Contains Nonbinding Recommendations 
Draft-Not for Implementation 
 
 
 
Evaluating the Public Health Importance 
of Food Allergens Other Than the Major 
Food Allergens Listed in the Federal 
Food, Drug, and Cosmetic Act:  
Guidance for FDA Staff and Stakeholders  
 
Draft Guidance  
This guidance is being distributed for comment purposes only. 
 
 
Although you can comment on any guidance document at any time (see 21 CFR 10.115(g)(5)), 
to ensure that FDA considers your comment on this draft guidance document before we begin 
work on the final version of the guidance document, submit either electronic or written 
comments on the draft guidance document within 120 days of publication in the Federal Register 
of the notice announcing the availability of the draft guidance document. 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-2021-
N-0553 listed in the notice of availability that publishes in the Federal Register.  
 
For questions regarding this draft guidance document, contact the Center for Food Safety and 
Applied Nutrition (CFSAN) at CFSANCompliancePolicy@FDA.HHS.GOV. 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Food Safety and Applied Nutrition 
 
April 2022 
   
 
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Table of Contents 
 
 
I.  Introduction ....................................................................................................................... 4 
 
II.  Definitions and Abbreviations Used in This Guidance ................................................. 5 
 
A.  Definitions of Terms Used in This Guidance .................................................................. 5 
 
B.  Table of Abbreviations Used in This Guidance ............................................................. 9 
 
III.  Background ..................................................................................................................... 10 
 
A.  What is Food Allergy? .................................................................................................... 10 
 
B.  Preventing IgE-mediated Food Allergic Reactions ...................................................... 12 
 
C.  FDAs Regulations, Guidance, Assistance, and Communications Applicable to Food 
Allergens .......................................................................................................................... 13 
 
1. Regulatory framework applicable to food allergens in the United States ........................ 13 
2. FDAs Food Code ............................................................................................................. 17 
3. FDAs communications to the public ................................................................................ 17 
 
D.  Specific Requests for FDA to Evaluate Certain Foods as Food Allergens of Public 
Health Importance .......................................................................................................... 17 
 
IV.  Scientific Factors Relevant to the Public Health Importance of a Non-Listed Food 
Allergen ............................................................................................................................ 18 
 
A.  Evidence of IgE-mediated Food Allergy ....................................................................... 19 
 
B.  Prevalence of IgE-mediated Food Allergy .................................................................... 21 
 
C.  Severity of IgE-mediated Food Allergic Reactions ...................................................... 24 
 
D.  Allergenic Potency .......................................................................................................... 27 
 
V.  Identifying and Systematically Evaluating the Body of Evidence Applicable to Our 
Scientific Factors ............................................................................................................. 29 
 
A.  Preliminary Identification of Published Scientific Literature .................................... 30 
 
B.  Preliminary Identification of Community Reports in Surveillance Databases and 
Other Sources .................................................................................................................. 30 
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C.  Systematic Evaluation of Published Scientific Literature and Community Reports 31 
 
1. Narrowing the identified body of published scientific literature ...................................... 31 
2. Systematic evaluation of the strength of the identified evidence ...................................... 32 
3. Systematic evaluation of community reports .................................................................... 35 
4. Systematic evaluation of the severity of an IgE-mediated food allergic reaction ............ 36 
 
VI.  FDAs Evaluation of the Public Health Importance of a Non-Listed Food Allergen 37 
 
A.  FDAs Evaluation of the Identified Body of Evidence Applicable to Our Scientific 
Factors ............................................................................................................................. 37 
 
1. Factor #1: Evidence of IgE-mediated food allergy .......................................................... 38 
2. Factor #2: Prevalence of an IgE-mediated food allergy in the U.S. population .............. 39 
3. Factor #3: Severity of IgE-mediated food allergic reactions ........................................... 40 
4. Factor #4: Allergenic potency .......................................................................................... 41 
 
B.  FDAs Evaluation of Information Relevant to the Labeling and Production of Food 
Containing a Food Allergen ........................................................................................... 42 
 
C.  How FDA Intends to Consider the Total Body of Evidence ....................................... 43 
 
VII.  Stakeholder Submission of a Citizen Petition .............................................................. 43 
 
VIII.  References ........................................................................................................................ 44 
 
IX.  Appendix A  Additional Considerations ......................................................................... 48 
 
A.    Community Reports Regarding Food Allergens ....................................................... 48 
 
B.  Codex Criteria for Evaluating the Public Health Importance of Food Allergens .... 49 
 
C.  Development of Other Examples of Criteria for Evaluating the Public Health 
Importance of Food Allergens ....................................................................................... 51 
 
D.  Report of the National Academies of Sciences, Engineering, and Medicine on Food 
Allergy .............................................................................................................................. 51 
 
 
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Evaluating the Public Health Importance 
of Food Allergens Other Than the Major 
Food Allergens Listed in the Federal 
Food, Drug, and Cosmetic Act:
 
Guidance for FDA Staff and 
1
Stakeholders   
 
 
This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
Administration (FDA or we) on this topic.  It does not establish any rights for any person and is 
not binding on FDA or the public.  You can use an alternative approach if it satisfies the 
requirements of the applicable statutes and regulations.  To discuss an alternative approach, 
contact the FDA staff responsible for this guidance as listed on the title page. 
 
I.  Introduction  
 
This guidance is intended for: 
 
  FDA staff who are responsible for evaluating, on FDAs initiative or in response to a 
citizen petition submitted in accordance with 21 CFR 10.30, the public health 
importance of a non-listed food allergen, which for the purpose of this guidance 
means a food allergen other than one of the major food allergens (i.e., milk, eggs, 
fish, Crustacean shellfish, tree nuts, wheat, peanuts, soybeans, and sesame2) listed in 
the Federal Food, Drug, and Cosmetic Act (FD&C Act); and  
  Stakeholders who intend to submit a citizen petition asking FDA to establish 
regulatory requirements based on the public health importance of a non-listed food 
allergen (applicable stakeholders) or who are interested in how FDA generally 
intends to evaluate the public health importance of such food allergens.  
 
This guidance addresses substances that are currently consumed in food or have previously been 
consumed in food, within or outside the United States, such that there is a body of information 
 
1 This guidance has been prepared by the Compliance Policy Staff in the Office of Compliance, the Food Labeling 
and Standards Staff in the Office of Nutrition and Food Labeling, and the Office of Regulations and Policy, all in the 
Center for Food Safety and Applied Nutrition at the U.S. Food and Drug Administration. 
2 In April 2021, the Food Allergy Safety, Treatment, Education, and Research Act of 2021 (FASTER Act) amended 
section 201(qq) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) to add sesame to the definition of major 
food allergen.  This amendment applies to any food that is introduced or delivered for introduction into interstate 
commerce on or after January 1, 2023 (Public Law 117-11). 
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about adverse reactions experienced by consumers who ingest the substance.3  This guidance 
does not address the potential that a substance that would be new to the food supply might be a 
food allergen.  This guidance also does not address scientific research regarding potential cross-
reactivity to a known food allergen and how this research could help determine whether a 
substance in food could be a food allergen.4 
 
This guidance describes the approach we generally intend to take when we evaluate the public 
health importance of a non-listed food allergen by specifying: 
 
  The scientific factors that we generally intend to consider when evaluating the public 
health importance of a non-listed food allergen;  
  Other information, relevant to the labeling and production of food containing the food 
allergen, that we generally intend to consider when evaluating the public health 
importance of a non-listed food allergen; and 
  Our recommendations for how to identify and evaluate the body of evidence 
applicable to an evaluation of the public health importance of a non-listed food 
allergen.  
 
The contents of this document do not have the force and effect of law and are not meant to bind 
the public in any way, unless specifically incorporated into a contract.  This document is 
intended only to provide clarity to the public regarding existing requirements under the law.  
FDA guidance documents, including this guidance, should be viewed only as recommendations, 
unless specific regulatory or statutory requirements are cited.  The use of the word should in 
FDA guidance documents means that something is suggested or recommended, but not required.  
 
II.  Definitions and Abbreviations Used in This Guidance 
 
A. Definitions of Terms Used in This Guidance 
 
Table 1 defines several terms for the purpose of this guidance. 
 
Table 1. Definitions of some terms used in this guidance 
Term  What It Means 
Anaphylaxis  An acute, potentially life-threatening syndrome with 
multi-systemic manifestations due to the rapid release 
of inflammatory mediators 
Allergen cross-contact  The unintentional incorporation of a food allergen into 
a food 
 
3 The term food is defined in section 201(f) of the FD&C Act (21 U.S.C. 321(f)) and means (1) articles used for 
food or drink for man or other animals, (2) chewing gum, and (3) articles used for components of any such article.  
Food also includes dietary supplements, as defined in section 201(ff) of the FD&C Act (21 U.S.C. 321(ff)).  This 
guidance pertains to human food. 
4 For information on the topic of clinically cross-reactive food allergy, see section IV.A. 
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Term  What It Means 
Allergenic potency  The amount of food allergenic protein required to 
elicit an IgE-mediated food allergic reaction in an 
already sensitized individual 
Applicable stakeholder  A stakeholder who intends to submit a citizen petition 
asking us to evaluate the public health importance of a 
non-listed food allergen 
Clinically cross-reactive food allergy  Cross-reactivity in which the Immunoglobulin E 
antibody (IgE) directed to one food binds to another 
food and causes IgE-mediated responses (including 
clinical symptoms) to that other food.  (See also the 
definition of cross-reactivity.)  
Community report   A report, regarding a known or suspected food 
allergen in a food product, that is submitted to a 
surveillance database, a research query, or other 
request for information, or that is otherwise collected 
and described (e.g., as a patient case study or a 
diagnostic food challenge study reported in the 
scientific literature).  A community report can be 
submitted or prepared by consumers, health care 
professionals, industry, researchers, government 
agencies, non-government agencies, or other 
stakeholders.  Some community reports (such as 
adverse event reports and case studies) describe an 
allergic reaction experienced by an individual to a 
food product, whereas other community reports 
(usually called product complaints) call FDAs 
attention to a potential problem (such as labeling that 
does not disclose that a food product is or contains a 
food allergen).  See Appendix A for further discussion 
on community reports. 
Cross-reactivity  Reactivity of the immune system observed when a 
protein in one food shares characteristics with a 
protein from another substance food.  (See also the 
definition of clinically cross-reactive food allergy.) 
Documented sensitized individual  An individual with documented evidence of IgE 
sensitization to relevant food or component(s) of food 
(e.g., confirmed by positive skin percutaneous test 
(SPT) or in vitro allergen specific IgE test) 
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Term  What It Means 
Food  The term food is defined in section 201(f) of the 
FD&C Act and means (1) articles used for food or 
drink for man or other animals, (2) chewing gum, and 
(3) articles used for components of any such article 
(21 U.S.C. 321(f)).  Food includes dietary 
supplements, as defined in section 201(ff) of the 
FD&C Act (21 U.S.C. 321(ff)).  This guidance 
pertains to human food. 
Food allergen  The food or component(s) of a food (often a protein) 
that elicits specific, IgE-mediated immunologic 
reactions (Ref. 1 and Ref. 2) 
Food allergic reaction   A reaction, characterized by a set of clinical 
symptoms, experienced by a sensitized individual 
exposed to a food allergen 
Food allergy  An adverse health effect arising from a specific 
immune response that occurs reproducibly on 
exposure to a given food (Ref. 1 and Ref. 2) 
Food challenge  A clinical procedure or intervention in which 
gradually increasing food doses are administered to 
elicit reactivity to the food.  Food challenges can be 
unblinded (open), single-blinded (in which only the 
researcher doing the study knows what the participant 
is receiving), or double-blinded blinded (in which 
neither the researcher nor the participant know what 
the participant is receiving). 
Food hypersensitivity  An adverse food reaction, occurring in a population of 
sensitive individuals, that can be either mediated by 
immune mechanisms (i.e., food allergy) or mediated 
by mechanisms that are not immune mechanisms (i.e., 
food intolerance) 
Food intolerance  Food adverse reaction that is not immune-mediated 
(e.g., lactose intolerance) 
Frequency doseresponse  The population distribution of doses eliciting or 
provoking an IgE-mediated food allergic reaction 
Historical information  Generally available information (e.g., in published 
scientific literature and in community reports)  
Major food allergen  Milk, eggs, fish, Crustacean shellfish, tree nuts, wheat, 
peanuts, soybeans, and sesame (effective January 1, 
2023) and, with few exceptions, a food ingredient that 
contains protein derived from one of these foods (see 
section 201(qq) of the FD&C Act) 
Objective signs of food allergy  Symptoms that are elicited by food challenge and 
visible or ascertainable to an observer (e.g., hives, 
swelling, wheezing) 
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Term  What It Means 
Oral allergy syndrome  Food allergic condition limited to tingling, itching, or 
swelling of the lips or mouth after oral contact with 
food allergen 
Probable food allergy rate  Prevalence estimate of food allergy derived from 
questionnaires in a population of self-reported allergic 
individuals 
Reactivity (or elicitation)   Development of allergic signs or symptoms when the 
food or component(s) of food is consumed 
Self-reported allergic individual  An individual with self-reported history of food 
allergic reactions (i.e., typical and reproducible 
symptoms in close temporal association (e.g., within a 
few hours) of food consumption) and self-reported 
doctor-confirmed diagnosis with evidence of IgE 
sensitization to relevant food or component(s) of food 
(e.g., positive reaction in SPT or in vitro allergen 
specific IgE test)  
Self-reported reactive individual  An individual who self-reports having had a food 
allergic reaction without also self-reporting evidence 
of IgE sensitization to relevant food or component(s) 
of food 
Self-reported sensitized individual  An individual who self-reports evidence of IgE 
sensitization to relevant food or component(s) of food 
(e.g., a self-report of positive SPT or in vitro allergen 
specific IgE test) without also self-reporting food 
allergic reaction 
Sensitization  Production of IgE specific to the food or component(s) 
of food 
Severity dose-response  The gradient of severity of IgE-mediated food allergic 
reactions caused by the food 
Subjective symptoms of food allergy  Symptoms that are elicited by food challenge but not 
visible or ascertainable to an observer (e.g., tingling, 
chest tightness, nausea) 
Threshold    Level below which it is unlikely that a food allergic 
(as described in scientific literature) 
individual would experience an adverse effect (Ref. 
3) 
 In food challenge studies, the challenge dose interval 
between the highest challenge dose not to elicit an 
objective sign or symptom and the lowest challenge 
dose to elicit an objective sign or symptom (Ref. 4 
and Ref. 5) 
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Term  What It Means 
Well-characterized allergic individual  An individual with documented history of IgE-
mediated food allergic reactions [i.e., typical and 
reproducible clinical allergic signs or symptoms in 
close temporal association (e.g., within a few hours) of 
food consumption or positive food challenge] and 
documented evidence of IgE sensitization to relevant 
food or component(s) of food (e.g., positive reaction 
in SPT or in vitro allergen specific IgE test) 
 
B. Table of Abbreviations Used in This Guidance 
 
See Table 2 for abbreviations used in this guidance. 
 
