Regulatory Framework for Substances 
Intended for Use in Human Food or 
Animal Food on the Basis of the 
Generally Recognized as Safe (GRAS) 
Provision of the Federal Food, Drug, and 
Cosmetic Act: Guidance for Industry 
 
 
Additional copies are available from: 
Office of Food Additive Safety (HFS-200) 
Center for Food Safety and Applied Nutrition 
Food and Drug Administration 
5001 Campus Drive 
College Park, MD 20740 
(Tel) 240-402-1200 
http://www.fda.gov/Food Guidances  
and 
Division of Animal Feeds (HFV-220) 
Office of Surveillance and Compliance 
Center for Veterinary Medicine 
Food and Drug Administration 
7519 Standish Place 
Rockville, MD 20855 
(Tel) 240-402-7077 
http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/u
cm042450.htm  
 
You may submit electronic or written comments regarding this guidance at any time. Submit 
electronic comments to https://www/regulations.gov.  Submit written comments to the Dockets 
Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, 
Rockville, MD 20852. All comments should be identified with the docket number FDA-2016-D-
4484 and with the title of the guidance document.  
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Food Safety and Applied Nutrition 
Center for Veterinary Medicine 
 
November 2017  Contains Nonbinding Recommendations 
Table of Contents 
I.  Introduction 
II.  Background 
A.  What You Need to Know About the Laws and Regulations Applicable to Substances 
Added to Foods 
B.  What You Need to Know About the GRAS Notification Procedure 
III.  Discussion and Recommendations 
A.  GRAS Criteria 
B.  GRAS Notification Procedure 
C.  Safety Assessment 
D.  GRAS Panels 
E.  Additional Information Regarding a Substance Intended for Use in Animal Food 
IV.  References 
Appendix 
 
  Contains Nonbinding Recommendations 
Regulatory Framework for Substances 
Intended for Use in Human Food or 
Animal Food on the Basis of the 
Generally Recognized as Safe (GRAS) 
Provision of the Federal Food, Drug, and 
Cosmetic Act: Guidance for Industry
1  
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or we) 
on this topic. It does not establish any rights for any person and is not binding on FDA or the 
public. You can use an alternative approach if it satisfies the requirements of the applicable 
statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible 
for this guidance as listed on the title page.  
 
 
 
I.  Introduction 
This guidance is intended for any person (you) who intends to market a food substance on the 
basis of a conclusion that the substance is GRAS under the conditions of its intended use (a 
GRAS conclusion), including a manufacturer of the food substance, a manufacturer of a food 
product containing the food substance, and a distributor of a food product containing the food 
substance.2  We are issuing this guidance to:  
  Direct you to the statutory and regulatory criteria that govern eligibility for classification 
of a substance as GRAS under the conditions of its intended use, and remind you of your 
responsibilities to comply with those criteria;  
  Advise you to carefully consider whether the intended use of the food substance fully 
satisfies the criteria for eligibility for classification as GRAS and is lawful under sections 
201(s) and 409 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and our 
regulations in Title 21 of the Code of Federal Regulations (21 CFR);  
                                                 
1 This guidance has been prepared by the Office of Food Additive Safety in the Center for Food Safety and Applied 
Nutrition (CFSAN) and the Division of Animal Feeds in the Office of Surveillance and Compliance in the Center 
for Veterinary Medicine (CVM) at the U.S. Food and Drug Administration.  
2 FDA finalized the framework for the GRAS notification procedure and revised the regulatory criteria for eligibility 
for classification as GRAS in 2016 (81 FR 54960, Federal Register of August 17, 2016). The effective date of this 
rule is October 17, 2016.  
  1  Contains Nonbinding Recommendations 
  Remind you that a GRAS conclusion based upon scientific procedures requires the same 
quantity and quality of scientific evidence as is required to obtain approval of a food 
additive and direct you to a series of our guidance documents that address scientific 
issues associated with demonstrating the safety of a food substance;  
  Remind you that a GRAS conclusion based on common use in food requires evidence of 
a substantial history of consumption prior to January 1, 1958;  
  Remind you that all GRAS conclusions must be considered in context based on the 
knowledge and information available at a point in time, because scientific knowledge and 
information about a particular substance can evolve and sometimes change over time;  
  Strongly encourage you to contact us and follow the available procedures for our 
oversight of GRAS conclusions by submitting a GRAS Notice to us in accordance with 
the procedures in 21 CFR part 170, subpart E (for a substance that would be used in 
human food) or 21 CFR part 570, subpart E (for a substance that would be used in animal 
food); and 
  Recommend that you use the framework for a GRAS notice in documenting a GRAS 
conclusion if you decide to market a food substance on the basis of an independent 
GRAS conclusion (i.e., a GRAS conclusion that you do not submit to FDA as a GRAS 
notice). 
  
We also are issuing this guidance to advise you that when a substance is not GRAS under the 
conditions of its intended use (or is not otherwise excepted from the definition of food additive 
in section 201(s) of the FD&C Act), that use of the substance is a food additive use subject to 
FDAs premarket review as mandated by the FD&C Act. Any food that is, or bears or contains, 
an unapproved food additive is deemed unsafe and is therefore adulterated under the FD&C Act. 
When a substance added to food is not GRAS (and is not otherwise excepted from the definition 
of a food additive) and is not approved as a food additive under the conditions of its intended 
use, we can take various actions, including issuing a warning letter (which we make public on 
our Web site) to companies that manufacture or distribute the food additive and/or food 
containing the food additive; issuing a public alert; and taking enforcement action to stop 
distribution of the food substance and foods containing it on the grounds that such foods are or 
contain an unlawful food additive. As appropriate, we can issue a declaratory order determining 
that the substance is not GRAS under the conditions of its intended use and is a food additive 
subject to section 409 of the FD&C Act. As we implement the GRAS notification procedure that 
is established in 21 CFR part 170, subpart E and 21 CFR part 570, subpart E, we intend to 
continue to closely monitor and assess the ramifications of the use of substances without food 
additive approval or evaluation by FDA through the GRAS notification procedure. We intend to 
take action as appropriate, particularly when the available data and information raise a safety 
concern about the use of a substance.  
FDA's guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe our current thinking on a topic and should be viewed 
only as recommendations, unless specific regulatory or statutory requirements are cited. The use 
of the word should in FDA guidances means that something is suggested or recommended, but 
not required.  
  2  Contains Nonbinding Recommendations 
II.  Background 
A.  What You Need to Know About the Laws and Regulations 
Applicable to Substances Added to Foods 
In 1958, Congress enacted the Food Additives Amendment (the 1958 amendment) to the FD&C 
Act. The 1958 amendment requires that, before a food additive may be used in food, FDA must 
establish a regulation prescribing the conditions under which the additive may be safely used. 
The 1958 amendment defined the terms food additive (section 201(s) of the FD&C Act) and 
unsafe food additive (section 409(a) of the FD&C Act), established a premarket approval 
process for food additives section (409(b) through (g) of the FD&C Act), and amended the food 
adulteration provisions of the FD&C Act to deem adulterated any food that is, or bears or 
contains, any food additive that is unsafe within the meaning of section 409 of the FD&C Act 
(see section 402(a)(2)(C) of the FD&C Act). 
Section 201(s) of the FD&C Act defines a food additive as any substance the intended use of 
which results or may reasonably be expected to result, directly or indirectly, in its becoming a 
component or otherwise affecting the characteristics of any food . . . if such substance is not 
generally recognized, among experts qualified by scientific training and experience to evaluate 
its safety, as having been adequately shown through scientific procedures (or, in the case of a 
substance used in food prior to January 1, 1958, through either scientific procedures or 
experience based on common use in food) to be safe under the conditions of its intended use ... 
3 Under this definition, a substance that is GRAS under the conditions of its intended use is not a 
food additive and is therefore not subject to mandatory premarket review by FDA under 
section 409 of the FD&C Act.   
We have established regulations implementing the GRAS provision of section 201(s) of the 
FD&C Act in part 170 (21 CFR part 170) and part 570 (21 CFR part 570) for human food and 
animal food, respectively. In particular, we have established criteria for eligibility for 
classification as GRAS (21 CFR 170.30 and 570.30), including general criteria (21 CFR 
170.30(a) and 570.30(a)), specific criteria for general recognition of safety through scientific 
procedures (21 CFR 170.30(b) and 570.30(b)), and specific criteria for general recognition of 
safety through experience based on common use in food (21 CFR 170.30(c) and 570.30(c)). 
Although we originally established these criteria in 1971 (36 FR 12093; June 25, 1971), we 
revised these criteria in 1976 (41 FR 53600; December 7, 1976). In 1988, we clarified that the 
criteria for eligibility for classification as GRAS through experience based on common use in 
food for a substance intended for use in human food could be based on common use in food 
                                                 
