Contains Nonbinding Recommendations  
 
 
Best Practices for  Convening  a GRAS 
Panel:  
Guidance  for Industry   
 
 
Additional copies are available from:  
Office of Food Additive  Safety  
Center for Food Safety and Applied Nutrition  
Food and Drug Administration  
  5001 Campus Drive    
College Park, MD 20740 
240-402-1200 
https://www.fda.gov/FoodGuidances  
 
You may submit either 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-
2017-D-0085.  
For questions regarding this document as it relates to substances used in human food, contact the  
Center for Food Safety and Applied Nutrition (CFSAN) at 240-402-1200.  
For  questions regarding this document as it relates to substances used in animal food, contact the  
Center for Veterinary  Medicine (CVM) at 240-402-7002. 
 
 
 
U.S. Department of Health and Human Services  
Food and Drug Administration  
Center for  Food Safety and Applied Nutrition  
Center for Veterinary Medicine  
  
December 2022  
 
OMB Control No. 0910-0911 
Current expiration date  available at https://www.reginfo.gov.  
*See additional PRA statements in Section VI of  this guidance document.  
 
   
  Contains Nonbinding Recommendations 
 
 
 
Table of Contents 
 I. Introduction
   
II. Background
   
A.  Statutory and Regulatory Framework for Substances Added to Food 
B.  GRAS Notification Procedure 
C.  Evidence for General Recognition 
1. General Availability 
2. General Acceptance 
D.  2010 Report of the Government Accountability Office 
III.  Key Ideas Relevant to Our Recommendations
   
A.  Bias 
B.  Balance of Expertise 
C.  Procedures for Organizing a Scientific Panel and Managing Its 
Deliberations 
D.  Conflict of Interest and Appearance Issues 
1. Federal Regulations and FDA Guidances 
2. Policies and Literature Regarding Conflict of Interest and Appearance Issues 
IV. Definitions
 
V. Recommendations
   
A.  Introduction 
1. Recommendations Related to Selecting GRAS Panel Members 
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2. Recommendations Related to the Operation of the GRAS Panel and to the Submission of a Notice 
to FDA 
3. Other Recommendations 
B.  Appropriate and Balanced Expertise in a GRAS Panel 
1. General Considerations When Convening a GRAS Panel 
2. Appropriate Expertise in a GRAS Panel 
3. Number of Members of a GRAS Panel 
C.  Assessment and Management of Procedural Issues Associated with the 
Organization and Deliberations of a GRAS Panel 
D.  Assessment and Management of Conflict of Interest and Appearance 
Issues of Potential GRAS Panel Members 
1. Overview 
2. Identifying Conflict of Interest and Appearance Issues 
3. Criteria for Evaluating Identified Conflicts of Interest and Appearance Issues and Strategies for 
Managing Identified Conflicts of Interest and Appearance Issues 
4. Documentation of Conflicts of Interest, Appearance Issues, and Rationales for Waivers 
5. Format of a Written GRAS Panel Policy 
E.  Information Provided to a GRAS Panel 
F.  Documenting the Deliberations and Conclusions of a GRAS Panel 
G.  Considerations When a GRAS Notice is Submitted to FDA 
H.  Considerations When a GRAS Notice is Not Submitted to FDA 
I.  Honoraria Provided to Members of a GRAS Panel 
VI. Paperwork Reduction Act of 1995
 
VII. References
   
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Best Practices  for Convening  a GRAS 
Panel:  
Guidance  for Industry1 
 
 
 
This guidance represents the Food and Drug Administration's (FDA's) current  thinking on this  
topic.  It does not create  or confer any rights  for  or on any person and does not operate to bind 
FDA or the public.  You can use an alternative approach if the approach satisfies the 
requirements of the applicable statutes and regulations.  If you want to discuss an alternative  
approach, contact  the FDA staff  responsible  for  implementing this guidance.  If  you cannot  
identify  the appropriate FDA  staff,  call the  appropriate  telephone number listed on the title page  
of this guidance.  
 
 
 
I.   Introduction  
This guidance document is intended to provide  our  recommendations  on best practices for  
convening a GRAS  panel.   By GRAS, we mean generally recognized as safe.   See section  
II.A for a  discussion of the GRAS provision of  the Federal Food, Drug, and Cosmetic  Act  
(FD&C Act).  By GRAS panel, we mean a panel of qualified experts who independently 
evaluate whether the available scientific data, information, and methods  establish  that a  
substance  is  safe under the conditions of its intended use in human food or animal  food as part of  
an evaluation of whether adding that  substance  to food is lawful under  the  GRAS provision of  
the FD&C Act.  
In general, FDAs guidance documents do not establish legally enforceable responsibilities.   
Instead, guidances describe FDAs 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.  
In this document, we refer to a person who is responsible for  a conclusion that a substance may  
be used in food on the basis of  the GRAS provision of the FD&C Act as the proponent of  
 
1  This  guidance  has  been prepared  jointly  by the  Division of  Food  Ingredients  in the  Office  of  Food Additive  Safety 
in  the  Center  for  Food  Safety  and  Applied  Nutrition,  and  the  Division  of Animal  Feeds  in  the  Office  of  Surveillance  
and  Compliance  in  the  Center for Veterinary  Medicine  at the  U.S.  Food  and  Drug Administration.   
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GRAS status for that substance under the conditions of its intended use.   In many cases, the 
process whereby the proponent evaluates whether the  available data and information support a  
conclusion that a substance is GRAS under the  conditions of its  intended  use need not include  a 
GRAS panel.   However, in some cases,  the proponent  might  decide that  the opinion of  a  GRAS  
panel  may be useful.   Depending on the outcome  of the GRAS panels analysis, the proponent  
could either  reach  a conclusion regarding the safety of the substance under the conditions of its  
intended use, or be advised of one or  more  issues  (such as gaps in the data  and information, or  
alternative  interpretations of the available data and information) that warrant investigation before  
a conclusion can be drawn about whether  the substance  is safe under the  conditions  of  its  
intended use.   
Importantly, the outcome of a panels deliberations does not  create or confer general  recognition 
of  the  safety of the  use of an ingredient.  Rather, it could provide evidence  supporting the  
proponents  contention that there is  general acceptance based on generally available  information 
among relevant scientific communities.   When the outcome of the GRAS panels analysis 
supports the proponents  conclusion that a substance is safe under the  conditions of its intended 
use, in essence  the proponent  is relying  on  the members of the GRAS panel  to act  as a  
representative sample2  of  the  larger scientific community  knowledgeable about the  safety of  
substances directly or indirectly added to food.  In so doing, the proponent  relies on the outcome  
of the GRAS panels analysis  to support the proponents conclusion that the  safety of the  
intended use is  generally recognized  by qualified experts.   Whether a GRAS panel is a 
sufficiently representative  sample  with respect to  the larger scientific community depends on  a 
number  of factors, such  as the subject matter expertise of  the members of  the GRAS panel and  
whether the  members of the GRAS panel are  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.  Unless both criteria, i.e., generally  
available and generally accepted,  are  satisfied, there would be no basis for a  conclusion of  
GRAS status based on a  GRAS panel  opinion  (see Response 11, 81 FR  54960 at  54974, 
August 17, 2016).   
A  GRAS panel is  just one mechanism that proponents have used to provide  evidence of  general  
acceptance  in support of  their GRAS  conclusion.  In most  cases,  a well-supported  GRAS  
conclusion  will not require an analysis by a  GRAS panel  (see Figure  1).  We suggest that  
proponents  considering whether a GRAS panel would be useful  in supporting their  GRAS  
conclusion  consult with FDA before embarking on such an effort.   In addition, we realize that it  
can be challenging to identify, screen, and select a comprehensive panel  of qualified experts  
when specialized  expertise applicable to the scientific considerations associated with the 
intended conditions of use of a food substance  is  needed, given the potentially finite number of  
 
2  In other  words,  the  panel  functions  as  a  sample  of  the  scientific  community,  and thus  the  views  of the  panel  
members  can provide  evidence  of  their  respective  disciplines  generally accepted views  on  a particular question.   
However,  if  there is  reason  to  believe that  the sample is  unrepresentative in  some  way,  the credibility  of  the panels  
views  as  evidence of  general  acceptance  could  be  significantly  reduced.  
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experts who would be both qualified and available to serve  on a GRAS panel.  Thus, it may be  
worth considering whether the  effort to convene a GRAS panel is warranted in any particular  
case before allocating resources to  it.  
This guidance document is  intended for  and directed to:  
    Those proponents who intend to consider the opinion of a GRAS panel in reaching a  
conclusion that the  intended use of a  substance  in human food or animal  food is GRAS;   
    Those persons who assemble a GRAS panel and provide  the framework for its  
deliberations (organizers); and/or  
    Those persons who are interested  in  our views and recommendations on best practices for  
convening a  GRAS panel.  
The recommendations in  this guidance address best practices for convening a GRAS panel  to:  
    Identify GRAS panel members who have appropriate and balanced expertise;   
    Take steps to reduce  the risk that bias (or the appearance of bias) will affect the  
credibility of the GRAS panels output (often called a GRAS panel report), including  
the assessment of potential GRAS panel members for conflict of interest and the  
appearance of conflict of interest; and  
    Limit the data and information provided to a GRAS panel to public  information (e.g., by 
not providing the GRAS panel with information such as trade  secret information).   
The recommendations in this guidance reiterate  certain statutory and regulatory considerations  
that we have previously discussed regarding the  use of a GRAS panel in addressing the GRAS  
provision of the FD&C Act related to food and food additives  (81 FR 54960 at 54966, 54994, 
and 55000).  However, this guidance document  is not intended to address  the statutory and 
regulatory criteria that govern eligibility  for classification of a substance  as GRAS under the  
conditions of its  intended  use  or  to describe the proponents  responsibilities for complying with 
those statutory and regulatory criteria.   For the most recent discussions of  those statutory and  
regulatory criteria, see the final rule entitled Substances Generally Recognized as Safe (81 FR  
54960  (the  GRAS final rule)) and our guidances  entitled 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  
(the regulatory framework guidance)  (Ref.  1)  and Frequently Asked Questions  About GRAS  for  
Substances  Intended for  Use in Human or Animal Food: Guidance for Industry  (the  GRAS  
FAQs) (Ref.  2).  
Rather, this guidance includes  recommendations  for GRAS panels  that are informed by  federal  
law, regulations, and FDA guidance  documents related to FDA advisory committee  members.   
Our reference to these  requirements  and guidances  is solely for the purpose of discussing 
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concepts that are  relevant to conflict of interest issues for GRAS panels  (the topic of this  
guidance), rather than to imply  that FDA bears the same organizing  role  in relation to a GRAS  
panel  as  it does for an  FDA advisory committee  or to imply that  the processes are wholly  
analogous.   In addition, for more background and information, this guidance notes some 
available conflict of interest  policies from  other organizations.   This  guidance  is intended to 
support the  organizers of GRAS panels in  their own  development of procedures for convening 
GRAS panels.  
II.   Background  
A.  Statutory and Regulatory Framework for Substances  Added to Food  
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  
 