Table 2. Abbreviations used in this guidance 
Abbreviation  What It Means 
1999 Codex criteria  Criteria, recommended to Codex by the Food Allergens 
Labelling Panel, for determining whether there are foods, in 
addition to the list of foods adopted by Codex in 1999, whose 
presence should always be declared in the list of ingredients on 
a food label because of their allergenic properties 
Allergen labeling  The major food allergen labeling requirements in section 
requirements of the FD&C  403(w) of the FD&C Act 
Act 
CAERS  CFSAN Adverse Event Reporting System 
CGMP  Current good manufacturing practice 
CFSAN  Center for Food Safety and Applied Nutrition 
Codex  Codex Alimentarius Commission 
DBPCFC  Double-blinded, placebo-controlled food challenge 
ED   Eliciting dose 
ED01, ED05, ED10, ED50  Eliciting dose required to produce an IgE-mediated food 
allergic reaction in 1%, 5%, 10%, or 50 % of the allergic 
population, respectively 
ER  Emergency room 
FDA  U.S. Food and Drug Administration 
FD&C Act  Federal Food, Drug, and Cosmetic Act 
FALCPA  Food Allergen Labeling and Consumer Protection Act of 2004 
FASTER Act  Food Allergy Safety, Treatment, Education, and Research Act 
of 2021 
GRADE  Grading of Recommendations Assessment, Development, and 
Evaluation 
IgE  Immunoglobulin E antibody 
IgE-mediated food allergy  Food allergy that is mediated by IgE 
ILSI-EU  International Life Sciences Institute-Europe 
NASEM  National Academies of Sciences, Engineering, and Medicine 
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Abbreviation  What It Means 
NASEM Report  A 2016 report, issued by NASEM, entitled Finding a Path to 
Safety in Food Allergy: Assessment of the Global Burden, 
Causes, Prevention, Management and Public Policy  
Non-listed food allergen  A food allergen other than one of the major food allergens (i.e., 
milk, eggs, fish, Crustacean shellfish, tree nuts, wheat, peanuts, 
soybeans, and sesame (sesame effective January 1, 2023)) listed 
in the FD&C Act 
OAS  Oral allergy syndrome 
OFC  Oral food challenge open or single-blinded (but not double-
blinded) 
Part 117  Current Good Manufacturing Practice, Hazard Analysis, and 
Risk-Based Preventive Controls for Human Food in 21 CFR 
part 117 
Preventive controls  The requirements (primarily in subparts C and G of 21 CFR 
requirements  part 117, with associated requirements in subparts A, D, E, and 
F of part 117) for domestic and foreign facilities that are 
required to register under section 415 of the FD&C Act to 
establish and implement hazard analysis and risk-based 
preventive controls for human food 
SPT  Skin percutaneous test (skin prick test) 
 
III.  Background  
 
A. What is Food Allergy?  
 
Food allergy is a form of food hypersensitivity.  Adverse reactions to food due to food 
hypersensitivity can be broadly grouped into reactions that are mediated by either immune 
mechanisms (food allergic reactions) or non-immune mechanisms (primarily food intolerances) 
(Ref. 1).  For example:  
 
  Adverse reactions that are immune-mediated can be caused by: 
  IgE-mediated mechanisms (e.g., IgE-mediated anaphylactic reaction to peanuts); 
o
  Non-IgE-mediated mechanisms (e.g., adverse reaction to gluten in the case of 
o
celiac disease);  
  Mixed immune mechanisms (e.g., eosinophilic gastroenteropathies5); or  
o
  Cell-mediated mechanisms (e.g., contact dermatitis).  
o
  Adverse reactions that are not immune-mediated can be caused by: 
  Metabolic mechanisms (e.g., lactose intolerance);  
o
  Pharmacologic mechanisms (e.g., reaction to caffeine);  
o
  Toxicological mechanisms (e.g., scombroid toxin poisoning); or 
o
 
5 Although IgE-mediated responses to foods associated with this group of disorders have been identified, the main 
pathogenesis of this group of disorders is believed to be non IgE-mediated. 
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  Other idiopathic (undefined) mechanisms (e.g., reactions to sulfites). 
o
 
Food allergy can be broadly defined as an adverse health effect arising from a specific immune 
response that occurs reproducibly on exposure to a given food (Ref. 1 and Ref. 2).  A food 
allergen is the food or component(s) (often a protein) of a food that elicits specific immunologic 
reactions (Ref. 1). 
 
While many different types of food allergies have been identified, food allergies that are 
recognized to be the most severe and immediately life-threatening are those that are mediated by 
immunoglobulin E antibodies (IgE) because IgE-mediated food allergic reactions are capable of 
triggering anaphylaxis, which can be fatal (Ref. 1 and Ref. 3).  Immune-mediated mechanisms 
that are not IgE-mediated (such as mechanisms associated with celiac disease and contact 
dermatitis), and mechanisms that are not immune-mediated (such as lactose intolerance) 
typically are not associated with anaphylaxis or other immediately life-threatening conditions.  
 
IgE-mediated food allergic reactions can occur within a few minutes to hours after a sensitized 
individual consumes the applicable food allergen.6  IgE-mediated food allergic reactions can 
have a wide range of clinical manifestations that, if untreated, can lead to serious adverse health 
consequences, including death (Ref. 1 and Ref. 2).  IgE-mediated food allergic reactions can 
involve a single organ system such as the skin (e.g., pruritis, erythema, urticaria, angioedema, 
eczema), eyes (e.g., conjunctivitis, periorbital swelling), nose (e.g., rhinitis, sneezing), oral cavity 
(e.g., swelling and itching of lips, tongue, or palate), or gastrointestinal tract (e.g., reflux, colic, 
abdominal pain, nausea, vomiting, diarrhea).  The most severe IgE-mediated food allergic 
reactions (generally referred to as anaphylaxis) involve the shock organs of the respiratory 
tract or cardiovascular system and involve signs or symptoms7 such as cough, wheezing, 
difficulty breathing, swelling of the larynx or vocal cords, fainting, and low blood pressure.  
These anaphylactic reactions can lead to loss of consciousness, asphyxiation, shock, or death. 
 
The focus of this guidance is IgE-mediated food allergy, which is a type of food hypersensitivity 
that has been studied extensively and is associated with the most severe and immediately life-
threatening allergic reactions, including anaphylaxis.  Likewise, the discussions in this guidance 
of food allergens is limited to those foods that elicit IgE-mediated immune reactions.8  
   
 
6 The Food Allergen Labeling and Consumer Protection Act of 2004 (FALCPA) identifies eight major food 
allergens (or food groups): milk, eggs, fish (e.g., bass, flounder, cod), crustacean shellfish (e.g., shrimp, crab, 
lobster), tree nuts (e.g., almonds, walnuts, pecans), peanuts, wheat, and soybeans.  At the time that FALCPA was 
enacted, these eight foods were believed to account for 90 percent of food allergies and most serious reactions to 
foods (section 202(2)(A) of FALCPA (21 U.S.C. 343 note); Ref. 6 and Ref. 7).  More than 160 foods are known to 
cause IgE-mediated food allergic reactions of varying severity, many with relatively low prevalence rates, with some 
as low as single cases (Ref. 7). 
7 See Table 1 for the definitions of objective signs of food allergy and subjective symptoms of food allergy. In 
the remainder of this guidance, we generally refer to signs or symptoms without noting that signs are objective 
and symptoms are subjective.  
8 A food allergen may also be associated with reactions that are not IgE-mediated or not immune mediated. 
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B. Preventing IgE-mediated Food Allergic Reactions 
 
Although treatments for IgE-mediated food allergies currently are being developed, the most 
effective strategy for preventing IgE-mediated food allergic reactions is for allergic consumers to 
avoid foods that are or contain food allergens.9  Constant food vigilance and fear of accidental 
life-threatening reactions with every meal are daily, patient-centered challenges that can 
accompany management of IgE-mediated food allergy.  These patient-centered challenges have 
been shown to negatively impact the quality of life of food allergic individuals and their 
caregivers (Ref. 2).  
 
As discussed in section IV.A, some consumers have clinically cross-reactive IgE-mediated food 
allergies (Ref. 11) in which a consumer who experiences an IgE-mediated allergic reaction to 
one food allergen (e.g., cashews, which are a tree nut) also experiences IgE-mediated allergic 
reactions to another food allergen (e.g., pistachios, which also are a tree nut (Ref. 1)).  While 
most individuals with cross-reactive allergies to foods, such as tree nuts, understand the reaction 
risks for cross-reactivity and are cautioned to avoid all tree nuts to prevent allergic reactions, 
other cross-reactive food allergies may not be known or obvious to the food allergic consumer.  
In the latter case, because individuals known to be allergic to a food allergen may have inherent 
potential for IgE-mediated reactions to other cross-reactive food allergens, first-time and/or any 
inadvertent consumption of a cross-reactive food allergen by this allergic individual(s) can also 
lead to allergic reactions.  A particularly challenging situation is one in which a food allergen has 
not been on the U.S. market for an extended period of time or is not commonly used as an 
ingredient in food, because potential cross-reactivity to the food allergen would not be well-
recognized in the allergic population.10  
 
As discussed in section III.C.1, in general the FD&C Act and our implementing regulations 
broadly apply to the production of food that is or contains a food allergen through statutory and 
regulatory provisions regarding: (1) food labeling; (2) food production; and (3) the safety of 
substances added to food.  The label of packaged foods provides allergic consumers and their 
caregivers information that they can use to avoid foods that contain food allergens.  The most 
relevant information is the food allergen source from which a food or food ingredient is derived.  
For example, the source of the food tofu is the major food allergen soy, and the source of the 
ingredient lactoferrin is the major food allergen milk.  The potential for allergen cross-
contact can be reduced or eliminated through CGMPs and preventive controls.  The CGMP 
requirements and preventive controls requirements apply only to the already identified major 
food allergens. 
 
Complete avoidance of food allergens remains difficult.  This is exemplified by the high 
percentage (40-50%) of food allergic individuals who report reactions to major food allergens 
and other foods in the community every year (Ref. 1, Ref. 13, and Ref. 14).  A subset of these 
 
9 FDA recently approved the use of oral immunotherapy to treat children and adolescents with peanut allergies (Ref. 
8).  The oral immunotherapy is indicated for the mitigation of allergic reactions, including anaphylaxis, that can 
occur with accidental exposure to peanut (Ref. 9 and Ref. 10).  Oral immunotherapy currently is available only for 
peanuts, is used in combination with a peanut avoidance diet, and is not a cure. 
10 For example, see Consumer Advice on Lupin (Ref. 12), advising that people who are allergic to peanuts could 
also react to lupin, a legume belonging to the same plant family as peanuts. 
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IgE-mediated food allergic reactions results in anaphylaxis presenting to emergency rooms (Ref. 
2).  Causes for these reactions are multifactorial  e.g., they can be due to consumption of non-
packaged food products in which labeling of the already identified food allergens is not required, 
allergen cross-contact during food production, or unclear or absent allergen information on 
packaged food products when a food allergen is not an already identified major food allergen 
subject to the allergen labeling requirements of the FD&C Act (Ref. 13).  For example, a food 
allergen that is not a major food allergen and is added as a spice, flavoring, or color may be 
declared using a collective term as allowed for in 21 CFR 101.22.  As another example, the food 
allergen source of a food or ingredient that is not an already identified major food allergen is not 
required to be disclosed as part of the common or usual name of the food or ingredient.11 
 
C. FDAs Regulations, Guidance, Assistance, and Communications 
Applicable to Food Allergens  
 
1.  Regulatory framework applicable to food allergens in the United States 
 
In general, the provisions of the FD&C Act and our implementing regulations that are most 
relevant to food that is or contains a food allergen address: (1) food labeling; (2) food production 
(e.g., manufacturing, processing, packing, and holding food); and (3) the safety of substances 
added to food. 
 
With respect to food labeling, the general misbranding provisions in section 403 of the FD&C 
Act (21 U.S.C. 343) provide us with broad authority to provide consumers with information, on 
the food label, about substances in the food, including substances that are food allergens.  We 
have established several regulations that implement these misbranding provisions of the FD&C 
Act and also specify some special circumstances that may be relevant to some food allergens.  
For example, a food label must bear the common or usual name of the food, if it has one, and the 
common or usual name of each ingredient if the food is made from two or more ingredients 
(section 403(i) of the FD&C Act (21 U.S.C. 343(i))).  A common or usual name must accurately 
identify or describe, in as simple and direct terms as possible, the basic nature of the food or its 
characterizing properties or ingredients and can either be the name established by common use or 
the name required by a regulation (21 CFR 102.5).  For example, the label of a food made with 
sugar must declare this ingredient by its common or usual name (sugar) rather than the 
chemical name sucrose (see 21 CFR 101.4(b)(20); section 403(i) of the FD&C Act)).  
However, specific labeling provisions apply to the declaration of some food ingredients.  For 
example, spices, natural flavor, and artificial flavor may be declared using a collective term (e.g., 
spice, natural flavor, or artificial flavor, respectively) without identifying the particular 
spice or flavor, except for substances obtained by cutting, grinding, drying, pulping, or similar 
processing of tissues derived from fruit, vegetable, meat, fish, or poultry (e.g., powdered or 
granulated onions, garlic powder, and celery powder), which are commonly understood by 
consumers to be food rather than flavor and must be declared by their common or usual name 
(see 21 CFR 101.22(h)(1) and (3)).12  Likewise, some colorings may be declared using the 
 
11 For example, our food labeling regulations do not currently require that the common or usual name tahini 
disclose the food allergen source  sesame. 
12 For the purpose of this guidance:  
 
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collective term color (see 21 CFR 101.22(k)(2)).  As another example, incidental additives that 
are present in a food at insignificant levels and do not have any technical or functional effect in 
that food are exempt from the ingredient declaration requirements (see 21 CFR 101.100(a)(3)).13 
 
In 2004, the Food Allergen Labeling and Consumer Protection Act of 2004 (FALCPA) amended 
the FD&C Act to provide us with additional, specific authority regarding the labeling of a food 
(other than a raw agricultural commodity) that bears or contains a major food allergen.14  
Under section 403(w) of the FD&C Act (21 U.S.C. 343(w)), a food is misbranded if it contains a 
major food allergen and fails to declare that major food allergen on its label in the manner 
specified using the major food allergens common or usual name, including the name of the food 
source from which the major food allergen is derived.  Section 201(qq)(1) of the FD&C Act (21 
U.S.C. 321(qq)(1)) defines a major food allergen, in part, as any of the following: 
 
  Milk,  
  Egg,  
  Fish (e.g., bass, flounder, or cod),  
  Crustacean shellfish (e.g., crab, lobster, or shrimp),  
  Tree nuts (e.g., almonds, pecans, or walnuts),  
  Wheat,  
  Peanuts, and  
  Soybeans. 
 
When FALCPA was enacted, these eight foods and food groups, out of more than 160 identified 
food allergens, accounted for 90% of IgE-mediated food allergic reactions in the U.S.  When 
drafting FALCPA, Congress made clear that the new statutory requirements did not alter our 
existing authority under the FD&C Act to require a label or labeling for other food allergens (21 
U.S.C. 343 note).  Also, section 403(x) of the FD&C Act gives us explicit authority to require by 
 
  We use variations of the term declare when that term is used in the FD&C Act, our regulations, or an 
FDA guidance document to describe information that is present on a food label.  For example, the label 
requirements in 21 CFR 101.4 for the designation of ingredients and our Guidance for Industry: Questions 
and Answers Regarding Food Allergens, Including the Food Allergen Labeling and Consumer Protection 
Act of 2004 (Edition 4) (Ref. 15) both use variations of the term declare when describing information 
presented on a food label.  Likewise, we use variations of the term undeclared when describing a label 
that does not comply with label requirements in the FD&C Act or our food labeling regulations. 
  We use variations of the term disclose when discussing information that is present on a food label but is 
not specified in the FD&C Act, our regulations, or an FDA guidance document.  For example, we use 
variations of the term disclose to describe voluntary declaration of the food allergen source of a food 
allergen that is not a major food allergen.  Likewise, we use variations of the term undisclosed when 
describing a label that does not provide label information, such as the food allergen source of a food 
allergen that is not a major food allergen, and when describing a food allergen that our food labeling 
regulations allow to be declared with a collective term (such as spice or flavor). 
13 An example of an incidental additive is a processing aid that is added to a food during the processing of such food 
but is removed in some manner from the food before the food is packaged in its finished form (see 21 CFR 
101.100(a)(3)(ii)(a)). 
14 We issued guidance to help the public understand our implementation of the amendments, including what foods 
and manufacturers are subject to the amendments and labeling requirements (Ref. 15).  We also issued guidance to 
clarify the information we need when considering whether to exempt certain ingredients derived from major food 
allergens from the allergen labeling requirements (Ref. 16). 
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regulation the disclosure of spices, flavorings, colorings, or incidental additives that are, or 
contain, food allergens other than the eight major food allergens.15  
 
In April 2021, the Food Allergy Safety, Treatment, Education, and Research Act of 2021 
(FASTER Act) amended section 201(qq) of the FD&C Act to add sesame to the definition of 
major food allergen.  This amendment applies to any food that is introduced or delivered for 
introduction into interstate commerce on or after January 1, 2023 (Public Law 117-11). 
 
