Contains Nonbinding Recommendations 
Food Allergen Labeling Exemption Petitions 
and Notifications: 
Guidance for Industry 
Additional copies are available from: 
Office of Food Additive Safety, HFS-205 
Center for Food Safety and Applied Nutrition 
Food and Drug Administration 
5001 Campus Drive
College Park, MD  20740
(Tel) 240-402-1200  
http://www.fda.gov/FoodGuidances
You may submit either electronic or written comments regarding this guidance at any time. 
Submit electronic comments to http://www.regulations.gov. Submit written comments on the 
guidance to the Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should 
be identified with the docket number listed in the notice of availability that publishes in the 
Federal Register.  
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Food Safety and Applied Nutrition 
June 2015 
Petitions and Notifications Guidance Page 1 of 18  Contains Nonbinding Recommendations 
 
 
Table of Contents  
 
 
 
I.   Introduction   
 
II.   Statutory Authority  
 
 
III. Recommendations for Preparing Submissions   
 
IV. Additional Information for Petitions  
 
V.  Additional Information for Notifications 
 
VI. Appendices 
 
 
 
 
 
Petitions and Notifications Guidance Page 2 of 18  Contains Nonbinding Recommendations 
 
 
Food Allergen Labeling Exemption Petitions 
and Notifications 
 
Guidance for Industry 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this topic.  It 
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.  
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance.  
 
 
 
I.  Introduction 
This document describes the data that FDAs Center for Food Safety and Applied Nutrition 
(CFSAN or we) will consider when evaluating petitions and notifications seeking exemptions 
from the labeling requirements of section 403(w)(1) of the Federal Food, Drug, and Cosmetic 
Act (the FD&C Act) regarding ingredients derived from major food allergens.   
This guidance is intended to address the relevant issues for most submitters1, but some 
recommendations may not be applicable in all cases.  If a recommendation does not appear to 
apply to a particular ingredient or use, the submitter should explain briefly why the scientific 
evidence recommended here is not needed for that ingredient or use.  We also encourage 
potential submitters to consult us before submission to discuss any questions or data needs.  
Information on allergen labeling requirements for conventional foods and dietary supplements 
can be found at 
http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/Aller
gens/default.htm.  
 
FDA's guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidance documents describe our current thinking on a topic and 
should be viewed only as recommendations unless specific regulatory or statutory requirements 
                                                 
1 We use the term submitters to mean any party who submits a petition or notification seeking an exemption from 
the labeling requirements for major food allergens. 
Petitions and Notifications Guidance Page 3 of 18  Contains Nonbinding Recommendations 
are cited. The use of the word should in FDA guidance means that something is suggested or 
recommended, but not required. 
II. Statutory Authority 
The Food Allergen Labeling and Consumer Protection Act of 2004 (FALCPA) (Title II of Public 
Law 108-282) amended the FD&C Act by defining the term major food allergen and stating 
that foods regulated under the FD&C Act are misbranded unless they declare the presence of 
each major food allergen on the product label using the common or usual name of that major 
food allergen.  Section 201(qq) of the FD&C Act (21 U.S.C. 321(qq)) now defines a major food 
allergen as [m]ilk, 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 
and also as a food ingredient that contains protein derived from these foods.  The definition 
excludes any highly refined oil derived from a major food allergen and any ingredient derived 
from such highly refined oil.  
  
In some cases, the production of an ingredient derived from a major food allergen may alter or 
eliminate the allergenic proteins in that derived ingredient to such an extent that it does not 
contain allergenic protein.  In addition, a major food allergen may be used as an ingredient or as 
a component of an ingredient such that the level of allergenic protein in finished food products 
does not cause an allergic response that poses a risk to human health.  Therefore, FALCPA 
provides two mechanisms through which such ingredients may become exempt from the labeling 
requirement of section 403(w)(1) of the FD&C Act.  An ingredient may obtain an exemption 
through submission and approval of a petition containing scientific evidence that demonstrates 
that the ingredient does not cause an allergic response that poses a risk to human health 
(section 403(w)(6) of the FD&C Act).  This section also states that the burden shall be on the 
petitioner to provide scientific evidence (including the analytical method used to produce the 
evidence) that demonstrates that such food ingredient, as derived by the method specified in the 
petition, does not cause an allergic response that poses a risk to human health.  Alternately, an 
ingredient may become exempt through submission of a notification containing scientific 
evidence showing that the ingredient does not contain allergenic protein or that there has been 
a previous determination through a premarket approval process under section 409 of the FD&C 
Act that the ingredient does not cause an allergic response that poses a risk to human health 
(section 403(w)(7) of the FD&C Act).  
 