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.  
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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)).  
B.  GRAS Notification Procedure  
In 2016, we issued a  final rule establishing the  GRAS notification procedure (Generally  
Recognized as Safe (GRAS) Notice) 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 (81 FR  
54960).   That final  rule  completed the rulemaking that we initiated through a proposed rule  (62 
FR 18938, April 17, 1997) and a notice  reopening the comment period for the proposed rule  to 
update comments  and to solicit comment on specific issues (reopening notice) (75 FR 81536, 
December 28, 2010).   
The GRAS final rule  provides  that any person may notify FDA 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 
person's conclusion that  the substance is GRAS under the  conditions of its intended use.  A 
submission containing this view (a  GRAS notice) must contain seven parts, including an 
explanation of  how the generally available data and information relied  on to  establish safety  
provide a basis for the proponents  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(b)  
and 570.250(b)).  
C.  Evidence  for General  Recognition  
For  a substance to  be eligible  for GRAS status under the  conditions of its intended use, the  
publicly available data and information must satisfy the safety standard for a food additive  in 
accordance  with section  409(c)(5)(C) of the  FD&C Act.   Furthermore, there must be common 
knowledge throughout the expert scientific community knowledgeable  about the  safety of  
substances directly or indirectly added to food  that there is reasonable  certainty that the  
substance is not  harmful under  the intended  conditions of use  (see 21 CFR 170.30(a) and 
570.30(a)).  This requirement of  general recognition  is itself composed of both general  
availability and general acceptance aspects.    
1.   General Availability  
As discussed  in GRAS  rulemaking documents, publication in a peer-reviewed  scientific journal 
is the usual  mechanism  to establish  that scientific information is generally available  (see 
Response 8, 81 FR 54960 at 54973; 62 FR  18938 at 18940).      
 2.   General Acceptance  
There are a variety of ways to  provide evidence  of general  acceptance.  The type of  evidence  
necessary in a particular  case will depend on the  properties  and intended use of an ingredient as  
well  as the  state of the science and  the available public data.   
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A  GRAS panel is just one mechanism that proponents have used to provide  evidence of  general  
acceptance, thus supporting the  proponents  GRAS  conclusion (see Response 13,  81 FR 54960 at  
54975).  However, use of a GRAS panel is not the only mechanism  for doing so.  While  it is true  
that some  GRAS notices evaluated by FDA have included statements from a GRAS  panel, in our  
view,  the presence and conclusions of the panel  were not essential evidence supporting the  
proponents  GRAS conclusion for  most of these notices.   
Conversely, the use of  a  GRAS panel does not necessarily mean that  the  general acceptance 
aspect of the  criteria for eligibility for GRAS  status  has  been met (see Response 13, 81 FR 54960 
at  54975).    
Figure 1  illustrates  the continuum of value that the output of  a GRAS panel could contribute to a  
proponents  GRAS conclusion, ranging from  likely unnecessary to potentially useful to likely  
insufficient.  Table 1, further discussed below, provides examples when  a GRAS panel may be 
either unnecessary    because there is likely already sufficient evidence of general  acceptance  -- 
or insufficient    because  it is unlikely  that a GRAS panel could provide  credible evidence of  
general  acceptance  -- to  satisfy the generally accepted  aspect of the criteria  for eligibility for 
GRAS status.   In cases  where the proponent is unsure of  the  potential value of a GRAS panel in 
helping  to satisfy  the general  acceptance criteria, the proponent should  consult with FDA.  
Figure  1: Continuum of Value  for  GRAS Panels in Providing Evidence of General  
Acceptance  
Likely Unnecessary  Potentially useful  Likely Insufficient 
 
Table  1: Examples of Scenarios Where  GRAS  Panels Are Likely Unnecessary or 
Insufficient to Provide Evidence of General Acceptance  
GRAS Panel  Likely  Unnecessary   GRAS Panel  Likely  Insufficient  
Published results  in the primary scientific   Ongoing scientific discussion or controversy 
literature raise no questions that  experts  about safety  concerns raised by available data  
would need to interpret and resolve  (see d.   (see d. Basis for concluding expert  
Basis for  concluding expert consensus,  62  consensus, 62 FR  18938 at  18949)  
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GRAS Panel  Likely  Unnecessary   GRAS Panel  Likely  Insufficient  
FR 18938 at  18949; see Response 13,  81 FR  
54960 at  54975)  
Publication of  data and information in the   Safe level of intake is in  a narrow range  (see 
primary scientific literature has been   1. Establishing General  Recognition of  
supplemented by publication of data  and  Safety, 62 FR  18938 at  18943)  
information in the secondary literature, such 
as scientific review articles, textbooks, and  
compendia  (see C. Elements of the GRAS  
Standard,  62 FR  18938 at  18940  through 
18941; see  Responses 10, 11, and 13, 81 FR  
54960 at  54974  through 54975)  
Publication of  data and information in  the   Severe conflict among experts  regarding the  
primary scientific literature has been   safety of the use of a substance  (United States  
supplemented by the opinion or   v. An Article of Drug* * * 4,680 Pails, 725 
recommendation of an authoritative  body [...]   F.2d 976 at 990 (5th  Cir. 1984); Premo  
on a broad or specific issue that  is related to  a  Pharmaceutical Laboratories v. United  
GRAS  conclusion  (see C. Elements of the  States, 629 F.2d 795 at 803 (2d Cir. 1980))  
GRAS Standard,  62 FR 18940  through 
18941;  see Response 13,  81 FR  54960 at  
54975)  
 
In most  cases, a well-supported GRAS conclusion will not  need  an analysis by  a GRAS panel as 
evidence of general  acceptance (the left-hand side of Figure  1;  the left-hand examples in Table  
1).  Depending on the specifics of the intended use of a substance, peer-reviewed primary safety 
studies, secondary reviews of primary literature, or the findings of an authoritative body could 
provide adequate evidence of general acceptance.   Each of these three types of evidence  is 
discussed below.   
    Published peer-reviewed primary studies.  In many cases, the type of  evidence provided 
by published peer-reviewed primary studies  consistent with  generally  accepted safety  
assessment strategies  is  sufficient to satisfy  both  the general availability as well as  the  
general acceptance aspects of the GRAS criteria.  We stated in the GRAS  proposed rule 
that there could be a basis to conclude that  there is expert consensus4  that the published 
results of a  particular safety study (i.e., the primary scientific  literature) establish the  
safety of a substance for its intended use if  the study raises no safety questions that  
experts would need to interpret and resolve  (62 FR  18938 at 18943).   We  also noted this  
point in  the  GRAS final rule (see Response 13, 81 FR 54960 at 54975).  However, 
 
4  In  general,  FDA  describes  this  concept  using  general  acceptance  rather  than  expert  consensus,  a term  derived  
from  case  law,  for reasons  discussed in  the  GRAS  Final  Rule  (81  FR  54960 at  55007).   We  use  the  term  expert  
consensus  where  we  are  quoting directly  from  the  proposed rule  within  the  paragraph.  
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...data published  in the primary scientific  literature  may not provide a basis for expert 
consensus if those data raise unresolved safety questions  (62 FR  18938 at  18949).  
    Secondary literature.  In some cases, the type of evidence provided by secondary 
literature, such as  reviews of published primary literature,  may be sufficient and  
appropriate  to satisfy the  general acceptance  aspect of the GRAS criteria.  In the GRAS  
proposed rule, we noted that publication of data  and information in the primary scientific  
literature  can be  supplemented by publication of data and information in the secondary 
scientific literature, such as scientific review articles, textbooks, and compendia (see C.  
Elements of  the GRAS Standard, 62 FR 18938 at 18940  through 18941).  In the GRAS  
final rule, we further observed that there may  be  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 (see Response 17, 81 FR  54960 at  54976).   We also  
noted that technical literature  from the Joint Expert Committee on Food Additives  
(JECFA, a joint committee of the Food and Agriculture Organization/World Health  
Organization) can  provide evidence that generally available safety data and information  
are generally accepted (see section III.A.1 of Ref. 3).  
    Findings of  an authoritative body.  The  findings  of an authoritative body are  another type  
of evidence  that could be used to support the  general  acceptance aspect  of the GRAS  
criteria.  As an  example, this  could include the opinion or  recommendation of an 
authoritative body such as the National Academy of Sciences  on a broad or specific issue  
that is related to a GRAS  conclusion  (see C. Elements of the GRAS Standard,  62 FR  
18938 at  18940  through 18941).  The findings of an authoritative body may also be  the  
most  appropriate  type  of evidence to support  general acceptance  in  those cases where  the  
safe level of intake is a narrow range because the difference between the  intended or  
recommended dietary intake  (e.g., of a nutrient)  and the intake at which the substance  
exhibits toxic properties  is small.   In  such  cases, the opinions  or recommendations of the  
authoritative body may provide  evidence of  general acceptance, thus  supporting  a 
proponents conclusion  that that the  safety of a substance under the  conditions of its  
intended use is generally accepted by qualified experts (see Response 13,  81 FR 54960 at  
54975).     
By contrast, although unanimity among experts  regarding the safety of a substance  is  not  
required, an ongoing scientific discussion or controversy about safety concerns raised by 
available data would make it difficult to provide  a basis  for expert consensus  about the safety of  
the substance for its  intended use  (see d. Basis  for concluding expert consensus, 62 FR  18938 
at  18949).  While  mere conflict  among experts is not enough to preclude a finding of general  
recognition [of safety] (United States v. Articles of Food and Drug (Coli-Trol  80), 518 F.2d 743 
at 746 (5th Cir. 1975)), it does not exist if there  is a genuine  dispute  among qualified experts  that  
the use of  the substance is safe (See,  e.g., Premo Pharmaceutical Laboratories v. United States, 
629 F.2d 795 at 803 through 804 (2d  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)).  In such cases  (the right-hand side of  
Figure 1;  the right-hand column of Table 1), the type of evidence provided by a GRAS  panel, no 
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matter how  well constructed, may not be appropriate or sufficient  to support the general  
acceptance aspect of the  criteria for eligibility  for GRAS status through scientific procedures.  
Finally, there are occasionally circumstances in  which a GRAS panel may provide the 
appropriate type of evidence to support the general acceptance aspect of the criteria for eligibility  
for GRAS status through scientific procedures  (the middle of  Figure 1).  For  example, as  noted in 
the proposed rule, the  opinion of  an expert panel is  [...] useful when multiple studies bearing on 
the safety of a substance are published but there are no secondary sources that evaluate these 
studies and draw general conclusions based on this comprehensive body of knowledge (62 FR  
18938 at 18943).  A GRAS panel may also be useful  if the  published results of a particular  
safety  study  [...] raises safety questions that  require additional data to be resolved (62 FR 
18938 at 18943).  In such cases where published primary or  even secondary literature  might not  
be sufficient, a well-constructed GRAS panel may provide  the type of  evidence necessary to 
conclude that the published safety data are generally accepted.  
D.  2010 Report of the Government Accountability Office   
From 2008 to 2010, the  Government Accountability Office (GAO) conducted a study related to 
ingredients  used in human food on the basis of the GRAS provision in section 201(s)  of the  
FD&C Act.   In 2010, GAO issued a report  (Ref. 4; the GAO report) that included a number of  
recommendations for FDA.   The GAO report recommended that FDA develop a strategy to 
minimize the potential  for conflicts  of interest, including issuing guidance for  companies on 
conflict of interest, and we requested comment  on issuing such a guidance in our  reopening 
notice  (75 FR 81536 at 81542).   In the GRAS final rule, we stated  our  intent to  issue such  
guidance  (see Response  125, 81 FR  54960 at 55026).   This guidance addresses conflict of  
interest as part of the  best practices for convening a GRAS panel.  
III.    Key Ideas  Relevant to  Our Recommendations  
As noted in the Introduction, among other things,  this guidance document  recommends best  
practices to  reduce the risk that bias (or the appearance of bias) will  affect  the credibility of the  
GRAS panels output  (often called a  GRAS panel report), including the assessment  of  
potential GRAS panel members for conflict of interest and  the appearance of conflict of interest.   
In developing these recommendations, we considered  federal law,  regulations,  and FDA 
guidances,  as well as published  literature  and conflict of interest policies  from several  
organizations  (e.g., the National Academies  of  Sciences, Engineering, and Medicine  (NASEM)  
and the  National Academy of Medicine (NAM);  (see sections III.B through III.D))  that have  
developed policies to  address topics such as bias, balance of expertise, procedures for  organizing  
a scientific panel and  managing its deliberations,  conflict of interest, and  the appearance of  
conflict of interest, for  use by their own organizations (or the  scientific community at large) 
during the conduct of scientific research.   In  this section, we summarize key ideas from these 
sources that are relevant to  our  recommendations.   
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A.  Bias  
Bias is a particular  tendency,  trend,  inclination,  feeling,  or  opinion,  especially  one  that  is  
preconceived  or  unreasoned  (Ref.  5)  and can operate either for or against an outcome  that the  
sponsor of an investigation might view as the preferred outcome  (Ref.  6).   Bias can be created  
both by cognitive patterns (Ref.  7  and  Ref.  8)5  and by factors  such as the  potential  for financial  
gain and can operate at  both an individual  level  and  a group level.  Individuals  may be more  
vulnerable to bias when they have  competing interests (Ref.  9  and Ref.  10).   
The credibility of an  opinion  from a  panel of scientific experts  can be  undermined if  one or more  
members is, or  is perceived to be, biased.   Although bias typically operates at a subconscious 
level and  is difficult  for external observers  to identify or even for individuals  to self-assess (Ref.  
11, Appendix D), the risk of bias can be reduced if the organizer of  a scientific panel  of experts 
identifies  and addresses  sources of potential bias  during the assembly and deliberations  of the  
panel.  
In sections III.B  through III.D, this document discusses the following  sources of potential bias 
that are particularly relevant for when a panel  of scientific experts  is  being convened:  
    Balance of expertise6;  
    Procedures for  organizing a  scientific  panel  and managing its  deliberations;  and  
    Conflict of interest  and  an appearance issue  (i.e., an interest or relationship that may  
create the appearance that an individual lacks impartiality on an issue).   
B.  Balance of Expertise  
The significant omission of any required discipline or subdiscipline  might  seriously compromise  
the quality of the  panels analysis and judgments, even if  the  panel  is composed of highly 
qualified individuals.  NASEM  issued a policy (the NASEM  policy) (Ref.  12) emphasizing  that 
the knowledge, experience, and perspectives of potential  members of a committee convened by 
 