With respect to food production, our regulation entitled Current Good Manufacturing Practice, 
Hazard Analysis, and Risk-Based Preventive Controls for Human Food (21 CFR part 117; part 
117) establishes requirements applicable to establishments that manufacture, process, pack, or 
hold human food.  Part 117 includes current good manufacturing practice (CGMP) requirements 
to prevent allergen cross-contact.  Allergen cross-contact is the unintentional incorporation of a 
food allergen into a food; part 117 defines food allergen to mean a major food allergen as 
defined in section 201(qq) of the FD&C Act.  (See the definitions of allergen cross-contact and 
food allergen in 21 CFR 117.3.)  Allergen cross-contact occurs between foods that have 
different food allergen profiles (the food allergen sources present or absent in a food).  The 
processing characteristics of a food can affect the potential for allergen cross-contact to occur.  
For example, when using shared equipment, it is more difficult to prevent allergen cross-contact 
when producing foods with high viscosity (such as nut butters) and using only dry cleaning 
methods than when producing foods with low viscosity (such as many beverages) and using wet 
cleaning methods due to challenges associated with cleaning all traces of a high-viscosity food 
from shared food-contact surfaces using dry cleaning methods.  As another example, when using 
adjacent processing lines, it is more difficult to prevent allergen cross-contact when producing 
foods (such as peanuts and milk powder) that are prone to the creation of dust than when 
producing foods (such as many beverages) that are not prone to the creation of dust. 
 
Part 117 also establishes specific requirements (commonly called preventive controls 
requirements) for domestic and foreign facilities that are required to register under section 415 
of the FD&C Act to establish and implement hazard analysis and risk-based preventive controls 
for human food as mandated by the FDA Food Safety Modernization Act of 2011 (FSMA).  
With few exceptions,16 these preventive controls requirements specify that food manufacturers 
must implement a food safety plan that includes a hazard analysis to identify known or 
reasonably foreseeable hazards that require a preventive control.  Preventive controls must 
significantly minimize or prevent hazards.  When a hazard requiring a preventive control is a 
 
15 We relied on this authority, in part, to require the labeling of carmine and cochineal extract in foods (see  73.100 
and 74 FR 207, January 5, 2009).  
16 See 21 CFR 117.5 for the exemptions from the preventive controls requirements.  For example, the preventive 
controls requirements do not apply to a facility that is a qualified facility (e.g., because it is a very small business) 
as that term is defined in part 117.  (Alternative requirements apply to these facilities.)  The preventive controls 
requirements also do not apply with respect to activities that are subject to "hazard analysis and critical control 
point" requirements in 21 CFR part 120 (for juice) or 21 CFR part 123 (for seafood) if a facility is required to 
comply with, and is in compliance with, 21 CFR part 120 or 21 CFR part 123, respectively, with respect to such 
activities.  In addition, nonprofit food establishments, restaurants, and retail food establishments are not required to 
register as a food facility (see 21 CFR 1.226) and generally are inspected by State or local regulatory agencies, often 
under State or local laws and regulations based on FDAs Food Code, which is a model code available for adoption 
by local, state, and other jurisdictions to apply to food establishments at the retail level that provide food directly to 
consumers (Ref. 17).  
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major food allergen, preventive controls also must ensure that the food manufactured, processed, 
packed, or held by the facility will not be adulterated under section 402 of the FD&C Act or 
misbranded under section 403(w) of the FD&C Act.  (See 21 CFR 117.126, 117.130(a)(1) and 
(b)(1)(ii), and 117.135(a)(1), (c)(2), and (c)(3).)  
 
With respect to the safety of substances added to food, under sections 201(s) and 409 of the 
FD&C Act (21 U.S.C. 321(s) and 21 U.S.C. 348), any substance that is intentionally added to 
food is a food additive that is subject to premarket review and approval by FDA, unless the 
substance is generally recognized, among qualified experts, as having been adequately shown to 
be safe under the conditions of its intended use (commonly referred to as a generally recognized 
as safe or GRAS substance), or unless the use of the substance is otherwise excepted from the 
definition of a food additive (e.g., if the substance meets the definition of color additive in 
section 201(t) of the FD&C Act).  The procedures for premarket review and approval of a food 
additive petition are established in 21 CFR part 171.  A notification procedure whereby any 
person may notify FDA of a conclusion that a substance is GRAS under the conditions of its 
intended use is established in 21 CFR part 170, subpart E. 
 
Under sections 201(t) and 721 of the FD&C Act (21 U.S.C. 321(t) and 21 U.S.C. 379), a 
substance that meets the definition of color additive must be listed in an Agency regulation 
prescribing the conditions under which such additive may be safely used.  In contrast to the 
definition of food additive, the definition of color additive has no provision for GRAS substances 
and, thus, all substances that are color additives are subject to premarket review and listing by 
FDA.  The procedures for premarket review of a color additive petition are established in 21 
CFR part 71. 
 
When available, information regarding IgE-mediated food allergic reactions that are known to 
occur reproducibly on exposure to a given food substance are relevant to an evaluation of the 
safety of a substance under the conditions of its intended use.  In most circumstances when a 
substance is subject to premarket review and approval by FDA, the substance is not already in 
the U.S. food supply and, thus, reactivity information from prior food exposure by the U.S. 
population would not be available during FDAs premarket review.  However, we can and have 
used our authorities regarding the safety of substances added to food to amend the conditions of 
use specified in a regulation if information regarding allergic reactions to a food substance 
becomes available after that food substance has entered the U.S. food supply.  For example, in 
2009 we relied, in part, on the authority in sections 201(t) and 721 of the FD&C Act to revise our 
requirements for cochineal extract and carmine17 by requiring their declaration by name on the 
label of all food products18 that contain these color additives (see  73.100 and 74 FR 207, 
January 5, 2009).  
 
17 Cochineal extract is a color additive that is permitted for use in foods and drugs in the United States.  The related 
color additive carmine is permitted for use in foods, drugs, and cosmetics.  The Color Additive Amendments of 
1960 (Public Law 86618, 74 Stat. 397) amended the FD&C Act to add the definition of color additive, establish 
conditions under which color additives may be safely used and require FDA to publish a provisional list of color 
additives that were already in use or were certified as color additives prior to July 12, 1960.  FDA included both 
cochineal extract and carmine in this provisional list.  Following FDAs review of color additive petitions submitted 
in 1964 (for carmine) and 1968 (for cochineal extract), FDA permanently listed both carmine and cochineal extract 
in the color additive regulations. 
18 The revised requirements also apply to the label of all cosmetic products that contain cochineal extract or carmine. 
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2.  FDAs Food Code 
 
Food allergen information has been included in FDAs Food Code19 (Ref. 17) since 2005 and 
includes a definition of major food allergen and a provision under Demonstration of 
Knowledge [Subparagraph 2-102.11(C)(9)] specifying that the person in charge of a food 
establishment shall have an understanding of the foods identified as major food allergens and the 
symptoms that a major food allergen could cause in a sensitive individual.  The Food Code also 
allows integration of the allergen labeling requirements of the FD&C Act (see Table 2 for 
definition) to reflect the additional requirements that apply to food that is packaged at the retail 
level [Subparagraph 3-602.11(B)(5)].  However, the allergen labeling requirements of the FD&C 
Act do not apply to foods provided by a retail food establishment that are placed in a wrapper or 
container in response to a consumer's order - such as the paper or box used to convey a sandwich 
that has been prepared in response to a consumer's order. 
 
3.  FDAs communications to the public 
 
We make safety information available to stakeholders on our Web site (https://www.fda.gov).  
For example, we have issued Consumer Advice on Lupin (Ref. 12), advising that people who 
are allergic to peanuts could also react to lupin, a legume belonging to the same plant family as 
peanuts. 
 
D. Specific Requests for FDA to Evaluate Certain Foods as Food Allergens 
of Public Health Importance  
 
Since FALCPA was enacted, we have received several requests to evaluate a food as a food 
allergen of public health importance.  For example: 
 
  In 2008, we received a citizen petition asking us to [amend] ... FALCPA to include 
barley and rye in the list of common allergens requiring disclosure on packaging (Ref. 
18); 
  In 2014, we received a citizen petition asking us to require that sesame seeds and sesame 
products be regulated in a manner similar to a major allergen under FALCPA and listed 
specifically by name (sesame) in ingredient lists of foods, and to add sesame to the list 
of allergens in a 2005 Compliance Policy Guide Sec. 555.250 Statement of Policy for 
Labeling and Preventing Cross-contact of Common Food Allergens (Ref. 19) to address 
both labeling and cross-contact issues related to sesame in food manufacturing practices 
(Ref. 20); and 
  In 2015, we received a citizen petition asking us to issue a regulation to include garlic as 
an ingredient or allergen on food labels and specifically require food labels to list garlic 
as an allergen (Ref. 21).  
 
19 FDA publishes the Food Code, a model that assists food control jurisdictions at all levels of government by 
providing them with a scientifically sound technical and legal basis for regulating the retail and food service 
segment of the industry (restaurants and grocery stores and institutions such as nursing homes).  Local, state, tribal, 
and federal regulators use the FDA Food Code as a model to develop or update their own food safety rules and to be 
consistent with national food regulatory policy. 
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The data and information submitted in support of these requests varied.  We denied the request 
regarding barley and rye because the petition did not include adequate information to show that 
rye and barley are common causes of severe IgE-mediated food allergies (Ref. 22).  We denied 
the request regarding garlic because: (1) the petition did not provide evidence to show that garlic 
is a common cause of severe food allergies; and (2) garlic is not considered a spice for purposes 
of ingredient labeling and must be declared as garlic rather than being declared collectively 
under the term spice (21 CFR 101.22(a)(2)).  Thus, consumers who are allergic to garlic can 
avoid consuming it by examining the ingredient statements on the foods they purchase and 
avoiding those foods where garlic is listed (Ref. 23).  
 
We responded to the request regarding sesame by publishing a notice inviting additional data and 
other information on the prevalence and severity of sesame allergies in the United States and the 
prevalence of sesame-containing foods that are sold in the United States but are not required to 
declare sesame by name as an ingredient (83 FR 54594 (October 30, 2018)).  We stated our 
interest in learning more about the prevalence and severity of sesame allergies in the United 
States and the prevalence of sesame-containing foods sold in the United States that are not 
required to declare sesame as an ingredient.  We also stated that we were requesting this data and 
other information to inform possible regulatory action on sesame to protect and promote the 
public health.  Key scientific data requested for sesame fell into the following two categories: 
 
  Prevalence of allergies and allergic reactions due to sesame in the United States, 
including the proportion of allergic reactions attributed to undisclosed sesame in food 
products; and 
  Prevalence and amounts of undisclosed sesame in foods. 
 
After considering the data and information submitted to that notice, we announced the 
availability for public comment of a draft guidance document titled, Voluntary Disclosure of 
Sesame as an Allergen: Guidance for Industry (Draft Guidance) (Ref. 24) (85 FR 71920 
(November 12, 2020)).  This guidance initiative was intended to provide food manufacturers 
with FDAs current views on sesame as an allergen and provide recommendations regarding the 
voluntary disclosure of sesame in certain circumstances where such disclosure is not currently 
required, as well as help individuals who are allergic to sesame identify those foods that contain 
sesame as an ingredient.20 
 
IV.  Scientific Factors Relevant to the Public Health Importance of 
a Non-Listed Food Allergen 
 
We have identified the following scientific factors that we generally intend to consider when 
evaluating the public health importance of a food allergen in the United States:  
 
  Factor #1: evidence of IgE-mediated food allergy  
  Factor #2: the prevalence of an IgE-mediated food allergy in the U.S. population 
 
20 The FASTER Act amended section 201(qq) of the FD&C Act to add sesame to the definition of major food 
allergen, effective January 1, 2023. 
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  Factor #3: the severity of IgE-mediated food allergic reactions  
  Factor #4: the allergenic potency  
 
Our scientific factors are consistent with the 1999 Codex criteria (Ref. 25), the revised criteria 
recommended by the International Life Sciences Institute-Europe (ILSI-EU) (Ref. 26), published 
frameworks from ILSI-EU and public, private, and academic partners in Europe for the 
evaluation of public health importance of a food allergen (Ref. 26 and Ref. 27), publications 
from ILSI-EU and public, private, and academic partners in Europe that evaluate published 
frameworks (Ref. 28 and Ref. 29), and the National Academy of Sciences, Engineering and 
Medicine (NASEM) (Ref. 2; the NASEM report).  See Appendix A for further discussion of 
these criteria and frameworks. 
 
A. Evidence of IgE-mediated Food Allergy 
 
An IgE-mediated food allergic reaction is characterized by a two-step immune process  i.e., 
sensitization and reactivity.  Sensitization is the production of IgE specific to the food or food 
component, often a protein.  Reactivity (or elicitation) is the development of clinical allergic 
signs or symptoms when the food or component of food is consumed.  The sensitization and 
reactivity steps can occur independently in certain individuals, so that evidence of sensitization 
alone, or reactivity alone, does not establish clear evidence that an adverse reaction to a food is 
an IgE-mediated food allergic reaction.  Therefore, the best approach to a doctor diagnosis of 
IgE-mediated food allergy is robust evidence of a cause-effect relationship between oral 
exposure to the food or component of food and elicitation of signs or symptoms (which 
demonstrates reactivity) in individuals who are known to be sensitized to the food (which 
demonstrates sensitization).  
 
Evidence of IgE-mediated food allergy can be obtained from several sources and methodologies, 
provided that the sources and methodologies provide evidence of both sensitization and 
reactivity.  The gold standard method for obtaining evidence of IgE-mediated food allergy is 
the double-blinded, placebo-controlled food challenge (DBPCFC) in a population of documented 
sensitized individuals, because reactivity to food exposure is directly and impartially assessed in 
documented sensitized individuals.  By documented sensitized individuals, we mean individuals 
with documented evidence of IgE sensitization to the relevant food or component(s) of food 
(e.g., evidence confirmed by skin percutaneous test (SPT; often called skin prick test) or in vitro 
allergen specific IgE test), but without documented evidence of IgE-mediated food allergic 
reaction.  Conducting the DBPCFC in documented sensitized individuals satisfies the first 
criterion (sensitization), and elicitation of clinical allergic signs or symptoms during the food 
challenge provides evidence for the second criterion (reactivity).  However, outside of 
specialized clinical centers, DBPCFC are rarely performed.  
 