To evaluate these petitions and notifications, we will consider scientific evidence that describes- 
 
  1.  The identity or composition of the ingredient; 
  2.  The methods used to produce the ingredient; 
  3.  The methods used to characterize the ingredient; 
  4.  The intended use of the ingredient in food; and 
5a. For a petition, data and information, including the expected level of consumer 
exposure to the ingredient, that demonstrate that the ingredient when manufactured 
and used as described does not cause an allergic response that poses a risk to human 
health; or  
Petitions and Notifications Guidance Page 4 of 18  Contains Nonbinding Recommendations 
5b. For a notification, data and information that demonstrate that the ingredient when 
manufactured as described does not contain allergenic protein, or documentation of a 
previous determination under a process pursuant to section 409 of the FD&C Act that 
the ingredient does not cause an allergic response that poses a risk to human health.  
 
We will evaluate this scientific evidence only for the specific ingredient and specific use(s) 
identified in the submission.  
 
FDA recognizes that there are several methods that can be used to demonstrate that an ingredient 
meets the standards in 403(w)(6) and 403(w)(7) of the FD&C Act.  Each submitter may 
determine which approach is most appropriate for the specific ingredient and specific use(s) 
identified in the submission.   
 
III. Recommendations for Preparing Submissions  
 
A.  Determining Need for Submission 
 
The following points should be considered in determining whether to submit a petition or 
notification:   
 
  An ingredient derived from a major food allergen that does not contain protein is not 
subject to the labeling requirements described in section 403(w)(1) of the FD&C Act.  
We are aware that there are some technologies (e.g., distillation) that may be able to 
produce protein-free ingredients because of the nature of the process and fundamental 
biochemical properties of proteins, peptides, and amino acids.  When other technologies 
are used to produce an ingredient, information and expertise available to the 
manufacturer should make it possible to identify and apply the appropriate analytic 
methods to ensure that the ingredient does not contain protein.  The methods used should 
be shown to be sufficiently accurate and sensitive under the conditions of use, including 
consideration of extraction efficiencies and possible interferences, should be scientifically 
appropriate, and sufficiently sensitive to demonstrate that no proteins or peptide 
fragments are present in the ingredient.  Manufacturers should also consider potential 
batch to batch variation in the composition of the ingredient.  Manufacturers may discuss 
methodological issues with us.   
  A petition should be used to demonstrate that an ingredient derived from a major food 
allergen that may contain allergenic proteins, or derivatives of allergenic proteins such as 
peptide fragments, does not cause an allergic response that poses a risk to human health 
in food allergic individuals. 
  A notification should be used to demonstrate that an ingredient that may contain proteins 
or protein fragments derived from a major food allergen does not contain allergenic 
protein. 
 
B.  General 
 
Each submission should contain information identifying the organization and individual 
primarily responsible for the submission.  This should include the name of the individual and 
Petitions and Notifications Guidance Page 5 of 18  Contains Nonbinding Recommendations 
organization, a complete mailing address, a physical address if this differs from the mailing 
address, phone and fax numbers, and an electronic mail (email) address for the organization and 
for a primary contact.  A joint submission from several organizations should include complete 
information for each organization.  
 
C.  Ingredient Description 
 
For the purposes of this guidance document, ingredients include substances that are-  
 
  Derived (e.g., through chemical, biochemical, mechanical, fermentation or 
bioengineering processes) from a major food allergen and that contain proteins or 
peptides  
 
A submission should provide a complete description of the ingredient including- 
 
  Name  Both the common or usual name and any scientific name(s) of the ingredient; 
  Source  The major food allergen source of the ingredient, if this is not obvious from the 
name, or the major food allergen sources used in the manufacture or engineering of the 
ingredient;  
  Properties  The chemical and biological properties or characteristics of the ingredient 
including molecular structure, sequence, etc., as appropriate;   
  Standards  Any existing food standards of identity or specifications for the ingredient, 
such as from the FDAs food standards of identity regulations, Food Chemicals Codex, or 
Codex Alimentarius; and 
  Composition - The composition of the ingredient, including the methods used to 
determine composition, and batch-to-batch variation in composition should be described.  
If the ingredient contains more than one component, all components, including non-
allergens, (including carriers or diluents), as well as the relative proportion of each in the 
ingredient should be described. 
   
