CPSC Staff’s Strong Sensitizer Guidance Document 

For a product containing a strong sensitizer to be considered a hazardous substance and to 

require cautionary labeling under the FHSA,

1 the product must be capable of causing substantial 

personal injury or substantial illness during, or as a result of, customary or reasonably 

foreseeable handling or use, including reasonably foreseeable ingestion by children.

2

 This 

requires consideration of the route and the level of exposure that can be expected to be presented 

by the strong sensitizer as it exists in the particular substance.

3 Therefore, determining whether a 

cautionary label is required must occur on a product-by-product basis, and it is not based solely 

on the presence of a strong sensitizer in a product. 

The designation of a substance as a “strong sensitizer” is a Commission-made determination. 

Once the Commission has designated a substance as a “strong sensitizer,” CPSC staff believes 

that consideration of the “complexity of the mixture (“matrix”)” is important in the risk 

characterization of a strong sensitizing chemical because the predominant exposure of the 

general population to sensitizers in consumer products will be in the form of mixtures and not the 

“pure” compound. The matrix components also can enhance the sensitizing capability of a 

substance in that mixture. For example, surfactants, a broad class of chemicals, are common in 

consumer products as processing agents and detergents. Surfactants like sodium lauryl sulfate 

are known to enhance the allergenicity of some chemicals. The Commission makes a decision to

declare a substance a “strong sensitizer,” but the risk characterization is based on the product as a 

whole. Risk characterization and risk management (e.g., label, no label, or ban) would have to 

take into consideration the form in which the sensitizer is present in the actual product. A 

chemical matrix is the formulation in which the sensitizing agent is present. 

 

If a substance containing a strong sensitizer is a hazardous substance under the FHSA, the 

product would require cautionary labeling, including the signal words: “Caution,” or “Warning,” 

and include an affirmative statement, such as: “May Produce Allergic Reaction by Skin 

Contact.”4

 While the FHSA does not require manufacturers to perform any specific battery of 

toxicological tests to assess the potential risk of chronic hazards, the manufacturer is required to 

label appropriately and in accordance with FHSA requirements, a product that is intended or 

packaged in a form suitable for use in the household. However, if a toy or other article intended 

for use by children is or contains a hazardous substance that a child could access, the product, by 

definition, is a banned hazardous substance, unless specifically exempted.

5

 1

The FHSA, 15 U.S.C. §1261(p), requires cautionary labeling for any article intended or packaged for household use 

if it contains a hazardous substance.

2

16 C.F.R. §1500.3(b)(4)(i)(A). 3 The term “substance” for strong sensitizers can mean both the chemical and products containing the chemical. For 

example, “paraphenylenediamine and products containing it,” are listed as meeting the definition for “strong 

sensitizer” in FHSA section 1500.13, “Listing of `strong sensitizer’ substances.” 4 Congress, in enacting the FHSA, did not intend that precautionary labeling be required on all products. A strong 

sensitizer must be a substance that affects a significant portion of the population and produces substantial illness. 

Report No. 1158, Calendar No. 1197, March 10, 1960; 86th Congress. Hazardous Substances for Household Use. 5

15 U.S.C. §1261(f)(1(A); id. §1261(q)(1).
The following sections of this guidance document take a stepwise approach in clarifying each 

component of the strong sensitizer supplemental definition. Each section incorporates the 

current science rationale behind potential decision making. These guidelines are intended to aid 

manufacturers and other stakeholders in understanding how CPSC staff would assess whether a 

substance could be considered a “strong sensitizer.” The following sections quote the relevant 

part of the definition and provide guidance concerning that part of the definition.

I. Sensitizer

Sensitizer. A sensitizer is a substance that is capable of inducing a state of 

immunologically mediated hypersensitivity (including allergic photosensitivity) following 

a variable period of exposure to that substance. Hypersensitivity to a substance will 

become evident by an allergic reaction elicited upon reexposure to the same substance.