When a DBPCFC is not available, other historical information (i.e., from the scientific literature 
or community reports) can still provide robust evidence of IgE-mediated food allergy, provided 
that the information provides evidence of both sensitization and reactivity.  For example, under 
appropriate conditions, a positive open or single-blinded oral food challenge (OFC) in a 
documented sensitized individual can provide robust evidence of IgE-mediated food allergy.  
Also, evidence of IgE-mediated food allergy can be obtained from historical information 
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describing observations or reports of typical, reproducible, and temporally related signs or 
symptoms of IgE-mediated food allergic reactions in sensitized individuals, including 
documented sensitized individuals and self-reported sensitized individuals.  Evidence of clinical 
reactivity in documented sensitized individuals, in whom IgE sensitization has been confirmed, 
is more robust evidence of IgE-mediated food allergy than evidence in self-reported sensitized 
individuals, in whom IgE sensitization is not confirmed.  Similarly, evidence of positive OFC or 
other observations of typical, reproducible, and temporally related signs or symptoms associated 
with food consumption consistent with IgE-mediated allergy is more robust evidence of IgE-
mediated food reactivity than reports of unspecified allergic reaction to food alone.  Evaluating 
reactivity information from sensitized individuals in these datasets is important, because it 
reduces the potential for signs or symptoms reported as food allergic reactions to be due to 
confounders such as an intolerance that might be associated with the food.21 
 
Research has identified and characterized specific proteins that have allergenic properties and 
occur in many different foods.  These food allergenic proteins have been recognized by reputable 
national and international organizations.  For example, the World Health Organization and 
International Union of Immunological Societies (WHO/IUIS) Allergen Nomenclature Sub-
committee is an international organization responsible for maintaining and developing a unique, 
unambiguous and systematic nomenclature for allergenic proteins and maintains an allergen 
database that contains approved and officially recognized allergens (Ref. 30).  Identification of a 
protein from a food in the database maintained by the WHO/IUS Allergen Nomenclature Sub-
committee is supporting evidence that the food or component(s) of food is a food allergen  i.e., 
that adverse reactions to the food or component(s) of food are IgE-mediated.22  
 
Clinical evidence of foods or food components (such as proteins) causing IgE-mediated reactions 
from exposure by non-oral routes (e.g., skin, inhalation) can be used as supporting evidence that 
an adverse reaction to a food or component of food is IgE-mediated, but generally would not be 
sufficient, by itself, to be considered definitive evidence that an adverse reaction to a food or 
component of food is IgE-mediated.  The most definitive evidence of IgE-mediated food allergy 
is from reactions observed or associated with oral or sublingual (i.e., under the tongue) exposure.  
 
Observations in historical information regarding food elimination diets that lead to resolution of 
chronic signs or symptoms such as eczema or persistent gastrointestinal complaints in 
individuals with self-reported sensitization to the food generally do not provide robust evidence 
of IgE-mediated food allergy unless accompanied by documentation of sensitization and 
information that typical signs or symptoms are also elicited by food consumption or food 
challenge in those individuals in a time frame consistent with an IgE-mediated reaction.  
 
21 For example, the symptoms of lactose intolerance can be a confounder in the diagnosis of milk allergy in 
individual patients. 
22 See the WHO/IUS submission form for the criteria for submission of a new allergen to the WHO/IUIS allergen 
nomenclature database (Ref. 31).  Section 2.5 of the submission form states: Allergens are incorporated into the 
Official List of Allergens only if protein-specific binding of IgE from at least 5 sera of patients allergic to the 
respective allergen source, and NOT to those without allergy to the source (preference: test with sera from 3 allergic 
to other sources and 2 without allergies).  IgE binding should be tested (demonstrated) to the purified (natural or 
recombinant) allergen, as well as to an extract of the source material that represents the source of allergy (e.g. fruit, 
pollen, insect, animal parts).  Section 2.5.1 of the submission form requires evidence of both reactivity and IgE 
sensitization. 
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In clinically cross-reactive food allergy, IgE directed to a food allergen in one food can bind to, 
and cause IgE-mediated reactions to, an allergen in another food, likely due to the presence of 
similar proteins in both foods (Ref. 11).  As such, historical information, or observed data, 
regarding clinically cross-reactive food allergies (Ref. 11) to a food in individuals sensitized to 
other cross-reactive foods may provide further evidence of IgE-mediated allergy to that food.  
For example, a consumer who is known to be allergic to one food allergen (e.g., cashews) could 
eat a pistachio and experience an immediate allergic reaction.  Because both cashews and 
pistachios are tree nuts and have been recognized to be cross-reactive allergens (Ref. 1), 
evidence of clinically cross-reactive food allergy to pistachio in a cashew allergic consumer is 
likely to provide evidence that the individual has IgE-mediated food allergy to pistachio as well.  
However, while cross-reactive food allergies are important concerns to consider for food 
allergens, the most definitive evidence that the food causes IgE-mediated food allergy for the 
purposes of this guidance is evidence that the food directly causes IgE-mediated reactions in 
individuals who are sensitized to the food.23  
 
B. Prevalence of IgE-mediated Food Allergy 
 
Information to estimate the prevalence of IgE-mediated food allergy has come from a number of 
different sources and methodologies, including prospective data from clinic patients who have 
undergone systematic diagnostic evaluation with clinical testing to the food, self-reported data of 
food allergy (e.g., responses to questionnaire surveys), review of IgE-mediated food allergic 
reactions in community reports, and retrospective review of patient medical records with 
diagnosis codes related to food allergy.  Because there are many different types of food 
hypersensitivities that are not IgE-mediated and other disease processes that may mimic allergic 
reactions, the most robust estimate of the prevalence rate of an IgE-mediated food allergy is 
obtained from a defined population of individuals with: (1) documented history of IgE-mediated 
food allergic reactions (i.e., typical and reproducible signs or symptoms in close temporal 
association (e.g., within a few hours) of food consumption or positive food challenge); and (2) 
documented evidence of IgE sensitization to the relevant food or food proteins (e.g., positive 
reaction in SPT or in vitro allergen specific IgE test) (Ref. 1 and Ref. 2).  For the purpose of this 
guidance, we refer to such individuals as well-characterized allergic individuals.  However, 
obtaining this type of prevalence rate estimate at the national level is difficult.  The 2016 
NASEM report (Ref. 2) found that evidence on the true prevalence of food allergy in the 
[United States] is obscured by insufficient or inconsistent data and variable methodology.  This 
report did not find prevalence rate estimations for any IgE-mediated food allergy relevant to the 
U.S. population based on DBPCFC or other robust clinical parameters.  Instead, epidemiological 
studies that estimate probable food allergy rates in the general population in the United States 
are based on self-reported responses to questionnaires distributed to a defined number of 
participants (commonly called reporters).  
 
 
23 This guidance only addresses food allergy caused by substances that are currently consumed in food or have 
previously been consumed in food and does not address scientific research regarding potential cross-reactivity to a 
known food allergen and how this research could help determine whether a substance in food could be a food 
allergen. 
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In some epidemiological studies to estimate probable food allergy rates, the questionnaires only 
ask for self-reported information about the foods associated with allergic reactions, whereas in 
other epidemiological studies to estimate probable food allergy rates, the questionnaires also ask 
for self-reported information about signs or symptoms, treatment, doctor visits, diagnostic tools, 
and doctor diagnosis in addition to self-reported information about the foods associated with 
allergic reactions.  Neither type of epidemiological study can clearly establish that the reporters 
are well-characterized allergic individuals, because the data collected during these studies are 
self-reported rather than clinically documented.  However, the design of the questionnaires used 
in these studies can increase the probability that the self-reports correctly report food allergy.  
For example, food allergy rates estimated from epidemiological studies in the general population 
based only on self-reports of foods associated with an allergic reaction tend to overestimate 
population prevalence estimates of IgE-mediated allergy to the food (Ref. 1), because many 
reporters confuse food allergy for other forms of adverse food reactions.  This overestimation 
may be reduced when the questionnaires also ask for self-reported information about signs or 
symptoms of the allergic reaction(s), treatment or doctor visit, diagnostic tools, and doctor 
diagnosis in addition to self-reported information about the foods associated with allergic 
reactions, because a trained health professional who evaluates the data from the questionnaires 
could review the additional data to determine whether it is consistent with typical, reproducible, 
and temporally related signs or symptoms of an allergic reaction and whether there may be 
evidence of IgE sensitization. 
 
The most robust estimates of probable food allergy rates are obtained from epidemiological 
studies that: (1) use validated questionnaires and consistent methods to assess the type and 
characteristics of signs or symptoms experienced during allergic reactions; (2) collect self-
reported data from a randomly selected, nationally representative population; (3) ask the 
reporters to self-report all foods that cause a food allergic reaction (rather than prompt the 
reporters about only specific foods that cause a food allergic reaction); and (4) ask reporters to 
describe signs or symptoms, treatment or doctor visits, diagnostic tools, and doctor diagnosis 
related to food allergy.  Asking reporters to identify all foods that cause a food allergy or food 
allergic reaction can help to provide comparative information on the relative frequency of food 
allergies to specific food allergens, identify food allergens that have higher or lower prevalence 
in the population studied, and provide comparative information on the relative number and 
frequency of IgE-mediated food allergic reactions reported for each food.  Asking reporters to 
also describe the associated adverse effects (signs or symptoms of the allergic reaction(s), 
treatment or doctor visits, diagnostic tools, and doctor diagnosis) can help strengthen the 
individual self-reports as likely, or probable, IgE-mediated food allergic reactions. 
 
Another type of epidemiological study that has been used (Ref. 32) to estimate the prevalence 
rate for a food allergen is an epidemiological study in which researchers look for evidence of IgE 
sensitization in blood samples collected from the general population.  Although this type of study 
can identify sensitized individuals, it provides no evidence that exposure to the food elicits an 
allergic reaction in the sensitized individuals and could overestimate the prevalence rate of a 
food allergen, because some of the sensitized individuals might not be allergic individuals.  
Several types of prevalence data generally are not sufficiently robust, by themselves, to estimate 
prevalence of IgE-mediated food allergy.  For example, the following types of prevalence data 
generally are not robust for the reasons given:  
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  Prevalence estimates based on IgE sensitization rates or other clinical parameters 
from local or regional U.S. populations (e.g., academic clinical center patient 
populations, and individuals presenting to local or regional hospital systems)  such 
data are not nationally representative of the U.S. population.  
  Prevalence data from other countries or geographical areas  the U.S. population 
might have different genetic background, consumption frequencies, or practices for 
the food(s).  
  Information about the frequency of IgE-mediated food allergy and/or IgE-mediated 
food allergic reactions in community reports from non-questionnaire methods, such 
as surveillance databases  such reports usually describe a number of allergic 
individuals without providing sufficient information to understand the baseline 
number of allergic or non-allergic individuals in the population of reporters.  
  Information about the frequency of IgE-mediated food allergy and/or IgE-mediated 
food allergic reactions from surveys based on retrospective review of patient medical 
records with diagnosis codes related to food allergy  such diagnosis codes are not 
always specific for IgE-mediated food allergy.  
 
Prevalence information is more likely to be available for foods that have been on the U.S. market 
for an extended period of time or are commonly used as an ingredient in food.  In addition, the 
probable food allergy rate of individual foods generally is not static.  Food consumption patterns 
can change over time  e.g., when newly developed food products that use a food allergen as an 
ingredient lead to an increased consumption of that food allergen by the U.S population.  As a 
result, information queried over successive time periods could identify changes in probable food 
allergy rates for individual foods.  When multiple reports regarding prevalence data are 
available, the most recent prevalence reports (e.g., data obtained in the prior 10 years) would 
more closely reflect the prevalence of allergy to the food in the current population. 
 
In 2004, FALCPA discussed the prevalence of the eight foods that it identified as the major food 
allergens collectively, stating that these eight foods represented about 90% of all food allergies in 
the U.S. population and that approximately 2% of adults and about 5% of infants and young 
children in the United States suffer from food allergies.  In 2010, published U.S. food allergy 
guidelines estimated probable food allergy rates based on self-reported food allergy symptoms to 
each of these eight major food allergens in the U.S. population to be in the range of 0.3 percent 
to 3 percent (Ref. 1).  Based on more recent 2015-2016 U.S. national surveys (Ref. 33 and Ref. 
34), individual probable food allergy rates based on self-reported symptoms highly suggestive of 
IgE-mediated allergy alone (convincing food allergy) for each of these eight major food 
allergens were estimated to be in the range of 0.6 to 2.9% and 0.5 to 2.2% for adults and 
children, respectively.  Individual probable food allergy rates based on more robust parameters 
of self-reported convincing symptoms and doctor diagnosis (confirmed food allergy) for 
these eight major food allergens in children were estimated to be in the range of 0.2 to 1.8% 
(Ref. 33).  The 2015-2016 U.S. national surveys also reported individual probable food allergy 
rates for sesame (Ref. 33 and Ref. 34). 
 
See Table 3 for estimated prevalence of IgE-mediated food allergy in the U.S. population for the 
already identified major food allergens based on probable food allergy rates.  
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Table 3. Estimated prevalence of probable food allergy to individual already-identified 
major food allergens in the U.S. population 
Population  Milk  Soy  Peanut  Tree Nuts  Fish  Shellfish  Egg  Wheat  Sesame 
(effective 
1/1/23) 
All ages, self- 3.0  0-0.6  0.6  0-4.1  0.6  1.2  1.0  0.2-1.3  N/A 
reported 
symptoms (% 
total) (Ref. 1)* 
Children,  1.9  0.5  2.2  1.2  0.6  1.3  0.9  0.5  0.2 
(convincing) 
symptoms 
alone (age 0-
17; % total) 
(Ref. 33) 
Children,  1.0  0.2  1.8  0.9  0.3  0.8  0.7  0.3  0.1 
(confirmed) 
signs or 
symptoms and 
doctor 
diagnosis (age 
0-17; % total) 
(Ref. 33) 
Adults,  1.9  0.6  1.8  1.2  0.9  2.9  0.8  0.8  0.2 
(convincing) 
symptoms 
alone (age 
18+; % total) 
(Ref. 34) 
* The authors reviewed the available data and reported the prevalence of probable food allergy as either a single 
number or a range based on the findings of their review. 
 
C. Severity of IgE-mediated Food Allergic Reactions 
 
As discussed in section III.A, IgE-mediated food allergic reactions can have a wide range of 
clinical manifestations that can involve a single or multiple organ systems.  These clinical 
manifestations can range from relatively mild local reactions to severe anaphylactic reactions.  
Without prompt medical intervention with epinephrine or other treatment measures, severe 
clinical manifestations can progress to various adverse health outcomes, including asphyxiation, 
respiratory distress, or cardiovascular collapse, often resulting in hospitalization.  Severe allergic 
reactions can be fatal; an analysis of temporal patterns and demographic associations for 
anaphylaxis in the United States from 1999 to 2010 identified 164 fatalities associated with 
anaphylactic reactions to food allergens (Ref. 33).  
 
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There currently are no validated biomarkers for assessing or predicting reaction severity, and it is 
likely that several factors (e.g., individual sensitivity, the amount and characteristics of the food 
consumed, underlying co-morbid conditions such as asthma, and the effects of other foods and 
drugs) all interact to determine the course and severity of each IgE-mediated food allergic 
reaction (Ref. 1).  However, data obtained from clinical studies and from community reports can 
be used to evaluate the severity of IgE-mediated food allergic reactions at both the individual and 
population levels.  Evidence of the severity of an IgE-mediated food allergic reaction collected 
from clinical studies, in which a trained health care professional reports or describes, and 
documents, signs or symptoms generally is more robust than evidence collected from community 
reports, in which signs or symptoms are self-reported by individuals and may not be objectively 
scrutinized.  
 
One approach to evaluating severity data obtained from clinical studies or from community 
reports is the Grading of Recommendations Assessment, Development and Evaluation 
(GRADE) system, which provides a comprehensive and transparent methodology to develop 
recommendations for the diagnosis, treatment, and management of patients (Ref. 35).  A 
scientific publication describes a GRADE system for scoring the severity of an IgE-mediated 
food allergic reaction to an eliciting dose of food (Ref. 36).  This GRADE system was developed 
by integrating eight published schemes or grading systems for the severity of IgE-mediated food 
allergic reactions, each of which was independently developed and widely recognized (Ref. 36).  
Another approach to evaluating severity data obtained from information such as DBPCFC 
studies and from community reports is PRACTALL (Ref. 37), which has a numerical grading 
system for several distinct types of allergic reactions (skin, upper respiratory, lower respiratory, 
gastrointestinal, and cardiovascular/neurologic).  
 
Factors that are important in characterizing the severity of reaction(s) to the food include the type 
of elicited signs or symptom(s), the extent of organ involvement, use of certain medications 
(such as epinephrine autoinjector) to manage reactions, evidence of reaction leading to medical 
visit or hospitalization, or other adverse health consequence.  In general, signs or symptoms 
graded as moderate or severe in this GRADE system pose more risk to the health of allergic 
individuals than signs or symptoms graded as mild.  
 
See Table 7 in section V.C.4 for an example of a GRADE system for severity data.  The GRADE 
system in Table 7 is adapted from the GRADE systems published in Ref. 36 and Ref. 37. 
 