5  Examples  of  cognitive patterns  that  can  create bias  (Ref.  7  and  Ref.  8)  include:  
   Availability  bias  (i.e.,  the  tendency  to  assume  that  the  most  available  evidence  is  the  most  relevant);  
   Confirmation  bias  (i.e.,  the  tendency  to  look  for  or  interpret  subsequent  data  to  support  an  initial  
hypothesis);   
   Order  of  effects  bias  (i.e.,  the  tendency  to  overweigh  or  recall  more  about  information  received  at  the 
beginning  and end  of  an exchange);  
   Outcome  bias  (i.e.,  the  tendency  to  interpret  data  in  ways  that  support  a  more  benign or  preferred outcome);   
   Posterior  probability bias  (i.e.,  the  tendency to assume  that  a  history  of  certain outcomes  or  causes  can be  
extrapolated  to  the present  assessment);   
   Search satisficing  (i.e.,  the  tendency  to stop gathering information  once  sufficient  information has  been 
gathered  to form  a  hypothesis);  and  
   Redundancy bias  (i.e.,  the  tendency to accord more  weight  to data  that  is  greater  in  quantity or  volume).  
6  Members  of  a  GRAS  panel  should  have the appropriate scientific expertise in  order  to  evaluate safety.   This 
discussion is  focused  on the  need  for  the  panel  to have  a  balance  of  expertise.  
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NASEM  must be thoughtfully and carefully assessed and balanced in terms of the subtleties and  
complexities of the particular scientific, technical,  and other  issues to be addressed,  and the  
functions to  be performed by the committee.   The  NASEM  policy points out that failure  to 
include  an appropriate discipline  can compromise the quality of a panels analysis and  
judgments, and that,  even within a particular discipline,  there may be  important differences  and 
distinctions  within the field that require careful consideration in the committee composition  and  
appointment process.  
C.  Procedures for Organizing a Scientific Panel  and Managing Its  
Deliberations  
Several  organizations  policies and publications  address sources of potential bias that could 
occur  as a result of  procedures for organizing small groups such as scientific expert panels and 
managing their  deliberations  (Ref.  11  through Ref.  19).   NAM  has issued  a report  (the  NAM  
report) (Ref. 11)  that discusses  sources of potential bias in development of clinical practice 
guidelines.7   The  NAM  report states that the  adoption of  explicit, systematic methods for  
reviewing evidence and developing and documenting practice guidelines  is an important strategy 
for reducing the opportunities for bias, whether the source  might be intellectual and professional 
preconceptions, financial interests, or something else.   Immediately below, we describe some 
examples from published literature  of how the composition  and organization  of a  scientific  
expert panel, and procedures for managing its deliberations, could introduce potential  bias into 
the panels deliberations.  
    Seniority or  perceived status among panel members could influence  the extent  to which 
members are willing to  volunteer information or raise objections  (Ref.  13).   Such effects 
on the composition of the panel have the potential to introduce bias  in the  kinds of data  
and information considered by the group.  
    The leader (whether formal or informal) of a panel could shape the group's norms around 
evaluation  of information and decision-making, moving  the panels focus  either towards  
sharing and discussion of information or toward consensus  (Ref.  14).  Such influence has  
the potential to lead to bias in the kinds of information considered and the weight  
attached to various kinds  of data.  A consensus-focused norm  can also discourage 
members from voicing dissenting opinions (Ref.  13).  
    An effect called illusory transactive memory can occur when a group that does not  hear  
any discussion of significant issues associated with a topic assigned to  a particular 
member of  the group later believes  that they heard an actual  discussion to the effect that  
there were no significant issues even though the group actually did not hear any 
discussion at all (Ref.  15).   (In other  words, the lack of discussion of a topic can  translate 
in the  mind to an affirmation that there are no  issues related  to  that topic.)   If a panel  
member does not share significant information  identified  in his or her discipline-specific 
review, other members of the panel could later recall that no significant information  
was found.  This in turn has the potential to bias  group assessments  about  the overall  
weight of  the evidence.  
 
7  When  NAM  issued  its  report,  the  name  of  the  organization  was  the  Institute  of  Medicine.   
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    The way in which information is presented to a  panel could create bias.  Framing the  
charge  to the panel to emphasize potential risks  or potential benefits has  the potential to  
create bias toward particular avenues of reasoning or a particular decision (Ref. 16  and 
Ref.  17).  Furthermore, the order  in which information is presented to the panel has the  
potential  to lead to bias in the importance it is assigned by participants  (Ref.  18  and Ref.  
19).  
D.  Conflict of Interest  and Appearance Issues  
1.   Federal  Regulations and  FDA Guidances   
As noted in the Introduction, this guidance includes recommendations  for  GRAS panels that  are  
informed by federal law, regulations, and FDA guidance documents  related to FDA advisory 
committee members.  With respect to  FDA advisory committees, we use the term conflict of  
interest when we are referring to  a  conflict of interest within the meaning of 5 CFR part 2640  
and the term appearance issue when we are referring  to an  interest or relationship within  the 
meaning of 5 CFR 2635.502 (section 502).  A  GRAS panel  is not a  federal advisory  committee  
under the Federal Advisory Committee Act  (FACA) (5 U.S.C. App.),  and a GRAS panel and  its 
members are not affiliated with the  federal government.  Therefore,  our reference to these 
requirements and guidance, which generally do not  apply to GRAS  panels  or GRAS  panel  
members,  is  solely  for the purpose of discussing concepts  that are relevant to conflict of interest 
and appearance issues for GRAS panels.  
FDAs  advisory committees provide independent  expert  advice to us  on scientific, technical, and 
policy matters related to the development and evaluation of FDA-regulated products.  Although 
advisory committees provide recommendations  to  us, we  make the final  decisions.   FDAs  
advisory committee process has some similarities to the GRAS panel process that is the subject  
of this document.  For  example, both processes consider  scientific and  technical matters and both  
processes provide information to a  second party (FDA or the proponent) who uses the  
information to reach a decision.  In addition, the  credibility of the conclusions of an advisory 
committee or GRAS panel can be undermined when one or more  members of the committee or 
panel has a conflict of interest or  an appearance  issue and, thus, both the  FDA advisory 
committee process and  the GRAS panel process can benefit  from established, clear, transparent  
criteria for identifying and managing conflicts of interest and appearance issues.   However,  
FDAs relationship to a  GRAS panel is not equivalent  to an FDA advisory committee.  Instead, 
the GRAS panel organizer (together with the proponent, if these roles are distinct) stands in an  
analogous relationship to the panel as we do to an FDA advisory committee.  Thus, any decisions  
regarding, for example,  the design or application of waivers  are the responsibility of the GRAS  
panel organizer or proponent.  
The  regulations and  guidances applicable to participation in an FDA advisory committee are 
intended to provide transparency, clarity, and consistency for the advisory committee process 
and enhance public  trust  in the advisory committee process.   The statutory and regulatory 
requirements for determining whether an advisory committee member  (a special government 
employee; SGE)  has  a potential conflict of interest and whether participation in an advisory  
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committee meeting  is appropriate  are found in 18 U.S.C. 208(b), 21 U.S.C. 379d-1, and 5 CFR  
part 2640.   Where such a conflict exists,  these statutory and regulatory requirements  permit us to  
grant a waiver allowing  SGE participation  in an  advisory committee meeting when statutory  
criteria are  met; for  example, when the need for  the individual's services  outweighs the potential  
for a conflict of interest created by the financial interest involved (5 CFR 2640.302).   A draft 
guidance  that we issued for public comment (Ref. 20; FDAs draft  appearances guidance)  will,  
when finalized,  describe our process  for evaluating whether an advisory committee member has  
potentially disqualifying interests or relationships that  fall into the category of appearance 
issues under section 502 rather than financial interests that may create a  recusal obligation  
under  federal conflict of interest laws.   
Regulations  concerning the  prohibition of  conflicts of interest under 18 U.S.C. 208(a)  explain 
that an employee  (including an advisory committee SGE)  may not participate in any particular 
matter  8  (5 CFR 2640.103(a)(1))  that would have  a direct  and predictable effect  9  (5 CFR 
2640.103(a)(3))  on their interests.   As explained in FDAs draft appearances guidance  (Ref.  20),  
5 CFR 2635.502 (section 502) addresses interests or relationships that may create the  
appearance that an individual lacks impartiality on an issue.  Section 502 implements  the ethical 
principle that a  government employee should be  impartial in performing official duties, meaning  
that the employee must not give preferential treatment to any  private organization or individual 
or use public office for  private gain.   To the extent that an  individuals performance  of official 
duties  might appear  to benefit the  individual or certain other individuals close to the individual, 
the individual should  take appropriate steps to avoid even an  appearance of violating  these 
ethical principles.   Section 502 places the initial  burden of identifying potential appearance  
issues  on the  potential advisory committee  member,10  who reports interests related to  the subject 
matter of the meeting on Form FDA 3410  (Ref.  21).   Form FDA 3410 asks for information about  
current and  past financial interests that directly relate  to the particular matter.   Form FDA 3410 
also asks  for information about any other  interests or relationships that might give  rise to an 
appearance issue.   The member may make a  threshold judgment as to whether the  information 
would cause a reasonable person to question his  or her participation, and so inform  FDA.   
 