D.  Ingredient Preparation or Manufacture  
 
The method(s) or procedure(s) used to prepare or manufacture the ingredient should be described 
completely, particularly those steps that alter the amount, relative composition, or biochemical 
state of the proteins present.  This description should include, for example- 
 
  Physical treatments  such as grinding, pressing, filtration;  
  Temperature treatments  such as heating, cooking, baking, retorting; 
  Chemical treatments  such as solvent extraction, hydrolysis (both enzymatic and non-
enzymatic), cross-linking; 
  Growth conditions (if relevant)  such as the composition of the growth or nutrient media 
used in the manufacture of enzymes or organisms; and/or  
  Bioengineering process (if relevant)  such as details of the construct, transformation 
event, and DNA and amino acid sequences.   
 
The description of the manufacturing or preparation process should include- 
Petitions and Notifications Guidance Page 6 of 18  Contains Nonbinding Recommendations 
 
  The conditions used at each step in manufacturing or preparation from raw material to the 
final ingredient.  This should include (as applicable) a full description of time, 
temperature, pH, pressure, volume, and acceptable range for each;  
  Information on how process conditions are monitored and controlled at each step; 
  A description of any testing that is done to measure or characterize proteins or peptides in 
the ingredient during or after processing (including quality assurance testing and 
information describing the validation of these tests); and 
  Statistics on batch-to-batch variations in ingredient characteristics, particularly those 
related to protein content, identity, and structure.  
 
E.  Ingredient Protein Characterization 
 
The submission should provide a chemical and biological characterization of the ingredient, 
including details of the methods used for analysis of the ingredient, particularly for the proteins 
or peptides in the ingredient.  For ingredients that are or that contain peptide fragments, this 
should include information on the distribution of peptide fragment sizes and whether these 
peptide fragments are large enough to be immunologically-relevant.  This should include- 
 
  The amount of total protein or peptide present, including information on the method(s) 
used to measure these proteins or peptides;   
  Characterization of the proteins or peptides, including - 
  The number (and range) and sizes (molecular weight or amino acid length) of the 
o
proteins and peptides; and 
  The biochemical characteristics of these proteins and peptides (including 
o
sequences if known), and the methods used to determine these characteristics. The 
description of the methods used should include sufficient information to evaluate 
the precision and accuracy of the method; 
  Batch-to-batch variation in the amounts and characteristics of the proteins and peptides 
from analysis of multiple batches of the ingredient; and 
  The amount and molecular characteristics of allergenic protein or peptides present (if 
possible), including a description of the method used to determine these characteristics.   
 
F.  Ingredient Application 
 
To help us evaluate potential consumer exposure, the submission should describe the intended 
use (or uses) of the ingredient in the final food product(s).  This should include- 
 
  Intended use level for each food or food application; 
  Information on variations from the intended level that occur normally during manufacture 
of the final food product(s);   
  Information on any technical effects that limit the maximum amount of the ingredient 
that can be used; 
  Information on the method of incorporation of the ingredient into foods (if relevant); and  
  Information on any methods that are (or can be) used to measure the amount of the 
ingredient in foods.  
Petitions and Notifications Guidance Page 7 of 18  Contains Nonbinding Recommendations 
 
G.  Methods 
 
Our ability to evaluate the scientific evidence in a submission can be affected by the extent to 
which the submission describes the methods used to obtain that evidence and an understanding 
of how these methods were validated.  Therefore, for each analytical method used to characterize 
the ingredient, we recommend that a submission describe- 
 
  The method as used, including the sources of any test kits, special reagents, and 
analytical equipment; 
  The rationale for using a particular method, including a discussion of the benefits and 
limitations of the particular method;   
  The process used to validate the method for use with the specific ingredient or food.  
Note that the use of internal kit standards or simple spiking procedures are generally not 
sufficient to validate that a method is performing as intended and that there are no 
interferences (either positive or negative);   
  The recovery and/or extraction efficiency of the assay when used with the specific 
ingredient or food; 
  The Limit of Detection (LOD), Limit of Quantitation (LOQ), and precision of the assay 
(if applicable); 
  The sampling plan used  describing how samples were taken, how many were analyzed; 
and 
  The statistics of the sampling results  such as the mean and standard deviation.  
 
Enzyme-linked immunosorbent assay (ELISA)-based methods are the most widely used methods 
for detecting or measuring food allergens.  However, given the limitations of ELISA-based 
methods, submitters should consider using additional analytical methods, such as using 
polymerase chain reaction (PCR) or mass spectrometry, to supplement data obtained using 
ELISA assays. 
 
H.  Environmental Assessment 
 
Under 21 CFR part 25, all applications or petitions requesting agency action require the 
preparation of an environmental assessment or a claim of categorical exclusion.  Please contact 
FDA for further information related to the FDAs regulations in 21 CFR part 25 regarding the 
procedural provisions under the National Environmental Policy Act of 1969.  
 