6

 

Hypersensitivity or allergy results when the immune system responds to a specific 

allergen in an exaggerated or inappropriate manner. These reactions have been divided 

into four types (Types I, II, III and IV), representing four different mechanisms leading to 

the body’s response to the allergens. For hypersensitivity Types I, II and III, exposure to

an allergen results in the production of specific antibodies (e.g., Immunoglobulin M 

[IgM], IgG or IgE). Some substances may not have defined specific IgE responses but 

exhibit other immunologically mediated characteristics of sensitizers. Therefore, these 

substances can be classified as sensitizers, based upon the other characteristics.7

 Allergic 

responses typically are the result of a two-step process: (1) induction (sensitization) 

which requires sufficient or cumulative exposure (dose) to induce an immune response 

with few or no symptoms, and (2) elicitation when an individual who has been sensitized 

demonstrates symptoms upon subsequent exposure. 

Due to the nature of the immune system, in order for an individual to become sensitized 

to a particular substance, there is a lag sensitization phase (induction), followed by a 

secondary immune response (elicitation phase). The amount of time and the amount of 

exposure (the variable period of exposure and the dose) required for sensitization will 

depend upon the individual.8

 In the scientific community, it is generally considered that 

time is required for sensitization to develop; it is unusual, although not impossible, for 

simultaneous sensitization and elicitation to occur upon first exposure. Because of the 

latent period, the first contact (and often repeated contacts), even with relatively high 

concentrations of a sensitizer, can go undetected because no signs or symptoms of allergy 

occur. Individuals who are sensitized, but who do not exhibit clinically detectable 

sensitization (i.e., do not exhibit symptoms) when challenged, are characterized as having 

“subclinical sensitization.” When challenged a second time in a clinical setting, these 

individuals can have a stronger than expected response. 

 6 Updated strong sensitizer supplemental definition 16 C.F.R. §1500.3(c)(5). 7 The production of IgE antibodies is typical of Type I hypersensitivity reactions (e.g., rhinitis, urticaria). 8 It typically takes 7 to 14 days for an immune response to develop.
It is important to distinguish a “sensitizer” response from what could be an “irritant 

response.”9 Irritant responses occur without sensitization. An irritant is any agent that is 

capable of producing cell damage and/or an inflammatory response in any individual if 

applied for sufficient time and concentration. Irritants include substances and activities 

such as water, detergents, solvents, acids, alkalis, adhesives and friction. Some mild 

irritants may require prolonged or repeated exposure before symptoms occur, while other 

irritants can produce an immediate reaction and may even resemble a thermal burn. 

Irritant symptoms can occur within minutes of exposure, while allergic reactions (e.g.,

type IV hypersensitivity) may take 6 to 24 hours to produce symptoms. Furthermore, 

irritant symptoms are localized to the area of contact. Allergic responses (e.g., allergic 

contact dermatitis) can be localized but may also have widespread skin involvement, 

particularly in patients with strong sensitization.

In the future, with progress in the science, a definition for each functional class of 

allergen (e.g., protein, chemical) or target organ (e.g., respiratory, ocular, skin) may be 

necessary. However, at this time, insufficient evidence exists to separate clearly the 

sensitization characteristics (e.g., mechanisms of sensitization) of the different target 

organs.

II. Significant Potential for Hypersensitivity

Before designating any substance as a “strong sensitizer,” the Commission shall find 

that the substance has significant potential for causing hypersensitivity. Significant 

potential for causing hypersensitivity is a relative determination that must be made 

separately for each substance. It may be based on chemical or functional properties of 

the substance; documented medical evidence of hypersensitivity reactions upon 

subsequent exposure to the same substance obtained from epidemiological surveys or 

individual case reports; controlled in vitro or in vivo experimental studies; and, 

susceptibility profiles (e.g., genetics, age, gender, atopic status) in non-sensitized or 

allergic subjects.10

In determining whether a substance is a “strong” sensitizer, the Commission shall 

consider the available data for a number of factors, following a weight-of-evidence 

approach. The following factors (if available), ranked in descending order of 

importance, should be considered:

(A) well-conducted clinical and diagnostic studies;

(B) epidemiological studies, with a preference for general population studies over 

occupational studies; 

(C) well-conducted animal studies;

(D) well-conducted in vitro test studies;

 9 An “irritant response” is a non-immune mediated response and one that results from direct injury to the tissue. An 

irritant is any agent that is capable of producing cell damage in any individual if applied for sufficient time and 

concentration. 

10 Updated strong sensitizer supplemental definition 16 C.F.R. §1500.3(c)(5).
(E) cross-reactivity data; 

(F) case histories.