8  The term particular  matter  includes  only  matters  that  involve  deliberation,  decision,  or  action  that  is  focused  
upon  the  interests  of  specific persons,  or  a discrete and  identifiable class  of  persons.   It  does  not  cover  consideration  
or  adoption  of  broad policy  options  directed  to the  interests  of  a  large  and diverse  group  of  persons  such as  actions  
that  will  affect  all  companies  or  the  economy  in  general  (5  CFR 2640.103(a)(1)).   
9  A  particular  matter  will  have  a  direct  effect  on  a  financial  interest  if  there  is  a  close  causal  link between any  
decision  or  action  to  be taken  in  the matter  and  any  expected  effect  of  the matter  on  the financial  interest.   An  effect  
may be  direct  even  though it  does  not  occur  immediately.   A  particular  matter  will  not  have a direct  effect  on  a 
financial  interest,  however,  if  the  chain of  causation is  attenuated or  is  contingent  upon  the  occurrence  of  events  that  
are speculative  or  that  are independent  of,  and  unrelated  to,  the matter.   A  particular  matter  that  has  an  effect on  a 
financial  interest  only  as  a  consequence  of  its  effects  on the  general  economy does  not  have  a  direct  effect  for  the  
purposes  of  this  guidance.   See  5  CFR  2640.103(a)(3)(i).  
A  particular  matter  will  have a predictable  effect  if  there is  a real,  as  opposed  to  a  speculative,  possibility  that  the  
matter  will  affect the  financial  interest.   It  is  not  necessary,  however,  that  the  magnitude  of  the  gain  or  loss  be  
known,  and  the  dollar  amount  of  the  gain  or  loss  is  immaterial.   See  5  CFR  2640.103(a)(3)(ii).  
10  Advisory committee  members  are  considered to  be  special  government  employees  during  their  service.  
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Section 502 identifies covered  relationships11  and specific circumstances that  may cause a 
reasonable person to question  a members impartiality.12   
FDA has issued a guidance (Ref.  22;  FDAs waiver guidance) that  describes the basis for public 
disclosure of certain  financial interests by SGEs  and regular  government employees  participating  
in an  advisory committee meeting and  provides a format for FDA  waivers allowing participation 
in these meetings.  FDAs waiver  guidance also explains how  and when these documents will be  
made publicly available  by FDA.  
While the  FDA  advisory committee process has some similarities to the GRAS panel process,  
there are some important differences.   One difference is  that the statutes  and regulations  
applicable to FDAs advisory committee process expressly  provide for  circumstances in which 
FDA may grant a waiver that would  allow an individual to participate in  an advisory committee  
meeting, in either a voting or non-voting capacity, even though the individual has a  conflict of  
interest (18 U.S.C.  208(b)(3), 5 CFR 2640.302, 21 CFR  14.80).   FDA discloses such waivers as 
part of the  record of the  advisory committee process (Ref.  22).   In contrast, if a proponent allows  
an individual to participate in a GRAS panel, in either a voting or non-voting capacity, even 
though the individual has a conflict  of interest, there generally would not be a public  process  
(such as a public meeting) whereby the proponent could disclose the conflict and  the reasons for  
waiver;  the lack of a public process to make a waived conflict of interest transparent presents a 
challenge to the proponent of the substance  for waiving a  conflict of  interest or an appearance  
issue without undermining the credibility of  the  GRAS panels opinion.   
Another  difference is that the  primary  function  of the GRAS panel  from FDAs  perspective  is to  
reflect  the views of the broader scientific community, rather than to reach a scientific  judgement 
on specific data and information.   FDAs  advisory committees  often provide  advice to FDA in  
cases where data are  incomplete, contradictory, or preliminary, and we are  seeking input on a  
decision or  path forward in the  face of these  challenges.  A GRAS conclusion, on the other hand, 
is meant to  be based  on publicly available  safety data  that  are  generally  accepted  by experts.   The  
function of a GRAS panel is bound up with the extent  to which it appears likely that  most other  
scientists with similar training would  reach a  similar judgement.   This is  distinct from providing  
advice  to FDA  on an unresolved scientific issue  to inform  our  decisions, as well as from the 
question of  whether a scientific judgement  is defensible or consistent with the available data.   
 
11  Examples  of  covered relationships  include  those  with persons  in the  members  household and with persons  in 
certain business  relationships.  
12  Examples  include  where  the  particular  matter  coming  before  the  advisory  committee  is  likely  to  have  a  direct  and  
predictable effect on  the  current  financial  interest  of  a member  of  the advisory committee members  household,  and  
where  a  person (or  entity)  with whom  the  advisory  committee  member  has a covered  relationship is  or represents  
a party  to  the  matter coming  before  the advisory  committee.   Section 502 includes  examples  of  covered  
relationship  (e.g.,  a  person or  entity for  which the  member  has,  within the  last  year,  served as  an  employee,  officer,  
director,  consultant,  agent,  attorney,  trustee,  contractor,  or  general  partner)  and  party  to  the matter  (in  most  cases,  
any  sponsor  of  the  product(s)  coming before  the  advisory committee).  
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2.  Policies and Literature  Regarding Conflict  of  Interest  and Appearance Issues  
Several  organizations policies and  literature  address conflict of interest and appearance issues,  
and we have  summarized them below.  
a.   The  NASEM  Policy  
The  NASEM  policy  explains that the FACA  includes certain  specific requirements regarding  
work performed by NASEM  for the U.S. government, including  certain requirements  relating to  
committee composition and balance  and conflict  of interest.  The  NASEM  policy emphasizes 
that conclusions by fully competent committees can be undermined by allegations of conflict of  
interest or lack of balance and objectivity.  
The  NASEM  policy addresses both conflict of interest and appearance issues.   The  NASEM  
policy uses the term "conflict of interest" to mean any financial or other interest which conflicts  
with the service of  the individual because it could:  (1) significantly impair the individual's  
objectivity;  or (2) create an unfair competitive advantage  for  any person or organization.  Except  
for those situations  in which the  institution determines  that a  conflict of interest is unavoidable  
and promptly and publicly discloses  the conflict  of interest, no individual  can be appointed to 
serve (or continue  to serve) on a committee of the institution used in the development of reports  
if the individual has a  conflict of interest that is  relevant to  the functions to be performed.   The  
NASEM  policy considers that  appearance issues (which the NASEM  policy  discusses as 
questions of lack of objectivity and bias)  ordinarily relate  to views stated  or positions  taken that 
are largely intellectually motivated or that arise from the close identification or association of an  
individual with a particular point of view or the positions or perspectives  of a particular group.   
Sources of potential  bias in  the context  of appearance issues are not necessarily disqualifying for 
purposes of  committee service.   The existence of  a possible bias would be a factor to be taken  
into account in the overall composition of the committee.  However, the  NASEM  policy notes  
that some  appearance issues may be so substantial that they  preclude committee service (e.g.,  
where one is totally committed to a particular point of view and unwilling, or reasonably 
perceived to be unwilling, to consider other perspectives or relevant evidence to the contrary).   
b.   The  NAM Report  
In 2007, NAM  appointed the Committee on Conflict of Interest in Medical  Research, Education, 
and Practice to examine conflicts of interest in  medicine and to recommend steps to  identify,  
limit, and  manage conflicts of interest without negatively affecting constructive  collaborations.  
The  NAM  report defines conflict of  interest  as a set of  circumstances that creates a risk that  
professional judgment or actions regarding a primary interest  will be unduly influenced by a  
secondary interest  (Ref. 11).  The committee  stated  that financial interests  are  the  most readily  
identified and regulated and also  noted that  a financial interest does not have to be great for the 
influence to be undue, citing social  science research on the effects of small gifts, particularly in  
the context  of a sustained relationship.  The committee acknowledged that other secondary 
interests may  also influence professional decisions, including professional advancement, 
personal  achievement, and favors  to friends, family, and colleagues.  The committee noted that 
conflicts  are not binary, and proposed criteria for assessing both the  likelihood of undue  
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influence as well as the seriousness of the harm  that could  result.  The committee also proposed 
criteria for evaluating conflict of interest policies, including proportionality, transparency,  
accountability, and fairness.  The committee discussed the role of disclosure in such  policies,  
viewing it as a necessary  but insufficient element  and recommending that disclosures be  
sufficiently specific  and comprehensive  (with  no minimum dollar threshold) to allow others to  
assess the severity  of the conflict.  
In addition to general principles and recommendations, the  NAM  report discusses  conflicts of 
interest in a  number of different areas, including  the development of clinical practice  guidelines.   
The  NAM  report recommends that groups developing such guidelines:  
    Appoint a chair without a conflict of interest;  
    Limit members with conflicting  interests to  a distinct minority of the panel; and   
    Publicly disclose relevant conflicts  of interest.  
c.   Other Published Reports  
A report (Ref.  23) by a joint task force of the American College of Cardiology Foundation and 
the American Heart Association discusses codes of conduct  in human subjects  research,  
including both financial  and non-financial conflicts of interest.  The report notes that  many non-
financial  incentives exist and are well recognized within the academic community.   
A systematic review  (Ref.  24) of conflict of interest in  the development of clinical practice  
guidelines defines such conflicts in accordance with  the 2009  NAM  report  (primary versus 
secondary interests);  states that such  conflicts  are an important potential source of bias in  
guideline development;  and notes that the secondary interest in such conflicts may be financial or  
non-financial.   The authors observe that intellectual  interests are increasingly recognized and  
may be powerful  motivators for researchers, systematic reviewers, and guideline authors.  
A report (Ref.  25) by members of the American College of Chest Physicians involved  in  
development of clinical  practice guidelines recommends placing equal emphasis on both 
financial and intellectual conflicts of interest.   The report defines intellectual conflicts as 
academic activities that create the potential for an attachment to a specific  point of view that 
could unduly affect an individual's judgment about a specific recommendation.  Such activities 
include  receipt of a grant or participation in  research or commentary directly related  to  that 
recommendation.  
The National Comprehensive Cancer Network (Ref.  26) considers conflicts of interest, or the  
appearance of such conflicts, as a source of potential bias in  the development of treatment  
guidelines that could compromise or diminish the integrity of such guidelines.  Conflicts  
encompass financial interests as well as organizational affiliations, activities, or other interests  
that could impair objectivity or create an unfair competitive advantage.  Recommendations and 
practices  include the  following, with additional restrictions on the interests and activities of 
chairs and  vice-chairs:  
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    Public disclosure of all  conflicts by guideline development panel members;   
    Exclusion of potential members with financial conflicts above a threshold;  
    Recusal  of members from  specific matters as warranted; and   
    Removal of  members if  no longer  able to serve effectively due to the number of recusals.  
IV. Definitions   
For purposes of this document, we define the following terms  below.  
Ad hoc GRAS panel    A GRAS panel that is  convened on a temporary basis.  
Appearance issue    An interest or relationship that  may create the appearance that  an individual  
lacks impartiality on an issue  (see 5 CFR 2635.502  for guidance on the process used by federal  
agencies for  analyzing and resolving  appearance issues).   Whereas conflicts of interest include  
financial  interests that can be directly and predictably affected by the work of the GRAS panel, 
appearance issues include a broader  and more complex set of interests and relationships that  
could cause a reasonable person to question  impartiality.  
Conclusion of GRAS status/GRAS conclusion    A conclusion that a substance is GRAS under  
the conditions of its intended use.  
GRAS    Generally recognized as safe.  
GRAS  panel    A panel13  of qualified experts who independently evaluate  whether the  available 
scientific data, information, and methods establish that  a substance is safe under the conditions of  
its intended use in human food or animal food as part of  an evaluation of  whether adding that  
substance  to food is lawful under  the  GRAS provision of the FD&C Act.   The panel may be  
convened for evaluation of a single ingredient (ad hoc panel) or for  longer periods of  time to 
evaluate multiple substances (standing panel).   
Notifier    The person (e.g., an individual, partnership, corporation, association, or other legal 
entity) who is responsible for a GRAS notice submitted to FDA, even if another person (such as  
an attorney, agent, or qualified expert) prepares or submits  the notice or provides an opinion 
about the basis for a conclusion of GRAS status.  
Organizer   The party (such as a proponent, an employee of the proponent, or an attorney or  
agent who acts on behalf of a proponent)  who assembles a GRAS panel.   
Proponent    The  party who takes  responsibility for  a conclusion of  GRAS  status.   
 