IV.  Additional Information for Petitions 
 
A petition for a labeling exemption must contain scientific evidence showing that the ingredient 
does not cause an allergic response that poses a risk to human health under section 403 of the 
FD&C Act.  Appendix 1 contains a detailed discussion of FDAs thinking on what constitutes an 
allergic response that poses a risk to human health.  In general, we consider any of the possible 
objective allergic reactions as an allergic response that poses a risk to human health in 
evaluating the scientific evidence presented in petitions requesting labeling exemptions for 
specific ingredients.  In addition, subjective reactions that are associated with objective reactions 
Petitions and Notifications Guidance Page 8 of 18  Contains Nonbinding Recommendations 
at higher doses or that are of sufficient severity to stop a dose escalation study also may be 
considered allergic responses that pose a risk to human health.  If subjective reactions were 
observed or recorded in a clinical study, we recommend that the petition include a discussion of 
how those data were used, or why they were not used.  There are two types of scientific evidence 
that can generally be used, along with consumer exposure data, to demonstrate this: clinical 
testing (either in vivo or in vitro) and risk modeling.     
 
A.  Consumer Exposure 
 
Risk for food allergic individuals is a function of multiple factors.  The factors that are relevant 
for evaluating petitions are the amount of allergenic protein present in a food and the amount of 
that food consumed in a single eating occasion.  Therefore, a petition should include information 
on the expected consumer exposure from consumption of the final food product(s) containing the 
ingredient.  We suggest that this information include- 
 
  Information on actual consumption levels for each intended food or food use at the mid-
range, and at the 90% and 95% levels for consumers of that food; 
  For ingredients that might be used in multiple foods, an estimated integrated consumption 
level at a single eating occasion (such as a complete meal); and  
  Information on differential consumption patterns for consumers of different ages, 
genders, or ethnicity. 
 
If necessary, the submitter should consider several different consumption scenarios to address 
various consumption patterns such as different consumption patterns in children and adults for 
some foods or different exposure levels from multiple uses of an ingredient.  
 
B.  Clinical Testing  Oral Provocation Studies 
 
Clinical testing by oral food challenge of food allergic individuals is the most reliable way to 
assess the ability of a food or ingredient to provoke an allergic response in food allergic 
individuals.  The double-blind, placebo-controlled food challenge is considered to be the best 
format for an oral challenge but single blind or open challenges may also be appropriate 
depending on the nature of the product and the food allergic individuals involved.   
 
Regardless of the specific format used, we emphasize that to the extent possible the patient 
population involved should be fully described, that each patient challenged be characterized, and 
that the form, dosing, and delivery system for the test material be appropriate.  Studies that fail to 
address one or more of these points are less able to demonstrate that the ingredient does not 
cause an allergic response that poses a risk to human health.  Data describing the result of oral 
food challenges should include:  
 
  Information on the individuals challenged, such as- 
  The number of individuals enrolled and challenged in each study;  
o
  All available clinical information for each individual challenged [e.g., age, 
o
gender, nationality/ race, skin prick test or in vitro immunoglobulin E (IgE; the 
class of antibodies involved in allergic reactions) results if these are available, 
Petitions and Notifications Guidance Page 9 of 18  Contains Nonbinding Recommendations 
medical history, history of food allergic disease (e.g., frequency and severity of 
prior reactions), co-morbidities] and any medications that were used during the 
challenge; and   
  Information supporting that, at the time of testing, all individuals challenged were 
o
allergic to the major food allergen that was the source of the ingredient and that 
they represent the range of sensitivities in the allergic population for that major 
food allergen.  
 
  Information on the clinical protocol used, such as- 
  A description of the subject recruitment and randomization procedures; 
o
  Relevant inclusion and exclusion criteria for subject selection; 
o
  A description of the clinical primary endpoints; 
o
  A description of the material used in the challenge, including form and 
o
preparation of the material, and (if available) information on the relative 
concentration and distributions of allergenic proteins in the test material; 
  The carrier or matrix used;   
o
  The dosing pattern used, including-  
o
  All dose levels administered;   
  The time intervals between administered doses; 
  A description of how each dose is quantified (for example, as amount of 
whole food, amount of the specific ingredient, or amount of protein); 
  An indication of whether each dose level is reported as a discrete or 
cumulative dose; and   
  Information on how and when the placebos (if any) were administered;  
  A description of how responses were reported or measured, including-  
o
  The clinical criteria used, including information on whether both 
subjective and objective responses were recorded; and 
  Information on whether the severity of the response was measured, and if 
so how severity was classified;  
  A complete statistical analysis of the results (based on study subject number and clinical 
endpoints); and  
  A description of any other factors that we should consider when interpreting the results.    
 