3 The definition of food additive in section 201(s) of the FD&C Act also excepts: (1) Pesticide chemical residues 
in or on a raw agricultural commodity or processed food; (2) pesticide chemicals; (3) color additives; (4) substances 
used in accordance with a prior sanction (i.e., a sanction or approval granted prior to the enactment of the Food 
Additives Amendment of 1958 under the FD&C Act, the Poultry Products Inspection Act, or the Meat Inspection 
Act); (5) new animal drugs; and (6) dietary ingredients in or intended for use in a dietary supplement. Thus, use of a 
substance as a dietary ingredient in a dietary supplement is not eligible for classification as GRAS. In addition, 
under section 201(s) of the FD&C Act, the GRAS provision applies to the definition of a food additive only; there is 
no corresponding provision in the definition (in section 201(t) of the FD&C Act) of a color additive. 
  3  Contains Nonbinding Recommendations 
outside, as well as in, the United States (53 FR 16544; May 10, 1988).4 We revised these criteria 
in 2016 (81 FR 54869, August 17, 2016). In this document, we refer to the final rule establishing 
these revised GRAS criteria as the GRAS final rule. 
Immediately below, we provide the criteria for eligibility for classification as GRAS as 
established in 21 CFR 170.30(a) through (c) for a substance intended for use in human food. The 
corresponding criteria for a substance intended for use in animal food are in 21 CFR 570.30(a) 
through (c). See section IV.E in this document for additional information about the GRAS 
criteria established in 21 CFR 570.30 for a substance intended for use in animal food.  
21 CFR 170.30 Eligibility for classification as generally recognized as safe (GRAS). 
(a) General recognition of safety may be based only on the views of experts qualified by 
scientific training and experience to evaluate the safety of substances directly or 
indirectly added to food. The basis of such views may be either (1) scientific procedures 
or (2) in the case of a substance used in food prior to January 1, 1958, through experience 
based on common use in food. General recognition of safety requires common 
knowledge throughout the scientific community knowledgeable about the safety of 
substances directly or indirectly added to food that there is reasonable certainty that the 
substance is not harmful under the conditions of its intended use (see  170.3(i)).  
(b) General recognition of safety based upon scientific procedures shall require the same 
quantity and quality of scientific evidence as is required to obtain approval of a food 
additive. General recognition of safety through scientific procedures shall be based upon 
the application of generally available and accepted scientific data, information, or 
methods, which ordinarily are published, as well as the application of scientific 
principles, and may be corroborated by the application of unpublished scientific data, 
information, or methods.  
(c)(1) General recognition 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. General recognition of safety 
through experience based on common use in food prior to January 1, 1958, shall be based 
solely on food use of the substance prior to January 1, 1958, and shall ordinarily be based 
upon generally available data and information. An ingredient not in common use in food 
prior to January 1, 1958, may achieve general recognition of safety only through 
scientific procedures. 
(c)(2) A substance used in food prior to January 1, 1958, may be generally recognized as 
safe through experience based on its common use in food when that use occurred 
exclusively or primarily outside of the United States if the information about the 
experience establishes that the substance is safe under the conditions of its intended use 
within the meaning of section 201(u) of the FD&C Act (see also  170.3(i)). Common 
use in food prior to January 1, 1958, that occurred outside of the United States shall be 
                                                 
4 In 2016, we made a corresponding clarification to the criteria for eligibility for classification as GRAS through 
experience based on common use in food for a substance intended for use in animal food (81 FR 54960, August 17, 
2016). 
  4  Contains Nonbinding Recommendations 
documented by published or other information and shall be corroborated by information 
from a second, independent source that confirms the history and circumstances of use of 
the substance.  The information used to document and to corroborate the history and 
circumstances of use of the substance must be generally available; that is, it must be 
widely available in the country in which the history of use has occurred and readily 
available to interested qualified experts in the United States. A person who concludes that 
a use of a substance is GRAS through experience based on its common use in food 
outside of the United States should notify FDA of that view in accordance with subpart E 
of part 170. 
As we noted in the GRAS final rule, we use the term GRAS panel to mean a panel of 
individuals convened for the purpose of evaluating whether the available scientific data, 
information, and methods establish that a substance is safe under the conditions of its intended 
use in food (81 FR 54960 at 54964). A GRAS panel is not required to demonstrate that a 
substance is GRAS under the conditions of its intended use, but is one mechanism that the 
regulated industry has used to demonstrate that the safety of a substance under the conditions of 
its intended use is generally recognized by qualified experts (81 FR 54960 at 54975). 
Under the framework established by sections 201(s) and 409 of the FD&C Act and our 
regulations, it is the substance under its intended conditions of use, rather than the substance 
itself, that is eligible for the GRAS provision. A substance that is GRAS for a particular use may 
be marketed for that use without our review and approval. However, when the GRAS criteria are 
not met or when the use of the substance is not otherwise excepted from the statutory definition 
of a food additive, the use of the substance in food is subject to premarket approval by FDA as 
mandated by the FD&C Act. In such circumstances, and in the absence of an effective food 
additive regulation, FDA can take enforcement action to stop distribution of food containing the 
unapproved food additive on the grounds that such food is adulterated. (See the discussion in 
section I of this guidance.) 
B.  What You Need to Know About the GRAS Notification Procedure 
In the GRAS final rule, we also established a GRAS notification procedure in part 170, subpart E 
(for a substance intended for use in human food) and in part 570, subpart E (for a substance 
intended for use in animal food). Using the GRAS notification procedure, any person may notify 
us of a view that a substance is not subject to the premarket approval requirements of section 409 
of the FD&C Act based on that persons conclusion that the substance is GRAS under the 
conditions of its intended use.  
A GRAS Notice has seven parts: 
  Part 1: Signed statements and a certification (21 CFR 170.225 and 21 CFR 570.225);  
  Part 2: The identity, method of manufacture, specifications, and physical or technical 
effect of the notified substance (21 CFR 170.230 and 21 CFR 570.230); 
  Part 3: Dietary exposure (21 CFR 170.235 and 21 CFR 570.235)5; 
                                                 
5 Part 3 of a GRAS notice for a substance intended for use in animal food addresses both target animal and human 
exposures and is entitled Target animal and human exposures. 
  5  Contains Nonbinding Recommendations 
  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 (21 CFR 170.240 and 21 CFR 570.240); 
  Part 5: Evidence of a substantial history of consumption of the substance for food use 
prior to January 1, 1958, if a GRAS conclusion is based on common use of the substance 
in food prior to 1958 (21 CFR 170.245 and 21 CFR 570.245)6;  
  Part 6: A narrative that provides the basis for your GRAS conclusion, including why the 
scientific data, information, methods, and principles described in the notice provide a 
basis for your conclusion that the notified substance is generally recognized, among 
qualified experts, to be safe under the conditions of its intended use (21 CFR 170.250 and 
21 CFR 570.250); and 
  Part 7: A list of the data and information that you discuss in the narrative of your GRAS 
notice, specifying which of these data and information are generally available, and which 
of these data and information are not generally available (21 CFR 170.255 and 21 CFR 
570.255). 
 
We make a list of filed GRAS notices readily accessible to the public (21 CFR 170.275(b)(1) and 
21 CFR 570.275(b)(1)). We respond to a filed GRAS notice by letter, and we also make the text 
of these letters readily accessible to the public (21 CFR 170.275(b)(2) and (3) and 21 CFR 
570.275(b)(2) and (3)). The data and information in a GRAS notice are considered a mandatory, 
rather than voluntary, submission for purposes of their status under the Freedom of Information 
Act and our public information requirements in 21 CFR part 20, and are available for public 
disclosure in accordance with 21 CFR part 20 as of the date that we receive a GRAS notice. (See 
21 CFR 170.275(a) and 21 CFR 570.275(a)).  
See 21 CFR part 170, subpart E, and 21 CFR part 570, subpart E, for the complete regulatory 
requirements applicable to the GRAS notification procedure for a substance intended for use in 
human food or animal food, respectively.  
III.  Discussion and Recommendations  
A.  GRAS Criteria 
Fundamental to all GRAS conclusions is the criterion that general recognition of safety requires 
common knowledge throughout the scientific community knowledgeable about the safety of 
substances directly or indirectly added to food that there is reasonable certainty that the 
substance is not harmful under the conditions of its intended use (see 21 CFR 170.30(a) and 21 
CFR 570.30(a)). In addition, the criteria for eligibility for classification as GRAS through 
scientific procedures require that general recognition of safety through scientific procedures be 
based upon the application of generally available and accepted scientific data, information, or 
                                                 