The most robust evidence of the severity of an IgE-mediated food allergic reaction is collected 
from a study that reports objective signs in well-characterized allergic individuals evaluated in a 
clinical setting (e.g., clinic, hospital), that are classified according to a scientifically accepted 
classification system and treated using an accepted algorithm.  In general, the clinical setting of 
such studies provides a context to assess severity of reaction due to real-life allergen exposures 
in a population of well-characterized allergic individuals presenting to clinical care facilities.  
This information may also help provide information on the total magnitude of severe reactions in 
the population to understand the public health burden of allergic reactions to the food.  
 
Documentation of objective signs observed during food challenge studies that are conducted in 
well-characterized allergic individuals, evaluated as part of a research protocol or clinical 
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evaluation, are also useful.  However, these studies may provide less robust evidence of the 
severity of an IgE-mediated food allergic reaction in allergic individuals than real-life allergen 
exposures because such food challenge studies generally are conducted in a step wise manner to 
enhance subject safety.  As such, most challenges are conducted with a slow escalation of food 
allergen exposure and terminated at the first sign of an objective reaction prior to elicitation of 
severe allergic reactions in most participants (Ref. 1 and Ref. 2).  Thus, food challenge studies 
may not capture the total magnitude of potential severe reactions from exposure to the food 
allergen.  
 
Evidence of the severity of an IgE-mediated food allergic reaction can be collected from 
community reports.  The quality of the evidence depends on the type of signs or symptoms and 
the individuals reporting the signs or symptoms.  For example, as shown in Table 6 in section 
V.C.2, the quality of the evidence is greater when: 
 
  The community reports are from well-characterized allergic individuals; 
  The reported reactions are objective (i.e., signs such as hives, swelling, and wheezing 
that are visible to an observer) rather than subjective (i.e., symptoms such as tingling 
and chest tightness that are not visible to an observer); and 
  The reported signs or symptoms are typical of allergic reactions. 
 
In 2004, FALCPA discussed the severity of eight major food allergens collectively, stating that 
roughly 30,000 individuals require emergency room treatment each year and 150 individuals die 
each year because of allergic reactions to food.  To assess more current markers of severity for 
major food allergens, we reviewed published scientific literature that identified some objective 
measures on number or frequency of severe IgE-mediated food allergic reactions reported in 
U.S. children or adults with probable food allergy to individual already identified major food 
allergens, including sesame (Ref. 33 and Ref. 34).  See Table 4 for the severity information that 
we extracted from this published scientific literature.  
 
Table 4. Objective measures of severity of IgE-mediated food allergic reactions in US 
children (ages 0-17) or adults (age 18+) with probable food allergy to individual already 
identified major food allergens 
Children or  Milk  Soy  Peanut  Tree  Fish  Shellfish  Egg  Wheat  Sesame 
adults with  Nuts  (effective 
probable food  1/1/23) 
allergy 
% of children  25.3  36.8  59.2  56.1  49.0  48.7  28.1  36.7  27.2 
reported to have 
severe food 
allergy (Ref. 
33) 
% of children  47.1  53.5  50.4  49.4  69.8  54.9  56.4  43.7  58.2 
reported to have 
ER* visits- 
lifetime 
 (Ref. 33) 
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Children or  Milk  Soy  Peanut  Tree  Fish  Shellfish  Egg  Wheat  Sesame 
adults with  Nuts  (effective 
probable food  1/1/23) 
allergy 
% of adults  39.3  45.4  67.8  61.3  56.5  56.8  39.4  42.6  39.7 
reporting severe 
reactions 
 (Ref. 34) 
% of adults  47.0  48.3  62.3  54.3  60.1  45.3  55.0  43.6  66.2 
reporting ER 
visits- lifetime 
(Ref. 34) 
* ER = emergency room 
 
D. Allergenic Potency  
 
All food allergens that cause IgE-mediated food allergy have the potential to cause anaphylaxis 
or other severe health consequences if the food allergen is consumed (Ref. 1 and Ref. 2).  
Allergenic potency is the amount of food allergenic protein required to elicit an Ig-E mediated 
food allergic reaction in a sensitized individual (Ref. 26).   
 
Allergenic potency can vary between individuals and foods.  An example of a measure of 
allergenic potency of a food allergen is the lowest amount (or threshold) of a food allergen 
required to cause an IgE-mediated food allergic reaction.  This can be measured at an individual 
or population level.24  Evidence regarding the potency of a food allergen can be collected from 
studies conducted in a large number of allergic individuals; it also can be collected from case or 
community reports.  As with evidence regarding the severity of an IgE-mediated food allergic 
reaction, evidence regarding the potency of a food allergen generally is more robust when it is 
collected from studies, in which a trained health care professional reports or describes, and 
documents, information (rather than from community reports, in which information is self-
reported).  
 
One useful endpoint for assessing the allergenic potency of an individual food is the frequency 
dose-response  i.e., the population distribution of doses eliciting or provoking an IgE-mediated 
food allergic reaction (Ref. 26).  The most robust measure to determine frequency dose-response 
is data collected from graded food challenge studies conducted over a wide range of doses in a 
large number of well-characterized allergic individuals.25  In such studies, the amount of food 
allergen (in grams of protein) is measured prior to consumption and given in escalating doses 
 
24 This threshold measure of allergenic potency can help provide information about the potential for any incidental 
exposure to food to cause an allergic reaction in an individual or in a population of individuals (Ref. 26 and Ref. 27).   
25 The ED information obtained from these studies is similar to the lowest observed adverse effect level (LOAEL) 
obtained from toxicological studies (Ref. 3). 
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until a food allergic reaction is observed.26,27  The challenge dose associated with the observed 
reaction is called the eliciting dose (ED) and this dose represents the relative potency of the food 
allergen for that given individual.  Distributions of individual ED information can be modeled to 
generate probabilities of reactions at a given ED within the population of challenge subjects.  For 
example, international efforts, by organizations such as the Allergen Bureau of Australia & New 
Zealand, have applied quantitative risk modeling approaches to studies of threshold28 EDs to 
food(s) from different food challenge study datasets to determine population ED distributions for 
different food(s) (Ref. 38 and Ref. 39).  From these ED distributions, probabilistic information 
on what EDs could cause a reaction in a given percentage of food allergic individuals within the 
population can be estimated.  For example, dose potencies can be estimated from EDs predicted 
to produce an IgE-mediated food allergic reaction in 1 percent, 5 percent, or 10 percent of the 
allergic population (referred to as the ED01, ED05, or ED10, respectively).  Also, a measure of 
mean dose potency could then be the ED predicted to produce an IgE-mediated food allergic 
reaction in 50 percent of a specific allergic population (referred to as the ED50).  This mean 
potency provides a robust statistical estimate to compare potencies between different food 
allergens (Ref. 27).  
 
Another endpoint for assessing allergenic potency is the severity doseresponse  i.e., the 
gradient of severity of IgE-mediated food allergic reactions caused by the food.  The probability 
of a severe IgE-mediated food allergic reaction from a relatively small amount of a food allergen 
is greater when the severity dose-response ratio is high (i.e., the food allergen has a high 
probability of severe IgE-mediated food allergic reactions from low dose exposures)29 (Ref. 26). 
 
Currently, at the individual level, the most robust measure of allergenic potency is ED 
information obtained from a graded food challenge study.  However, individual allergenic dose 
potency information can also be obtained through evaluation of case or community reports when 
the allergen dose exposure can be estimated from quantitative information about both the amount 
of food product likely consumed during a reaction and the concentration30 of food allergen in 
that food product.  Quantitative information about both the amount of food product consumed 
(e.g., in grams or ounces of food product) and the concentration of food allergen in that food 
product (e.g., parts per million (ppm)) can distinguish between circumstances in which an IgE-
mediated food allergic reaction associated with a relatively small amount of food product is due 
 
26 The DBPCFC is considered to be the best format for an oral challenge, but single blinded or open challenges 
could also be appropriate depending on the nature of the product and the food allergic population (e.g., infants). 
27 See Guidance for Industry: Food Allergen Labeling Exemption Petitions and Notifications (Ref. 16) for details 
regarding our recommendations for relevant clinical information to be assessed from challenge study data.  The 
recommended clinical information includes specifying the number of individuals enrolled and challenged in each 
study, obtaining clinical information for each individual challenged (such as age, gender, nationality/race, skin prick 
test or food-specific IgE levels, history of food allergic disease (e.g., frequency and severity of prior reactions), co-
morbidities, and assessing information on elicited symptoms to understand potential dose-response severity. 
28 The threshold ED in this case is the challenge dose interval between the highest challenge dose not to elicit an 
objective reaction/symptom, i.e., no observed adverse effect level (NOAEL), and the ED or LOAEL, i.e., lowest 
challenge dose to elicit an objective reaction (Ref. 4 and Ref. 5). 
29 Obtaining reliable severity dose-response data from food challenges may be difficult because food challenges are 
often terminated before severe or anaphylactic responses are elicited. 
30 The concentration could be obtained from the manufacturer of the food product or determined by analysis.  When 
the concentration is known, the allergen dose exposure can be calculated by multiplying the amount of food product 
reported to be consumed by the concentration of allergen in that food product. 
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to high allergenic dose potency (when the concentration of food allergen in that small amount of 
food product is relatively low) or is due to a high concentration of the food allergen in that food 
product.  In contrast, qualitative information about the amount of food product consumed (e.g., a 
single bite) without any quantitative information about the concentration of food allergen in that 
food product provides less robust information on allergenic dose potency, because it cannot 
distinguish between circumstances in which an IgE-mediated food allergic reaction associated 
with a relatively small amount of food product is due to high allergenic dose potency or is due to 
a high concentration of the food allergen in that food product. 
 
Data from animal or in vitro/ex vivo models of IgE-mediated food allergy can provide 
information relevant to determining allergenic potency, but generally are considered supporting 
data that are used in combination with  not instead of  human data.  
 
FALCPA did not discuss measures of allergenic potency, which were not generally available in 
2004.  See Table 5 for allergenic potency information for the already identified major food 
allergens based on more recent published scientific literature (Ref. 8 and Ref. 40).  
 
Table 5. Potency reported in the scientific literature for the already identified major food 
allergens  
Measure  Milk  Soy  Peanut  Tree Nuts  Fish  Shellfish  Egg  Wheat  Sesame 
of  (effective 
Potency  1/1/23) 
ED01  0.3  0.7  0.7   0.2  1.3  30.8  0.2  1.1  0.2 
(mg  (shrimp) 
(hazelnut) 
protein)* 
 0.04 
(Ref. 8) 
(walnut) 
ED50  192  2858  236   728  793  18867  134  279  443 
(mg  (shrimp) 
(hazelnut) 
protein)*
 360 
* (Ref. 
(walnut) 
40)  
* ED01 represents the cumulative eliciting dose predicted to produce an IgE-mediated food allergic reaction in 1 
percent of a specific allergic population.  
**ED50 represents the cumulative eliciting dose predicted to produce an IgE-mediated food allergic reaction in 50 
percent of a specific allergic population. 
 
V.  Identifying and Systematically Evaluating the Body of 
Evidence Applicable to Our Scientific Factors  
 
In this guidance, we focus on the identification and evaluation of historical information  i.e., 
generally available information (e.g., in published scientific literature and in community reports), 
because in most circumstances we expect that such historical information will be the principal 
information that FDA staff or applicable stakeholders will consider when evaluating when 
whether a food allergen is of public health importance.  (See the definition of historical 
information in Table 1.)  However, we do not intend this focus on historical information to 
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preclude FDA staff or applicable stakeholders from conducting new studies or otherwise 
obtaining information that does not satisfy the definition of historical information.  
 
A. Preliminary Identification of Published Scientific Literature 
 
FDA staff and applicable stakeholders should conduct a preliminary identification of published 
scientific literature applicable to our scientific factors through a systematic identification of 
published abstracts of available English language scientific literature.  Applicable scientific 
literature includes published studies (such as clinical, animal, in vitro, and ex vivo studies) as 
well as publicly available scientific information provided by reputable national and international 
organizations.31  
 
Examples of key words to use during searches are allergy, IgE and IgE-mediated, natural history, 
prevention, treatment/desensitization, prevalence, potency, threshold/eliciting dose, dose 
response, anaphylaxis, severity, cross-reactivity, adverse reactions or events, food analytical 
surveys, consumer studies, and quality of life.  
 
B. Preliminary Identification of Community Reports in Surveillance 
Databases and Other Sources 
 
FDA staff and applicable stakeholders should conduct a preliminary identification of community 
reports that are not in the published scientific literature by conducting a systematic review of: 
 
   Publicly available surveillance databases32 (such as the CFSAN Adverse Event 
Reporting System (CAERS)) for: 
  Adverse event reports regarding food products that disclose the presence of the 
o
food allergen; and 
  Product complaints about food products that do not disclose the presence of the 
o
food allergen; and 
  Other sources describing community reports, such as an FDA request for data and 
other information and information submitted to the docket established at 
https://www.regulations.gov for such a request.  
 
   
 
31 An example of such an organization is the World Health Organization and International Union of Immunological 
Societies (WHO/IUIS) Allergen Nomenclature Sub-committee (Ref. 30). 
32 FDA staff could also access information in agency databases that are not publicly available.  For example, if FDA 
found consumer complaints in a non-public agency database, we could consider that information and, as appropriate, 
place redacted information into the administrative record of the rulemaking.  Examples of relevant information 
sources are ORADDS (Office of Regulatory Affairs Reporting, Analysis, and Decision Support System) and RES 
(FDA Recall Enterprise System). 
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C. Systematic Evaluation of Published Scientific Literature and 
Community Reports  
 
1.  Narrowing the identified body of published scientific literature 
 
FDA staff and applicable stakeholders should narrow the identified body of published scientific 
literature to those most likely to be relevant to our scientific factors before conducting a 
substantive review of the full text of the identified publications.  One example of an approach to 
doing so is to systematically review and classify the scientific abstracts identified during the 
published scientific literature review as to their likely significance  e.g., as critical, 
supplemental, or neither critical nor supplemental as follows: 
 
  Examples of Scientific Abstracts that Could Be Classified as Critical 
  Human data; 
o
  Exposure: oral, sublingual; 
o
  Study identifies and characterizes food allergenic proteins and/or food allergic 
o
individuals; 
  Original research or systematic reviews, controlled trials, experimental studies, 
o
descriptive studies (comparative, correlation, or case-controlled studies), expert 
committee reports, or opinions or clinical experience of respected authorities, 
laboratory-based studies, case reports; and 
  Study purpose relevant to incidence/prevalence/natural history; food challenge- 
o
diagnosis, threshold; treatment/management/prevention of food-induced 
anaphylaxis and other acute IgE-mediated food allergic reactions; analytical 
product surveys and/or label reviews; consumer avoidance practice surveys; 
quality of life 
  Examples of Scientific Abstracts that Could Be Classified as Supplemental 
  Experimental animal data (through oral challenge route);  
o
  In vitro or ex vivo studies of dose response to food;  
o
  Non-oral route of exposure: skin, inhalation, or other non-oral route; and 
o
  Non IgE-mediated reactions to the food33  
o
  Neither critical nor supplemental  articles cannot be classified as either critical or 
supplemental.  
 
Following such a classification, a more thorough review could focus on those scientific 
publications classified as critical, extend to review of scientific publications classified as 
supplemental as necessary and appropriate (e.g., if there are insufficient data and information 
available in scientific publications classified as critical), and exclude scientific publications 
classified as neither critical nor supplemental.  
 
 
33 Non-IgE-mediated reactions to food allergens may be captured in probable food allergy rates and other 
community report data. 
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Another example of an approach to narrowing the identified body of published scientific 
literature to those most likely to be relevant to our scientific factors is to focus the substantive 
review on those scientific publications that could be scored High using a GRADE system 
(such as that shown in Table 6 in section V.C.2) if such publications applicable to our scientific 
factors are available. 
 