The National Institutes of Health, National Institute of Allergy and Infectious Diseases 
sponsored an expert panel that published Guidelines for the Diagnosis and Management of 
Food Allergy in the United States: Report of the NIAID-Sponsored Expert Panel. The 
guidelines include the expert panels recommendations and overall discussion of the use of oral 
challenge studies, including the rationale for using oral challenge studies, and the potential 
benefits and harms. (http://www.niaid.nih.gov/topics/foodallergy/clinical/Pages/default.aspx).  
The European Academy of Allergy and Clinical Immunology has published similar guidelines. 
(http://www.eaaci.org/attachments/EAACI-
%20Food%20Allergy%20Management%20&%20Diagnosis.pdf ).  
 
Note that we expect all clinical studies involving human subjects submitted in support of a 
petition to be carried out in conformance with the FDA Human Subject Protection Regulations 
(http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm155713.htm) or 
Petitions and Notifications Guidance Page 10 of 18  Contains Nonbinding Recommendations 
equivalent protection and standards including Good Clinical Practice (GCP2) in the country 
where the studies were conducted.  
 
C. Clinical Testing  Skin Prick, In Vitro and Other Studies 
 
The ability of an ingredient to cause an allergic response in food allergic individuals can also be 
assessed using diagnostic procedures such as skin prick tests or by in vitro testing using sera 
from food allergic individuals to assess whether IgE from these individuals will bind to proteins 
and peptides in the ingredient.  There are several forms of in vitro assay that can be used to 
characterize the interaction between sera from allergic individuals and the proteins in food 
ingredients.  Depending on the format of the assay used, such studies can produce information on 
which proteins in the food are recognized by antibodies from allergic individuals, on 
immunologic relationships between foods or proteins, on the levels of IgE antibodies in 
individual sera, and on the kinetics of antigen-antibody interactions.  By comparing antibody 
binding properties of the ingredient in the petition (or from proteins contained in that ingredient) 
to the antibody binding properties of the source major food allergen, it may be possible to 
demonstrate that the ingredient will not cause allergic responses.   
 
Regardless of the specific testing format used, we encourage submitters to test a statistically 
significant number of well characterized food allergic individuals.  Appropriate procedures 
should be used to ensure that any interfering medications have been withdrawn for an 
appropriate period, that no confounding conditions are present (particularly for skin prick 
testing), and that appropriate positive and negative controls (such as histamine and saline for skin 
prick tests) are used.  Each in vitro assay should be validated and fully controlled and data from 
all tests should be presented.  Because food allergic individuals may be sensitive to different sets 
of specific proteins in a major food allergen, we encourage submitters to report results from 
testing each serum individually.   
 
The data describing the results for each method should include- 
 
  The number of test subjects and individual sera used;  
  The criteria used for selecting test and control subjects and sera, including any relevant 
inclusion or exclusion criteria;  
  Information on each subject or serum donor [e.g., age, gender, nationality/ race, medical 
history, history of food allergic disease (e.g., frequency and severity of prior reactions, 
co-morbidities, etc.), current medications during the challenge].  It is critical that 
sufficient data be provided to demonstrate that all individuals tested or donating test sera 
are allergic to the major food allergen that was the source of the ingredient and that they 
are representative of the allergic population for that major food allergen and that all 
control individuals or donors of sera are not allergic to the major food allergen;  
  For skin prick testing, a detailed description of the testing procedure used (e.g., the 
testing apparatus and method  i.e., prick, etc., where the extracts were placed on the 
                                                 
2 GCP is a standard for designing, conducting, recording and reporting trials that involve the participation of human 
subjects.  See the web page Running Clinical Trials on the FDA web site for more information. 
(http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/default.htm) 
Petitions and Notifications Guidance Page 11 of 18  Contains Nonbinding Recommendations 
skin, how skin test results were clinically assessed by wheal size and/or flare, etc.) as well 
as all positive and negative control procedures and the criteria used to determine whether 
there was a positive response;  
  For in vitro serum testing, a detailed description of the assay procedure or procedures 
used (e.g., Western blot, ELISA), including all internal controls and validations;  
  Complete characterization of all materials tested, particularly if extracts or derivatives of 
whole foods or ingredients are used, including a description of the procedures used to 
prepare the test material.  This information should be sufficient to demonstrate that the 
test material is representative of the ingredient or of the proteins and protein derivatives 
contained in the ingredient; 
  A complete description of the results and of the data analysis, including statistical 
analysis; and   
  A discussion of the limitations of the data submitted. 
 
New methods for assessing allergenicity and allergen-specific IgE-mediated responses are being 
developed. Until such methods have been fully validated, we recommend that they only be used 
as supporting data in conjunction with either skin prick or in vitro serum testing.  
 