6 For a substance intended for use in human food, evidence of a substantial history of consumption of the food 
substance is by a significant number of consumers. For a substance intended for use in animal food, evidence of a 
substantial history of consumption of the food substance is by a significant number of animals of the species to 
which the substance is intended to be fed ... and ... by humans consuming human foods derived from food-
producing animals. 
  6  Contains Nonbinding Recommendations 
methods, which ordinarily are published, as well as the application of scientific principles (21 
CFR 170.30(b) and 21 CFR 570.30(b)). Although general recognition of safety through scientific 
procedures may be corroborated by the application of unpublished scientific data, information, or 
methods (21 CFR 170.30(b) and 21 CFR 570.30(b)), to satisfy GRAS criteria qualified experts 
must be able to conclude that the substance is not harmful under the conditions of its intended 
use without access to corroborative information. For example, there could be no basis for a 
conclusion of GRAS status if trade secret information (or other non-public information) is 
necessary for qualified experts to reach a conclusion that the substance is safe under the 
conditions of its intended use. Importantly, all GRAS conclusions must be considered in context 
based on the knowledge and information available at a point in time, because scientific 
knowledge and information about a particular substance can evolve and sometimes change over 
time. 
During the rulemaking leading to the GRAS final rule, we received several comments regarding 
the GRAS criteria in 21 CFR 170.30(a) through (c) and 21 CFR 570.30(a) through (c). The 
preamble of the GRAS final rule describes those comments and responds to them. We believe 
that these preamble discussions will be useful to any person who intends to market a food 
substance on the basis of a GRAS conclusion, and recommend that you refer to these preamble 
discussions in the GRAS final rule if you intend to do so. For your convenience, in the Appendix 
of this guidance we present some of the key discussions extracted from the preamble of the 
GRAS final rule regarding GRAS criteria. Importantly, you should consider these extracts in the 
context of the complete preamble discussion in the GRAS final rule. In addition, be advised that 
the GRAS final rule discusses issues raised by comments we received under the rulemaking 
process; considerations other than those discussed in the GRAS final rule may play a role in a 
specific evaluation of whether a use of a substance in food satisfies GRAS criteria.  
B.  GRAS Notification Procedure 
We strongly encourage you to submit a GRAS notice to us if you intend to market a food 
substance on the basis of a GRAS conclusion even though neither the FD&C Act nor our 
regulations in 21 CFR require you to do so. Submitting a GRAS notice to us represents prudent 
practice for those who claim an exclusion from a statutory requirement.  
If you decide that your GRAS conclusion will be an independent GRAS conclusion that is not 
submitted to us, we believe that the provisions of the GRAS notification procedure will 
nonetheless be a useful resource for you. Therefore, we recommend that you: 
  Use the provisions of the GRAS notification procedure in our regulations as guidance. 
For example, the requirements in Part 3 of a GRAS notice make clear that a GRAS 
conclusion requires consideration of dietary exposure for a substance intended to be used 
in human food; when the substance would be used in animal food, the requirements in 
Part 3 of a GRAS notice make clear that a GRAS conclusion requires consideration of 
target animal and human food exposures. Likewise, the requirements in Part 6 of a 
GRAS notice demonstrate the importance of a complete and balanced evaluation of all 
applicable data and information, including data and information that are, or may appear 
to be, inconsistent with a GRAS conclusion.  
  7  Contains Nonbinding Recommendations 
  Retain the data and information that support your independent GRAS conclusion and 
organize these data and information according to the organization presented by Parts 1 
through 7 of a GRAS notice. Doing so would facilitate our evaluation of that 
independent GRAS conclusion if circumstances warrant  e.g., if we have cause to 
question your independent GRAS conclusion.  
  Make the basis for your independent GRAS conclusion publicly available (e.g., by 
placing a publicly accessible document analogous to the narrative of a GRAS notice, a 
report of any GRAS panel (if you convene a GRAS panel), or both a narrative and a 
report of a GRAS panel on your Web site), because we make information about GRAS 
notices readily accessible to the public. 
  Refer to FDAs guidance entitled Frequently Asked Questions About GRAS for 
Substances Intended for Use in Human or Animal Food (Ref. 1), which generally 
applies to a conclusion of GRAS status for a substance intended for use in human food 
or animal food regardless of whether that conclusion of GRAS status is submitted to 
FDA as a GRAS notice.   
C.  Safety Assessment 
We address scientific issues associated with demonstrating the safety of a food substance in a 
series of guidance documents on our Web sites. For a substance intended for use in human food, 
see Ref. 2 through Ref. 9. For a substance intended for use in animal food, see Ref. 9 through 
Ref. 14 and Ref. 30.7 We recommend that you periodically check the Web sites for CFSAN (Ref. 
31) and CVM (Ref. 32) where we provide guidance for industry for any new guidance or 
revisions to current guidance. 
Currently, some of our scientific guidance documents are expressly directed to evaluation of the 
safety of food additives. For example, our guidance entitled Recommendations for Submission 
of Chemical and Technological Data for Direct Food Additive Petitions (Ref. 4) currently is 
structured to address the specific requirements of a food additive petition submitted to CFSAN 
for a substance intended for use in human food. Likewise, our guidance entitled 
Recommendations for Preparation and Submission of Animal Food Additive Petitions (Ref. 
10) addresses the specific recommendations for a food additive petition submitted to CVM for a 
substance intended to be used in animal food. However, many of the recommendations in these 
guidances could be useful to any person who evaluates whether a substance is GRAS under the 
conditions of its intended use. As resources allow, we intend to re-visit these scientific guidance 
documents to determine whether and how to modify them to clarify that our guidance on 
evaluating the safety of a food substance applies regardless of whether the substance would be 
used in food as a food additive or as a GRAS substance. Regardless of any implication (in the 
title or text of these guidance documents) that the subject of the document applies to a food 
additive, we recommend that you consider that the scientific recommendations in these guidance 
documents may also apply to substances that would be used in food on the basis of a GRAS 
conclusion.  
                                                 
