drug, determinations of food additive status or subject to section 409 of the Federal and Cosmetic Act based on your prior sanction status pursuant to this Food, Drug, and Cosmetic Act. conclusion that the substance is GRAS review shall be handled pursuant to * * * * * under the conditions of its intended use §§ 170.35, 170.38, and 180.1 of this ■ 11. Add subpart E, consisting of in accordance with § 170.30. chapter. Affirmation of GRAS status §§ 170.203 through 170.285, to read as Notified substance means the shall be announced in part 184 or part follows: substance that is the subject of your 186 of this chapter. GRAS notice. * * * * * Subpart E—Generally Recognized as Notifier means the person (e.g., an (l) * * * Any change to the GRAS Safe (GRAS) Notice individual, partnership, corporation, status of a food ingredient in parts 182, association, or other legal entity) who is Sec. responsible for the GRAS notice, even if 184, or 186 of this chapter shall be 170.203 Definitions. accomplished pursuant to § 170.38. another person (such as an attorney, 170.205 Opportunity to submit a GRAS ■ 9. In § 170.35, revise paragraphs (a), notice. agent, or qualified expert) prepares or (b)(1), (3), and (4), and remove 170.210 How to send your GRAS notice to submits the notice or provides an paragraph (c) to read as follows: FDA. opinion about the basis for a conclusion 170.215 Incorporation into a GRAS notice. of GRAS status. § 170.35 Affirmation of generally 170.220 General requirements applicable to Qualified expert means an individual recognized as safe (GRAS) status. a GRAS notice. who is qualified by scientific training (a) The Commissioner, on his own 170.225 Part 1 of a GRAS notice: Signed and experience to evaluate the safety of mstockstill on DSK3G9T082PROD with RULES2 initiative, may affirm that a substance statements and certification. substances under the conditions of their 170.230 Part 2 of a GRAS notice: Identity, that directly or indirectly becomes a intended use in food. method of manufacture, specifications, component of food is GRAS under the and physical or technical effect. Supplement means any data and conditions of its intended use. 170.235 Part 3 of a GRAS notice: Dietary information that you submit regarding a (b)(1) If the Commissioner proposes exposure. filed GRAS notice after we respond to on his own initiative that a substance is 170.240 Part 4 of a GRAS notice: Self- your notice by letter in accordance with entitled to affirmation as GRAS under limiting levels of use. § 170.265(b)(1) or cease to evaluate your VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00090 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 55049 notice in accordance with secret or confidential commercial information, as well as favorable § 170.265(b)(3). information in Part 1 of your GRAS information, known to you and We, our, and us refer to the United notice. pertinent to the evaluation of the safety States Food and Drug Administration (c) In Part 1 of your GRAS notice, you and GRAS status of the use of the (FDA). must: substance; You and your refer to a notifier. (1) Inform us that you are submitting (10) State both the name and position a GRAS notice in accordance with this or title of the person who signs the § 170.205 Opportunity to submit a GRAS subpart; GRAS notice; and notice. (2) Provide the name and address of (11) When applicable, state as Any person may notify FDA of a view your organization; required by § 170.270 whether you: that a substance is not subject to the (3) Provide the name of the notified (i) Authorize us to send any trade premarket approval requirements of substance, using an appropriately secrets to the Food Safety and section 409 of the Federal Food, Drug, descriptive term; Inspection Service (FSIS) of the U.S. and Cosmetic Act based on that person’s (4) Describe the intended conditions Department of Agriculture; or conclusion that the substance is GRAS of use of the notified substance, (ii) Ask us to exclude any trade under the conditions of its intended use. including the foods in which the secrets from the copy of the GRAS substance will be used, the levels of use notice that we will send to FSIS. § 170.210 How to send your GRAS notice to FDA. in such foods, and the purposes for which the substance will be used, § 170.230 Part 2 of a GRAS notice: Identity, (a) Send your GRAS notice to the including, when appropriate, a method of manufacture, specifications, and Office of Food Additive Safety (HFS– description of a subpopulation expected physical or technical effect. 200), Center for Food Safety and to consume the notified substance; In Part 2 of your GRAS notice, you Applied Nutrition, Food and Drug (5) Inform us of the statutory basis for must include: Administration, 5001 Campus Drive, your conclusion of GRAS status (i.e., (a) Scientific data and information College Park, MD 20740. through scientific procedures in that identifies the notified substance. (b) When you submit your GRAS accordance with § 170.30(a) and (b) or (1) Examples of appropriate data and notice, you may do so either in an through experience based on common information include the chemical name, electronic format that is accessible for use in food in accordance with applicable registry numbers (such as a our evaluation or on paper. If you send § 170.30(a) and (c)); Chemical Abstracts Service (CAS) your GRAS notice on paper, a single (6) State your view that the notified registry number or an Enzyme paper copy is sufficient. substance is not subject to the premarket Commission (EC) number), empirical § 170.215 Incorporation into a GRAS approval requirements of the Federal formula, structural formula, quantitative notice. Food, Drug, and Cosmetic Act based on composition, and characteristic You may incorporate into your GRAS your conclusion that the notified properties. notice either specifically identified data substance is GRAS under the conditions (2) When the source of a notified and information that you previously of its intended use; substance is a biological material, you submitted to the Center for Food Safety (7) State that, if we ask to see the data must include data and information and Applied Nutrition (CFSAN), or and information that are the basis for sufficient to identify: specifically identified publicly available your conclusion of GRAS status, either (i) The taxonomic source (e.g., genus, data and information submitted by during or after our evaluation of your species) including, as applicable, data another party, when such data and notice, you will: and information at the sub-species level (i) Agree to make the data and (e.g., variety, strain); information remain in CFSAN’s records, information available to us; and (ii) The part of any plant or animal such as data and information contained (ii) Agree to both of the following used as the source; and in a previous GRAS notice or a food procedures for making the data and (iii) Any known toxicants that could additive petition. information available to us: be in the source; § 170.220 General requirements applicable (A) Upon our request, you will allow (b) A description of the method of to a GRAS notice. us to review and copy the data and manufacture of the notified substance in (a) A GRAS notice has seven parts as information during customary business sufficient detail to evaluate the safety of required by §§ 170.225 through 170.255. hours at the address you specify for the notified substance as manufactured; You must submit the data and where these data and information will (c) Specifications for food-grade information specified in each of these be available to us; and material; and parts on separate pages or sets of pages. (B) Upon our request, you will (d) When necessary to demonstrate (b) You must include each of the provide us with a complete copy of the safety, relevant data and information seven parts in your GRAS notice. If you data and information either in an bearing on the physical or other do not include a part, you must include electronic format that is accessible for technical effect the notified substance is with your GRAS notice an explanation our evaluation or on paper; intended to produce, including the of why that part does not apply to your (8) State your view as to whether any quantity of the notified substance GRAS notice. of the data and information in Parts 2 required to produce such effect. through 7 of your GRAS notice are § 170.225 Part 1 of a GRAS notice: Signed exempt from disclosure under the § 170.235 Part 3 of a GRAS notice: Dietary statements and certification. Freedom of Information Act, 5 U.S.C. exposure. mstockstill on DSK3G9T082PROD with RULES2 (a) Part 1 of your GRAS notice must 552 (e.g., as trade secret or as In part 3 of your GRAS notice, you be dated and signed by a responsible commercial or financial information must provide data and information official of your organization, or by your that is privileged or confidential). about dietary exposure (i.e., the amount attorney or agent. (9) Certify that, to the best of your of relevant substances that consumers (b) Except as required by paragraph knowledge, your GRAS notice is a are likely to eat or drink as part of a total (c)(8) of this section, you must not complete, representative, and balanced diet), regardless of whether your include any information that is trade submission that includes unfavorable conclusion of GRAS status is through VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00091 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 55050 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations scientific procedures or through dietary sources and taking into account § 170.260 Steps you may take before FDA experience based on common use in any chemically or pharmacologically responds to your GRAS notice. food, as follows: related substances in such diet; (a) You may submit a timely (a) You must provide an estimate of (2) In your explanation, you must amendment to your filed GRAS notice, dietary exposure to the notified identify what specific data and to update your GRAS notice or in substance that includes exposure from information that you discuss in response to a question from us, before its intended use and all sources in the accordance with paragraph (a)(1) of this we respond to your notice by letter in diet; and section are generally available, and what accordance with § 170.265(b)(1) or cease (b) When applicable, you must to evaluate your notice in accordance specific data and information that you provide an estimate of dietary exposure with § 170.265(b)(3). discuss in accordance with paragraph to any other substance that is expected (b) At any time before we respond to (a)(1) of this section are not generally to be formed in or on food because of your GRAS notice in accordance with available, by providing citations to the the use of the notified substance (e.g., § 170.265(b)(1), you may request in list of data and information that you hydrolytic products or reaction writing that we cease to evaluate your include in Part 7 of your GRAS notice products); GRAS notice. Your request does not in accordance with § 170.255; (c) When applicable, you must preclude you from submitting a future provide an estimate of dietary exposure (b) You must explain how the GRAS notice in accordance with this to any other substance that is present generally available data and information subpart with respect to the notified with the notified substance either that you rely on to establish safety in substance. naturally or due to its manufacture (e.g., accordance with paragraph (a) of this contaminants or by-products); section provide a basis for your § 170.265 What FDA will do with a GRAS (d) You must describe the source of conclusion that the notified substance is notice. any food consumption data that you use generally recognized, among qualified (a)(1) We will conduct an initial to estimate dietary exposure in experts, to be safe under the conditions evaluation of your submission to accordance with paragraphs (a) through of its intended use; determine whether to file it as a GRAS (c) of this section; and (c) You must either: notice for evaluation of your view that (e) You must explain any assumptions the notified substance is GRAS under you made to estimate dietary exposure (1) Identify, discuss, and place in the conditions of its intended use. in accordance with paragraphs (a) context, data and information that are, (2) If we file your submission as a through (c) of this section. or may appear to be, inconsistent