A. Considerations Used by CPSC Staff:

The determination of the significant potential for causing hypersensitivity is the 

cornerstone of the definition of “strong sensitizer.” The determination of risk of 

hypersensitivity should follow a weight-of-evidence approach, using all available 

validated tools. New data and methodologies continue to be developed; therefore, to 

specify particular assays would likely result in their replacement as new data and 

information become available. The factors for consideration of hypersensitivity potential 

are ranked and listed in order of importance in the definition, with the FHSA preference 

for human data over animal data. Occupational studies are considered a subset of 

epidemiological studies. Epidemiological studies (general population studies) are 

preferred over occupational studies because the general population is of concern to the 

CPSC, and the degree of sensitization in the workplace is likely greater than that of the 

general population due to greater exposure (both in time and concentration) to the 

sensitizing agent. Although providing helpful information regarding the potential 

sensitizing strength of a chemical, occupational data could exaggerate the estimation of 

the sensitizing strength of a chemical to the consumer scenario. If population data are 

lacking, worker sensitization prevalence could be used to estimate prevalence in the 

exposed general population by taking exposure and dose-response relationships into 

account. “Case histories” are studies typically on a single individual and are less helpful 

in providing information on sensitization in the general population. 

CPSC staff, when evaluating existing data from human and/or animal studies, takes the 

quality of the data into consideration.11 Criteria for a “well-conducted” study would 

include validated outcomes, relevant dosing and route of administration and use of 

appropriate controls. Studies should be carried out according to national and/or 

international test guidelines and according to good laboratory practice (GLP), compliance 

with good clinical practice (GCP), and good epidemiological practice (GEP).

1. Respiratory Sensitization: 

At this time, there are no validated in vitro or in vivo test methods for 

detecting and classifying respiratory sensitizers. There have been significant 

advances in the tools and methods available for hazard characterization of 

skin sensitizers, as discussed below; but progress has lagged for respiratory 

 11 Neither the FHSA, nor the Commission’s regulations require animal testing. The FHSA and its implementing 

regulations only require that a product be labeled to reflect the hazards associated with that product. While animal 

testing may be necessary in some cases, Commission policy supports limiting such tests to a minimum number of 

animals, and the policy also advocates measures that eliminate or reduce the pain or discomfort to animals that can 

be associated with such tests. In making the appropriate hazard determinations, manufacturers of products subject to 

the FHSA, should use existing alternatives to animal testing whenever possible. These include prior human 

experience, literature sources that record results of prior animal testing or limited human tests, and expert opinion.

Recommended procedures can be accessed on the Commission’s Web page at: 

http://www.cpsc.gov/BUSINFO/animaltesting.html.
sensitizers. Because recognized and validated test methods currently are not 

available, identification of respiratory sensitizers is based on the induction of 

specific respiratory hypersensitivity. Human evidence could consist of lung 

function tests supported by skin prick tests, serological analysis, and/or 

bronchial challenge tests. These tests should be complemented with medical 

history to support clinical relevance. Existing animal data can also be 

employed, although no standard animal respiratory hypersensitivity model 

exists. Skin sensitization data can also aid in the determination of whether a 

substance is a strong respiratory sensitizer because many substances known to 

induce skin responses also induce respiratory responses. 

2. Skin Sensitization: 

Historically, data on the skin sensitization potential of chemicals came from 

studies using human volunteers. Two tests for predicting whether a person 

will become sensitized to a substance are the Human Maximization Test 

(HMT) and the Human Repeat Insult Patch Tests (HRIPT).12 The HMT is no 

longer in use, due to ethical concerns about its potential to create adverse 

health consequences for the person being tested. Contract laboratories have 

performed the vast majority of human sensitization tests, particularly the 

HRIPT. There are a limited number of scientific publications with human 

sensitization data, of which much is derived from older studies. 

Prior to development of the Local Lymph Node Assay (LLNA), the Guinea 

Pig Maximization Test (GPMT) and the Buehler Assay (BA) had been the 

primary animal assays used to determine the skin sensitizing ability of a 

chemical. The GPMT is a highly sensitive method; however, some of the 

sensitivity arises due to the coadministration of a painful immune stimulant. 