13  A  panel  is  [a]  group  of  persons  selected  for  some  service  (such as  investigation or  arbitration).   Merriam-
Webster.com.   Accessed  on  October  31,  2019.  
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Qualified expert    An  individual who is  qualified by scientific  training and experience to 
evaluate the safety of substances  under the conditions of their  intended use  in food.  
Standing GRAS panel    A GRAS  panel that is convened on a permanent (or extended) basis.  
Written  GRAS panel  policy    A written policy to govern procedures for  assembling and 
managing  a  GRAS panel, including an assessment  of  the potential for bias created by  a conflict 
of interest or an appearance issue in an individual  under  consideration for  selection as a member  
of a GRAS  panel  and including strategies for managing conflicts and appearance issues.  
V.   Recommendations   
A.  Introduction  
Convening a GRAS panel and relying on the GRAS panel  as a representative sample  of  the  
larger scientific community knowledgeable about the safety of substances  directly or indirectly  
added to food is one mechanism  that  proponents  have used to support  their  conclusion  that the  
safety of a substance under the  conditions of its intended use  in human food or animal food is  
generally recognized.  However, the  use of a GRAS panel is  not the only mechanism  for doing 
so,  and the use of a GRAS panel does not necessarily  mean  that the GRAS criteria have been  
met.   As discussed in section  II.A, we have established  criteria for eligibility for classification as  
GRAS in 21 CFR 170.30 and 21 CFR 570.30 for substances intended for  use in human food and 
animal food, respectively.   A GRAS  panel is not  a required element of these criteria.  
In the remainder of the recommendations section of this guidance, we discuss detailed 
recommendations related to selecting GRAS  panel members, the operation of a GRAS panel, 
submitting  a GRAS notice to FDA, and other recommendations as summarized  immediately  
below.   As noted previously, a GRAS panel is just one mechanism that proponents have used to 
demonstrate that  the safety of a substance under  the conditions of its intended use is generally 
accepted  by qualified experts.  It may be worth considering  whether the  effort to convene  a  
GRAS panel  is warranted in any particular case before allocating resources to it.   
1.   Recommendations Related to Selecting GRAS Panel Members  
To  convene  a GRAS panel that can  effectively  evaluate the available scientific data, information,  
and methods and act as a  representative sample  with respect to  the larger scientific community of 
qualified experts,  and  to reduce the risk that bias (or the appearance of bias) will  affect  the  
credibility of the GRAS panel  report, as discussed in more detail in sections V.B through V.D,  
we recommend that  the  organizer  (whether  it be  a proponent  who has identified a need for a  
GRAS panel or a third party in the business of convening such panels)  establish  and implement a 
written GRAS panel policy14  that includes general principles  and procedures for:  
 
14  A  proponent  who intends  to convene  the  panel  themselves  and does  not  expect  to convene  further  panels  in the  
foreseeable future  could  also  consider  documenting the  ways  in which they identified  and  managed sources  of  
potential  bias  described  in  this  guidance  as  part  of  their  documentation  of  the  overall  GRAS  conclusion.   
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    Assessing  and balancing  the knowledge, experience, and perspectives of  potential GRAS  
panel members in  terms of the subtleties and complexities of the particular scientific  and  
technical issues applicable to  a  food substance  and its intended use in human food or  
animal food;   
    Considering and taking  steps to address procedural  issues associated with the 
organization and deliberations of the GRAS panel;   
    Considering  and taking  steps to assess potential GRAS panel members for conflicts of  
interest  and appearance issues;  
    Documenting  how the organizer applied the written GRAS panel policy to the selection 
and vetting of each member of  the  GRAS panel; and  
    Taking  steps  to provide  transparency and clarity regarding the  selection and vetting of  
each member of the GRAS panel.  
2.   Recommendations Related to the Operation of the GRAS Panel and to the  
Submission of a Notice  to FDA  
As discussed in section  II.B, we have established a GRAS notification procedure (in  21 CFR  part 
170, subpart E and part 570, subpart  E for substances intended for use in human food and animal  
food, respectively) through which  any interested person may notify us of  a conclusion that a  
substance  is  GRAS under the conditions of its intended use in food.   Our experience with GRAS  
notices in which the person who submitted the GRAS notice (notifier) reported  the findings of 
a GRAS panel, as well as comments we received  during the rulemaking to establish  the GRAS  
notification procedure,15  have informed the  recommendations  in sections  V.E  through V.H  for:  
    The information that the  proponent of a GRAS conclusion would provide to the GRAS  
panel;   
    Documenting the deliberations  and output of  a GRAS panel;   
    Considerations when a GRAS notice is submitted to FDA; and  
    Considerations when a GRAS notice is not submitted to FDA.   
3.   Other Recommendations  
    In section V.I, we provide our recommendations  regarding honoraria provided to a GRAS  
panel.   
 
15  See,  e.g.,  the  discussion  in  section  I.E  of  the  GRAS  final  rule  and  Comment/Response  8,  11 through 13,  58, 69,  
and 78  in the  GRAS  final  rule  (81  FR  54960).   
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We received fewer than  a dozen GRAS notices where the statutory basis for the notifiers 
conclusion of GRAS status was through experience based on common use in food (Ref. 27).   
Therefore, in this guidance, we focus on best practices applicable to  a GRAS panel that is 
convened when the statutory basis for the proponents conclusion of GRAS status  is through 
scientific procedures.  
B.  Appropriate and Balanced Expertise in a GRAS Panel  
1.   General Considerations When Convening a GRAS Panel  
We recommend that  the  organizer, the proponents attorney or agent, or  employees of the  
proponent, organizer, or  the proponents attorney or agent not be members of a GRAS  panel,  
because such individuals generally would have a conflict of  interest due  to a direct  and 
predictable financial interest  in the outcome of the panels deliberations (see the examples of  
conflict of interest in  Table  3).   However, if such an individual has specialized  experience that  
could be helpful to a GRAS panel, the proponent  or organizer  could consider whether that  
individual could act as a scientific advisor to  the  GRAS panel by providing factual information  
to the GRAS panel without participating in any of the GRAS panels deliberations.   
Alternatively, the proponent or organizer  could consider having that individual participate  in 
deliberations of the GRAS panel without providing an opinion that would be included in  any 
report generated by the  GRAS panel; such participation would be analogous to non-voting 
members who are granted a waiver  per 5 CFR part 2640 when necessary to afford essential  
expertise to  an FDA advisory committee.   The potential value of  such an individuals  
participation, even in an advisory or non-voting capacity, should be carefully weighed against  
the introduction of another significant source of potential bias,  which could reduce  the credibility 
of the  GRAS  panel as a representative sample with respect to the views  of the broader expert 
community.  
2.   Appropriate Expertise in a GRAS Panel  
We recommend that  the  organizer consider  individuals with  expertise that reflects the physical,  
chemical, and biological  properties of the food substance  and the scientific questions that arise in  
relation to the conditions  of its  intended use.   At a minimum, we recommend that  a GRAS panel  
include members with expertise suitable  to establish the identity  and properties of the ingredient 
(e.g., chemistry,  biochemistry,  protein chemistry,  or microbiology) as well as expertise in  
toxicology  and  exposure assessment, because our experience with  GRAS  notices demonstrates 
that these scientific disciplines broadly apply  to  most safety  evaluations.   For substances 
intended for  use in animal food, a GRAS panel should include members with expertise  suitable 
to establish the identity and properties of the  ingredient  (e.g., chemistry, biochemistry, protein 
chemistry, or microbiology), expertise in toxicology  and exposure assessment, as well as 
expertise suitable  to evaluate the safety of the substance under the conditions of its intended use 
for the  target animal(s) and, when added to food for food-producing animals, for humans  
consuming human food(s) derived from these animals.  While one individual may have expertise  
in multiple areas, it may  be difficult for a  single individual to represent  the broader views of  
multiple scientific  disciplines  credibly.   See Table  2  for examples of additional recommended  
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expertise on a GRAS panel based on the food substance and/or the conditions of its intended use.  
Note that in cases where specialized expertise is appropriate, it  is generally  supplemental  and  
complementary to the core disciplines identified above.  Not every GRAS panel member need be  
versed in  food ingredient safety assessment,  as long as they  are in dialogue with other members 
who are. 
Table  2.Examples of  Recommended Expertise on a GRAS Panel Based on the Food  
Substance or the Conditions of  its Intended Use  
Food Substance  or  Conditions  of  its  Intended Use    Recommended  Expertise  
Enzyme  produced from  a  microorganism   Microbiology;  enzymology  
Botanically-derived substance   Plant  chemistry  
Substance  that  could have  allergenic  properties   Allergy  
Use  in infant  formula   Pediatric  nutrition  
Substance  that  has  a  specific physiologic effect   Expertise  to  address  the  long-term  significance  
of  the  physiological  effect  in the  general  
population or  in relevant  subpopulations  
Complex ingredient,  or  ingredient  defined partly by  its   Chemistry;  food manufacturing;  food  processing  
method of  manufacture  
Microbial  ingredient   Microbiology;  immunology  
Substance intended to supply a  nutrient   Nutrition  
Substance  intended  for  a  technical  effect  (e.g.,  emulsifier,   Chemistry;  food manufacturing;  food  processing   
binder)  
 