D.  Risk-Based Methods   
 
Absent direct clinical or challenge data, a submitter may be able to demonstrate that an 
ingredient will not cause an allergic response that poses a risk to human health by risk modeling 
using data on consumer exposure to the ingredient and published data on the distribution of 
minimal eliciting doses in the sensitive population.  Previously, FDA determined that this 
modeling could be done using either a risk assessment or safety assessment-based approach 
(Approaches to Establish Thresholds for Major Food Allergens and for Gluten in Food, 2006) 
(Threshold Report).  FDA also determined that the risk assessment-based approach is more 
transparent and scientifically rigorous than the safety assessment-based approach, and should be 
used when sufficient data are available.  For either the risk assessment-based or safety 
assessment-based approach, we encourage pre-submission consultation with FDA.   
 
Risk Assessment-Based Approach 
The risk assessment-based approach combines data on the distribution of minimal eliciting doses 
in the entire food allergic population with data on consumption and exposure to estimate the 
probability that a food allergic individual will experience an allergic response.  This approach 
allows analysis of different consumption scenarios as well as consideration of special 
populations.  One major advantage of the risk assessment-based approach is that it provides 
explicit information on the uncertainties associated with the reaction probabilities.  
 
If risk assessment-based modeling is used, the petition should describe- 
 
  The clinical data used to model the distribution of sensitivities to the major food allergen 
in the food allergic population.  This should include citation of published data and 
submission of any unpublished data used.  These data should include a complete 
description of how the clinical studies were conducted;   
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  The statistical techniques used to develop the dose distribution model (or models) and of 
all the statistical and model uncertainties.  If possible, the petition also should describe 
the effect of using alternate modeling approaches; 
  The data and statistical techniques used to model the distribution of the major food 
allergen in finished foods that incorporate the ingredient;  
  The data uncertainties, including the uncertainties associated with combining data from 
different challenge studies (if relevant), the effects of factors used to exclude individuals 
from the studies;   
  The data and statistical techniques used to model consumption of the final food by food 
allergic individuals.  If consumption patterns differ between subpopulations (such as 
between adults and children), the petition should model each subpopulation 
independently; 
  The models and procedures used to estimate the probability of allergic responses by food 
allergic individuals;   
  The results of the modeling, including all ranges and uncertainties; and 
  How these results demonstrate that the ingredient does not cause an allergic response that 
poses a risk to human health.  
 
Safety Assessment-Based Analysis 
If sufficient data are not available for risk assessment modeling, it may be possible to assess 
whether an ingredient will cause an allergic response that poses a risk to human health by using a 
safety assessment-based analysis.  A safety assessment-based analysis uses the Lowest Observed 
Adverse Event Level (LOAEL) or No Observed Adverse Event Level (NOAEL) for the most 
sensitive individual in the food allergic population and one or more uncertainty factors to 
estimate an exposure level that is unlikely to cause an allergic response in food allergic 
individuals.  This level can be compared to expected actual consumption of the ingredient to 
estimate expected risk.  Because a safety assessment does not consider the entire food allergic 
population, this type of analysis will be most appropriate in situations where the clinical testing 
data are very limited or indirect.  
 
If a safety assessment is used, the petition should describe- 
 
  The clinical data used to estimate the LOAEL and NOAEL in the food allergic 
population.  This should include all pertinent information on the methodologies of the 
challenge studies used to identify these levels as well as all citations of published data 
and descriptions of any unpublished data used.  The studies used to generate these data 
should meet the criteria described for direct clinical testing of the ingredient;   
  How the LOAEL and NOAEL were determined based on the clinical data.  In particular, 
we suggest that the petition describe all types of responses, e.g., subjective or objective, 
noted in the challenge data and how the submitter considered the responses in 
determining the LOAEL and/or NOAEL; 
  The uncertainty factors that the submitter applied and the rationale for these factors.  This 
discussion should include a description of the uncertainties associated with small data 
sets or with extrapolation from indirect data.  Other factors to consider include 
uncertainties associated with comparing data from different challenge studies, exclusion 
of sensitive populations; and  
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  How these results demonstrate that the ingredient does not cause an allergic response that 
poses a risk to human health.  
 
E.  Other data 
 
The petition may include additional relevant information, such as from animal testing (see 
Appendix 2), clinical case reports, or in vitro studies.  If additional information is included, we 
recommend that the submitter describe how it generated or obtained the additional information.  
For laboratory studies, this should include a complete description of study methods and controls 
and of how the results were analyzed.  
 