This method involves injecting under the skin of the animal the possible 

sensitizer being tested, as well as applying it to the surface of the skin. The 

BA uses repeat closed topical applications (filter papers containing the test 

sensitizer of interest are covered with a patch and taped to the skin in order to 

enhance absorption of the substance). The GPMT is regarded as a more 

sensitive assay that, for certain substances, also may overestimate the 

sensitization hazard for the compound tested. The BA is less sensitive and 

may underestimate the sensitization potential of a compound.

In 1997, the LLNA was proposed by the test method developers to ICCVAM 

as a standalone alternative method to the GPMT and the BA for skin 

sensitization hazard identification.13 In 1999, based on the validation database 

and performance of the test method, the LLNA was recommended by 

ICCVAM as an alternative test method for assessing the skin sensitization 

 12 These tests vary with regard to the number of induction patch tests, the placing of the patches, and the use of a 

maximization step (an amplifying step during the challenge phase, this step involves co-treatment of the test 

sensitizer of interest with an irritant in order to enhance a potential response). 13 The LLNA provides a yes/no answer about whether a substance is a sensitizer.
potential of most types of substances. The consensus of the ICCVAM

scientific peer review panel was that the LLNA performed as well as the 

GPMT and BA for hazard identification of strong-to-moderate chemical 

sensitizing [dermal] agents but lacked strength in predicting accurately some 

weak sensitizers and some strong irritants. The LLNA provides several

advantages compared to the guinea pig assays, including elimination of 

potential pain and distress, use of fewer animals, shorter test duration, a more 

objective end point, less test substance required, and the availability of doseresponse information. U.S. regulatory agencies (including the CPSC) 

accepted the LLNA as a valid alternative test method for allergic contact 

dermatitis testing. The LLNA was adopted as a test guideline (test guideline 

[TG] 429) in 2002, by the Organization for Economic and Cooperative 

Development (OECD).

On March 9, 2010, the Commission voted unanimously to approve ICCVAM 

recommendations including: (1) updates to the test method protocol; (2)

establishment of performance standards; and (3) a modified form of the assay, 

the reduced Local Lymph Node Assay (rLLNA). The revised LLNA test 

method protocol and the LLNA performance standards encourage the 

reduction, refinement, or replacement of animals in testing. On January 26, 

2011, the Commission voted to approve the recommendations of ICCVAM 

regarding an expanded applicability domain and two nonradioactive versions 

of the LLNA: (1) the Bromodeoxyuridine Enzyme-linked Immunosorbent 

Assay (BrdU-ELISA); (2) the Daicel Chemical Industries version 

(LLNA:DA), which have been adopted by the OECD, as Test Guideline 442B 

and Test Guideline 442A, respectively. These alternative, nonradioactive 

LLNA test method protocols encourage the reduction, refinement, or 

replacement of animals in testing, and the data indicate that the methods are 

scientifically valid methods. In this context, these alternative LLNA methods 

and the expanded applicability domain may result in additional data that could 

be used to make a determination of whether an undiluted chemical or a 

mixture is a “strong sensitizer.”

There are inherent problems with testing of mixtures and formulations, and 

this applies across all toxicity test methods, not just the LLNA. The agency 

encourages ICCVAM to continue to accrue data, because the ICCVAM 

revised addendum on the applicability domain for the LLNA does not 

consider many classes of formulations to which humans may be exposed. On 

December 28, 2011, the Commission voted to approve the recommendation of 

ICCVAM regarding the LLNA with regard to its ability to determine the 

potency of a sensitizing substance. Staff’s recommendation is that the LLNA 

should not be considered a standalone assay for skin sensitization potency 

classification. However, based on the strength of the analysis provided and 

the currently available database of LLNA data, this assay can be a valuable 

tool in a weight-of-evidence evaluation for determining the skin sensitization 

potency of a substance. The agency also encouraged ICCVAM to continue to 
accrue data. Although the existing National Toxicology Program Interagency 

Center for the Evaluation of Alternative Toxicological Methods (NICEATM) 

database of LLNA test data is large (more than 600 substances), most of the 

available data consists of substances that are moderate, weak, or 

nonsensitizers, classes of substances that fall outside the CPSC’s jurisdiction. 

There are strengths and weaknesses with each of the aforementioned assays; 

however, CPSC staff believes that all could be used in a weight-of-evidence 

evaluation under the FHSA. 