In some cases, the substance is  already used in food but, for example, there has been a significant  
change in the manufacturing process; there would be an increased level  of the substance 
compared to the levels already in use; or the  intended use of the substance would be different  
from existing uses.  As noted elsewhere in this document, in many  cases, the process whereby  
the proponent evaluates  whether the  available data and information support a conclusion that a  
substance  is  GRAS under the conditions of its intended use need not include a GRAS panel.  
However, if  a proponent  decides  to convene a GRAS panel in such circumstances, the emphasis 
in selecting  members of a GRAS panel  should be on the expertise necessary to assess the change.   
For example, if there has been a significant change in the manufacturing process, a chemist,  
biochemist, or food technologist  should evaluate  the potential for toxic contaminants  or 
impurities associated with the new process, and  a toxicologist or other scientist with expertise 
applicable  to the nature  of those contaminants or impurities  should evaluate the safety of the 
substance produced using the new manufacturing process.  For increased use levels, the key  
expertise would be toxicology or a related  scientific discipline to evaluate whether the available  
data and information support the safety of an increased exposure to the substance.   If the  
intended use of the substance would be significantly different from existing uses, an individual  
with expertise in exposure assessment should evaluate the new estimated dietary exposure and 
one or more  individuals  with expertise in the potential toxicological or physiological effects of 
the substance under the  new conditions of use  should evaluate whether  the available data and 
information support the safety of the  substance under the new conditions of use.  In  the case of  a 
substance intended for use in animal food, for example,  if the intended use of the substance  
would be for different animal species, an individual with expertise in assessing safety for the  
target animal, and potentially for human food(s) derived  from the  target animal, should evaluate 
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animal and human exposures  and possible toxicological  and physiological  effects of  the  
substance under the new conditions of use.  
To optimize the applicable experience of the GRAS panel members, we recommend  that  an  
organizer who convenes a GRAS panel convene  an ad hoc GRAS panel rather  than a  standing 
GRAS panel.   However, a standing GRAS panel could be appropriate when considering a class  
of substances closely related by conditions of use, function, or other properties, where the  
experience and expertise of the panel  members align with the scientific questions applicable to  
that class of substances,  or if a  standing GRAS panel is supplemented with members with  
additional expertise to address the physical, chemical, and biological properties of a specific food 
substance  and the complexity of the  scientific questions  that arise  in relation to the conditions of 
its intended use.   One issue with standing  GRAS  panels  is the potential for development of a  
particular group perspective over  time,16  which may reduce  the ability to credibly represent the  
views of the broader scientific community.   The organizer of  such a panel  may wish to consider  
strategies for occasionally calibrating or cross-checking the panels perspective  to ensure it  
remains representative.  
3.   Number of Members of  a GRAS Panel  
We recommend that the  organizer determine  the total number of GRAS panel members, as well 
as the number of GRAS panel members with  the same expertise, based on  the substance, the 
complexity of the  scientific issues associated with the conditions of its intended use, and the 
available data and information about the substance.   As noted above, when the evidence for  
safety  comprises published peer-reviewed  scientific literature  consistent with  generally  accepted  
safety  assessment strategies, a GRAS panel of  any size may be unnecessary.  However, when  the  
available data and information relevant to the intended conditions of use of the substance involve  
complex  scientific issues that  experts would need to  interpret and resolve, we recommend that  
the organizer consider having multiple representatives with expertise applicable  to those  
scientific issues so that there can be genuine discussion and critical analysis on those complex  
scientific issues.   
From FDAs perspective, the goal of a GRAS panel, unlike a federal advisory committee,  is to  
provide some evidence of the generally accepted  view in one or more scientific disciplines 
regarding the underlying publicly available safety data.  Diverse scientific views can be 
extremely valuable in testing the robustness of a potential scientific acceptance, and we 
encourage panel organizers to consider taking advantage of diverse scientific viewpoints to  
enhance the credibility of the panel as a representative sample  of  the broader community.  
However, the GRAS panels  function is to adequately  represent a scientific community of 
qualified scientific experts rather  than society as  a whole, and we do not anticipate or  
recommend  that GRAS panel members participate as representatives of  a specific societal sector.    
Importantly, although general  recognition of safety does not require unanimous agreement, 
general recognition of safety does not exist if there is a genuine dispute among qualified experts  
 
16  This  can also be  an issue  if  ad hoc  GRAS  panels  are  repeatedly populated from  a  small  pool  of  individuals.  
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that  the use of a substance is safe (See, e.g., United States v. Articles of Drug Consisting of  
Following: 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)) or a severe conflict  among 
experts  regarding the safety of  the use of a substance (United States  v. An Article of Drug 4,680 
Pails, 725 F.2d 976, 990 (1st  Cir. 1984);  Premo Pharmaceutical Laboratories v. United States, 
629 F.2d 795, 803 (2d Cir. 1980)).   Thus, when generally available data  and information  
document  a  genuine dispute, or severe conflict, in the larger  scientific community, a  GRAS panel  
report  could not provide  evidence  that the available data and information are generally 
accepted even if  multiple members of a GRAS panel have expertise in  a particular  scientific 
discipline.   Instead, the  GRAS panel report would more appropriately be  a resource for the  
proponent  to use in identifying data gaps and information about ongoing scientific debate and 
dispute.  
C.  Assessment and Management of Procedural Issues  Associated with 
the Organization and Deliberations of a GRAS  Panel   
We recommend that  a written GRAS panel policy address the potential  for  bias that could occur  
through procedures associated  with  the  organization and deliberations  of  a GRAS panel  by:  
    Establishing  clear roles and responsibilities for each member of the GRAS panel;  
    Establishing  clear decision-making procedures that the GRAS  panel will follow;   
    Specifying  whether the charge to the GRAS panel  will inform the  members of the GRAS  
panel about  the potential for bias  (e.g., due to cognitive patterns); and  
    Considering  factors such as seniority  or perceived status among panel members and  the 
leadership skills of an individual who would be the formal  leader of  the  GRAS panel (or  
likely to become the  informal leader if the organizer does not appoint a  formal leader).   
We also  recommend  that the proponent take appropriate steps to avoid  influencing the  
deliberations of the GRAS panel    e.g., by formulating  the  charge to  the panel in neutral, 
unbiased language;  limiting communication with the GRAS panel  to  the minimum necessary to 
manage the  affairs of the GRAS panel efficiently  and effectively; and  then awaiting  the outcome.  
 
D.  Assessment  and Management of Conflict of Interest  and Appearance  
Issues  of Potential GRAS Panel Members  
1.   Overview  
We recommend that  a written  GRAS panel  policy address  the potential for conflict of interest  
and appearance issues  during the selection and vetting of GRAS panel members.   We also  
recommend  that a written  GRAS panel  policy be  publicly available and provide for  transparency  
by  allowing  outside parties to assess the  process used to assess and manage  conflicts  of interest 
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and appearance  issues  in members of  the GRAS  panel.  We discuss in more detail our  
recommendations for a  written GRAS panel policy  to address the following factors:  
    The process for identifying conflicts of interest and appearance issues;  
    Criteria for  evaluating identified conflicts of interest and appearance issues, including 
criteria for automatic or routine exclusion from panel membership, and strategies for 
managing conflicts of interest and appearance issues; and  
    Documentation of conflicts  of interest, appearance issues,  and rationales for waivers.  
2.  Identifying Conflict of Interest and Appearance  Issues  
We recommend that  a written GRAS panel policy include a process  for identifying competing 
interests, including conflicts of interest and appearance issues.  For the purposes of  this  
document, conflicts of interest include  financial interests that  can be directly and predictably  
affected by the work of the GRAS panel, whereas appearance issues include a broader and more 
complex set  of interests and relationships that could cause  a reasonable person to question 
impartiality.   See Table 3 for examples of sources of conflict  of interest.  See Table 4 for 
examples of  appearance issues.17  In our view, both sources of potential bias  (conflict of interest 
and appearance issues) have similar significance with respect  to a GRAS  panels core function of  
providing evidence of community views, as described in III.D.1.  From FDAs perspective, the  
primary function of the  GRAS panel is to reflect the views of the broader scientific community,  
rather than to reach a  scientific  judgement on specific data and information.  A GRAS conclusion 
is meant to be based on publicly available safety  data which  are generally accepted  by experts.   
Therefore, the  function of a  GRAS panel  is bound up with the extent to  which it appears likely  
that  most other scientists with similar training would reach a similar judgement.   This is distinct 
from the question of whether a scientific  judgement is defensible or consistent with the available  
data.   See section  II.C.2.  
Table  3.Examples of Conflict of Interest  
Source  of  Conflict  of  Interest  
Ownership of  any  equity of  an affected  entity (excluding  equity  held through a  publicly traded diversified (i.e.,  
non-food  sector  specific)  mutual  fund)  
Compensation for  services,  such as  management  or  consulting services  to  an affected entity (excluding 
honoraria  for service  on the  GRAS  panel;  see  section  V.I  for  recommendations  regarding honoraria)  
A  role as  director,  officer,  trustee,  general  partner,  or  employee of  an  affected  entity  (including  trade and  
professional  associations)  
 
17  Examples  in both tables  are  drawn from  18  U.S.C.  208,  5 CFR  parts  2635  and 2640,  and  FDAs  guidance  on  
advisory committees  (Ref.  20  and Ref.  22),  as  well  as  from  our review  of the  NAM report  (Ref.  11),  the  NASEM  
policy  (Ref.  12),  the  codes  of  conduct  for  the  American  College  of  Cardiology Foundation and  the  American  Heart  
Association  (Ref.  23),  and a  sample  draft  guidance  submitted to  the  public  docket  for FDAs  rulemaking  to establish  
the  GRAS  notification procedure  (Ref.  28).   As  noted in section III.D,  our  recommendations  are  informed  by  federal  
law,  regulations,  and  FDA guidance  documents  related  to  advisory committee  members  and  our  reference  to  these  
requirements  and  guidance  is  solely for  the  purpose  of  discussing  concepts  that  are  relevant  to conflict  of  interest  
issues  for GRAS  panels.    
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Source  of  Conflict  of  Interest  
Funding  for  research  purposes  from  an affected entity,  regardless  of  whether  there  is  post-grant oversight  
A  debt  relationship  of  any  kind with an affected entity,  whether  as  lender,  borrower,  holder  of  debentures,  or  
the  like  
Any of  the  above  examples  with respect  to  a  spouse,  minor  child,  general  partner,  or  prospective  employer  
  
Table  4.Examples of  Appearance Issues  
Appearance  Issue  
Direct  and  predictable  effect  on  the  current  financial  interest  of  a  household member,  including  adult  children 
and parents,  as  well non-relatives  in  residence  
Having  or  seeking a  business,  contractual,  or  other  financial  relationship  with an  affected  entity  
Having  a  household member,  or  relative  with a  close  personal  relationship  who  is  an  affected  entity  
Serving  in  the last  year  as  an  employee,  officer,  director,  consultant,  agent,  attorney,  trustee,  contractor,  or  
general  partner  for  an  affected  entity  
Having  a  spouse,  parent,  or  dependent  child who currently serves  or  is  seeking  to  serve as  an  employee,  officer,  
director,  consultant,  contractor,  agent,  attorney,  trustee,  or  general  partner  of  an  affected  entity  
Being  an  active  participant  in  an  organization  that  is  an  affected  entity  
Consistently and  strongly  advocating  specific  views  or  positions  on  a  scientific  issue  relevant  to  safety  
assessment  
Having  ones  own  work as  a  key element  of  the  relevant  evidence  for  safety of  the  substance  under  the  
conditions  of  its  intended use  
  
3.  Criteria for Evaluating  Identified Conflicts of Interest and Appearance Issues and 
Strategies  for Managing Identified Conflicts of Interest and Appearance Issues  
We recommend that  a written GRAS panel policy establish pre-existing criteria for evaluating  
the significance of conflicts of  interest and appearance issues.   Conflicts  of  interest are ordinarily  
financial.  Some  policy frameworks, including  FDA guidance  (Ref. 22)  discussed above, as well  
as other  policies  from certain organizations  (Ref.  26), ordinarily exclude  members  with  
significant financial conflicts of interest  from a committee  or panel.  These frameworks assess 
the significance of a conflict in  terms of the dollar value,  although other factors  such  as the  
duration of the interest or value relative to overall assets could also be considered.   Appearance 
issues, on  the other hand, are often more complex and less clear-cut and may not be amenable to 
quantification in the same way.  Factors that could potentially be considered in assessing the 
significance of an appearance issue include:  
    The nature of a  relationship of interest, including  history and current status of the 
relationship;   
    The effect that a particular conclusion would have upon the financial interests of  a person 
involved in a  relationship  of interest;   
    The  extent to which a person has committed  to or is associated with a particular point of 
view  on a matter relevant to the decision; and  
    The degree  to which research conducted by the person bears  on the specific questions  
before  the GRAS panel. 
 