with GRAS notice, we will send you a letter your conclusion of GRAS status, that informs you of the date of filing. § 170.240 Part 4 of a GRAS notice: Self- regardless of whether those data and (3) If we do not file your submission limiting levels of use. information are generally available; or as a GRAS notice, we will send you a In circumstances where the amount of (2) State that you have reviewed the letter that informs you of that fact and the notified substance that can be added available data and information and are provides our reasons for not filing the to food is limited because food not aware of any data and information submission as a GRAS notice. containing levels of the notified that are, or may appear to be, (4) We will consider any timely substance above a particular level inconsistent with your conclusion of amendment that you submit to a filed would become unpalatable or GRAS status; GRAS notice, to update your GRAS technologically impractical, in Part 4 of notice or in response to a question from your GRAS notice you must include (d) If you view any of the data and information in your notice as exempt us, before we respond to you by letter data and information on such self- in accordance with paragraph (b)(1) of limiting levels of use. from disclosure under the Freedom of Information Act, you must identify the this section, if we deem that doing so is § 170.245 Part 5 of a GRAS notice: specific data and information; and feasible within the timeframes Experience based on common use in food established in paragraph (b) of this (e) For non-public, safety-related data section. If we deem that considering before 1958. and information considered in reaching your amendment is not feasible within If the statutory basis for your a conclusion of GRAS status, you must conclusion of GRAS status is through the timeframes established in paragraph explain how there could be a basis for (b) of this section or if we have granted experience based on common use in a conclusion of GRAS status if qualified food, in Part 5 of your GRAS notice you your request to cease to evaluate your experts do not have access to such data notice, we will inform you that we are must include evidence of a substantial and information. history of consumption of the notified not considering your amendment. substance for food use by a significant § 170.255 Part 7 of a GRAS notice: List of (b)(1) Within 180 days of filing, we number of consumers prior to January 1, supporting data and information in your will respond to you by letter based on 1958. GRAS notice. our evaluation of your notice. We may extend the 180 day timeframe by 90 § 170.250 Part 6 of a GRAS notice: (a) In part 7 of your GRAS notice, you days on an as needed basis. Narrative. must include a list of all of the data and (2) If we extend the timeframe, we In Part 6 of your GRAS notice, you information that you discuss in Part 6 of will inform you in writing of the must include a narrative that provides your GRAS notice to provide a basis for extension as soon as practicable but no the basis for your conclusion of GRAS your view that the notified substance is later than within 180 days of filing. status, in which: safe under the conditions of its intended (3) If you ask us to cease to evaluate mstockstill on DSK3G9T082PROD with RULES2 (a)(1) You must explain why the data use as described in accordance with your GRAS notice in accordance with and information in your notice provide § 170.250(a)(1). § 170.260(b), we will send you a letter a basis for your view that the notified (b) You must specify which data and informing you of our decision regarding substance is safe under the conditions of information that you list in accordance your request. its intended use. In your explanation, with paragraph (a) of this section are (c) If circumstances warrant, we will you must address the safety of the generally available, and which data and send you a subsequent letter about the notified substance, considering all information are not generally available. notice. VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00092 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 55051 § 170.270 Procedures that apply when the from public disclosure in accordance Authority: 21 U.S.C. 321, 342, 348, 371. intended conditions of use of a notified with part 20 of this chapter. substance include use in a product or ■ 15. In § 186.1, revise the first sentence products subject to regulation by the Food § 170.280 Submission of a supplement. of paragraph (a), and revise the fifth Safety and Inspection Service (FSIS) of the If circumstances warrant, you may sentence and remove the last sentence United States Department of Agriculture. submit a supplement to a filed GRAS of paragraph (b)(1) to read as follows. If the intended conditions of use of notice after we respond to your notice § 186.1 Substances added indirectly to the notified substance include use in a by letter in accordance with human food affirmed as generally product or products subject to § 170.265(b)(1) or cease to evaluate your recognized as safe (GRAS). regulation by FSIS under statutes that it notice in accordance with (a) The indirect human food administers: § 170.265(b)(3). ingredients listed in this part have been (a) When applicable, you must reviewed by the Food and Drug include in your GRAS notice a § 170.285 Disposition of pending GRAS affirmation petitions. Administration and affirmed to be statement as to whether you: generally recognized as safe (GRAS) for (1) Authorize us to send any trade Because the procedure to submit a the purposes and under the conditions secrets to FSIS; or GRAS notice is replacing the former prescribed, providing they comply with (2) Ask us to exclude any trade secrets process to submit a GRAS affirmation the purity specifications listed in this from the copy of the GRAS notice that petition, the following will happen to a part or, in the absence of purity we will send to FSIS. filed GRAS affirmation petition that is specifications, are of a purity suitable (b)(1) We will forward a copy of a pending on October 17, 2016. for their intended use in accordance GRAS notice or relevant portions (a) On October 17, 2016, we will close with § 170.30(h)(1) of this chapter. thereof