7 As noted in section IV.E, other guidance documents directed to animal drug products provide information that is 
relevant to CVMs evaluation of the safety of substances used in animal food (Ref. 15 through Ref. 29), and we 
recommend that you also refer to these guidance documents.  
  8  Contains Nonbinding Recommendations 
D.  GRAS Panels 
We intend to issue for public comment draft guidance providing recommendations regarding the 
use of a GRAS panel, including the potential for conflict of interest, in the near future. If you 
convene a GRAS panel, we recommend that you consult any final guidance that we issue 
regarding the use of a GRAS panel. 
E.  Additional Information Regarding a Substance Intended for Use 
in Animal Food  
Some animals are used to produce food for humans and, thus, both the GRAS criteria in 21 CFR 
570.30(a) through (c) and the submission requirements for a GRAS notice for a substance 
intended for use in animal food address the safety of a food substance for both the target animal 
and for humans consuming human food derived from food-producing animals. See the full 
regulatory text of 21 CFR 570.30(a) through (c), and the full regulatory text of 21 CFR part 570, 
subpart E, for the specific requirements. 
Section IV lists a series of guidance documents on specific issues related to the safety of a 
substance for both the target animals and humans consuming human food derived from food-
producing animals (Ref. 9 through Ref. 29). Although some of these guidance documents (i.e., 
Ref. 15 through Ref. 29) discuss animal drug products, we refer you to these guidance 
documents because they provide information that is relevant to our evaluation of the safety of 
substances used in animal food. For example, we evaluate the human food safety of tissue 
residues present in edible tissues in a similar manner for new animal drugs intended for use in 
food-producing animals and for food substances used in foods for food-producing animals. We 
recommend that you consider that the scientific recommendations in these guidance documents 
may also apply to substances that would be used in animal food on the basis of a GRAS 
conclusion. 
IV.  References  
Ref. 1. FDA, Frequently Asked Questions About GRAS for Substances Intended for Use in 
Human or Animal Food, 
(http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm
061846.htm), 2016. 
Ref. 2. FDA, Guidance for Industry: Assessing the Effects of Significant Manufacturing 
Process Changes, Including Emerging Technologies, on the Safety and Regulatory Status of 
Food Ingredients and Food Contact Substances, Including Food Ingredients that Are Color 
Additives, 
(http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm
300661.htm), 2014.  
Ref. 3. FDA, Guidance for Industry: Estimating Dietary Intake of Substances in Food, 
(http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm
074725.htm), 2006.  
  9  Contains Nonbinding Recommendations 
Ref. 4. FDA, Guidance for Industry: Recommendations for Submission of Chemical and 
Technological Data for Direct Food Additive Petitions, 
(http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm
124917.htm), 2009.  
Ref. 5. FDA, Guidance for Industry: Microbiological Considerations for Antimicrobial Food 
Additive Submissions, 
(http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm
230417.htm), 2008.  
Ref. 6. FDA, Guidance for Industry: Enzyme Preparations: Recommendations for Submission 
of Chemical and Technological Data for Food Additive Petitions and GRAS Notices, 
(http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/Ingr
edientsAdditivesGRASPackaging/ucm217685.htm), 2010.  
Ref. 7. FDA, Guidance for Industry: Summary Table of Recommended Toxicological Testing 
for Additives Used in Food, (2006), 
(http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm
054658.htm), 2006.  
Ref. 8. FDA, Guidance for Industry and Other Stakeholders: Toxicological Principles for the 
Safety Assessment of Food Ingredients. Redbook 2000, 
(http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/Ingr
edientsAdditivesGRASPackaging/ucm2006826.htm), 2007.   
Ref. 9. FDA, Guidance for Industry: Considering Whether an FDA-Regulated Product Involves 
the Application of Nanotechnology, 
(http://www.fda.gov/RegulatoryInformation/Guidances/ucm257698.htm), 2014.  
Ref. 10. FDA, Guidance for Industry: Recommendations for Preparation and Submission of 
Animal Food Additive Petitions (# 221), 
(http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/Guidancef
orIndustry/UCM367746.pdf), 2015.  
Ref. 11. FDA, Guidance for Industry: Target Animal Safety and Effectiveness Protocol 
Development and Submission (#215), 
(http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/Guidancef
orIndustry/UCM241787.pdf), 2011. 
Ref. 12. FDA, Guidance for Industry: Evaluation of the Utility of Food Additives in Diet Fed to 
Aquatic Animals (#53), 
(http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/
ucm053413.htm), 1994. 
Ref. 13. FDA, Guidance for Industry: Validation of Analytical Procedures: Definition and 
Terminology (#63), 
(http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/Guidancef
orIndustry/UCM052377.pdf), 1999. 
  10  Contains Nonbinding Recommendations 
Ref. 14. FDA, Guidance for Industry: Validation of Analytical Procedures: Methodology, Final 
Guidance (#64), 
(http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/Guidancef
orIndustry/UCM052379.pdf), 2010. 
Ref. 15. FDA, Guidance for Industry: General Principles for Evaluating the Human Food Safety 
of New Animal Drugs Used in Food-Producing Animals (#3), 
(http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/Guidancef
orIndustry/UCM052180.pdf), 2016. 
Ref. 16. FDA, Guidance for Industry: Studies to Evaluate the Safety of Residues of Veterinary 
Drugs in Human Food: General Approach to Testing VICH GL33 (#149), 
(http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/Guidancef
orIndustry/UCM052521.pdf), 2009. 
Ref. 17. FDA, Guidance for Industry: Studies to Evaluate the Safety of Residues of Veterinary 
Drugs in Human Food: Genotoxicity Testing VICH GL23 (#116), 
(http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/Guidancef
orIndustry/UCM052656.pdf), 2015. 
Ref. 18. FDA, Guidance for Industry: Studies to Evaluate the Safety of Residues of Veterinary 
Drugs in Human Food: Carcinogenicity Testing VICH GL28 (#141), 
(http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/Guidancef
orIndustry/UCM052527.pdf), 2006. 
Ref. 19. FDA, Guidance for Industry: Safety Studies for Veterinary Drug Residues in Human 
Food: Reproduction Toxicity Testing VICH GL22 (#115), 
(http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/Guidancef
orIndustry/UCM052655.pdf), 2006. 
Ref. 20. FDA, Guidance for Industry: Studies to Evaluate the Safety of Residues of Veterinary 
Drugs in Human Food: Repeat-Dose (90-Day) Toxicity Testing VICH GL31 (#147), 
(http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/Guidancef
orIndustry/UCM052523.pdf), 2006. 
Ref. 21. FDA, Guidance for Industry: Studies to Evaluate the Safety of Residues of Veterinary 
Drugs in Human Food: Developmental Toxicity Testing VICH GL32 (#148), 
(http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/Guidancef
orIndustry/UCM052522.pdf), 2006. 
Ref. 22. FDA, Guidance for Industry: Studies to Evaluate the Safety of Residues of Veterinary 
Drugs in Human Food: Repeat-Dose (Chronic) Toxicity Testing VICH GL37 (#160), 
(http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/Guidancef
orIndustry/UCM052505.pdf), 2006. 
Ref. 23. FDA, Guidance for Industry: Studies to Evaluate the Metabolism and Residue Kinetics 
of Veterinary Drugs in Food-producing Animals: Metabolism Study to Determine the Quantity 
and Identify the Nature of Residues (MRK) VICH GL46 (#205), 
  11  Contains Nonbinding Recommendations 
(http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/Guidancef
orIndustry/UCM207939.pdf), 2011. 
Ref. 24. FDA, Guidance for Industry: Studies to Evaluate the Metabolism and Residue Kinetics 
of Veterinary Drugs in Food-Producing Animals: Comparative Metabolism Studies in 
Laboratory Animals VICH GL47 (#206), 
(http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/Guidancef
orIndustry/UCM207940.pdf), 2011. 
Ref. 25. FDA, Guidance for Industry: Studies to Evaluate the Metabolism and Residue Kinetics 
of Veterinary Drugs in Food-Producing Animals: Marker Residue Depletion Studies to Establish 
Product Withdrawal Periods VICH GL48 (#207), 
(http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/Guidancef
orIndustry/UCM207941.pdf), 2015. 
Ref. 26. FDA, Guidance for Industry: Studies to Evaluate the Metabolism and Residue Kinetics 
of Veterinary Drugs in Food-Producing Animals: Validation of Analytical Methods used in 
Residue Depletion Studies VICH GL49 (#208), 
(http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/Guidancef
orIndustry/UCM207942.pdf), 2015. 
Ref. 27. FDA, Guidance for Industry: Evaluating the Safety of Antimicrobial New Animal 
Drugs with Regard to Their Microbiological Effects on Bacteria of Human Health Concern 
(#152), 
(http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/Guidancef
orIndustry/UCM052519.pdf), 2003. 
Ref. 28. FDA, Guidance for Industry: Studies to Evaluate the Safety of Residues of Veterinary 
Drugs in Human Food: General Approach to Establish a Microbiological ADI VICH GL36(R) 
(#159), 
(http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/Guidancef
orIndustry/UCM124674.pdf), 2013. 
Ref. 29. FDA, Guidance for Industry: Target Animal Safety for Veterinary Pharmaceutical 
Products VICH GL43 (#185), 
(http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/Guidancef
orIndustry/UCM052464.pdf), 2009. 
Ref. 30. FDA, Guidance for Industry: Use of Nanomaterials in Food for Animals (# 220), 
(http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/Guidancef
orIndustry/UCM401508.pdf), 2015.  
Ref. 31. FDA, Food Guidance Documents, 
(http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/defa
ult.htm), 2017. 
  12  Contains Nonbinding Recommendations 
Ref. 32. FDA, Guidance for Industry, 
(http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/
default.htm), 2017.  
 