Currently, no in vitro or in silico14 systems have undergone validation for 

determining skin sensitizing potential. Both approaches are evolving 

methodologies and are actively being pursued to reduce the number of 

expensive laboratory and animal experiments performed. Multiple in vitro

test methods for skin sensitization are in pre-validation review. CPSC staff 

expects that none of these methods, each relating to a specific mechanistic 

step occurring in skin sensitization, will be accepted as a standalone method 

and instead will be part of an integrated testing strategy. The validation of 

some of these in vitro methods may be completed in the next couple of years. 

CPSC staff expects that an integrated testing strategy for skin sensitization 

may be available within the next 5 years.

 

3. Other Factors: 

CSPC staff considers the term “non-sensitized” to be an appropriate term for 

what would be considered the control general population because it includes 

both non-exposed individuals and exposed individuals who are not sensitized 

to the allergens. 

There is a complex relationship among the following: exposure to allergens, 

the development of allergic sensitization, and the onset and exacerbation of 

allergic diseases. Genetic factors have been shown to play a role in 

susceptibility to allergy and asthma. Parents with asthma have more than a 60 

percent greater chance of having at least one child with asthma.15 Significant 

progress has recently been made in identifying genes responsible for 

susceptibility to allergic diseases. More than 35 genes (e.g., several variants 

of the IL-13 gene differentially promote mechanisms that lead to allergic 

inflammation) have been associated with asthma or related allergic diseases in 

multiple populations. However, none of these genes has been shown so far to 

 14In silico data is a computational approach, using sophisticated computer models for the determination of a 

sensitizing potential. 15 Kimata et. al., Public Health 2005 Dec, 119(12):1145-9; Becker AW et. al., JACI 2004, 113(4):650-6; Ryan PH 

et. al., JACI 2005, 116(2):279-84; Sandin A et. al., Pediatr Allergy Immunol 2004, 15(4):316-22; Guillet MH et. al., 

Ann Dermatol Venereol 2004, 131(1Pt1):35-7; Meglio P et. al., J Investig Clin Immunol 2002, 12(4):250-6.
contribute to risk in all populations studied.16 The incidence of asthma has 

risen dramatically in the past 20 years; the number of asthma cases in the 

United States for all age groups has increased by at least 75 percent over the 

past 2 decades, while the rate among children under the age of 5 has increased 

more than 160 percent, and it continues to rise.17 This is a period far too short 

to reflect any significant changes in the gene pool. This supports the 

important role that other susceptibility factors and the environment may have 

on the development of allergic diseases like asthma. The importance of age, 

gender, race, and occupation in the development of allergies has been shown 

in many studies. 

Differences may exist between susceptibility to respiratory allergens and to 

dermal allergens, such that neonates/infants may have increased susceptibility 

to respiratory allergens but potentially not to skin allergens. However, 

neonatal infants have acquired allergic contact dermatitis from vinyl 

identification bands, nickel, neomycin, ethylenediamine, thimerosal, 

merbromlin (mercurochrome), balsam of Peru, rubber chemicals in shoes, and 

poison ivy.18 More research is necessary to determine whether these 

differences between susceptibility to respiratory allergens and skin allergens 

exist. 

Currently, there is conflicting data to determine age-specific susceptibility to 

skin allergens; however, this may change as more information becomes 

available because recent publications indicate that allergic dermatitis is the 

most common skin condition in children under the age of 11 years. In 

addition, the percentage of children diagnosed with allergic dermatitis has 

increased more than 300 percent since the 1960s.19 CPSC staff believes that 

children should be considered to be at increased risk to respiratory sensitizers 

and that skin sensitizers should be evaluated on a case-by-case basis when 

estimating potential risks associated with exposures to substances that are 

considered to be “strong sensitizers.” CPSC staff will consider susceptibility 

qualifiers (e.g., genetics, age, gender, and atopic status) in their evaluation of 

the potential of a substance to cause significant hypersensitivity. 

 16 Ober C et. al., Curr Opin Immunol. 2005 Dec, 17(6):670-8; Osmola A et. al., Acta Dermatovenerol Croat 2005, 

13(2):122-6. Hoffjan S et. al., J Mol Med 2005 Sep, 83(9):682-92. 17 Centers for Disease Control and Prevention (CDC), April 24, 1998. “Surveillance for Asthma – United States, 

1960−1995.” MMWR Surveillance Summaries 47(SS-1):1-28; Akinbami et al., NCHS Data Brief 2012, No.94, 

“Trends in Asthma Prevalence, Health Care Use, and Mortality in the United States, 2001−2010.