to FSIS; the docket for any GRAS affirmation * * * (2) We will exclude any trade secrets petition that is still pending as of (b) * * * unless you have authorized us to do so October 17, 2016. (1) * * * In such a case, a in accordance with paragraph (a)(1) of (b) Any person who submitted a manufacturer may not rely on the this section; and GRAS affirmation petition described in regulation as authorizing that use but (c) We will ask FSIS to advise this section may submit a GRAS notice shall have a basis to conclude that the whether the intended conditions of use as described in this subpart and request use is GRAS or shall use the ingredient comply with applicable statutes and that we incorporate the GRAS in accordance with a food additive regulations, or, if not, whether the use affirmation petition as described in regulation. * * * of the substance would be permitted in § 170.215. products under FSIS’ jurisdiction under * * * * * specified conditions or restrictions. PART 184—DIRECT FOOD SUBSTANCES AFFIRMED AS PART 570—FOOD ADDITIVES (d) As appropriate, we will inform you of the advice we receive from FSIS GENERALLY RECOGNIZED AS SAFE ■ 16. The authority citation for part 570 in the letter we send you in accordance continues to read as follows: ■ 12. The authority citation for part 184 with § 170.265(b)(1). continues to read as follows: Authority: 21 U.S.C. 321, 341, 342, 346a, § 170.275 Public disclosure of a GRAS 348, 371. Authority: 21 U.S.C. 321, 342, 348, 371. notice. ■ 17. In § 570.3, revise paragraphs (f), ■ 13. In § 184.1, revise the first sentence (a) The data and information in a (h), the first sentence of (i), and (k), and GRAS notice (including data and of paragraph (a), and revise the fifth add paragraph (n) to read as follows: information submitted in any sentence and remove the last sentence amendment or supplement to your of paragraph (b)(1) to read as follows. § 570.3 Definitions. GRAS notice or incorporated into your § 184.1 Substances added directly to * * * * * GRAS notice) are: human food affirmed as generally (f) Common use in food means a (1) Considered a mandatory, rather recognized as safe (GRAS). substantial history of consumption of a than voluntary, submission for purposes (a) The direct human food ingredients substance by a significant number of of their status under the Freedom of listed in this part have been reviewed by animals of the species to which the Information Act and our public the Food and Drug Administration and substance is intended to be fed (and, for information requirements in part 20 of affirmed to be generally recognized as food-producing animals fed with such this chapter; and safe (GRAS) for the purposes and under substance, also means a substantial (2) Available for public disclosure in the conditions prescribed. * * * history of consumption by humans accordance with part 20 of this chapter (b) * * * consuming human foods derived from as of the date that we receive your (1) * * * In such a case, a those food-producing animals), prior to GRAS notice. manufacturer may not rely on the January 1, 1958. (b) We will make the following regulation as authorizing that use but * * * * * readily accessible to the public: shall have a basis to conclude that that (h) Scientific procedures include the (1) A list of filed GRAS notices, use is GRAS or shall use the ingredient application of scientific data (including, including the information described in in accordance with a food additive as appropriate, data from human, § 170.225(c)(2) through (c)(5); regulation. * * * animal, analytical, or other scientific (2) The text of any letter that we issue studies), information, and methods, mstockstill on DSK3G9T082PROD with RULES2 * * * * * under § 170.265(b)(1) or (c); and whether published or unpublished, as (3) The text of any letter that we issue PART 186—INDIRECT FOOD well as the application of scientific under § 170.265(b)(3) if we grant your SUBSTANCES AFFIRMED AS principles, appropriate to establish the request that we cease to evaluate your GENERALLY RECOGNIZED AS SAFE safety of a substance under the notice. conditions of its intended use. (c) We will disclose all remaining data ■ 14. The authority citation for part 186 (i) Safe or safety means that there is and information that are not exempt continues to read as follows: a reasonable certainty in the minds of VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00093 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 55052 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations competent scientists that the substance (2) A substance used in food prior to ■ 19. In § 570.35, revise paragraphs (a), is not harmful under the conditions of January 1, 1958, may be generally (b)(1), (3), and (4), and remove its intended use. * * * recognized as safe through experience paragraph (c) to read as follows: * * * * * based on its common use in food when § 570.35 Affirmation of generally (k) General recognition of safety shall that use occurred exclusively or recognized as safe (GRAS) status. be in accordance with § 570.30. primarily outside of the United States if the information about the experience (a) The Commissioner, on his own * * * * * initiative, may affirm that a substance (n) Food-producing animal means an establishes that the substance is safe under the conditions of its intended use that directly or indirectly becomes a animal used to produce human food. component of food is GRAS under the within the meaning of section 201(u) of ■ 18. In § 570.30, revise the last conditions of its intended use. the Federal Food, Drug, and Cosmetic sentence of paragraph; (a); revise (b)(1) If the Commissioner proposes Act (see also § 570.3(i)) for both the on his own initiative that a substance is paragraphs (b) through (d); and revise target animal and for humans entitled to affirmation as GRAS under the last sentence in paragraph (i) to read consuming human food derived from the conditions of its intended use, he as follows: food-producing animals. Common use will place all of the data and § 570.30 Eligibility for classification as in food prior to January 1, 1958, that information on which he relies on generally recognized as safe (GRAS). occurred outside of the United States public file in the office