Appendix 
In the Federal Register of August 17, 2016 (81 FR 54960), we published a final rule that 
amended and clarified the criteria in our regulations for when the use of a substance in food for 
humans or animals is not subject to the premarket approval requirements of the FD&C Act 
because the substance is GRAS under the conditions of its intended use. That final rule also 
established a voluntary notification procedure under which any person may notify us of a 
conclusion that a substance is GRAS under the conditions of its intended use.  
For your convenience, in this Appendix we present some of the key discussions extracted from 
the preamble of the GRAS final rule regarding GRAS criteria. Importantly, you should consider 
these extracts in the context of the complete preamble discussion in the GRAS final rule. In 
addition, be advised that the GRAS final rule discusses issues raised by comments we received 
under the rulemaking process; considerations other than those discussed in the GRAS final rule 
may play a role in a specific evaluation of whether a use of a substance in food satisfies GRAS 
criteria. 
Several of the extracts cite references. Those references are available in the GRAS final rule 
published in the Federal Register and are distinct from the references listed in section IV of this 
guidance. You should refer to the GRAS final rule to identify these references. 
Likewise, several of the extracts cite to specific sections or tables in the GRAS final rule or to 
additional responses to specific comments. You should refer to the GRAS final rule for the cited 
discussions.  
Extracts from the GRAS final rule:  
(Comment 8) One comment asserts that the criterion for the generally available data or 
information establishing safety to ordinarily be published is artificial. Other comments point out 
that information that is not published can nonetheless be considered generally available. Some 
comments object to the proposed amendment to the criteria for eligibility for classification as 
GRAS through scientific procedures and assert that it would de-emphasize or eliminate the 
existing criterion for peer-reviewed studies.  
(Response 8) Regardless of whether the data and information are published or 
unpublished, under the revised criteria a GRAS conclusion must be based on data and 
information that are generally available and accepted, and as such, are publicly available. As we 
stated in the proposed rule, the common knowledge element of the GRAS standard precludes a 
GRAS conclusion if the data and information (e.g., as evaluated by a GRAS panel) are only 
available in files that are not publicly accessible, such as in confidential industry files (62 FR 
18938 at 18943). We disagree that the criterion for the generally available data or information 
establishing safety to ordinarily be published is artificial. Publication in a peer-reviewed 
  13  Contains Nonbinding Recommendations 
scientific journal is the usual mechanism to establish that scientific information is generally 
available, provided that the journal is representative of scientific publications accessed by the 
expert scientific community (62 FR 18938 at 18943). Nonetheless, the revised criteria provide 
flexibility for supporting a conclusion of GRAS status through the application of scientific data, 
information, or methods that are generally available through a mechanism other than publication 
in a peer-reviewed scientific journal, such as publication in a textbook and other sources of 
technical literature. One example of another source of technical literature is the Joint Expert 
Committee on Food Additives (JECFA, a joint committee of the Food and Agriculture 
Organization/World Health Organization). We note, however, that the mere fact that data and 
information are published or otherwise publicly available does not satisfy the criteria for general 
recognition of safety. Regardless of the mechanism of making data and information generally 
available to qualified experts, it must be plausible that qualified experts would be accessing those 
data and information using that mechanism. For example, scientists who routinely access peer-
reviewed journals in electronic form on the Internet may avoid Internet publications about a 
scientific topic when the publication is not associated with a reputable scientific institution.  
We have not changed our position on the importance of peer review. The basis for GRAS 
status continues to be the application of generally available scientific data, information, and 
methods, which ordinarily are published (and, thus, are subject to peer review as part of the 
scientific publication process for most journals). We continue to believe that whether scientific 
data, information, and methods have been peer reviewed before publication in a scientific journal 
that is representative of scientific publications accessed by the expert scientific community is a 
factor that bears on the objectivity and scientific merit of study, and is a variable we consider in 
determining whether experts accept the report of a scientific investigation as a credible report 
and whether there is general knowledge of the scientific investigation. 
CFSANs 2010 experience document (Ref. 18) provides factual information on how 
CFSAN already has interpreted the criteria for eligibility for classification of GRAS status 
through scientific procedures for GRAS notices CFSAN received during the Interim Pilot 
program (see section III.A.1 of CFSANs 2010 experience document), and we intend to continue 
this approach in the future. In most cases, a submitted GRAS notice described a mixture of 
information published in peer-reviewed journals, information (such as in textbooks) that was 
generally available in a form other than a peer-reviewed journal, and unpublished information. 
As shown in table 1 in CFSANs 2016 experience document, CFSAN had no questions about 
GRAS status based on this mixture of information in approximately 81 percent of the GRAS 
notices CFSAN evaluated between 1998 and 2015 (Ref. 19). Importantly, CFSANs evaluation 
of the basis for a conclusion that a use of a food substance is GRAS in addition to being safe was 
a case-by-case evaluation. As discussed in section III.A.4 of CFSANs 2010 experience 
document, in some cases it was CFSANs view that the available data and information were 
sufficient to demonstrate safety, but not GRAS status, and CFSAN established a food additive 
regulation for the use of the substance in response to a food additive petition for that use (Ref. 
18).  
(Comment 9) Some comments state that all available relevant data, including unpublished 
data, should be used in evaluating GRAS status. Some of these comments cited the placement of 
the word ordinarily in the criteria for classification as GRAS through scientific procedures as 
support for this interpretation. Several comments urge us to interpret, in a flexible manner, the 
proposed criteria for the scientific data, information, methods or principles that establish safety 
to be generally available and accepted and ordinarily ... published.  
  14  Contains Nonbinding Recommendations 
(Response 9) We agree that all relevant data should be used in evaluating GRAS status, 
including unpublished data. However, regardless of whether data and information are published 
or unpublished, a GRAS conclusion based on scientific procedures must be based on data and 
information that are generally available and accepted, and as such, are publicly available (see 
Response 8). The GRAS criteria for scientific procedures, as established in 1976, state that the 
applicable data and information are ordinarily published and may be corroborated by 
unpublished data and information, and this rule retains these criteria. The common meaning of 
corroborate is to make more certain or confirm (Ref. 23). Although unpublished data and 
information can confirm a conclusion of GRAS status, to satisfy GRAS criteria qualified experts 
must be able to conclude that the substance is not harmful under the conditions of its intended 
use without access to corroborative information (see  170.30(a)). Under this rule, a notifier is 
required to explain how there could be a basis for a conclusion of GRAS status if qualified 
experts do not have access to non-public safety-related data and information considered in 
reaching a conclusion of GRAS status (see  170.250(e)).  
Whether data and information are corroborative of safety, rather than establish safety, 
depends on what those data and information are and how they relate to the safety assessment, not 
just whether they are published or otherwise publicly available. Whereas unpublished data and 
information that have a bearing on a safety conclusion, and therefore could help confirm a safety 
conclusion based on other data and information, in general, can only be considered as 
corroborative in the context of a GRAS conclusion, published data and information may be 
either the basis for a safety conclusion or corroborative of a safety conclusion, depending on the 
nature of the data and information. For example, a published 90-day toxicology study could be 
the basis for a safety conclusion, but a preliminary toxicology study conducted primarily for the 
purpose of selecting the doses to be used in that 90-day toxicology study is unlikely to be the 
basis for a safety conclusion, regardless of whether that preliminary toxicology study is 
published.  
See also the discussion in Response 58 regarding the requirement for you to submit a 
signed statement certifying that, to the best of your knowledge, your GRAS notice is a complete, 
representative, and balanced submission that includes unfavorable information, as well as 
favorable information, known to you and pertinent to the evaluation of the safety and GRAS 
status of the use of the substance ( 170.225(c)(9)). See also the discussion in section XVII 
regarding the requirement for your narrative to identify, and place in context, data and 
information that are, or may appear to be, inconsistent with your conclusion of GRAS status, 
regardless of whether those data and information are generally available ( 170.250(c)).  
(Comment 10) One comment asks us to explicitly acknowledge publication of 
information in the secondary scientific literature as a mechanism to satisfy the standard for 
general availability.  
(Response 10) We decline this request. In general, the secondary scientific literature 
includes publications (such as review articles, textbooks, and compendia) which disseminate the 
views of scientists who are critically evaluating a primary body of data and information already 
published in peer-reviewed scientific journals that are representative of scientific publications 
accessed by the expert scientific community (i.e., the primary scientific literature). Whether a 
publication in the secondary scientific literature satisfies the criteria for GRAS status through 
scientific procedures is a case-by-case determination that depends on the circumstances. See 
section III.A.1 of CFSANs 2010 experience document (Ref. 18) for examples of how CFSAN 
considered publications in the secondary scientific literature during the Interim Pilot program. 
  15  Contains Nonbinding Recommendations 
When the underlying data being reviewed in the secondary scientific literature are themselves 
generally available, a publication in the secondary scientific literature can provide evidence that 
the data and information discussed in the publication are generally accepted as well as generally 
available. If a publication in the secondary scientific literature discusses data and information 
that are available to the authors, but not previously published in the primary scientific literature, 
whether that publication could satisfy the generally available aspect of the criteria for 
eligibility for GRAS status through scientific procedures would depend on the nature and extent 
of the discussion in the publication. For example, a very general statement that a study was 
conducted and reported no adverse findings would not suffice to make the study generally 
available; instead, such a statement would merely be a generally available opinion about data 
and information, in that study, that are not generally available. Such a publication may satisfy the 
generally accepted aspect of the criteria for GRAS status through scientific procedures for that 
study, but would be insufficient, by itself, to satisfy the generally available aspect of those 
criteria. However, a comprehensive description in the secondary scientific literature of a 
previously unpublished study, including details similar to details that would be included in a 
publication in the primary scientific literature, may suffice to make the study published in the 
secondary scientific literature generally available. In such circumstances, the publication in the 
secondary scientific literature may be able to satisfy both the generally available and 
generally accepted aspects of the criteria for eligibility for GRAS status through scientific 
procedures for certain data and information.  
(Comment 11) One comment asks us to recognize that publication of an opinion of a 
specially convened expert panel would satisfy the standard for general availability because, in 
the comments view, review by such a panel would be equivalent to, or exceed, peer review. (By 
expert panel, we assume that the comment is referring to a GRAS panel, i.e., a panel of 
individuals convened for the purpose of evaluating whether the available scientific data, 
information, and methods establish that a substance is safe under the conditions of its intended 
use in food. See the discussion in section III.A.1 of CFSANs 2010 experience document (Ref. 
18).) 
(Response 11) We would consider publication of an opinion of a specially convened 
GRAS panel to be part of the secondary scientific literature as discussed in Response 10. As 
with any publication in the secondary scientific literature, when the underlying data being 
reviewed in a published GRAS panel opinion are themselves generally available, a published 
GRAS panel opinion could provide evidence that the data and information discussed in the 
publication are generally accepted, depending on factors such as the subject matter expertise of 
the members of the GRAS panel and whether the members of the GRAS panel would be 
considered representative of experts qualified by scientific training and experience to evaluate 
the safety of the substance under the conditions of its intended use. For example, a GRAS 
panel opinion published by scientists without expertise appropriate to address the applicable 
safety questions could not provide evidence that the conclusions in the publication are generally 
accepted.  
If a published GRAS panel opinion discusses data and information that are available to 
the members of the GRAS panel, but not generally available to qualified experts, whether that 
publication could satisfy the generally available aspect of the criteria for eligibility for GRAS 
status through scientific procedures would depend on the nature and extent of the discussion in 
the publication (see Response 10). Unless both criteria, i.e., generally available and generally 
  16  Contains Nonbinding Recommendations 
accepted, are satisfied, there would be no basis for a conclusion of GRAS status based on a 
published GRAS panel opinion. 
(Comment 12) One comment states that all available relevant data, including unpublished 
data, should be used in evaluating GRAS status, as long as any unpublished data are generated 
by appropriate and valid scientific methods as judged and reviewed by an external qualified 
GRAS panel and are accessible to FDA for review.  
(Response 12) We agree that all available relevant data should be used in evaluating 
whether a use of a substance in food is GRAS through scientific procedures. By all relevant 
data, we mean data that support a conclusion of GRAS status as well as data that are 
inconsistent with a conclusion of GRAS status, not just whether the data are published. (See  
170.225(c)(9) and 170.250(c) and the discussion in Response 58, Response 69, and Response 
78.) We also agree that it is appropriate for unpublished data to be generated by valid scientific 
methods and to be accessible to FDA for review (e.g., when such data are cited in a submission 
to FDA). In addition, we have acknowledged the practice of convening an external GRAS 
panel to evaluate whether the available scientific data, information, and methods demonstrate 
that a substance is safe under the conditions of its intended use in food (see section III.A.1 of 
CFSANs 2010 experience document) (Ref. 18). However, we disagree that information that is 
not generally available to qualified experts could be used as evidence for a GRAS conclusion 
merely because a GRAS panel has reviewed it. Such information would need to be considered, 
but generally would only be corroborative of safety. (See Response 9 and Response 11.)  
... 
(Comment 16) One comment asks us to require that both toxicology and exposure data be 
published because a safety assessment for the use of a substance in food requires consideration 
of both.  
(Response 16) We agree that a safety assessment for the use of a substance in food 
requires consideration of both safety information (such as toxicology studies) and dietary 
exposure (i.e., the amount of the substance that consumers are likely to eat or drink). Toxicology 
data are ordinarily published.  
A premarket exposure assessment typically would be calculated by applying generally 
available and accepted methods to two types of data and information: (1) Generally available and 
accepted data about food consumption; and (2) specific food categories, and levels of use in 
those food categories, projected by the sponsor of a food additive petition or by the proponent of 
GRAS status (Ref. 24 and Ref. 25). Using generally available and accepted data about food 
consumption, a qualified expert who has access to the specific food categories and associated 
levels of use intended by the proponent of GRAS status can calculate an estimated dietary 
exposure. When the proponent of GRAS status submits a GRAS notice, the proponent must: (1) 
Provide data and information about dietary exposure (see  170.235); and (2) include a narrative 
that addresses the safety of the notified substance, considering all dietary sources (see  
170.250). Those calculations and discussions included in the GRAS notice are subject to the 
public disclosure provisions of this rule (see  170.275) and, thus, would be available to the 
expert scientific community. However, when the proponent of GRAS status does not submit a 
GRAS notice, the expert scientific community that does not have access to the specific food 
categories and associated levels of use would not be able to calculate an estimated dietary 
exposure. When the available data and information suggest that the specific food categories and 
associated levels of use must be carefully chosen to keep consumption of the substance in a safe 
range (e.g., when fortifying food with certain vitamins ), the expert scientific community that 
  17  Contains Nonbinding Recommendations 
does not have access to the specific food categories and associated levels of use would not be 
able to reach a conclusion about whether the substance is safe under the conditions of its 
intended use, and GRAS criteria would not be satisfied. 
After market entry of the substance, it may be appropriate to re-assess dietary exposure. 
For example, dietary exposure may need to be reassessed when a key assumption in the 
methodology is changed; as dietary consumption patterns change; when there is an unresolved 
question about consumer intake; when there is a small margin of exposure; or when other new 
information becomes available. As with a premarket exposure assessment, a postmarket 
exposure assessment typically would be calculated by applying generally available and accepted 
methods to two types of data and information: (1) Generally available and accepted data about 
food consumption; and (2) specific food categories, and levels of use in those food categories. In 
some cases, postmarket exposure assessments have been published so that the expert scientific 
community has access to them. For example, exposure assessments have been published for 
some sweeteners using relative sweetness as the basis of the estimate (Ref. 26). As another 