18 Fisher’s Contact Dermatitis, 2001, 5th edition, Rietschel RL and Fowler J, eds. Lippincott, Williams and Wilkins, 

New York.

19 American Academy of Allergy Asthma and Immunology (AAAAI), Allergy Statistics, Media Kit; and, Horan RF 

et al., JAMA 1992, 268: 2858-68; Atheron et.al. Community Practioner 2005, 78(7): 255−257; Matiz et.al. Giornale 

Italiano di Dermatologia E Venerologia 144(5): 541−546; Smith et.al. Pediatr Dermatol 2009, 26(3): 369−370; 

Thyssen et.al. Contact Dermatitis 2007, 57: 287−299.
Additional consideration may be given to Quantitative StructureActivity Relationships (QSARs), in silico data, specific human 

sensitization threshold values, other data on potency and sensitizer 

bioavailability, if data is available and the methods validated. 

Bioavailability is the dose of the allergen available to interact with a 

tissue. It is a reflection of how well the skin or another organ can 

absorb the allergen and the actual penetrating ability of the allergen, 

including such factors as size and composition of the chemical. 

QSARs or Quantitative Structure-Activity Relationships are mathematical 

models that relate a quantitative measure of chemical structure to biological 

activity. In silico data is a computational approach using sophisticated 

computer models for the determination of a sensitizing potential. QSARs and 

in silico approaches are evolving methodologies that have not been validated

yet; but CPSC staff believes that they may be useful and may be used as part 

of a weight-of-evidence approach and/or in an integrated testing strategy. 

These techniques are being pursued to reduce the numbers of expensive 

laboratory (in vitro) and animal (in vivo) experiments carried out.

B. Frequency of Occurrence and Severity of Reaction

Before the Commission designates any substance as a “strong” sensitizer, frequency of 

occurrence and range of severity of reactions in exposed subpopulations having average 

or high susceptibility will be considered. The minimal severity of a reaction for the 

purpose of designating a material as a “strong sensitizer” is a clinically important 

reaction. A clinically important reaction would be considered one with a significant 

impact on quality of life. Consideration should be given to the location of the 

hypersensitivity response, such as the face, hands and feet as well as persistence of 

clinical manifestations. For example, strong sensitizers may produce substantial illness, 

including any or all of the following:

o Substantial physical discomfort and distress

o Substantial hardship

o Functional or structural impairment

o Chronic morbidity

20 

The classification of a strong sensitizer under the FHSA is complex. As indicated by the 

statutory definition, careful consideration of the prevalence of sensitization (frequency of 

occurrence) and severity of response should be carried out in addition to evaluating a 

substance’s potential to cause sensitization in designating a substance as a strong 

sensitizer. Each component needs to be weighed in light of other available data. For 

example, a substance may be a common sensitizer due to widespread exposure to the 

general population; however, the reactions to exposure to the substance may be mild and 

 20 Updated strong sensitizer supplemental definition 16 C.F.R. §1500.3(c)(5).
the sensitizing strength (potency) low. Therefore, such a substance may not be 

designated a strong sensitizer even though it has a higher frequency of occurrence.

Data for the determination of a sensitization frequency cut-off limit, a tolerable level of 

sensitization/allergy prevalence, for the general population is limited because most 

epidemiological studies are performed on a subset of the general population, that is, on 

individuals who are already sensitized. Data are available on several chemicals that 

could serve as a template in deriving a frequency-of-occurrence limit; however, these 

chemicals are predominantly occupational sensitizers. Because the degree of 

sensitization in the workplace can be greater than that of the general population, due to 

greater exposure (both in time, concentration and product use) to the sensitizing agent, 

CPSC staff believes that caution should be employed in applying work-related 

frequencies of chemical sensitization to the consumer scenario. For example, the 

prevalence of latex allergy in healthcare workers ranges from 2.2 to 17 percent; for spina 

bifida patients, prevalence ranges from 29 to 65 percent; yet the prevalence for the 

general population is estimated to be below 1 percent.21 However, sensitization in the 

workplace can serve as a harbinger for consumer sensitization, as observed with the 

preservative MCI/MI,22 which was known as a workplace allergen when it first came into 

use. Since then, it has risen to be among the top 30 of allergic contact dermatitis 

allergens for the general population of North America.