of the Division (a) * * * General recognition of safety shall be documented by published or of Dockets Management and will requires common knowledge throughout other information and shall be publish in the Federal Register a notice the scientific community knowledgeable corroborated by information from a giving the name of the substance, its about the safety of substances directly or second, independent source that proposed uses, and any limitations indirectly added to food that there is confirms the history and circumstances proposed for purposes other than safety. reasonable certainty that the substance of use of the substance. The information * * * * * is not harmful to either the target animal used to document and to corroborate the (3) The Commissioner will evaluate or to humans consuming human food history and circumstances of use of the all comments received. If he concludes derived from food-producing animals substance must be generally available; that there is convincing evidence that under the conditions of its intended use that is, it must be widely available in the substance is GRAS under the (see § 570.3(i)). the country in which the history of use conditions of its intended use as (b) General recognition of safety based has occurred and readily available to described in § 570.30, he will publish a upon scientific procedures shall require interested qualified experts in the notice in the Federal Register listing the the same quantity and quality of United States. A person who concludes GRAS conditions of use in this scientific evidence as is required to that a use of a substance is GRAS subchapter E. obtain approval of a food additive. through experience based on its (4) If, after evaluation of the General recognition of safety through common use in food outside of the comments, the Commissioner concludes scientific procedures shall address United States should notify FDA of that that there is a lack of convincing safety for both the target animal and for view in accordance with subpart E of evidence that the substance is GRAS humans consuming human food derived this part. under the conditions of its intended use from food-producing animals and shall (d) The food ingredients listed as and that it should be considered a food be based upon the application of GRAS in part 582 of this chapter or additive subject to section 409 of the generally available and accepted affirmed as GRAS in part 584 of this Federal Food, Drug, and Cosmetic Act, scientific data, information, or methods, chapter do not include all substances he shall publish a notice thereof in the which ordinarily are published, as well that are generally recognized as safe for Federal Register in accordance with as the application of scientific their intended use in food. Because of § 570.38. principles, and may be corroborated by the large number of substances the ■ 20. In § 570.38, revise paragraph (a) to the application of unpublished intended use of which results or may read as follows: scientific data, information, or methods. reasonably be expected to result, (c)(1) General recognition of safety directly or indirectly, in their becoming § 570.38 Determination of food additive a component or otherwise affecting the status. through experience based on common use in food prior to January 1, 1958, characteristics of food, it is (a) The Commissioner may, in shall address safety for both the target impracticable to list all such substances accordance with § 570.35(b)(4), publish animal and for humans consuming that are GRAS. A food ingredient of a notice in the Federal Register human food derived from food- natural biological origin that has been determining that a substance is not producing animals and may be achieved widely consumed for its nutrient GRAS under the conditions of its without the quantity or quality of properties in the United States prior to intended use and is a food additive scientific procedures required for January 1, 1958, without known subject to section 409 of the Federal approval of a food additive. General detrimental effects, which is subject Food, Drug, and Cosmetic Act. recognition of safety through experience only to conventional processing as * * * * * based on common use in food prior to practiced prior to January 1, 1958, and ■ 21. Add and reserve subparts C and D. January 1, 1958, shall be based solely on for which no known safety hazard ■ 22. Add subpart E, consisting of food use of the substance in the same exists, will ordinarily be regarded as §§ 570.203 through 570.280, to read as animal species prior to January 1, 1958, GRAS without specific inclusion in part follows: mstockstill on DSK3G9T082PROD with RULES2 and shall ordinarily be based upon 582 or part 584 of this chapter. generally available data and * * * * * Subpart E—Generally Recognized as information. An ingredient not in (i) * * * Any use of such an Safe (GRAS) Notice common use in food prior to January 1, ingredient not in full compliance with Sec. 1958, may achieve general recognition each such established limitation shall 570.203 Definitions. of safety only through scientific require a food additive regulation. 570.205 Opportunity to submit a GRAS procedures. * * * * * notice. VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00094 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 55053 570.210 How to send your GRAS notice to Supplement means any data and (b) Except as required by paragraph FDA. information that you submit regarding a (c)(8) of this section, you must not 570.215 Incorporation into a GRAS notice. filed GRAS notice after we respond to include any information that is trade 570.220 General requirements applicable to your notice by letter in accordance with secret or confidential commercial a GRAS notice. 570.225 Part 1 of a GRAS notice: Signed § 570.265(b)(1) or cease to evaluate your information in Part 1 of your GRAS statements and certification. notice in accordance with notice. 