2.  Systematic evaluation of the strength of the identified evidence 
 
FDA staff and applicable stakeholders should grade each piece of the identified body of evidence 
based on a strength of evidence GRADE system.  See Table 6 for an example of such a GRADE 
system.  We developed and modified the GRADE system in Table 6 from the published 
scientific literature (Ref. 28 and Ref. 29).  We generally intend to use the GRADE system shown 
in Table 6 when we evaluate the strength of the identified scientific evidence. 
  
Table 6. GRADE system for scoring the strength of the evidence applicable to each 
scientific factor (developed and modified from Ref. 28 and Ref. 29) 
If the factor is ...  And the type of scientific evidence is ...  Then the strength of 
the evidence is ... 
Evidence of IgE- Historical information of positive DBPCFC  High (gold standard) 
mediated food allergy  in a population of documented sensitized 
individuals  
Evidence of IgE- Independent recognition of well- High  
mediated food allergy  characterized proteins from the food as 
clinically relevant food allergens by 
reputable national and international 
organizations 
Evidence of IgE- Historical information of typical,  High  
mediated food allergy  reproducible, and temporally-related signs or 
symptoms of IgE-mediated food allergic 
reactions in documented sensitized 
individuals  
Evidence of IgE- Historical information of typical,  Medium 
mediated food allergy  reproducible, and temporally-related signs or 
symptoms of food allergic reactions in self-
reported sensitized individuals  
Evidence of IgE- Historical information of typical,  Low 
mediated food allergy  reproducible, and temporally-related signs or 
symptoms of IgE-mediated food allergic 
reactions in individuals who are not 
sensitized and/or whose sensitization status 
is not reported  
Evidence of IgE- Historical information in documented or self- Low 
mediated food allergy  reported sensitized individuals who do not 
present typical, reproducible, and 
temporally-related signs or symptoms of 
IgE-mediated food allergic reactions 
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If the factor is ...  And the type of scientific evidence is ...  Then the strength of 
the evidence is ... 
Evidence of IgE- Elimination diets leading to resolution of  Low 
mediated food allergy  chronic signs or symptoms (e.g., eczema, 
gastrointestinal disturbances) in documented 
or self-reported sensitized individuals who 
do not present typical, reproducible, and 
temporally-related signs or symptoms of 
IgE-mediated food allergic reactions 
Evidence of IgE- Historical information regarding clinically  Low 
mediated food allergy  cross-reactive food allergies to the food in 
individuals sensitized to other cross-reactive 
foods  
Prevalence  Epidemiological studies in U.S. general  High 
population of prevalence rate estimates in 
well-characterized allergic individuals 
Prevalence  Epidemiological studies in the U.S. general  High to medium 
population to determine probable food 
allergy rate in self-reported allergic 
individuals based on the responses to 
questionnaires that ask about foods that elicit 
an allergic reaction, signs or symptoms of the 
allergic reaction(s), treatment or doctor visit, 
diagnostic tools, and doctor diagnosis 
Prevalence  Epidemiological studies in the U.S. general  Medium 
population to determine probable food 
allergy rate in self-reported reactive 
individuals based on the responses to 
questionnaires that only ask about foods that 
elicit an allergic reaction (without also 
asking for information on signs or 
symptoms, treatment or doctor visit, 
diagnostic tools, and doctor diagnosis)  
Prevalence  Epidemiological studies that look for  Medium  
evidence of IgE sensitization in the U.S. 
general population  
Prevalence  Prevalence data based on sensitization rates  Medium to low 
or other clinical parameters from populations 
outside the United States 
Prevalence  Prevalence data based on sensitization rates  Low 
or other clinical parameters from local or 
regional U.S. populations (e.g., academic 
clinical center patient populations, 
individuals presenting to local or regional 
hospital systems)  
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If the factor is ...  And the type of scientific evidence is ...  Then the strength of 
the evidence is ... 
Prevalence  Surveys based on retrospective review of  Low  
patient medical records with diagnosis codes 
related to food allergy 
Prevalence  Surveys based on review of frequency of  Low 
food allergic reactions in community reports 
from surveillance databases 
Severity  Objective signs, in well-characterized  High 
allergic individuals evaluated in a clinical 
setting (e.g., clinic, hospital), classified 
according to scientifically accepted 
classification system, and treated 
Severity  Documented report of fatality after exposure  High to medium 
to a food allergen 
Severity  Objective signs, in well-characterized  Medium 
allergic individuals, elicited by food 
challenge study 
Severity  Objective signs, typical of allergic reactions,  Medium  
reported in community reports from self-
reported or well-characterized allergic 
individuals  
Severity  Atypical and/or poorly-described objective  Low 
signs reported in community reports by self-
reported or well-characterized allergic 
individuals  
Severity  Subjective symptoms elicited by food  Low 
challenge study in self-reported or well-
characterized allergic individuals 
Potency  Graded food challenge studies with a wide  High 
range of doses to determine threshold EDs in 
adequate numbers of randomly selected well-
characterized allergic individuals 
Potency  Quantitative risk modeling of threshold EDs  High 
to food(s) from different challenge datasets 
to determine the distribution of EDs to 
food(s) in a population(s) of well-
characterized allergic individuals  
Potency  Case or community reports describing  Medium 
reactions to quantitatively estimated doses 
(amounts) of allergen in self-reported or 
well-characterized allergic individuals 
Potency  Case or community reports describing  Low 
reactions to qualitatively estimated doses 
(amounts) of allergen in self-reported or 
well-characterized allergic individuals 
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3.  Systematic evaluation of community reports 
 
FDA staff and applicable stakeholders should group the information based on the type of 
community report (e.g., individual patient case study; diagnostic food allergy study; adverse 
event report; product complaint) before systematically evaluating the information in each 
community report, because the information in a community report, and the quality of such 
information, can vary depending on the type of community report.  For example, solicited 
information obtained from a standardized questionnaire, information collected by objective 
observations, and information obtained by systematic review of reactions or reaction history by 
trained health care professionals are more likely to provide sufficient details to be analyzed than 
unsolicited information or information that is solicited without using a standardized 
questionnaire.  
 
As applicable to the type of community report and the information it contains, FDA staff and 
applicable stakeholders should identify the following information in each report for systematic 
evaluation:  
  Type of report (e.g., individual patient case study; diagnostic food allergy study; 
adverse event report; product complaint);  
  Detailed information about the reporters food allergies (e.g., type and number of 
food allergies, how diagnosed and whether there is documented evidence of food-
specific IgE sensitization and documented history of IgE-mediated food allergic 
reactions);  
  Consumer demographics and other pertinent clinical history (e.g., allergic conditions, 
such as eczema, asthma, allergic rhinitis, chronic urticaria, drug allergy or nonallergic 
medical conditions and medication use); name and type of product and whether the 
food allergen and its food allergen source were disclosed;  
  Detailed signs or symptoms (with emphasis on the severity of reaction);  
  Adverse health consequences (e.g., medication use or medical visit (including 
hospitalization));  
  Estimated amount of food product consumed; 
  Estimated concentration or amount (ideally in grams of food protein) of food allergen 
in food product consumed;  
  Photos of, or other evidence pertaining to, product labels or complaint information; 
and 
  Other relevant information from the report narrative. 
 
When systematically evaluating community reports classified as adverse event reports or product 
complaints, FDA staff and applicable stakeholders should also identify the following 
information: 
 
  Number of adverse event reports and product complaints regarding a food allergen 
that is:  
  Disclosed on the label of food products; and 
o
  Not disclosed on the label of food products; 
o
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  Frequency of severe adverse reactions reported to the food allergen that is: 
  Disclosed on the label of food products; and 
o
  Not disclosed on the label of food products; 
o
  The potential or suspected cause of an adverse event report or product complaint  
e.g.: 
  The label is incomplete or incorrect; 
o
  The food allergen source of a declared ingredient is not identified;  
o
  A spice, flavor, or color is declared using a collective term (e.g., spice, natural 
o
flavor, artificial flavor, or color) in the ingredient list;  
  The food allergen source is a clinically cross-reactive allergen (e.g., if a consumer 
o
who is allergic to peanuts eats a product containing lupin); or 
  A food allergen appears to have been unintentionally incorporated into a food 
o
during its manufacture (e.g., because a consumer who is allergic to a particular 
food allergen reports a food allergic reaction to a product that does not contain 
that particular food allergen as an ingredient). 
 
4.  Systematic evaluation of the severity of an IgE-mediated food allergic 
reaction  
 
FDA staff and applicable stakeholders should evaluate the severity of an IgE-mediated food 
allergic reaction described in the identified scientific evidence using a GRADE system.  See 
Table 7 for an example of such a GRADE system.34  The GRADE system in Table 7 is adapted 
from the GRADE system published in Ref. 36, with some modifications to signs or symptoms 
that could be classified as mild, moderate, or severe based on other GRADE systems (Ref. 37) 
and to classify the severity of an IgE-mediated food allergic reaction based on actual adverse 
health consequences or interventions (e.g., medication use, hospitalization) that may be found in 
adverse event data or reports.  
 
In evaluating severity of IgE-mediated food allergic reactions, FDA staff and applicable 
stakeholders also should consider available patient-centered information such as data from 
quality-of-life studies or questionnaires.  Although not part of the systematic grading of severity 
of an IgE-mediated food allergic reaction, such information addresses other health factors or 
potential comorbidities associated with allergy to the food such as patients experiences and 
perspectives about IgE-mediated food allergic reactions and allergen avoidance practices that 
may negatively impact the quality of life and psychosocial wellbeing of these individuals and 
their caregivers (Ref. 2). 
 
 
34 We generally intend to use the GRADE system shown in Table 7 when we evaluate the severity of an IgE-
mediated food allergic reaction described in the identified scientific evidence. 
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Table 7. GRADE system for scoring severity of an IgE-mediated food allergic reaction 
(adapted from Ref. 36 and Ref. 37) 
Grade  Objective signs or subjective symptoms within a  Objective signs or subjective 
single organ system  symptoms within multiple organ 
systems  
Mild   Skin (not generalized): eczema, erythema, flushing,  Not applicable; when signs or 
  symptoms appear in multiple 
pruritis, urticaria (hives), conjunctivitis, 
  organ systems, the signs or 
nonlaryngeal angioedema (e.g., lip swelling) 
  symptoms are considered either 
 Gastrointestinal (GI): OAS (oral allergy syndrome), 
  moderate or severe 
nausea alone, colic 
 
 Upper respiratory: rhinitis, nasal congestion, 
 
sneezing 
Moderate   Skin: generalized urticaria (hives), facial swelling  Combination of signs or symptoms 
in any two of the following organ 
 GI: abdominal pain, diarrhea, vomiting, cramps 
systems of mild/moderate grade: 
 Upper or mild lower respiratory: dyspnea, cough, 
chest or throat tightness   Skin; 
 Cardiovascular/neurologic (mild): tachycardia,   GI;  
dizziness, near syncope, tiredness/lethargy   Upper respiratory;  
 Reaction requiring emergency medical visit (no   Mild lower respiratory; or 
epinephrine) or loss of school/work activity   Cardiovascular/neurologic 
Severe   Lower respiratory: asthma, bronchoconstriction   Any combination of severe grade 
(drop in peak flow), wheezing, stridor, hoarseness,  signs or symptoms; or  
laryngeal edema (or throat closing)   Any combination of signs or 
 Cardiovascular/neurologic: arrhythmia, shock, fall  symptoms in three or more organ 
systems of mild/moderate grade 
in blood pressure, hypotension, cyanosis 
 Anaphylaxis, collapse 
 Reaction requiring epinephrine treatment 
 Reaction requiring hospitalization  
 Death 
 
VI.  FDAs Evaluation of the Public Health Importance of a Non-
Listed Food Allergen 
 
In this section, we describe FDAs evaluation of the identified body of evidence applicable to our 
scientific factors, FDAs evaluation of information relevant to the labeling and production of 
food containing a food allergen, and how we intend to consider the total body of evidence. 
 
A. FDAs Evaluation of the Identified Body of Evidence Applicable to Our 
Scientific Factors 
 
Sections VI.A.1 through VI.A.4 describe how we generally intend to weigh the evidence for each 
scientific factor.  We generally intend this evaluation to be a case-by-case approach (Ref. 27) 
based on a robust identified body of evidence  i.e., an identified body of evidence that receives 
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a GRADE of High or Medium using the GRADE system described in Table 6.  Therefore, it is 
unlikely that we would consider that a food or a component of food is a food allergen of public 
health importance if most or all of the available data and information have a GRADE of Low.  
 
1.  Factor #1: Evidence of IgE-mediated food allergy 
 
As discussed in section III.A, this document addresses the food allergies that have been most 
studied and understood clinically  i.e., IgE-mediated food allergies.  Therefore, the initial 
question for us to address when we evaluate the public health importance of a food or component 
of food as a food allergen is whether there is robust evidence that an adverse reaction to the food 
or component of food is IgE-mediated (Factor #1).  We generally expect to GRADE data 
addressing this initial question as High or Medium if the data provides evidence of a two-
step immune process  i.e., both sensitization and reactivity.  We generally do not expect to 
continue to evaluate the identified body of evidence applicable to Factors #2, #3, and #4 if the 
identified body of evidence applicable to Factor #1 does not provide robust evidence that an 
adverse reaction to a food or component of food is IgE-mediated.  
 
As discussed in section IV.A, the gold standard method for obtaining evidence demonstrating 
that an adverse reaction to a food or component of food is IgE-mediated is DBPCFC in a 
population of documented sensitized individuals.  We recommend that any request for us to 
evaluate a food or component of food as a food allergen of public health importance include data 
from a DBPCFC in a population of documented sensitized individuals whenever possible.  We 
generally intend to GRADE such data as High (see Table 6).  FDA staff and applicable 
stakeholders should determine whether one or more proteins that are present in a food have been 
included in a consensus database of well-characterized allergenic proteins, such as the one 
maintained by the WHO/IUIS allergen nomenclature Sub-committee (Ref. 30).  We generally 
intend to consider evidence obtained from DBPCFC in a population of documented sensitized 
individuals and evidence of one or more well-characterized allergenic proteins from a food, 
alone or in combination, as the most robust evidence supporting the initial question of whether 
an adverse reaction to a food or component of food is IgE-mediated.  
 
If data from a DBPCFC in a population of documented sensitized individuals are not available, 
we generally intend to evaluate, on a case-by-case basis, whether other data and information that 
can be GRADED as High or Medium, alone or in combination, provide robust evidence that 
an adverse reaction to a food or component of food is IgE-mediated.  For example: 
 
  We generally intend to GRADE as High historical information of typical, 
reproducible, and temporally-related signs or symptoms of IgE-mediated food allergic 
reactions in documented sensitized individuals (see Table 6).  Data obtained from 
documented sensitized individuals can reduce the potential for reported signs or 
symptoms of IgE-mediated food allergic reactions to be due to confounders such as 
an intolerance that might be associated with the food.  
  We generally intend to grade as Medium historical information of typical, 
reproducible, and temporally-related signs or symptoms of IgE-mediated food allergic 
reactions in self-reported sensitized individuals.  Because IgE sensitization to the food 
is self-reported but not confirmed, data obtained from self-reported sensitized 
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individuals can be confounded by factors such as an intolerance that might be 
associated with the food. 
 
We generally intend to GRADE as Low historical information that fails to provide evidence of 
a two-step immune process  i.e., both sensitization and reactivity (see Table 6).  
 
2.  Factor #2: Prevalence of an IgE-mediated food allergy in the U.S. population 
 
We recommend that any request for us to evaluate a food or component of food as a food 
allergen of public health importance include prevalence data with a GRADE of High or 
Medium as shown in Table 6.  However, we recognize that there could be circumstances in 
which we will need to evaluate the public health importance of a food allergen with minimal 
prevalence information  e.g., if a food allergen that causes IgE-mediated reactions is newly 
introduced to the U.S. food supply and there has not been enough time to design and execute 
prevalence studies. 
 