example, estimates of dietary exposure to caffeine have been published to address consumer 
intake and patterns of use (Ref. 27 through Ref. 29). However, as with a premarket exposure 
assessment, when a postmarket exposure assessment is not publicly available, the expert 
scientific community that does not have access to the specific food categories and associated 
levels of use would not be able to reach a conclusion about whether the substance is safe under 
the conditions of its intended use when the available data and information suggest that the 
specific food categories and associated levels of use must be carefully chosen to keep 
consumption of the substance in a safe range. 
(Comment 17) One comment asks us to recognize that published literature does not need 
to address a specific substance, but could involve publications on a class of substances or a 
related substance to support a conclusion that the use of a substance is GRAS through scientific 
procedures. 
(Response 17) We agree that published information for a specific substance is not always 
necessary to support a conclusion that the use of a substance is GRAS through scientific 
procedures. For example, there may be situations where the safety of the use of the substance in 
food can be demonstrated by relevant published information on a closely, structurally related 
compound. In such cases, the analysis leading to the conclusion of GRAS status should explain 
how the information on the closely, structurally related compound is relevant to the safety 
assessment of the substance being evaluated. In other cases, there may a body of information 
published in the primary or secondary literature about a class of substances, which reflect 
generally available and accepted data and information that can be called to bear on the safety 
assessment of a specific substance. For example, generally available metabolism information 
about commonly consumed components of food, such as carbohydrates, lipids, and proteins, 
could support a conclusion that a specific substance is GRAS under the conditions of its intended 
use.  
To help ensure that the data are, in fact, relevant to the safety assessment of the substance 
being evaluated, we strongly encourage any person who intends to rely on data and information 
regarding a class of substances, or a specific substance related to the substance that would be 
added to food, to submit any conclusion of GRAS status to FDA via the GRAS notification 
procedure. 
  18  Contains Nonbinding Recommendations 
(Comment 18) One comment states that the use of an approved food additive can, 
through the passage of time, become GRAS as the substance becomes widely used and as 
information about the substance becomes publicly available. 
(Response 18) We disagree that widespread use of an approved food additive as time 
passes has any bearing on the eligibility of this use for classification as GRAS. Eligibility for 
classification as GRAS through scientific procedures would depend on the status of the 
information--as generally available and generally accepted--rather than on the amount of time 
that a food additive has been used in food. However, in general, much of the data submitted for 
our review of a food additive contains unpublished data and trade secret or confidential 
information that is neither published nor otherwise generally available. Although the safety data 
are available for public disclosure under 21 CFR 171.1(h)(1), they typically are based on 
unpublished studies sponsored by the petitioner.  
See also the discussion in Response 19 regarding the impact of the passage of time and 
the discussion in Response 79 that the qualified experts who evaluate the basis for a conclusion 
that the notified substance is safe under the conditions of its intended use must not exclusively be 
FDAs experts.  
(Comment 19) One comment asks us to exclude uses of novel substances from 
consideration for eligibility for classification as GRAS. The comment asserts that novel or newly 
discovered uses of substances that are the subject of a conclusion of GRAS status are in conflict 
with the original intent of the 1958 amendment and the plain meaning of generally recognized, 
because there is no history of safe use for these substances. The comment also states that similar 
general recognition provisions for new drugs are not interpreted to allow industry-made safety 
determinations for new or novel drugs.  
(Response 19) We do not have a regulatory definition for a novel substance. As a 
general matter, section 201(s) of the FD&C Act provides two alternatives for general recognition 
of safety--through scientific procedures, or through experience based on common use in food. 
Section 201(s) does not limit eligibility, or otherwise exclude, the use of a substance from 
classification as GRAS through scientific procedures if there is no history of use. Likewise, 
section 201(s) does not limit eligibility, or otherwise exclude, the use of a substance from 
classification as GRAS through scientific procedures based on other criteria, such as whether a 
substance or its use in food is novel or newly discovered. Unlike the definition of a new 
drug in section 201(p) of the FD&C Act, section 201(s) does not require that a food ingredient 
be used to a material extent or for a material time under such conditions before it can become 
GRAS. Rather, the criteria for eligibility for classification as GRAS depend on whether generally 
available and accepted data and information establish that the substance is safe under the 
conditions of its intended use.  
However, a conclusion of GRAS status must be based on common knowledge throughout 
the scientific community knowledgeable about the safety of substances added to food that there 
is reasonable certainty that the substance is not harmful under the conditions of its intended use 
( 170.30(a)), and a substance cannot be considered GRAS when its characteristics are known to 
only a few experts (Final rule establishing GRAS criteria, 41 FR 53600, December 7, 1976). In 
addition, the passage of time is relevant in an evaluation of whether a substance is GRAS under 
the conditions of its intended use. In our 1974 proposed rule on general recognition of safety and 
prior sanctions for food ingredients, we acknowledged that there would be at least some gap 
between the gathering of the scientific knowledge necessary to provide the toxicological 
underpinning for general recognition of safety and the dissemination to and assimilation by the 
  19  Contains Nonbinding Recommendations 
scientific community of this material that is necessary for general recognition of safety to exist. 
(39 FR 34194 at 34194, September 23, 1974). More recently, the discussions in sections III.A.4 
and IV.K of CFSANs 2010 experience document (Ref. 18) show our approach to the time gap 
between the publication of safety data and the use of the published safety data to support a 
conclusion of GRAS status during the Interim Pilot program. See also Response 67 regarding 
nanotechnology applications in food substances.  
(Comment 20) One comment asserts that we must define the extent of agreement needed 
to establish a consensus among qualified experts, and that we must exclude from eligibility for 
classification as GRAS any substance whose safety has been called into question by expert 
authorities or authoritative entities within the scientific community. 
(Response 20) The proponent of a GRAS conclusion for a food substance must 
demonstrate that the conditions of use of the substance satisfy the definition of safe in our 
regulations (i.e., that there is reasonable certainty that the substance is not harmful under the 
conditions of its intended use (see  170.3(i)). The proponent of GRAS status also must 
demonstrate that there is common knowledge about this safety throughout the knowledgeable 
scientific community ( 170.30(a)). Although courts have established that general recognition of 
safety requires a consensus of expert opinion regarding the safety of the use of the substance, 
(see, e.g., United States v. Western Serum Co., Inc., 666 F.2d 335, 338 (9th Cir. 1982) (citing 
Weinberger v. Hynson, Westcott & Dunning, 412 U.S. 609, 629-32 (1973)), we disagree that we 
must define the extent of agreement needed to establish such a consensus. Courts have 
established that general recognition of safety does not require unanimous agreement. See, e.g., 
United States v. Articles of Drug * * * 5,906 Boxes, 745 F.2d 105, 119 n. 22 (1st Cir. 1984); 
United States v. Articles of Food and Drug (Coli-Trol 80), 518 F.2d 743, 746 (5th Cir. 1975) 
(What is required is not unanimous recognition but general recognition). Importantly, general 
recognition of safety does not exist if there is a genuine dispute among qualified experts that the 
use of a substance is safe. See, e.g., Premo Pharmaceutical Laboratories v. United States, 629 
F.2d 795, 803-4 (2nd Cir. 1980) (genuine dispute among qualified experts precludes finding of 
general recognition, and no general recognition existed as a matter of law where there was a 
sharp difference of expert opinion); United States v. Article of Food * * * Coco Rico, 752 F.2d 
11, 15 n 6 (1st Cir. 1985) (substance was not GRAS as a matter of law based on existence of 
genuine dispute among qualified experts regarding safety of use). For discussions of additional 
judicial decisions bearing on the criteria for eligibility for classification as GRAS, see the notice 
of declaratory order providing our final determination regarding partially hydrogenated oils (80 
FR 34650). 
A conclusion of GRAS status must be based on the totality of the publicly available and 
corroborative evidence about the safety of the substance under the conditions of its intended use, 
including both favorable and potentially unfavorable information. Thus, reports of expert 
authorities or authoritative entities within the scientific community may indicate that there is no 
general recognition of safety when the reports call into question the safety of a substance for use 
in food. However, we disagree that the outcome of an evaluation of such information can be 
predetermined as suggested by the comments. Regardless of whether particular scientific data 
and information lead experts to conclude that a substance is safe under the conditions of its 
intended use, or raise questions about the safety of the substance under the conditions of its 
intended use, the evaluation of whether a use of a substance in food is safe, and whether safety is 
generally recognized, is a case-by-case evaluation. For example, data and information that lead 
expert authorities or authoritative entities within the scientific community to raise a concern 
  20  Contains Nonbinding Recommendations 
about the safety of the substance under the conditions of its intended use in food would have 
reduced significance if the concern was related to a contaminant in the substance and 
scientifically valid data and information supplied by the proponent of GRAS status provide 
evidence that an improved method of manufacture eliminates that contaminant. 
See also Response 77, in which we explain that we proposed to provide the judicial 
interpretation of section 201(s) of the FD&C Act in the requirement for the comprehensive 
discussion of the notifiers basis for a conclusion of GRAS status to provide more context to 
notifiers than merely repeating the statutory language. However, as discussed in Response 77, we 
have decided to use the statutory language (i.e., generally recognized) rather than the proposed 
term consensus in the submission requirements for a GRAS notice to mirror the GRAS criteria 
in  170.30, which continue to use the statutory language rather than the consensus standard 
applied by the courts in applying the statutory language to specific situations.  
... 
(Comment 34) One comment suggests that the GRAS notification procedure would shift 
the burden of proof to FDA to demonstrate that a use of a substance is not safe or not GRAS 
after the substance is already on the market. 
(Response 34) We disagree. Under the FD&C Act, the burden of supporting a conclusion 
that a substance is GRAS under the conditions of its intended use is on the proponent of this 
conclusion. United States v. An Article of Food, 752 F.2d 11, 15 (1st Cir. P.R. 1985). This 
burden of proof remains after the substance is on the market regardless of whether the proponent 
asks FDA to evaluate that GRAS conclusion, and our rule does not change this. By establishing a 
process for the submission of GRAS notices for FDA to review, our rule encourages firms to 
seek our evaluation of their conclusions, before they introduce the substance into the market. 
... 
(Comment 58) Several comments support a requirement for a GRAS notice to include a 
certification statement similar to the certification statement that had been required in a GRAS 
affirmation petition. One comment agrees that the notifier should submit a statement that the 
notice is a representative and balanced submission, but does not agree that the notifier needs to 
certify the statement.  
(Response 58) The final rule requires a certification statement as described in the 2010 
notice, with one modification (see  170.225(c)(9)). We added that the statement certify that the 
GRAS notices is complete in addition to representative and balanced, to emphasize your 
responsibility to identify, discuss, and place in context, data and information that are, or may 
appear to be, inconsistent with a conclusion of GRAS status, regardless of whether those data 
and information are generally available (see the requirements of the narrative in Part 6 of a 
GRAS notice ( 170.250, in particular  170.250(c)). The certification is appropriate and 
necessary to underscore your legal responsibility for the conclusion of GRAS status. As 
discussed in the 2010 notice, the specific text of the certification statement that you must include 
in a GRAS notice is consistent with the specific text of the certification statement in the GRAS 
affirmation petition process that the notification procedure is replacing. The use of certification 
statements has become routine in other submissions to FDA for food programs (see, e.g., the 
certification statement in Part V of Form FDA 3480 (for a food contact notification submission) 
(Ref. 39); and the certification statement in Section 13 of Form FDA 3537 (for registration of a 
food facility) (Ref. 40)). 
By complete, we also mean that your GRAS notice identifies, and places in context, 
unpublished data and information that you believe corroborate GRAS status. For example, if you 
  21  Contains Nonbinding Recommendations 
conduct six toxicology studies, but only publish three of the studies, it may be that you consider 
the remaining three studies to be corroborative of safety. As an example, it may be that you were 
dissatisfied with the study design of one study, repeated that study with an improved study 
design, and published the study with the improved study design. If you consider that the findings 
of the unpublished studies corroborate safety, even if they do not establish it, a complete, 
representative, and balanced submission would briefly describe the unpublished studies. In 
addition, we expect that you would describe, and place in context, unpublished data and 
information if you consider that the findings of the unpublished data and information warrant 
sharing with any GRAS panel that you convene. See also the discussion in Response 69 and 
Response 78. 
... 
(Comment 69) Several comments address Issue 9a, i.e., whether the final rule should 
continue to stipulate that the method of manufacture exclude any trade secrets, as proposed. 
Some of these comments support stipulating that the method of manufacture exclude any trade 
secrets. The stated reasons varied. For example, some comments state that in the past experience 
of notifiers, it is generally possible to include sufficient information on the manufacturing 
process without disclosing trade secrets. One comment states that transparency, by both FDA 
and industry, and the use of publicly available information is critical to the continued success of 
the GRAS notification procedure. One comment states that the common knowledge element of 
the GRAS standard inherently limits the submission of confidential information and/or trade 
secrets by the notifier to substantiate a conclusion of GRAS status.  
Other comments point to the proposed requirement that a GRAS notice include detailed 
information about the ... method of manufacture (excluding any trade secrets ...) and question 
whether a method of manufacture that excludes trade secrets can be sufficiently detailed to meet 
the requirements of a GRAS notice. One comment recommends that we clarify the rule by 
requiring that the notice include appropriate information on the method of manufacture, 
sufficient to conduct an adequate safety review, so that confidential information would not be 
submitted when a very general and non-confidential description suffices.  
Several comments acknowledge that there may be situations where trade secret 
information is necessary to complete the description of the method of manufacture and 
recommend that the final rule provide flexibility for a notifier to provide trade secret information 
when appropriate (e.g., to help us evaluate the GRAS notice), and for FDA to protect trade 
secrets or other confidential information in a GRAS notice from public disclosure, just as we 
would in the case of submissions such as food additive petitions. To promote clarity and 
transparency, some of these comments recommend revising the rule to require that a notifier who 
includes trade secret information explain why the information is trade secret and why the trade 
secret information has a corroborative role in the safety assessment. Some comments emphasize 
that a notifier who submits trade secret information must mark the information as non-public. 
Other comments assert that information identified as trade secret or confidential information 
should only be allowed if the information is not critical to a conclusion of GRAS status.  
One comment suggests that a notifier could provide trade secret information to a GRAS 
panel for review on a confidential basis because deliberations of the panel would not necessarily 
be subject to public disclosure. One comment notes that supporting information can be valuable 
to a GRAS panel and allowing submission of confidential information in a GRAS notice could 
inform FDA of the full range of information taken into consideration by a GRAS panel. 
  22  Contains Nonbinding Recommendations 
Some comments cite our regulations for new drugs, premarket notification for medical 
devices, and premarket approval of medical devices as evidence that our regulations 
implementing FOIA specifically regard methods of manufacture as confidential and urge us to 
adopt a similar approach for GRAS notices. 
See also Comment 57. 
(Response 69) See Table 11, and the regulatory text in  170.230(b), 170.225(c)(8), 
170.250(d), and 170.250(e), for a series of changes we made to the rule to address these 
comments about the method of manufacture included in a GRAS notice, including comments 
about trade secret information associated with the method of manufacture. Although the changes 
in Parts 1 and 6 of a GRAS notice broadly apply to any non-public information, in this response 
we focus on how these provisions apply to trade secret information that you may include in the 
description of the method of manufacture. Collectively, these changes: (1) Emphasize that the 
description of the method of manufacture must be in sufficient detail to evaluate the safety of the 
notified substance as manufactured, without stipulating that the method of manufacture exclude 
any trade secrets ( 170.230(b)); (2) require the notifier to include a signed statement with his 
view as to whether the method of manufacture includes trade secret information ( 
170.225(c)(8)); (3) require the notifier to identify any trade secret information in the method of 
manufacture ( 170.250(d)); and (4) require the notifier to explain how there could be a basis for 
a conclusion of GRAS status if qualified experts do not have access to trade secret information 
that the notifier considered in concluding that the substance is safe under the conditions of its 
intended use ( 170.250(e)). See also Response 57, Response 78, and section XVII. 
 