V.  Additional Information for Notifications 
 
Under section 403 of the FD&C Act, a notification for a labeling exemption must contain 
scientific evidence showing that the ingredient does not contain allergenic protein or that there 
has been a previous determination through a premarket approval process under section 409 of the 
FD&C Act that the ingredient does not cause an allergic response that poses a risk to human 
health.  In the latter case, as part of the premarket approval process, we will work with the 
submitter regarding the process for submitting a notification under section 403(w)(7)(A)(ii) of 
the FD&C Act. 
 
A.   Protein Characterization. 
 
To demonstrate that a protein-containing ingredient does not contain allergenic protein, the 
notification should include a complete characterization of the protein (or proteins) and peptides 
that are present in the ingredient.  This includes the information described in Ingredient Protein 
Characterization above (Section III.E of this document).  In addition, the notification should 
contain evidence that the protein (or proteins) or peptides present are not allergenic.  In some 
cases, where the original major food allergen is known to have only one or a few well 
characterized allergenic proteins, this can be done by demonstrating that the protein or peptides 
in the ingredient are different from the known allergenic proteins.  However, because each 
allergic individual may be sensitive to different proteins in a food, in most cases we recommend 
that submitters use either in vivo or in vitro clinical data (as described above for a petition) to 
demonstrate that the ingredient does not contain allergenic protein.   
 
B.  Other data 
 
The notification may include additional relevant information, such as from animal testing (see 
Appendix 2), clinical case reports, or in vitro studies.  If additional information is included, we 
recommend that the submitter provide a complete description of how it was generated or 
obtained.  Laboratory studies should include a complete description of study methods and 
controls and of how the results were analyzed.  
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VI. Appendices 
 
Appendix 1 Allergic Responses that Pose a Risk to Human Health 
 
FDA considers the terms allergic response and allergic reaction to be equivalent for the 
purpose of this guidance.  To help us determine what scientific evidence is needed to 
demonstrate that a food ingredient does not cause an allergic response that poses a risk to human 
health, we have reviewed the available scientific literature on food allergic responses and 
response severity. 
 
We have defined food allergy as an IgE-mediated hypersensitivity to food (see Threshold 
Report).  Although non-IgE-mediated, mixed, and cell-mediated reactions have adverse health 
consequences, only IgE-mediated mechanisms have the potential to cause acute life-threatening 
reactions.  Further, IgE antibody-mediated reactions are the most common and of the greatest 
public health concern.  Therefore, we will continue to consider only IgE-mediated allergic 
responses as relevant to these petitions and notifications while noting that the labeling and 
exemption standards developed using this consideration will also be protective of food allergic 
individuals who experience other immune-mediated adverse reactions to foods.  
 
IgE-mediated responses are the result of a two-step process  sensitization and elicitation. 
Sensitization generates IgE antibodies that recognize specific proteins in food allergens.  These 
IgE antibodies bind to receptors on the surface of mediator cells lining various mucosal 
membranes of the body.  If an individual does not encounter a food allergen after becoming 
sensitized to that food allergen, there is no further biological response.  However, when an 
individual does encounter the food allergen that is recognized by the IgE antibodies, and 
sufficient protein is present, the protein interacts with, and cross-links, the IgE antibody-bound 
cell receptors.  This leads to the cellular release of inflammatory mediators responsible for the 
signs and symptoms of an allergic reaction.  Although the manifestation of an allergic response 
requires both sensitization and elicitation, allergen labeling under section 403(w)(1) of the 
FD&C Act is intended to protect the health of individuals who have food-specific allergies, i.e., 
those who have previously been sensitized.  Therefore, we consider allergic responses to be 
elicitation of IgE-mediated release of inflammatory mediators in food allergic individuals.    
 
IgE-mediated allergic reactions can occur within a few minutes to hours after a food allergic 
individual consumes a food allergen.  The reactions can result in a wide range of signs and 
symptoms, ranging from mild, reversible irritation to severe, life-threatening respiratory distress 
and shock.  Allergic reactions may involve a single organ system or multiple systems.  Specific 
organ systems include 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).  In severe reactions, the shock organs of the 
respiratory tract (e.g., cough, asthma, difficulty breathing, swelling around the larynx and vocal 
cords) and cardiovascular system (e.g., faintness, hypotension) are involved.  This can lead to 
loss of consciousness, asphyxiation, shock, or death.  
 
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An allergic reaction can produce responses that are subjective, objective, or both.  Subjective 
symptoms (e.g., mild nausea, itching, or gastrointestinal discomfort) are those that are 
experienced by the affected individual but that cannot be confirmed by an observer.  Objective 
signs (e.g., urticaria, vomiting, or wheezing) are those that can be observed by other individuals.  
Subjective symptoms may be precursors of objective signs.  
 