570.230 Part 2 of a GRAS notice: Identity, § 570.265(b)(3). (c) In Part 1 of your GRAS notice, you method of manufacture, specifications, We, our, and us refer to the United must: and physical or technical effect. States Food and Drug Administration (1) Inform us that you are submitting 570.235 Part 3 of a GRAS notice: Target (FDA). a GRAS notice in accordance with this animal and human exposures. You and your refer to a notifier. subpart; 570.240 Part 4 of a GRAS notice: Self- (2) Provide the name and address of limiting levels of use. § 570.205 Opportunity to submit a GRAS your organization; 570.245 Part 5 of a GRAS notice: notice. (3) Provide the name of the notified Experience based on common use in Any person may notify FDA of a view substance, using an appropriately food before 1958. that a substance is not subject to the descriptive term; 570.250 Part 6 of a GRAS notice: Narrative. premarket approval requirements of 570.255 Part 7 of a GRAS notice: List of (4) Describe the intended conditions supporting data and information in your section 409 of the Federal Food, Drug, of use of the notified substance, GRAS notice. and Cosmetic Act based on that person’s including stating whether the substance 570.260 Steps you may take before FDA conclusion that the substance is GRAS will be added to food (including responds to your GRAS notice. under the conditions of its intended use. drinking water) for animals in which the 570.265 What FDA will do with a GRAS substance will be used; identifying the notice. § 570.210 How to send your GRAS notice to FDA. foods to which it will be added, the 570.275 Public disclosure of a GRAS levels of use in such foods, and the notice. (a) Send your GRAS notice to the animal species for which these foods are 570.280 Submission of a supplement. Division of Animal Feeds (HFV–220), intended (including, when appropriate, Center for Veterinary Medicine, Food a description of a subpopulation Subpart E—Generally Recognized as and Drug Administration, 7519 Standish Safe (GRAS) Notice expected to consume the notified Pl., Rockville, MD 20855. substance); and the purposes for which (b) When you submit your GRAS § 570.203 Definitions. the substance will be used; notice, you may do so either in an (5) Inform us of the statutory basis for The definitions and interpretations of electronic format that is accessible for terms in § 570.3 apply to such terms your conclusion of GRAS status (i.e., our evaluation or on paper. If you send through scientific procedures in when used in this subpart. The your GRAS notice on paper, a single following definitions also apply: accordance with § 570.30(a) and (b) or paper copy is sufficient. through experience based on common Amendment means any data and information that you submit regarding a § 570.215 Incorporation into a GRAS use in animal food in accordance with filed GRAS notice before we respond to notice. § 570.30(a) and (c)); your notice by letter in accordance with You may incorporate into your GRAS (6) State your view that the notified § 570.265(b)(1) or cease to evaluate your notice either specifically identified data substance is not subject to the premarket notice in accordance with and information that you previously approval requirements of the Federal § 570.265(b)(3). submitted to the Center for Veterinary Food, Drug, and Cosmetic Act based on GRAS means generally recognized as Medicine (CVM), or specifically your conclusion that the notified safe. identified publicly available data and substance is GRAS under the conditions information submitted by another party, of its intended use; GRAS notice means a submission that when such data and information remain (7) State that, if we ask to see the data informs us of your view that a substance in CVM’s records, such as data and and information that are the basis for is not subject to the premarket approval information contained in a previous your conclusion of GRAS status, either requirements of the Federal Food, Drug, GRAS notice or a food additive petition. during or after our evaluation of your and Cosmetic Act based on your notice, you will: conclusion that the substance is GRAS (i) Agree to make the data and § 570.220 General requirements applicable under the conditions of its intended use to a GRAS notice. information available to us; and in accordance with § 570.30. (ii) Agree to both of the following (a) A GRAS notice has seven parts as Notified substance means the procedures for making the data and required by §§ 570.225 through 570.255. substance that is the subject of your information available to us: You must submit the data and GRAS notice. (A) Upon our request, you will allow information specified in each of these Notifier means the person (e.g., an parts on separate pages or sets of pages. us to review and copy the data and individual, partnership, corporation, (b) You must include each of the information during customary business association, or other legal entity) who is seven parts in your GRAS notice. If you hours at the address you specify for responsible for the GRAS notice, even if do not include a part, you must include where these data and information will another person (such as an attorney, with your GRAS notice an explanation be available to us; and agent, or qualified expert) prepares or of why that part does not apply to your (B) Upon our request, you will submits the notice or provides an GRAS notice. provide us with a complete copy of the mstockstill on DSK3G9T082PROD with RULES2 opinion about the basis for a conclusion data and information either in an of GRAS status. § 570.225 Part 1 of a GRAS notice: Signed electronic format that is accessible for Qualified expert means an individual statements and certification. our evaluation or on paper; who is qualified by scientific training (a) Part 1 of your GRAS notice must (8) State your view as to whether any and experience to evaluate the safety of be dated and signed by a responsible of the data and information in Parts 2 substances under the conditions of their official of your organization, or by your through 7 of your GRAS notice are intended use in animal food. attorney or agent. exempt from disclosure under the VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00095 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 55054 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations Freedom of Information Act, 5 U.S.C. procedures or through experience based § 570.245 Part 5 of a GRAS notice: 552 (e.g., as trade secret or as on common use in food, as follows: Experience based on common use in food