Table 1.--Requirements That Apply When a Notifier Includes Trade Secret or Other Non-Public Information in a 
GRAS Notice  
Final  Proposed  Description   Revision 
Designation in  Designation in 
the Regulatory  the Regulatory 
Text ()  Text () 
170.230(b)  170.36(c)(2)  In Part 2 of your GRAS notice, you must   We replaced detailed with 
include a description of the method of  sufficient detail to evaluate the 
manufacture in sufficient detail to  safety of the notified substance as 
evaluate the safety of the notified  manufactured 
substance as manufactured   We no longer stipulate that the 
description 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 
state your view as to whether any of the  information that the notifier views as 
data and information in Parts 2 through 7  non-public information to make 
of your GRAS notice are exempt from  FDA aware of that view. See 
disclosure under the FOIA (e.g., as trade  Response 57. 
secret or as commercial or financial 
information that is privileged or 
confidential). 
170.250(d)  N/A  In Part 6 of your GRAS notice (the  Requires a notifier who includes 
narrative), if you view any of the data  information that the notifier views as 
and information in your notice as  non-public information to identify 
exempt from disclosure under the FOIA,  the non-public information. See 
you must identify the specific data and  section XVII. 
information 
  23  Contains Nonbinding Recommendations 
Final  Proposed  Description   Revision 
Designation in  Designation in 
the Regulatory  the Regulatory 
Text ()  Text () 
170.250(e)    In Part 6 of your GRAS notice (the  Requires a notifier to place non-
narrative), you must explain how there  public information in the context of a 
could be a basis for a conclusion of  conclusion of GRAS status. See 
GRAS status if qualified experts  section XVII. 
generally do not have access to non-
public, safety-related data and 
information. 
170.275(c)  170.36(f)(1)  We will disclose all remaining data and  Uses active voice to emphasize that 
information that are not exempt from  we will apply the protections from 
public disclosure in accordance with part  public disclosure under the FOIA to 
20.  non-public information included in a 
GRAS notice 
 
