0792 - FALCPA guidance

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

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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

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Food Allergen Labeling Exemption Petitions
and Notifications
Guidance for Industry
This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes
and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for
implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate
number listed on the title page of this guidance.

I. Introduction
This document describes the data that FDA’s 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 submitters 1, 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.

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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 describes1. 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

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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

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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 FDA’s 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 nonallergens, (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 nonenzymatic), 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.

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•
•
•
•

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 o The number (and range) and sizes (molecular weight or amino acid length) of the
proteins and peptides; and
o The biochemical characteristics of these proteins and peptides (including
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.
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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 FDA’s 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 FDA’s 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
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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 midrange, 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 aso The number of individuals enrolled and challenged in each study;
o All available clinical information for each individual challenged [e.g., age,
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,

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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
o Information supporting that, at the time of testing, all individuals challenged were
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 aso 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
preparation of the material, and (if available) information on the relative
concentration and distributions of allergenic proteins in the test material;
o The carrier or matrix used;
o The dosing pattern used, including 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;
o A description of how responses were reported or measured, including 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 panel’s 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

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equivalent protection and standards including Good Clinical Practice (GCP 2) 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)

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•
•

•
•

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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