The European Union considers a substance to be a strong sensitizer if the frequency of 

sensitization to that substance in the general population is greater than or equal to 1 

percent. It is generally accepted by the scientific community that allergic contact 

dermatitis affects 1 percent of the general population worldwide. The Institute of 

Medicine (IOM) indicated that 20 percent of the general population will develop an 

allergy-related illness (sinusitis, rhinitis, bronchitis, asthma).23 However, with the rate of 

allergy in industrialized countries increasing dramatically over the past 2 decades, and 

with prevalence factors likely varying for each sensitizing agent, setting a sensitization 

frequency cut-off limit for a “strong sensitizer” at 1 percent may be overly protective or 

insufficiently protective. CPSC staff believes that identifying a substance as a “strong 

sensitizer” based on a sensitization frequency cut-off rate value is best considered on a 

case-by-case, weight-of-evidence criteria, if sufficient data are available. 

In the following section, CSPC staff discusses specific objective criteria for evaluating 

the severity of a reaction in the respiratory system and skin, to bring objectivity to an area 

of great subjectivity, by providing clinically sound and reproducible criteria for defining 

levels of impairment. 

 21 CPSC (2003) – “Petition on Natural Rubber Latex (HP 00-2).” Memorandum from J Elder and S Barone to the 

Commission, Todd Stevenson. October 10, 2003.

22 MCI/MI: methylchloroisothiasolinone/methylisothiasolinone; Pratt et al, Dermatitis 2004, 15(4): 176−183. 23 IOM (Institute of Medicine), 1993. Indoor Allergens: Assessing and Controlling Adverse Health Effects.

Washington DC, National Academy Press.
1. Determining the Severity of Respiratory and Skin Sensitization Responses

a. Respiratory

Airway hyper-responsiveness (AHR) is a characteristic feature of the lungs of 

asthmatic individuals, although AHR also can be found in individuals with 

non-allergic conditions of airflow obstruction (e.g., chronic obstructive 

pulmonary disease). Inhaled stimuli, such as environmental allergens, can 

increase airway inflammation and enhance AHR. Changes in AHR can be 

smaller in healthy subjects than those measured in asthmatic patients with 

persistent AHR; they are similar to the changes occurring in asthmatic patients 

with worsening asthma control. Therefore, measurements of AHR are useful 

diagnostic tools for the general population. 

Measures of airway responsiveness are based on the increased sensitivity of 

the airways to an inhaled constrictor (e.g., histamine, methacholine). These 

nonspecific tests are used frequently in making a diagnosis and can be 

performed quickly, safely, and reproducibly in a clinical or laboratory setting. 

The National Asthma Education and Prevention Program (NAEPP) was 

initiated in March 1989, to address the growing problem of asthma in the 

United States. The NAEPP is administered and coordinated by NIH’s 

National Heart, Lung, and Blood Institute (NHLBI). The NAEPP works with 

intermediaries, including major medical associations, voluntary health 

organizations, and community programs to educate patients, health 

professionals, and the public about asthma. The ultimate goal of the NAEPP is 

to enhance the quality of life for patients with asthma and decrease asthmarelated morbidity and mortality. The NAEPP Expert Panel report (#2) 

provides guidelines for the diagnosis of asthma.24 These guidelines suggest

that asthma severity should be based on symptomatic and functional 

assessments, including the frequency and severity of asthma symptoms, the 

frequency of rescue medication use, and objective measures of lung function. 

Although several publications indicate that the NAEPP guidelines may not 

provide clear delineations between all levels of symptoms within the severity 

classification,25 these guidelines are in line with the American Medical 

Association’s (AMA) respiratory impairment guidelines and tests 

recommended by the IOM. 

 24 NAEPP, National Institutes of Health/National Heart, Lung, and Blood Institute. NAEPP Expert Panel, Clinical 

Practice Guidelines. Expert panel report 2: Guidelines for the Diagnosis and Management of Asthma, volume 

publication no. 97-4051, Bethesda, MD, 1997; and NAEPP Expert Panel Report: Guidelines for the Diagnosis and 

Management of Asthma, Update on Selected Topics 2002. 25 Fuhlbrigge AL et al., Am J Respir Crit Care Med 2002, 166:1044-49; Rosenwasser LJ et al., Pharm Therap 2003 

June, 28(6):400-14
Tests of pulmonary function (particularly FEV1 and PEF measurements),

26 are 

considered the most useful, and they are the framework of the severity 

determination detailed in the NAEPP guidelines. Medical history, medication 

use, and symptomatology (type of symptom, severity, duration and manner of 

onset) are also considered. In the “Disease Severity Classification Scheme,” 

recommended in the current NAEPP guidelines, patients are assigned to the 

most severe grade of asthma in which any feature occurs. 