This rule establishes requirements for the information that a notifier submits to FDA in a 
GRAS notice. GRAS criteria require that any conclusion of GRAS status be based on common 
knowledge (see  170.30(a)) and, thus, there could be no basis for a conclusion of GRAS status 
if trade secret information (or other non-public information) is necessary for qualified experts to 
reach a conclusion that the notified substance is safe under the conditions of its intended use. In 
the particular case of a conclusion of GRAS status through scientific procedures, GRAS criteria 
require that the conclusion of GRAS status be based on data, information, and methods that are 
generally available (see  170.30(b)). Non-public information may be used to corroborate safety 
but cannot be used to establish safety; as discussed in Response 9, qualified experts must be able 
to conclude that the substance is not harmful under the conditions of its intended use without 
access to corroborative information (see  170.30(a)).  
We believe that it will be rare for a GRAS notice to include trade secret information. 
Likewise, we expect it will be rare that trade secret information would warrant sharing with 
members of a GRAS panel, because a notifier must write a non-confidential description of the 
method of manufacture to include in the GRAS notice and could share this non-confidential 
description, rather than trade secret information, with the GRAS panel. If the GRAS panel had 
questions about that description of the method of manufacture, we expect that the notifier would 
revise the description to address those questions rather than provide the GRAS panel with trade 
secret information to address those questions. If, however, a notifier does provide the GRAS 
panel with trade secret information, we agree that the notifier should inform us of the full range 
of information taken into consideration by the GRAS panel, consistent with the signed statement 
that the GRAS notice is a complete, representative, and balanced submission (see Response 58 
and  170.225(c)(9)). The notifier could do so either by including in his GRAS notice a non-
confidential description of the trade secret information that was shared, or by providing the trade 
secret information shared with a GRAS panel. Importantly, the notifier would be required to 
explain how there could be a basis for a conclusion of GRAS status if qualified experts generally 
do not have access to non-public, safety related data and information (see Response 78 and  
170.250(e)). If the public description of the method of manufacture that a notifier includes in a 
GRAS notice cannot provide sufficient detail to evaluate the safety of the notified substance as 
manufactured, there could be no basis to support a conclusion of GRAS status. However, if that 
public description meets the requirements of the rule to provide sufficient detail to evaluate the 
safety of the notified substance as manufactured (see  170.230(b)), it may be possible to explain 
  24  Contains Nonbinding Recommendations 
that trade secret information that a GRAS panel evaluated is corroborative of safety rather than 
necessary to demonstrate safety.  
Under  20.61, trade secrets and commercial or financial information which is privileged 
or confidential are exempt from public disclosure. Under  20.100(c)(7) and 171.1(h)(2)(i), 
manufacturing methods or processes, including quality control procedures, are exempt from 
public disclosure unless they have been previously disclosed to the public (as defined in  20.81) 
or they relate to a product or ingredient that has been abandoned. If a notifier believes that all 
information about the method of manufacture should be non-public, it is unlikely that the notifier 
has a basis to conclude that the notified substance is GRAS under the conditions of its intended 
use. The use of the substance would be a food additive use and, if the notifier submits a food 
additive petition for that use, our regulations governing a food additive petition would protect the 
information from public disclosure, as do our regulations for new drugs, premarket notification 
for medical devices, and premarket approval of medical devices. 
(Comment 78) One comment notes that industry has various options for handling 
confidential information. For example, confidential agreements are commonly used instruments 
to help maintain the confidentiality of proprietary trade secret information, and therefore 
qualified experts on GRAS panels can have access to such information if it is necessary for a 
conclusion of GRAS status. The comment asks us to require that notifiers indicate whether 
qualified experts (such as on the notifiers GRAS panel) had access to trade secrets when they 
concluded that the substance is safe under the conditions of its intended use.  
(Response 78) The rule establishes no requirements specific to a GRAS panel. However, 
we agree that it is appropriate for a notifier to indicate whether qualified experts (such as on the 
notifiers GRAS panel) who reviewed the data and information supporting safety had access to 
safety-related trade secrets in reaching a conclusion that the notified substance is safe under the 
conditions of its intended use. Therefore, we are requiring that a notifier explain how there could 
be a basis for a conclusion of GRAS status if qualified experts generally do not have access to 
non-public safety-related data and information (see  170.250(e)). This requirement applies to all 
non-public safety-related data and information, not just trade secret information, and is not 
limited to non-public safety-related data and information that are included in the notice. As 
requested by the comment, this requirement would apply if the notifier provided non-public 
safety-related information to outside experts (such as on a GRAS panel). As already discussed, if 
a GRAS panel considers non-public safety-related information that a notifier does not include in 
a GRAS notice, we also expect the notifier to inform us that the GRAS panel had access to such 
information, consistent with the notifiers signed statement that the GRAS notice is a complete, 
representative, and balanced submission (see  170.225(c)(9)) (see Response 58 and Response 
69).  
See also Table 11 and Table 15. The rule also requires that a notifier state his view as to 
whether any of the data and information in Parts 2 through 7 of a GRAS notice are exempt from 
disclosure under the FOIA (see  170.225(c)(8)) and identify what specific data and information 
in the notice are generally available, and what specific data and information in the notice are not 
generally available (see  170.250(a)(2) and (d)). Collectively, the requirements in  
170.225(c)(8) and (9) and 170.250(a)(2), (d), and (e) address the underlying issue in the 
comments request, i.e., that there must be a basis for a conclusion of GRAS status if some 
safety-related data and information that a notifier assesses in his deliberations are non-public 
(e.g., trade secret information or otherwise are confidential information), regardless of whether 
the notifier shares such information with a GRAS panel. If a GRAS notice does not provide a 
  25  Contains Nonbinding Recommendations 
basis for a conclusion that the notified substance is safe under the conditions of its intended use 
without access to such information, we would respond to the notice with an insufficient basis 
letter. If we respond with a no questions letter, and later determine that the GRAS notice was 
not complete (e.g., because it did not describe unpublished reports of investigations that are, or 
may appear to be, inconsistent with the conclusion of GRAS status), we may send the notifier a 
subsequent letter regarding the omission; such a letter would be readily accessible to the public 
( 170.265(c) and 170.275(b)(2)). 
 
 
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