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We recommend that  a written  GRAS panel  policy include strategies  for managing conflicts  and 
appearance issues.   These strategies could include:  
    Establishing  pre-existing criteria for excluding an individual  from service on a GRAS  
panel  based on a conflict of interest  or appearance issue of sufficient  significance, such  
as those  listed in  Table 3  and Table 4;18   
    Establishing  pre-existing criteria for waiving an exclusion  triggered by a conflict of 
interest or appearance issue;   
    Including  balancing viewpoints on a particular issue where  one or more  members  is  
strongly associated with a particular  viewpoint;  
    Disclosing  conflicts  of interest and appearance issues to all panel  members  to allow them 
to weigh this information  in their assessment of  the perspectives and contributions of  
various panel  members; and  
    Including some panel members who  have a conflict of interest or an appearance issue as 
non-voting  members who can still contribute to  deliberations,  albeit in an  advisory 
capacity only.  
Waivers and monetary thresholds for  acceptable conflicts are two commonly used strategies in  
assembling expert  panels.   We are not  recommending  specific criteria  for administering waivers  
or  defining specific  monetary thresholds, in part  because,  unlike  a federal advisory committee,  
GRAS panels are not organized by and do not report to FDA.  These decisions are the GRAS  
panel  organizers responsibility, and  we recommend that  each organizer  clearly document  their  
rationale  for whatever waiver or threshold  criteria they establish.  
We realize that it can be challenging  to identify,  screen, and  select a comprehensive panel of  
qualified experts  in light of the need  for specialized expertise  applicable  to the scientific  
considerations associated with the intended conditions of use of a food substance  and the finite  
number of  experts who are  both qualified  and  available to serve on a GRAS panel.   There  may  
be circumstances in which the need for the  individual's services outweighs the potential for  a  
conflict of interest  or appearance issue  in order to provide the GRAS panel essential expertise.19   
For this and other reasons it may be useful  to prepare  strategies of the  types  discussed above.   
However,  it is also  important to remember that a  GRAS panel is just one  mechanism that can be  
used to provide  evidence of general acceptance, and in many cases  a panel may not be necessary.   
In the  limited number of  cases where  there  are alternative interpretations of the available  data 
and  the proponent seeks the type of evidence of general acceptance that a GRAS panel could  
provide, successful management of sources of potential bias associated with the panel  becomes a 
 
18  As discussed  in  section  V.I.,  FDA  recognizes  that  GRAS  panel  members  are generally  compensated  for  their  time;  
we  are  not  suggesting that  such compensation  represents  an unacceptable  conflict  of  interest,  provided that  the  
compensation  is  independent  of  the  outcome.  
19  See,  e.g.,  the discussion  in  FDAs  draft  appearances  guidance (Ref.  21)  regarding  the criteria for  granting  a 
section 502  authorization  enabling  participation of  a  Special  Government  Employee  in an FDA advisory committee.   
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pressing concern.   In such cases, it may be necessary to find  ways to address the  challenges  
acknowledged above.  
4.   Documentation of Conflicts of  Interest, Appearance Issues, and Rationales for  
Waivers  
We  recommend that  a written GRAS panel policy describe how to document  that the process 
used for identifying and managing conflicts  of interest and appearance issues was implemented  
in the case of a particular GRAS panel.   We also recommend that the policy address  
documentation of all conflicts  of interest and  appearance issues identified in the process of  
forming a GRAS panel and how these issues  were managed, whether through waivers  or some  
other method.  This  may  include a discussion of the rationale for each waiver, along with the  
views of the organizer or proponent on the net  effect of  each conflict or  appearance issue on the  
ability of  the panel to  serve as a credible representative sample  of  the larger  scientific 
community.  As noted elsewhere in  this guidance, from FDAs perspective,  a key criterion for 
evaluating a GRAS panels conclusion is whether  qualified scientists with  similar training and  
experience  would likely reach the same conclusion.  This documentation  may  help in the  
interpretation of  the significance and strength of a GRAS panel conclusion where  the type  of  
evidence of  general acceptance  that a panel could provide  is necessary to support the common 
knowledge element of a  GRAS conclusion.       
5.   Format of a Written GRAS Panel Policy  
The  format of a  written GRAS  panel  policy should  promote clarity and transparency.   For  
example,  the policy could be structured as  a series of individual questions  followed by  a chart  
that organizes the flow of the  individual questions.   
E.  Information Provided to a GRAS Panel  
As noted in section V.A, in this guidance,  we focus on best practices applicable to a GRAS panel  
that  is convened when the statutory basis for the  proponents  conclusion of GRAS status is  
through scientific procedures.   When a conclusion of GRAS status is  through scientific  
procedures, general  recognition of safety is 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 (21 CFR 170.30(b)  and 570.30(b)).   
Although general  recognition of safety through scientific procedures may be corroborated by the  
application of unpublished scientific  data, information, or methods, to satisfy GRAS criteria 
qualified experts need to  be able  to conclude that the substance is not harmful under the  
conditions of its  intended use without access to corroborative information (81 FR  54960 at  
54973).   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 notified substance is safe under the conditions of its intended use (81 FR  
54960 at  55000).   Therefore, we recommend  that the organizer minimize  the amount of non-
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public  information provided to a GRAS panel  because  access to  unpublished or restricted  
information can make  it more difficult to  credibly identify what  outcome the  GRAS  panel would 
have reached without that information.  In cases where a proponent has identified a need for  a 
GRAS  panel, the  proponent  should carefully consider the  value  that the  GRAS  panels  exposure  
to confidential information would bring relative  to the potential for  reducing confidence that the  
GRAS  panels conclusion reflects general acceptance of  public data.   
An exception relates  to  data and  information that could raise a question about the safety of the  
substance under the  conditions of its intended use.   We  recommend that the  data  and information 
that the organizer  provides  to a GRAS panel include a description of  all  data and information that  
could raise such a safety  question, regardless  of whether  those data and  information are  publicly 
available.   Doing so is appropriate  to make the data and information provided  to the GRAS panel  
complete, representative, and balanced and would be consistent with the requirements we have  
established  for a GRAS  notice (see 21 CFR  170.250(c)  and 570.250(c)).  
In some cases, the proponent chooses to make the opinion of a GRAS panel public    e.g., by 
publishing the GRAS panel opinion in the peer reviewed scientific  literature.   Whether a 
published GRAS panel opinion that discusses data and information that are not generally 
available could  support  an independent GRAS conclusion would depend on factors such as  
whether the  published opinion includes details  similar to details that would be included in a  
publication in the primary scientific literature; 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 (81 FR 54960 at 54966).  
F.  Documenting the  Deliberations and Conclusions  of a  GRAS Panel  
The organizer should consider how to document  the deliberations and conclusions of a GRAS  
panel.   We recommend clear and  explicit  documentation of: (1)  the available data and  
information that  the GRAS panel reviewed; (2)  how the GRAS panel  handled its deliberations; 
and (3) the basis for the  conclusion of the GRAS  panel.  
As noted in section I of  this document, when the  members  of a  GRAS panel  agree that the 
generally available data  and information demonstrate that a substance is safe under the 
conditions of its  intended use, the  members of the GRAS panel  are serving  as a representative 
sample of  the larger scientific community knowledgeable about the safety of substances directly  
or indirectly added to food.  Therefore, the deliberations and  GRAS panel  report should address  
this  threshold question of whether  the  panel members agree that the generally available data and  
information  demonstrate that  substance would be  safe under the conditions of its intended use  
rather than  the subsequent question of  whether  the substance would be GRAS under the  
conditions of its  intended use.   It is  the  proponents  responsibility to subsequently draw a  
conclusion on whether the intended conditions of  use of the substance satisfy  the criteria for 
eligibility  for classification as GRAS.  
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We recommend that  each member of the GRAS  panel identify the particular data or information  
that  form  the basis  for his or her opinion on whether  the intended use of  the substance is safe, 
both during deliberations and in any written GRAS panel  report.   We also recommend that  
GRAS panel members avoid filling a  gap in the  available data and information through  
theoretical considerations and prior relevant  experience    e.g., making overly broad inferences 
(in the absence of data) about safety of the substance in question based on the properties of other  
substances that are related in some way, or based on professional  familiarity with a particular  
class of substances.   From a procedural perspective, this approach is a significant source of  
potential bias.  Members  of the GRAS panel should limit the  role of theoretical considerations  
and prior  relevant experience to  determining which of the available data and information are 
relevant to the safety of  the substance under the  conditions of its  intended use.   However, this  
recommendation is  not meant to discourage the  use of  well-established, rigorous methods  of  
extrapolation,  such as read-across practices and quantitative structure-activity relationships  (see 
Ref.  29, Ref. 30).  
As discussed in section  I of this document, the proponent  may  be  relying on  the deliberations and 
report of a  GRAS panel  to serve  as a representative sample  of  the  larger scientific community  
knowledgeable about  the safety of substances directly or  indirectly added to food.   Therefore, we  
recommend that the organizer establish  and  implement a mechanism to  demonstrate that  the 
deliberations  of a GRAS panel  and any GRAS panel  report broadly reflect the views of the  
scientific community  knowledgeable about the  safety of  substances directly or indirectly added 
to food in addition to  the individual views of each  panel member.   For example, each panel  
member could identify the  basis for concluding that  his or her view is representative of the views 
held by most scientists in the respective discipline.   
G.  Considerations When a GRAS Notice is Submitted to FDA  
Any person who submits a GRAS notice  to FDA must include a signed statement certifying that  
to the best of the notifiers knowledge, the GRAS notice  is a complete, representative, and 
balanced submission that includes unfavorable  information, as  well as favorable information,  
known to the notifier and pertinent  to the evaluation of the safety and GRAS status of the  
intended use of the substance (21 CFR 170.225(c)(9)  and 570.225(c)(9)).   The certification  
statement  is intended, in  part, to emphasize  the notifiers 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  (81 FR 54960  at  54994).   Thus, as already noted in section V.E, we recommend that  
the  data  and information that  organizer provides  to a GRAS panel include a description of all  
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 publicly available.   
The certification statement also is intended, in part, to communicate our  expectation that a  
notifier would describe, and place  in context, unpublished data and information  if the notifier 
considers that the  findings of the unpublished data and information warrant sharing with a GRAS  
panel (81 FR 54960  at  54994).   Although we recommend that the organizer minimize the amount  
of non-public information provided  to a GRAS panel  (see the discussion in section  V.E), a  
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notifier who does provide non-public information to a GRAS  panel should describe, and place  in 
context, those unpublished data and information in any GRAS notice  that  mentions the findings  
of a GRAS  panel.   This includes, for example, studies that the notifier considers  corroborative of  
safety  (81 FR 54960 at 55994) as well as any trade secret information regarding  the  method of 
manufacture  (81 FR 54960 at 55000).  
Any person who submits a GRAS  notice  must include a narrative that explains  how the generally 
available data and information  that the notifier relies on to  establish safety provide a basis for the  
notifiers 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 570.250).   For non-
public, safety-related data and information considered in reaching a conclusion of GRAS status, 
the notifier  must explain how there  could be a basis for a  conclusion of GRAS status if qualified  
experts do not have access to such data and information.   If non-public information  is provided 
to a GRAS  panel, the notifier would be required to explain how there could be a basis for a  
conclusion of GRAS status if  qualified experts  (other than those on the GRAS panel) do not have  
access to such data and  information  (21 CFR 170.250(e) and 570.250(e)).   As noted above, 
exposure  to non-public data and information can sometimes  make it  much harder  to credibly 
assert that the panels conclusion  is representative of  the  expert  scientific community  based on 
public data.  
In our  view, most GRAS conclusions  do not  need  a GRAS panel  (81 FR  54960 at  55026).   
However, in some cases,  we  might recommend consulting with us  on whether a GRAS panel  
could be useful in generating evidence of general  acceptance (see Figure 1).  Where a panels 
deliberations constitute  primary  evidence supporting  the general  acceptance aspect of the GRAS  
criteria for the intended use, FDA  would be unable to evaluate this evidence and the  significance  
of the GRAS conclusion unless  the  composition, deliberations, and the outcome  of  the  GRAS  
panel  are provided by the notifier.  
H.  Considerations When a GRAS Notice is Not Submitted to FDA  
The GRAS  criteria  (21 CFR 170.30(a) to (c) and 21 CFR 570.30(a) to (c))  apply regardless of  
whether  a conclusion of  GRAS status is submitted to us as a  GRAS notice  or whether it is  an 
independent conclusion of GRAS status that remains with the  proponent.   We advise any 
company that intends to market a food substance on the basis of  an independent conclusion of  
GRAS status to carefully consider  the recommendations  in this guidance and to apply them  to its  
own assembly and management  of a  GRAS panel.   However, as previously noted,  the outcome  
of a  GRAS panels deliberations  does not  create or confer general  recognition status on the use  
of an ingredient.  Rather, it can provide evidence  supporting the proponents contention that  
there is general acceptance based on  generally available information among  relevant scientific 
communities.   Ultimately, all decisions regarding the safe and lawful use of a substance in food,  
including decisions  about GRAS status, are subject to FDA review  (see, for  example  21 CFR 
170.38).  If  a question arises, a well-constructed GRAS panel for which all sources  of potential  
bias are addressed and managed may  be useful  to support  the proponents conclusion.   When a 
use of a substance does  not qualify for GRAS status or other  exceptions provided under section 
201(s) of  the FD&C Act, that use of the substance is  a food additive use subject to the  premarket 
33  
  Contains Nonbinding Recommendations  
 