commercial or financial information (a) For exposure to the target animal, before 1958. that is privileged or confidential); you must provide: If the statutory basis for your (9) Certify that, to the best of your (1) The amount of the notified conclusion of GRAS status is through knowledge, the GRAS notice is a substance that different target animal experience based on common use in complete, representative, and balanced species are likely to consume in the animal food, in Part 5 of your GRAS submission that includes unfavorable animal food (including drinking water) notice you must include evidence of a information, as well as favorable as part of the animal’s total diet, substantial history of consumption of information, known to you and including the intended use and all other the notified substance for food use by a pertinent to the evaluation of the safety sources in the total diet; and significant number of animals of the and GRAS status of the use of the (2) When applicable, the amount of species to which the substance is substance; and any other substance that is expected to intended to be fed prior to January 1, (10) State both the name and the be formed in or on food because of the 1958, and evidence of a substantial position or title of the person who signs use of the notified substance (e.g., history of consumption by humans the GRAS notice. hydrolytic products or reaction consuming human foods derived from products); food-producing animals prior to January § 570.230 Part 2 of a GRAS notice: Identity, (3) When applicable, the amount of 1, 1958. method of manufacture, specifications, and any other substance that is present with physical or technical effect. the notified substance either naturally § 570.250 Part 6 of a GRAS notice: In Part 2 of your GRAS notice, you or due to its manufacture (e.g., Narrative. must include: contaminants or by-products); In Part 6 of your GRAS notice, you (a) Scientific data and information (4) The data and information you rely must include a narrative that provides that identifies the notified substance. on to establish the amount of the the basis for your conclusion of GRAS (1) Examples of appropriate data and notified substance and the amounts of status, in which: information include the chemical name, any other substance in accordance with (a)(1) You must explain why the data applicable registry numbers (such as a paragraphs (a)(1) through (a)(3) of this and information in your notice provide Chemical Abstracts Service (CAS) section that different target animal a basis for your view that the notified registry number or an Enzyme species are likely to consume in the substance is safe under the conditions of Commission (EC) number), empirical animal food (including drinking water) its intended use for both the target formula, structural formula, quantitative as part of the animal’s total diet; and animal and for humans consuming composition, and characteristic (b) When the intended use is in food human food derived from food- properties. for food-producing animals, you must producing animals. In your explanation, (2) When the source of a notified provide: you must address the safety of the substance is a biological material, you (1) The potential quantities of any notified substance, considering all must include data and information residues that humans may be exposed to animal food (including drinking water) sufficient to identify: in edible animal tissues, including: as part of the animal’s total diet, taking (i) Residues of the notified substance; into account any chemically or (i) The taxonomic source (e.g., genus, (ii) Residues of any other substance pharmacologically related substances in species), including as applicable data that is expected to be formed in or on and information at the sub-species level such diet. In your explanation, you must the animal food because of the use of also address the safety of the notified (e.g., variety, strain); the notified substance; and (ii) The part of any plant or animal substance in regard to human exposure, (iii) Residues from any other used as the source; and considering all dietary sources and substance that is present with the (iii) Any known toxicants that could taking into account any chemically or notified substance whether naturally, be in the source; pharmacologically related substances; due to its manufacture (e.g., (2) In your explanation, you must (b) A description of the method of contaminants or by-products), or manufacture of the notified substance in identify what specific data and produced as a metabolite in edible sufficient detail to evaluate the safety of information that you discuss in animal tissues when the notified the notified substance as manufactured; accordance with paragraph (a)(1) of this substance is consumed by a food- (c) Specifications for material that is section are generally available, and what producing animal; and of appropriate grade for use in animal (2) The data and information you rely specific data and information that you food; and on to establish, in accordance with discuss in accordance with paragraph (d) When necessary to demonstrate paragraph (b)(1) of this section, the (a)(1) of this section are not generally safety, relevant data and information potential quantities of any residues that available, by providing citations to the bearing on the physical or other humans may be exposed to in edible list of data and information that you technical effect the notified substance is animal tissues. include in Part 7 of your GRAS notice intended to produce, including the in accordance with § 570.255; quantity of the notified substance § 570.240 Part 4 of a GRAS notice: Self- (b) You must explain how the required to produce such effect. limiting levels of use. generally available data and information In circumstances where the amount of that you rely on to establish safety in § 570.235 Part 3 of a GRAS notice: Target the notified substance that can be added accordance with paragraph (a) of this animal and human exposures. to animal food is limited because animal section provide a basis for your mstockstill on DSK3G9T082PROD with RULES2 In part 3 of your GRAS notice, you food containing levels of the notified conclusion that the notified substance is must provide