As discussed in section IV.B, prevalence rate estimations for any IgE-mediated food allergy 
based on DBPCFC or other robust clinical parameters are difficult to obtain at the national level, 
and the NASEM report (Ref. 2) did not find U.S. prevalence rate estimations for any IgE-
mediated food allergy based on this type of information.  Therefore, we generally expect 
prevalence data to be based on epidemiological studies to determine probable food allergy rates 
using self-reported data from questionnaires (see Table 6). 
 
When evaluating epidemiological studies to estimate probable food allergy rates based on self-
reported responses to questionnaires, the quality of evidence and information solicited, collected, 
and analyzed can vary widely.  Thus, we generally intend to give greatest weight and GRADE 
(High) to studies using questionnaires that: 
 
  Solicit and analyze information such as signs or symptoms, treatment or doctor visits, 
diagnostic tools, and doctor diagnosis in addition to self-report of food allergy;  
  Are directed to a random, nationally representative population in the United States 
rather than to a targeted population (e.g., to persons identified by physicians as 
potentially allergic to a specific food allergen);  
  Ask reporters about all foods that cause a food allergic reaction (rather than prompt 
reporters about specific foods that cause a food allergic reaction); and 
  Are relatively recent (e.g., data obtained in the prior 10 years).  
 
We generally intend to GRADE as Medium epidemiological studies to estimate probable food 
allergy rates in reactive individuals based on the responses to questionnaires that only ask about 
foods that elicit an allergic reaction (without also asking for any information on signs or 
symptoms, treatment or doctor visit, diagnostic tools, and doctor diagnosis) or the responses to 
questionnaires that solicit incomplete information on signs or symptoms, treatment or doctor 
visits, diagnostic tools, doctor diagnosis, and/or other methodologies to more effectively 
characterize self-reported allergic individuals.  
 
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We generally intend to GRADE as Medium an epidemiological study in which researchers 
look for evidence of IgE sensitization in blood samples collected from the general population, 
recognizing that this type of study could overestimate the prevalence rate of a food allergen, 
because some of the sensitized individuals might not be allergic individuals.  See Table 6 for 
examples of historical information that we generally intend to GRADE as Low. 
 
As shown in Table 6, we generally intend to GRADE as Low: 
 
  Prevalence estimations based on sensitization rates or other clinical parameters from 
selected U.S. populations (e.g., clinical center patient populations, individuals 
presenting to local or regional hospital systems, or from other countries or 
geographical areas) because such data are not nationally representative of the U.S. 
population;  
  Surveys based on retrospective review of patient medical records with diagnosis 
codes related to food allergy, because such diagnosis codes are not always specific for 
IgE-mediated food allergy; and 
  Surveys based on review of frequency of IgE-mediated food allergic reactions in 
community reports from surveillance databases, because such reports usually do not 
contain sufficient information to understand the baseline frequency (or denominator) 
of allergy to the food in the population of reporters.  
 
3.  Factor #3: Severity of IgE-mediated food allergic reactions  
 
We recommend that any request for us to evaluate a food or component of food as a food 
allergen of public health importance include severity data with a GRADE of High or 
Medium as shown in Table 6.  
 
Any food allergen has potential to cause a wide range of clinical manifestations.  These 
manifestations can involve a single organ system or multiple organ systems and can range from 
relatively mild reactions (e.g., sneezing) to severe anaphylaxis reactions that can lead to loss of 
consciousness, asphyxiation, or shock and can require use of epinephrine or lead to 
hospitalization or death.  We generally intend to use the GRADE system shown in Table 7 when 
we evaluate: 
 
  The actual severity of the IgE-mediated food allergic reaction; and 
  The relative number and frequency of severe reactions. 
 
To evaluate the actual severity of reported reactions to the food allergen, we generally intend to 
give the greatest weight to the following types of data regarding allergic signs or symptoms: 
 
  Objective signs, in well-characterized allergic individuals, that are confirmed by a 
physician as IgE-mediated, classified according to scientifically accepted 
classification system, and treated;  
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  Documented reports of fatality35 after exposure to the food allergen; 
  Objective signs, in well-characterized allergic individuals, elicited by a food 
challenge study; and 
  Objective signs that are typical of allergic reactions and reported in community 
reports from well-characterized or self-reported allergic individuals. 
 
We generally intend to GRADE as Low atypical and/or poorly-described objective signs by 
self-reported or well-characterized allergic individuals in community reports, as well as 
subjective symptoms in self-reported or well-characterized allergic individuals elicited by food 
challenge study (see Table 6). 
 
In evaluating the relative number and frequency of severe reactions to the food allergen, we 
generally intend to give the greatest weight to evidence demonstrating that: 
 
  The food causes a high number or frequency of anaphylaxis or other severe IgE-
mediated food allergic reactions per allergic individual or per population of allergic 
individuals;  
  Reactions cause high frequency of comorbidity, including negative patient-centered 
impacts on quality of life; and  
  Reactions cause a high number or frequency of serious public health sequalae (e.g., 
hospital visits), including evidence of fatality.  
 
4.  Factor #4: Allergenic potency 
 
We recommend that any request for us to evaluate a food or component of food as a food 
allergen of public health importance include potency data with a GRADE of High or 
Medium as shown in Table 6.  However, we recognize that there could be circumstances in 
which there will be minimal potency information  e.g., if a food allergen that causes IgE-
mediated reactions has a relatively short consumption history and there has not been enough time 
to design and execute potency studies.36  
 
We generally intend to GRADE as High allergen potency data obtained from: (1) 
prospectively designed graded food challenge studies with a wide range of doses to determine 
threshold EDs in adequate numbers of randomly selected well-characterized allergic individuals; 
or (2) quantitative risk modeling studies of threshold EDs to food(s) in a population(s) of well-
characterized allergic individuals (see Table 6).  In evaluating such potency data, we generally 
intend to give the greatest weight to:  
 
 
35 We generally intend to GRADE a report of a fatality after exposure to the food allergen as High when the 
reported fatality occurred in a well-characterized allergic individual and as Medium when there is insufficient 
information to confirm that the fatality occurred in a well-characterized allergic individual (see Table 6).  
36 Challenge studies to evaluate the potency of a food allergen generally are conducted as part of a clinical research 
study, rather than as a part of the doctor diagnosis of food allergy for individual patients.  Thus, potency data are 
generally less available than data on prevalence and severity. 
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  Data that provide EDs causing reactions at the mean population level (ED50) and 
those causing reactions in the most sensitive populations (ED1, ED5, or ED10) to 
allow comparisons with major food allergens; and  
  Data allowing assessment of severity doseresponse relationship (e.g., gradient of 
severity of IgE-mediated food allergic reactions) at the individual or population 
levels; robust evidence may include information on the relative severity of IgE-
mediated food allergic reactions at different ED levels, which would enable us to 
identify foods with a high probability of severe reactions from low dose exposures.  
 
We generally intend to GRADE as Medium allergen potency data obtained from case or 
community reports describing reactions to quantitatively estimated doses (amounts) of food 
allergen, derived from information detailing the amount of food product likely consumed during 
a reaction multiplied by the known or analyzed concentration (e.g., ppm) of food allergen in that 
food product, in self-reported or well-characterized allergic individuals (see Table 6).  
 
We generally intend to GRADE as Low allergen potency data obtained from case or 
community reports describing reactions to qualitatively estimated doses (amounts) of allergen in 
self-reported or well-characterized allergic individuals (see Table 6). 
 
In evaluating the public health importance of a food allergen based on the identified body of 
evidence: 
 
  We generally intend to give the greatest weight to evidence that there is a high 
probability of severe reactions from low dose exposures, because the probability for 
adverse health consequences from inadvertently consuming these foods at relatively 
minor food use levels is greater.  
  We also will consider the extent to which processing of the food allergen (or of food 
containing the food allergen) is known to impact the potency of the food allergen 
(e.g., if foods containing the food allergen are commonly cooked and cooking the 
food allergen, or food containing the food allergen, reduces the frequency dose-
response or severity dose-response).  
 
B. FDAs Evaluation of Information Relevant to the Labeling and 
Production of Food Containing a Food Allergen  
 
When we determine it to be useful to evaluate whether a food allergen is of public health 
importance, we may seek or request data and other information relevant to the labeling and 
production of food containing the food allergen, similar to the data and other information we 
requested for sesame.  Examples of such data and other information are: 
 
  Data and other information relevant to the prevalence in the United States of IgE-
mediated food allergic reactions that could be attributed to exposure to the food 
allergen that is not disclosed on the label of food products; 
  Prevalence and amounts of the undisclosed food allergen in foods; 
  Characteristics of food products and food production practices; 
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  Data from patient-centered studies or other patient-centered information (e.g., food 
allergy quality-of-life questionnaires) regarding patients experiences, perspectives, 
needs, and priorities regarding avoidance of foods that are or contain food allergens; 
and  
  Data on clinically cross-reactive IgE-mediated food allergies to the food and, if 
relevant, whether potential cross-reactivity to the food allergen would not be well-
recognized in the U.S. allergic population. 
 
C. How FDA Intends to Consider the Total Body of Evidence  
 
We generally intend to consider whether a food allergen is of public health importance: 
 
  Only when there is robust evidence of IgE-mediated food allergy (Factor #1);  
  After considering the prevalence, severity, and potency of the food allergen (Factors 
#2, #3, and #4) on a case-by-case basis, because the number of permutations 
regarding scientific factors #2, #3, and #4 is quite large;37 and 
  When applicable, after considering additional data and information regarding: 
  The prevalence in the United States of IgE-mediated food allergic reactions that 
o
could be attributed to exposure to the food allergen that is not disclosed on the 
label of food products; 
  Prevalence and amounts of the food allergen in foods that is not disclosed on the 
o
label of food products;  
  Characteristics of food products and food production practices;  
o
  Patient-centered studies or other patient-centered information; and 
o
  Clinically cross-reactive IgE-mediated food allergies to the food and, if relevant, 
o
whether potential cross-reactivity to the food allergen would not be well-
recognized in the U.S. allergic population.  
 
VII.  Stakeholder Submission of a Citizen Petition  
 
Any interested stakeholder may submit a citizen petition submitted in accordance with 21 CFR 
10.30 asking us to evaluate the public health importance of a non-listed food allergen.  In a 
citizen petition, applicable stakeholders should identify and evaluate the body of evidence 
applicable to each of the scientific factors listed in section IV of this guidance document as 
described in section V of this guidance.  Applicable stakeholders also should provide other 
information, such as the information relevant to the labeling and production of food containing a 
food allergen as described in section VI.B of this guidance document, when such information is 
available and relevant to the food allergen. 
 
   
 
37 For example, the prevalence and potency of a food allergy could be high, low, or unknown, and the severity of an 
IgE-mediated food allergic reaction could be mild, moderate, or severe. 
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VIII. 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 the notice of 
availability for this document publishes in the Federal Register, but websites are subject to 
change over time. 
 
1.   Boyce JA, Assaad A, Burks AW, et al.  Guidelines for the diagnosis and management of 
food allergy in the United States: report of the NIAID-sponsored expert panel.  J Allergy 
Clin Immunol 2010;126(6 Suppl):S1-58. 
 
2.   National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; 
Food and Nutrition Board; Committee on Food Allergies.  Finding a Path to Safety in Food 
Allergy: Assessment of the Global Burden, Causes, Prevention, Management and Public 
Policy.   Washington, DC: The National Academies Press, 2016.  Available at 
https://www.ncbi.nlm.nih.gov/books/NBK435943/. 
 
3.   Food and Drug Administration Threshold Working Group.  Approaches to Establish 
Thresholds for Major Food Allergens and for Gluten in Food.  2006.  Available at 
https://www.fda.gov/media/78205/download.* 
 
4.   Taylor SL, Hefle SL, Bindslev-Jensen C, et al.  A consensus protocol for the determination 
of the threshold doses for allergenic foods: how much is too much?  Clin Exp Allergy 
2004;34:689-95. 
 
5.   Crevel RWR, Briggs D, Hefle SL, et al.  Hazard characterization n food allergen risk 
assessment: the application of statistical approaches and the use of clinical data.  Food 
Chem Toxicol 2007;45:691-701. 
 
6.   Bousquet J, Bjorksten B, Bruijnzeel-Koomen CA, et al.  Scientific criteria and the selection 
of allergenic foods for product labelling.  Allergy 1998;53(47 Suppl):3-21. 
 
7.   Hefle SL, Nordlee JA, Taylor SL.  Allergenic foods.  Crit Rev Food Sci Nutr. 1996;36 
Suppl:S69-89. 
 
8.   Remington BC, Westerhout J, Meima MY, et al.  Updated population minimal eliciting dose 
distributions for use in risk assessment of 14 priority food allergens.  Food Chem Toxicol. 
2020;139:111259. 
 
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9.   PALFORZIA.  Available at https://www.fda.gov/vaccines-blood-
biologics/allergenics/palforzia.* 
 
10. Package insert  PALFORZIA.  Available at https://www.fda.gov/media/134838/download.* 
 
11. Sicherer SH.  Clinical implications of cross-reactive food allergens.  J Allergy Clin 
Immunol. 2001;108(6):881-90. 
 
12. Food and Drug Administration, Consumer Advice on Lupin, 2018.  Available at 
https://www.fda.gov/food/food-additives-petitions/consumer-advice-lupin.* 
 
13. Verrill L, Bruns R, Luccioli S.  Prevalence of self-reported food allergy in U.S. adults: 
2001, 2006, and 2010.  Allergy Asthma Proc. 2015;36(6):458-67.  
 
14. Blom WM, Michelsen-Huisman AD, van Os-Medendorp H, et al.  Accidental food allergy 
reactions: Products and undeclared ingredients.  J Allergy Clin Immunol.  2018;142(3):865-
875. 
 
15. Food and Drug Administration.  Guidance for Industry: Questions and Answers Regarding 
Food Allergens, Including the Food Allergen Labeling and Consumer Protection Act of 2004 
(Edition 4).  October 2006.  Available at https://www.fda.gov/media/117410/download.* 
 
16. Food and Drug Administration.  Guidance for Industry: Food Allergen Labeling Exemption 
Petitions and Notifications.  June 2015.  Available at 
https://www.fda.gov/media/88332/download.*  
 
17. Food and Drug Administration.  Food Code 2017.  Available at 
https://www.fda.gov/media/110822/download.* 
 
18. Citizen Petition CP-2008-P-0509, received September 10, 2008, submitted by Hallie Jane 
Davis.  Available at https://www.regulations.gov, Docket No. FDA-2008-P-0509, Document 
ID FDA-2008-P-0509-0001.* 
 
19. Food and Drug Administration.  Compliance Policy Guide Sec. 555.250 Statement of Policy 
for Labeling and Preventing Cross-contact of Common Food Allergens.  November 2005.  
Available at https://www.fda.gov/media/71940/download.* 
 
20. Citizen Petition CP-2014-P-2035, dated November 18, 2014, submitted by Dr. Carla M. 
Davis et al.  Available at https://www.regulations.gov, Docket No. FDA-2014-P-2035, 
Document ID FDA-2014-P-2035-0001.*  
 
21. Citizen Petition CP-2015-P-3139, dated August 26, 2015, submitted by Kimberly Kideckel.  
Available at https://www.regulations.gov, Docket No. FDA-2015-P-3139, Document ID 
FDA-2015-P-3139-0001.* 
 
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22. Letter dated February 6, 2018, from Douglas Stearn of FDA to Hallie Jane Davis.  Available 
at https://www.regulations.gov, Docket No. FDA-2008-P-0509, Document ID FDA-2008-P-
0509-0007.* 
 
23. Letter dated April 4, 2019, from Douglas Balentine of FDA to Kimberly Kideckel.  Available 
at https://www.regulations.gov, Docket No. FDA-2015-P-3139, Document ID FDA-2015-P-
3139-0004.*  
 
24. Food and Drug Administration.  Voluntary Disclosure of Sesame as an Allergen: Guidance 
for Industry (Draft Guidance).  November 2020.  Available at 
https://www.fda.gov/media/143521/download.  
 