 
 
approval  mandated by the FD&C Act.  Under Section 409 of  the FD&C Act, a food additive not  
approved for its  intended use  is deemed unsafe.  Any food that is, or bears or contains, a food 
additive that is unsafe  is adulterated under  section 402(A)(2) of the FD&C Act.   
I.   Honoraria Provided to Members of a GRAS Panel  
We recommend that  the  written GRAS panel policy address  the honoraria provided to a GRAS  
panel.  We recognize that  members  of  a GRAS panel are generally  compensated, and  in our  
opinion, such compensation is not  itself an unacceptable conflict.  However, an honorarium  
provided to members  of a  GRAS  panel  should not be contingent on the outcome of deliberations  
by a GRAS  panel.  We consider that  such conditional compensation creates an unacceptable  
conflict of interest  that undermines the  credibility of  a  GRAS panel  report.  
VI. Paperwork Reduction Act of 1995  
This guidance contains information collections that are subject to review  by the Office of  
Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-
3521). 
 
The time required  to complete  this  information collection is  estimated to average 20 hours per 
response, including the  time to  review  instructions, search  existing data resources, gather  the data 
needed, and complete and review the information collection.  There is  also a one-time estimated  
recordkeeping burden of 40 hours per response.  Send comments regarding this burden estimate  
or suggestions for reducing this burden to:   
 
Center for Food Safety and Applied Nutrition (HFS-255), Food and Drug Administration, 5001 
Campus Dr., College Park, MD 20740. 
 
An Agency may not conduct or sponsor, and a person is not required to respond to, a collection 
of information unless it  displays  a currently valid OMB control number.  The OMB control  
number for this information collection  is 0910-0911 (To find the current expiration date, search 
for this OMB  control no. available at  https://www.reginfo.gov). 
VII.   References   
The following references marked with an asterisk (*) are on  display  at the Dockets Management  
Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD  
20852, 240-402-7500 and are available for viewing by interested persons between 9 a.m. and 4 
p.m., Monday through Friday;  they also are available electronically at  
https://www.regulations.gov.  References without asterisks are not on public display  at  
https://www.regulations.gov  because they have copyright  restriction.  Some may be available at  
the website address,  if listed.  References without asterisks are available for viewing only at  the 
Dockets Management Staff.  FDA has verified  the website addresses,  as of the date this 
document publishes  in the  Federal Register, but websites are subject to change over  time.  
 
34  
  Contains Nonbinding Recommendations  
 
 
 
1.   U.S. Food and Drug Administration (2017).  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, available at https://www.fda.gov/media/109117/download.*  
 
2.   U.S. Food and Drug Administration (2016).  Frequently Asked Questions About GRAS for  
Substances  Intended for  Use in Human or Animal Food: Guidance for Industry, available at  
https://www.fda.gov/media/101042/download.*  
 
3.   Experience  with GRAS  Notices Under the 1997 Proposed Rule, Memorandum Dated  
November 4, 2010, from Linda S. Kahl of FDA to Docket No. FDA1997N0020.  See  
Reference 1 to the 2010 notice, available at  http://www.regulations.gov.*  
 
4.   United States Government Accountability Office (2010).  Report to Congressional  
Requestors  on Food Safety: FDA Should Strengthen Its Oversight of Food Ingredients  
Determined  to Be Generally Recognized as Safe (GRAS), Report No. GAO10246 
Available at  https://www.gao.gov/assets/gao-10-246.pdf.*  
 
5.   bias.  Dictionary.com.  Dictionary.com Unabridged.  Random House, Inc. 
http://www.dictionary.com/browse/bias. Accessed on  February 18, 2022.  
 
6.   The  Cochrane  Collaboration (2011).  Cochrane  Handbook for Systematic Reviews of  
Interventions.  Available at http://handbook.cochrane.org/front_page.htm   
 
7.   Croskerry P. (2002).  Achieving quality in clinical decision making: cognitive strategies and 
detection of bias.  Academic Emergency Medicine.  9:1184-1204.  
 
8.   Arnott D. (2006).  Cognitive biases  and decision support systems development: a design 
science approach.   Information Systems Journal.  16:55-78.*  
 
9.   Bazerman MH, Loewenstein G, Moore D. (2002).  Why good accountants do bad audits.  
Harvard Business Review.  80(11):96-102.*  
 
10.  Moore DA, Tanlu L, Bazerman MH. (2010).  Conflict of interest and the intrusion  of bias.   
Judgment and Decision Making.  5(1):37-53.*  
 
11.  Institute of Medicine (2009).  Full Report.  Conflict of Interest in Medical Research,  
Education, and Practice.  National Academies Press, 500 5th Street, NW, Lockbox 285, 
Washington, D.C. 20055.  
 
12.  The National Academies of Sciences, Engineering, and Medicine (2003).  Policy on 
Committee  Composition and Balance and Conflicts of Interest: For Committees Used in the  
Development of Reports.  The National Academies Press, 500  5th Street, NW, Washington, 
D.C. 20001.  
 
35  
  Contains Nonbinding Recommendations  
 
 
 
13.  Pagliari C,  Grimshaw J, Eccles M.  (2001).  The potential  influence of small group processes 
on guideline development.  Journal of Evaluation of Clinical Practice.  7(2):165-173.  
 
14.  Van Ginkel WP, van Knippenberg D. (2012).  Group leadership and shared task 
representations in decision making groups.  The Leadership Quarterly.  23:94-106.  
 
15.  Tschan F, Semmer NK, Gurtner A, Bizzari L, Spychiger M, Bruer M, Marsch SU. (2009).  
Explicit reasoning, confirmation bias, and illusory transactive memory: A  simulation study of  
group medical decision making.  Small Group Research.  40(3):271-300.  
 
16.  Cheng PY, Chiou WB. (2008).  Framing effects in group investment decision making: role of  
group polarization.  Psychological Reports.  102(1):283-292.  
 
17.  Milch KF, Weber EU, Appelt KC, Handgraaf  MJJ, Krantz DH. (2009).  From  individual 
preference  construction to group decisions: Framing effects and group processes.  
Organizational Behavior and Human Decision Processes.  108:242-255.  
 
18.  Jonas E, Schulz-Hardt S, Frey D, Thelen N. (2001).  Confirmation bias in sequential  
information search after preliminary decisions:  An  expansion of  dissonance theoretical  
research on selective exposure  to information.  Journal of Personality and Social Psychology.  
80(4):557-571.  
 
19.  Mancuso VF, Finomore VS, Rahill  KM, Blair EA, Funke GJ. (2014).  Effects of cognitive  
biases on distributed team decision making.  Proceedings of the Human Factors and 
Ergonomics  Society 58th Annual Meeting.  405-409.*  
 
20.  U.S. Food and Drug Administration (2016).  Procedures for Evaluating Appearance Issues 
and Granting Authorizations for Participation  in  FDA  Advisory Committees; Guidance for 
the Public, FDA Advisory Committee Members,  and FDA Staff (Draft Guidance).   Available 
at  https://www.fda.gov/media/98852/download.*  
 
21.  U.S. Department of Health and Human Services.  Form FDA 3410.  Available at  
https://www.fda.gov/media/70455/download.*  
 
22.  U.S. Food and Drug Administration (2014).  Public Availability of Advisory Committee  
Members' Financial Interest Information and Waivers: Guidance for  the Public, FDA  
Advisory Committee Members,  and  FDA Staff.   Available at  
https://www.fda.gov/media/83188/download.*  
 
23.  Alpert JS, Shine KI, Adams RJ, Antman EM, Kavey REW, Friedman L, Frye RL, Harrington  
RA, Korn D, Merz, JF, Ofili E. (2004).  Task Force 1: The ACCF and AHA codes of conduct  
in human subjects research.  Journal  of the American College  of Cardiology.  44(8):1724-
1728. Available at  http://www.sciencedirect.com/science/article/pii/S0735109704017139.   
 
36  
  Contains Nonbinding Recommendations  
 
 
 
24.  Norris SL, Kolmer HK, Ogden LA, Burda BU. (2011).  Conflict of Interest in Clinical  
Practice Guideline Development: A Systematic Review.   PLoS One.  6(10) e25153.  
Available at  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3198464/.  
 
25.  Guyatt G, Akl EA, Hirsh J, Kearon C, Crowther  M, Gutterman D, Zelman Lewis S, 
Nathanson I, Jaeschke R, Schnemann H. (2010).  The Vexing Problem of  Guidelines and 
Conflict of Interest: A Potential Solution.  Annals of Internal  Medicine.  152(11):738-741.  
 
26.  National Comprehensive Cancer Network (2014).  NCCN Disclosure Policies and Potential  
Conflicts  of Interest.   Available at https://www.nccn.org/about/disclosure.aspx.  
 
27.  GRAS  Notices, Search Results, Common Use in Food, 2022.* 
 
28.  Pew Charitable Trusts  (2013).  Attachment A. Draft guidance dated September 4, 2013 for  
consideration by FDA,  available at  http://www.regulations.gov in Docket No. FDA1997 
N0020 as an attachment to Comment ID FDA-1997-N-0020-0068.  
 
29.  OECD (2017).  Guidance on Grouping of Chemicals, Second Edition.  OECD Series on  
Testing  and Assessment.   Available at  https://www.oecd.org/publications/guidance-on-
grouping-of-chemicals-second-edition-9789264274679-en.htm.  
 
30.  Ball N, Cronin MT, Shen J, Blackburn K, Booth ED, Bouhifd M, Donley E, Egnash L, 
Hastings C, Juberg DR, Kleensang A, Kleinstreur N, Kroese ED, Lee AC, Luechtefeld T, 
Maertens A, Marty S, Naciff JM, Palmer J, Pamies D, Penman M, Richarz AN, Russo DP,  
Stuard SB, Patlewicz G, van Ravenzwaay B, Wu S, Hartung T. (2016).  Toward Good Read-
Across Practice (GRAP) Guidance.   ALTEX 33(2): 149-166.  
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