data and information substance above a particular level generally recognized, among qualified about exposure to the target animal and would become unpalatable or experts, to be safe under the conditions to humans consuming human food technologically impractical, in Part 4 of of its intended use for both the target derived from food-producing animals, your GRAS notice you must include animal and for humans consuming regardless of whether your conclusion data and information on such self- human food derived from food- of GRAS status is through scientific limiting levels of use. producing animals; VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00096 Fmt 4701 Sfmt 4700 E:\FR\FM\17AUR2.SGM 17AUR2 Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations 55055 (c) You must either: § 570.265(b)(1), you may request in (c) If circumstances warrant, we will (1) Identify, discuss, and place in writing that we cease to evaluate your send you a subsequent letter about the context, data and information that are, GRAS notice. Your request does not notice. or may appear to be, inconsistent with preclude you from submitting a future your conclusion of GRAS status, GRAS notice in accordance with this § 570.275 Public disclosure of a GRAS regardless of whether those data and notice. subpart with respect to the notified information are generally available; or substance. (a) The data and information in a (2) State that you have reviewed the GRAS notice (including data and available data and information and are § 570.265 What FDA will do with a GRAS information submitted in any not aware of any data and information notice. amendment or supplement to your that are, or may appear to be, (a)(1) We will conduct an initial GRAS notice, or incorporated into your inconsistent with your conclusion of evaluation of your submission to GRAS notice) are: GRAS status; determine whether to file it as a GRAS (1) Considered a mandatory, rather (d) If you view any of the data and notice for evaluation of your view that than voluntary, submission for purposes information in your notice as exempt the notified substance is GRAS under of their status under the Freedom of from disclosure under the Freedom of the conditions of its intended use. Information Act and our public Information Act, you must identify the (2) If we file your submission as a information requirements in part 20 of specific data and information; and GRAS notice, we will send you a letter this chapter; and (e) For non-public, safety-related data that informs you of the date of filing. and information considered in reaching (3) If we do not file your submission (2) Available for public disclosure in a conclusion of GRAS status, you must as a GRAS notice, we will send you a accordance with part 20 of this chapter explain how there could be a basis for letter that informs you of that fact and as of the date that we receive your a conclusion of GRAS status if qualified provide our reasons for not filing the GRAS notice. experts do not have access to such data submission as a GRAS notice. (b) We will make the following and information. (4) We will consider any timely readily accessible to the public: amendment that you submit to a filed (1) A list of filed GRAS notices, § 570.255 Part 7 of a GRAS notice: List of including the information described in supporting data and information in your GRAS notice, to update your GRAS GRAS notice. notice or in response to a question from § 570.225(c)(2) through (c)(5); us, before we respond to you by letter (2) The text of any letter that we issue (a) In part 7 of your GRAS notice, you in accordance with paragraph (b)(1) of under § 570.265(b)(1) or (c); and must include a list of all of the data and information that you discuss in Part 6 of this section, if we deem that doing so is (3) The text of any letter that we issue your GRAS notice to provide a basis for feasible within the timeframes under § 570.265(b)(3) if we grant your your view that the notified substance is established in paragraph (b) of this request that we cease to evaluate your safe under the conditions of its intended section. If we deem that considering notice. use as described in accordance with your amendment is not feasible within (c) We will disclose all remaining data § 570.250(a)(1). the timeframes established in paragraph and information that are not exempt (b) You must specify which data and (b) of this section or if we have granted from public disclosure in accordance information that you list in accordance your request to cease to evaluate your with part 20 of this chapter. with paragraph (a) of this section are notice, we will inform you that we are generally available, and which data and not considering your amendment. § 570.280 Submission of a supplement. information are not generally available. (b)(1) Within 180 days of filing, we If circumstances warrant, you may will respond to you by letter based on submit a supplement to a filed GRAS § 570.260 Steps you may take before FDA our evaluation of your notice. We may notice after we respond to your notice responds to your GRAS notice. extend the 180 day timeframe by 90 by letter in accordance with (a) You may submit a timely days on an as needed basis. § 570.265(b)(1) or cease to evaluate your amendment to your filed GRAS notice, (2) If we extend the timeframe, we notice in accordance with to update your GRAS notice or in will inform you in writing of the § 570.265(b)(3). response to a question from us, before extension as soon as practicable but no we respond to your notice by letter in later than within 180 days of filing. Dated: August 8, 2016. accordance with § 570.265(b)(1) or cease (3) If you ask us to cease to evaluate Jeremy Sharp, to evaluate your notice in accordance your GRAS notice in accordance with Deputy Commissioner for Policy, Planning, with § 570.265(b)(3). § 570.260(b), we will send you a letter Legislation and Analysis. (b) At any time before we respond to informing you of our decision regarding [FR Doc. 2016–19164 Filed 8–12–16; 11:15 am] your notice by letter in accordance with your request. BILLING CODE 4164–01–P mstockstill on DSK3G9T082PROD with RULES2 VerDate Sep<11>2014 17:25 Aug 16, 2016 Jkt 238001 PO 00000 Frm 00097 Fmt 4701 Sfmt 9990 E:\FR\FM\17AUR2.SGM 17AUR2