25. Joint Food and Agriculture Organization of the United Nations/World Health Organization 
Expert Committee on Food Additives.  Evaluation of certain food additives and 
contaminants: fifty-third report of the Joint FAO/WHO Expert Committee on Food 
Additives.  2000.  WHO Technical Report Series 896.  World Health Organization, Geneva.  
Available at https://apps.who.int/iris/handle/10665/42378. 
 
26. Bjorksten B, Crevel R, Hischenhuber C, et al.  Criteria for identifying allergenic foods of 
public health importance.  Regulatory Toxicology and Pharmacology 2008;51:42-52. 
 
27. Houben G, Burney P, Chan CH, et al.  Prioritisation of allergenic foods with respect to 
public health relevance: Report from an ILSI Europe Food Allergy Task Force Expert 
Group.  Food Chem Toxicol. 2016;89:8-18. 
 
28. van Bilsen JHM, Ronsmans S, Crevel RWR, et al.  Evaluation of scientific criteria for 
identifying allergenic foods of public health importance.  Regulatory Toxicology and 
Pharmacology 2011;60(3):281-289. 
 
29. Chung YJ, Ronsmans S, Crevel RWR, et al.  Application of scientific criteria to food 
allergens of public health importance.  Regulatory Toxicology and Pharmacology 
2012;64(2):315-23. 
 
30. World Health Organization and International Union of Immunological Societies Allergen 
Nomenclature Sub-committee.  Allergen Nomenclature.  Available at 
http://www.allergen.org. 
 
31. World Health Organization and International Union of Immunological Societies Allergen 
Nomenclature Sub-committee.  Submission of a new allergen to the WHO/IUIS allergen 
nomenclature database.  May 2017.  Available at http://allergen.org/submission.php. 
 
32. Liu AH, Jaramillo R, Sicherer SH, et al.  National prevalence and risk factors for food 
allergy and relationship to asthma: results from the National Health and Nutrition 
Examination Survey 2005-2006.  J Allergy Clin Immunol. 2010;126(4):798-806.e13.  
 
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33. Gupta RS, Warren CM, Smith BM et al.  The public health impact of parent-reported 
childhood food allergies in the United States.  Pediatrics. 2018;142(6):e20181235. 
 
34. Gupta RS, Warren CM, Smith BM, et al.  Prevalence and Severity of Food Allergies 
Among US Adults.  JAMA Netw Open. 2019;2(1):e185630. 
 
35. GRADE. Welcome to the GRADE Working Group.  Available at 
https://www.gradeworkinggroup.org/. 
 
36. Zhu J, Pouillot R, Kwegyir-Afful EK, et al.  A retrospective analysis of allergic reaction 
severities and minimal eliciting doses for peanut, milk, egg, and soy oral food challenges.  
Food Chem Toxicol. 2015;80:92-100. 
 
37. Sampson HA, van Wijk RG, Bindslev-Jensen C, et al.  Standardizing double-blind, placebo-
controlled oral food challenges: American Academy of Allergy, Asthma & Immunology-
European Academy of Allergy and Clinical Immunology PRACTALL consensus report.  J 
Allergy Clin Immunol. 2012;130(6):1260-74. 
 
38. Allen KJ, Remington BC, Baumert JL, et al.  Allergen reference doses for precautionary 
labeling (VITAL 2.0): clinical implications.  J Allergy Clin Immunol. 2014;133(1):156-64. 
 
39. Taylor SL, Baumert JL, Kruizinga AG, et al.  Establishment of Reference Doses for 
residues of allergenic foods: report of the VITAL Expert Panel.  Food Chem Toxicol. 
2014;63:9-17. 
 
40. Houben GF, Baumert JL, Blom WM, et al.  Full range of population Eliciting Dose values 
for 14 priority allergenic foods and recommendations for use in risk characterization.  Food 
Chem Toxicol. 2020;146:111831. 
 
41. Grabenhenrich LB, Dolle S, Moneret-Vautrin A, et al.  Anaphylaxis in children and 
adolescents: The European Anaphylaxis Registry.  J Allergy Clin Immunol. 
2016;137(4):1128-1137. 
 
42. Namork E, Fste CK, Stensby BA, et al.  Severe allergic reactions to food in Norway: a ten 
year survey of cases reported to the food allergy register.  Int J Environ Res Public Health 
2011;8(8):3144-55. 
 
43. Derby CJ, Gowland MH, Hourihane JO'B.  Sesame allergy in Britain: a questionnaire 
survey of members of the Anaphylaxis Campaign.  Pediat Allergy Immunol. 2005;16:171-
175. 
 
44. Codex Alimentarius Commission.  Report of the Forty-Fifth Session of the Codex 
Committee on Food Labelling.  2019.  Rep 19/FL.  Available at http://www.fao.org/fao-
who-codexalimentarius/sh-
proxy/en/?lnk=1&url=https%253A%252F%252Fworkspace.fao.org%252Fsites%252Fcodex
%252FMeetings%252FCX-714-45%252FFinal%252520Report%252FREP19_FLe.pdf. 
47 
  Contains Nonbinding Recommendations 
Draft-Not for Implementation 
 
45. Food and Agriculture Organization of the United Nations/World Health Organization.  
Summary report of the Ad hoc Joint FAO/WHO Expert Consultation on Risk Assessment of 
Food Allergens. Part 1: Review and validation of Codex priority allergen list through risk 
assessment.  2021.  Available at http://www.fao.org/3/cb4653en/cb4653en.pdf. 
 
46. Health Canada.  The Canadian Criteria for the Establishment of New Priority Food 
Allergens.  2010.  Available at https://www.hc-sc.gc.ca/fn-an/pubs/label-etiquet/crit/index-
eng.php. 
 
47. Food Standards Australia New Zealand.  Risk assessment  Proposal P1026: Lupin as an 
Allergen.  2017.  Available at 
https://www.foodstandards.govt.nz/code/proposals/Documents/P1026%20Lupin%20as%20a
n%20Allergen%20CFS%20SD1.pdf. 
 
IX.  Appendix A  Additional Considerations 
 
A. Community Reports Regarding Food Allergens 
 
For the purpose of this guidance, we use the term community report to mean a report, 
regarding a known or suspected food allergen in a food product, that is submitted to a 
surveillance database, a research query, or other request for information, or that is otherwise 
collected and described (e.g., as a patient case study or a diagnostic food challenge study 
reported in the scientific literature).  A community report can be submitted or prepared by 
consumers (i.e., be a self-report), health care professionals, industry, researchers, government 
agencies, non-government agencies, or other stakeholders.  Some community reports (such as 
adverse event reports and case studies) describe an allergic reaction experienced by an individual 
to a food product, whereas other community reports (usually called product complaints) call 
FDAs attention to a potential problem or concern (such as labeling that does not disclose a food 
product is or contains a food allergen).  
 
  Examples of surveillance databases are:  
  CAERS,38 which collects information on: 
o
  Adverse events regarding FDA-regulated products (such as an allergic 
reaction to a food product39); and 
  Product complaints regarding FDA-regulated products (such as complaints 
about products that do not appropriately declare a major food allergen as 
 
38 Information is submitted to CAERS through FDAs MedWatch system (https://www.fda.gov/safety/medwatch-
fda-safety-information-and-adverse-event-reporting-program) or to FDA regional offices. 
39 For example, consumers sometimes report an allergic reaction to a food product that contains an undeclared major 
food allergen that was not added to a food product as an ingredient, but is nonetheless present in the food product, 
possibly due to allergen cross-contact during production of the food product.  Consumers also sometimes report an 
allergic reaction to a food that is or contains a food allergen that is not a major food allergen.  
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required by the FD&C Act or that do not disclose the presence of a food 
allergen that is not a major food allergen40).  
  Anaphylaxis registries, such as the European Anaphylaxis Registry (Ref. 41) and 
o
the Norwegian Food Allergy Register (Ref. 42), which collects information on 
specifics of serious allergic reactions to foods occurring in patients who present to 
regional medical centers. 
  An example of a query is a questionnaire asking consumers to report allergies to a 
specific food or food product, or adverse events experienced with a specific food or 
food product (e.g., as part of systematic survey to understand prevalence or other 
scientific questions related to food allergy in a population of patients or consumers).  
For example, in 2005, researchers in the United Kingdom issued a questionnaire to 
400 persons who had reported allergic reactions to sesame (Ref. 43). 
  An example of another request for information is a public notice in which FDA 
invites data or other information regarding food allergies or allergic reactions (see, 
e.g., Sesame as an Allergen; Notice; Request for comments (Federal Register of 
October 30, 2018; 83 FR 54594)).41  
 
B. Codex Criteria for Evaluating the Public Health Importance of Food 
Allergens  
 
In 1999, the World Health Organization of the United Nations convened a Food Allergens 
Labelling Panel to provide guidance to a Joint Expert Committee on Food Additives (JECFA), 
which provides scientific recommendations to the Codex Alimentarius Commission (Codex) 
relating to food additives and ingredients in foods.  The Food Allergens Labelling Panel was 
asked to provide guidance on the following issues related to food allergies and intolerances:  
 
  Identifying criteria for adding substances to the Codex list of common allergenic 
foods, if found to be necessary; 
  Developing criteria for identifying products of foodstuffs on the Codex list for which 
labelling of the food source is not necessary; and  
  Considering ways in which FAO and WHO could provide guidance to JECFA on a 
continuing basis. 
 
In June 1999, Codex adopted a list of those foods or food products whose presence should 
always be declared in the list of ingredients on a food label, because of their allergenic properties 
(Ref. 25).  This list included: 
 
 
40 For example, some product complaints call our attention to food products that do not disclose the food allergen 
source of a food allergen that is not a major food allergen.  Other product complaints call our attention to food 
products that do not disclose a food allergen that is not a major food allergen as an ingredient because our food 
labeling regulations allow the food allergen to be declared with a collective term such as spice or flavoring. 
41 For example, the notice asked stakeholders to submit data and other information about prevalence of allergies and 
allergic reactions due to sesame in the United States directly to the docket established for the notice.  However, our 
communications about the notice also directed the public to submit individual adverse event reports due to sesame to 
CAERS rather than to the docket established for the notice. 
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  Cereals containing gluten42 and products of these; 
  Crustacea and products of these; 
  Egg and egg products; 
  Fish and fish products; 
  Peanuts, soybeans, and products of these; 
  Milk and milk products (lactose included); 
  Tree nuts and nut products; and 
  Sulfites in concentrations of 10 mg/kg or more. 
 
With respect to criteria for the addition of foodstuffs to the Codex list of common allergenic 
foods, the Food Allergens Labelling Panel recommended that the following criteria (the 1999 
Codex criteria) be applied: 
 
  The existence of a credible cause-and-effect relationship based upon positive double-
blind, placebo-controlled food challenge or unequivocal reports of reactions with 
typical features of severe food allergy or intolerance reactions. 
  There should be reports of severe systemic reactions following exposure to the 
foodstuff. 
  Whereas the Food Allergens Labelling Panel recognized the ideal criterion would be 
prevalence data in children and adults, supported by appropriate clinical studies, i.e., 
a double-blind, placebo-controlled food challenged from the general population of 
several countries, it noted that currently such information was only available for 
infants, in some countries, and for some foodstuffs.  Such information is rarely 
available for adults.  As an alternative, the Food Allergens Labelling Panel agreed 
that the use of such available data (e.g., comparative prevalence of the specific food 
allergy in groups of allergy patients from several countries backed up ideally by a 
double-blind, placebo-controlled food challenge) would be appropriate. 
 
In 2019, the Codex Committee on Food Labeling asked for FAO/WHO to convene an expert 
consultation to request from FAO/WHO scientific advice relating to the Codex list of common 
allergenic foods, including whether the published criteria for assessing additions and exclusions 
to the list is still current and appropriate and, subject to the advice from FAO/WHO on the 
criteria, whether there are foods and ingredients that should be added to or deleted from the list, 
clarification of the groupings of foods and ingredients in the list, and whether certain foods and 
ingredients, such as highly refined foods and ingredients, that are derived from the list of foods 
known to cause hypersensitivity can be exempted from mandatory declaration (Ref. 44).  
Starting in late November 2020, FAO/WHO held an expert consultation to address these 
 
42 FALCPA directed us to conduct rulemaking to define, and permit use of, the term gluten-free on the labeling 
of foods.  On August 5, 2013, FDA issued a final rule defining gluten-free for food labeling, which is intended to 
help consumers, especially those living with celiac disease, be confident that items labeled gluten-free meet a 
defined standard for gluten content (78 FR 47154).  Gluten-free is a voluntary claim that can be used by food 
manufacturers on food labels if they meet all the requirements of the regulations.  On August 13, 2020, FDA issued 
a final rule that establishes compliance requirements for the gluten-free labeling of fermented or hydrolyzed foods 
such as yogurt, sauerkraut, pickles, cheese, green olives, FDA-regulated beers and wines (e.g., generally those with 
less than 7 percent alcohol), and hydrolyzed plant proteins used to improve flavor or texture in processed foods such 
as soups, sauces, and seasonings (85 FR 49240).  
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questions.  In May 2021, FAO/WHO issued a summary report, which, among other things, 
identified prevalence of the immune-mediated hypersensitivity to a specific food, severity (i.e., 
proportion of severe objective reactions to a food/ingredient such an anaphylaxis), and the 
potency of food/ingredient (i.e., the amount of the food/ingredient required to cause objective 
signs) as the three key criteria that should be used to establish the priority allergen list (Ref. 45). 
 
C. Development of Other Examples of Criteria for Evaluating the Public 
Health Importance of Food Allergens  
 
Scientific reviews and opinion papers from research groups or organizations have suggested 
revisions to the 1999 Codex criteria.  For example, in 2008, the International Life Sciences 
Institute-Europe (ILSI-EU) recommended revising the 1999 Codex criteria (Ref. 26).  The ILSI-
EU revised criteria included clinical issues (diagnosis, potency of allergen, severity of 
reactions), population elements (prevalence, exposure), and modulating factors (food 
processing).  In addition to suggesting revised criteria, ILSI-EU also provided a framework for 
evaluating whether a food allergen other than those included in the 1999 Codex list of common 
allergenic foods warranted regulation (such as labeling requirements) by weighting the available 
data according to quality, using a ranking derived from evidence-based medicine (Ref. 26).  
ILSI-EU and others subsequently evaluated the application of the revised criteria (Ref. 28 and 
Ref. 29).  One publication concluded that the revised criteria were helpful in assessing known 
food allergens and excluding the food substances associated with non-IgE-mediated 
hypersensitivity reactions and that the framework for weighting the available data according to 
quality discriminated between publications that provided high, moderate, and low quality of 
evidence (Ref. 28).  The other publication concluded that the revised criteria presented a way 
forward for the identification of food allergens of public health importance and for prioritization 
of allergen risk management and future data gathering (Ref. 29).  Another publication applied a 
risk analysis cycle to food allergy and parameters for hazard scaling (Ref. 27).  
 
In addition, some national regulatory/public health agencies (e.g., Health Canada (Ref. 46) and 
Food Standards Australia New Zealand (Ref. 47)) have developed or described criteria or types 
of evidence required to establish new or priority food allergens of public health importance.  
These criteria have largely mirrored the 1999 Codex criteria.  
 
D. Report of the National Academies of Sciences, Engineering, and 
Medicine on Food Allergy 
 
In 2016, NASEM issued a report entitled Finding a Path to Safety in Food Allergy: Assessment 
of the Global Burden, Causes, Prevention, Management and Public Policy (Ref. 2).  One 
recommendation in the report was that ...public health authorities in individual countries decide 
on a periodic basis about which allergenic foods should be included in their priority lists based 
on scientific and clinical evidence of regional prevalence and severity of food allergies as well as 
allergen potency (Ref. 2).  The recommendations in the NASEM report focus on IgE-mediated 
food allergies, which have better defined underlying cellular mechanisms and physiological 
reactions. 
 
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