The signs and symptoms of an allergic reaction vary from one individual to another and may also 
vary for the same individual on different occasions.  Further, any individual sign or symptom 
may vary in intensity or duration.  For example, an allergic reaction might be manifested as a 
few small hives or as multiple large hives that cover most of the torso.  Reactions may subside 
spontaneously or progress in both the number of organ systems involved and severity.  Reactions 
that have a rapid onset and that involve multiple organ systems are generally considered to be 
anaphylaxis.  However, anaphylaxis may also present with a delayed and protracted course 
involving only one organ system. 
 
It is not known what determines the severity of an allergic reaction.  It is likely that several 
factors including individual sensitivity, the amount and characteristics of the food consumed, 
underlying co-morbid conditions (e.g., asthma), and the effects of other foods and drugs all 
interact to determine the course and severity of each allergic reaction.  There is evidence that 
some of the major food allergens (e.g., peanuts and tree nuts) are more likely to trigger severe 
reactions than others (e.g., wheat).  It is known that individual sensitivity varies over a wide 
range in the food allergic population.   
 
The FDA Allergen Threshold Working Group (Working Group) has previously considered the 
meaning of the phrase allergic response that poses a risk to human health in the report 
Approaches to Establish Thresholds for Major Food Allergens and for Gluten in Food (2006).  
At that time, the Working Group noted the lack of consensus on the applicability of subjective 
symptoms as biomarkers for severe allergic reactions and the very limited published data on 
subjective symptoms in clinical trials.  The Working Group also noted that there is a broad 
consensus that any of the initial objective reactions should be treated as equivalent in analyzing 
the results from clinical trials.  Therefore, the Working Group concluded that, in using either the 
risk assessment-based or safety assessment-based approach to establishing thresholds for major 
food allergens, those published studies reporting objective reactions should be used and that 
determinations ... should be based on evidence of the initial objective sign."  
 
These conclusions were evaluated by the FDA Food Advisory Committee (Committee) (July, 
2005).  In 2005, the Committee stated that ...it is appropriate to conclude that objective 
responses associated with allergic reactions pose risks to human health.  Further, the Committee 
recognized that information on subjective responses might be applicable in the safety 
assessment-based approach in that ...when a challenge study recorded the dose at which both 
subjective and objective responses occurred, that information can be used to select the 
appropriate uncertainty factor(s).   
 
Based on our review of the literature as of January 2013, we conclude that the same 
considerations discussed by the Working Group and the Committee for establishing thresholds 
also apply to determining which reactions constitute allergic responses that pose a risk to human 
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health.  In other words, an objective reaction in a clinical trial should be considered as 
indicative of a risk to human health regardless of the specific signs observed, and subjective 
symptoms generally should not be considered as indicative of a risk to human health in the 
absence of objective signs.   
 
Therefore, we consider an objective allergic reaction observed in a clinical trial as an allergic 
response that poses a risk to human health in evaluating the scientific evidence presented in 
petitions requesting labeling exemptions for specific ingredients.  In addition, subjective 
reactions that are associated with objective reactions at higher doses or that are of sufficient 
severity to stop a dose escalation study also may be considered allergic responses that pose a risk 
to human health.  If subjective reactions were observed or recorded in a clinical study, we 
recommend that the petition include a discussion of how those data were used, or why they were 
not used. 
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Appendix 2.  Animal Testing 
 
Animal models are widely used in toxicology testing to assess the potential effect of a substance 
in humans.  However, as of the date of this guidance document, no appropriate animal model 
systems have been developed or validated to test potential human allergenicity.  Although 
animals can be induced to become allergic to foods and proteins, there is no animal model that 
can differentiate between those foods that are commonly allergenic in humans and those that are 
not, or between allergenic and non-allergenic proteins in an individual food.  Further, there are 
no data indicating that the level of sensitivities in animals reflect those seen in humans, that 
animals respond in the same manner as humans to modification of allergenic proteins caused by 
processing, or that animals respond in the same manner as humans to matrix effects.  Therefore, 
we do not recommend the use of animal testing as an independent indicator of either the absence 
of allergenic protein or of whether an ingredient will cause an allergic response that poses a risk 
to human health. 
 
In some cases, a submitter may be able to use data from animal testing to supplement the primary 
data contained in a petition or notification.  For example, if the submitter cannot obtain data from 
a statistically valid number of sensitive individuals in clinical trials or serum studies, the human 
response data may be supplemented by more extensive animal testing.  In that case, we 
encourage submitters to discuss the design and condition of these tests with us before they make 
their submission.   
 
 
 
 
 
 
 
 
 
 
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