CPSC staff believes that the classification categories, “moderate persistent” 

and “severe persistent” should be considered “severe” responses, in line with 

the FHSA “strong sensitizer” supplemental definition. 

 26 FEV (forced expiratory volume) and PEF (peak expiratory flow)
 

Nighttime 

Symptoms Symptoms Lung Function Medications27 

Mild

Intermittent Occurring < 2x/ <2x/month FEV1 or PEF>80% Long-term: no

week; asymptomatic predicted; PEF daily medications 

and normal PEF variability <20% needed; systemic

between exacerbations; corticosteroids may

exacerbations brief be required for 

(few hours for a few exacerbations.

days); variable.

Mild

Persistent Occurring >2x per >2x/month FEV1 or PEF>80% Long-term: low-dose,

week but less than predicted, PEF inhaled corticosteroids;

1x/day; exacerbations variability 20%-30% or cromolyn sodium, 

can affect activity leukotriene modifiers,

levels. nedocromil or sustained

release theophylline.

Moderate

Persistent Daily; daily use of >1x/week FEV1 or PEF >60% Long-term: low-toshort-acting beta2 and <80% predicted; medium dose of 

agonists; exacerbations PEF variability >30% corticosteroids and

affect activity levels; long-acting inhaled 

exacerbations occur beta2 agonists or with

>1x/week; can last leukotriene modifier or

several days. theophylline. 

Severe

Persistent Continual; limited Frequent FEV1 or PEF < 60% Long-term: high-dose

physical activity; predicted; PEF corticosteroids and

frequent exacerbations variability >30% long-acting beta2

agonists and (if needed)

corticosteroid tablets or

syrup.

(FEV1=forced expiratory volume in one second, PEF=peak expiratory flow)

 27 Short-term therapy is the same for each of the four NAEPP classification groups: short-acting beta2 agonist 

inhaler (two to four puffs, as needed); intensity of treatment depends on severity; use of quick-relief more than 

2x/week indicates need to step up long-term control therapy.
b. Skin

Allergic contact dermatitis is characterized by erythematous macules 

(discolored spots) and papules (circumscribed solid elevated areas on the skin 

with no visible fluid, which usually precedes vesicle and pustule formation), 

edema, fluid-filled vesicles, or bullae (blisters), and chronically, by 

lichenification (thickening) and scaling. Diagnosis is primarily based on skin 

appearance and history of exposure. There is a lack of consensus as to which 

visual variables best reflect dermatitis severity and there is a lack of 

standardization in disease severity scoring. More than 50 different clinical 

scoring systems have been identified in the 93 randomized controlled clinical 

trials published between 1994 and 2001.28

The presence or absence of sleep disturbance, the number and location of 

involved sites, and the clinical course are the indicators of severity (i.e., 

criteria) that provide the best basis for making clinical decisions and severity 

scoring.29 Three systems were considered to assess severity: W-AZS, 

Emerson et al30 and IGADA (Investigator Global Atopic Dermatitis 

Assessment).31 These systems use some or all of the above-mentioned 

criteria. CSPC staff suggests using a simplified version of the W-AZS 

severity scoring system32 because it encompasses detailed assessment of both 

subjective and objective signs and symptoms of dermatitis. It is noteworthy 

for consideration of both acute and chronic skin manifestations of the disease, 

for its ease of use, and for its evaluation of pruritus (itching) and loss of sleep. 

CPSC staff would generally consider a severity score totaling from 99 points 

to 152 points to be “moderately severe” and a severity score of 153 or more to

be “severe.”

 28 Charman CR et al., Arch Dermatol 2005 Sep; 141:1146-51.

29 Williams HC, NEJM 2005 June; 352(22):2314-24. 30 Emerson RM et al., Br J Derm 2000; 142:288-97; who adapted the Rajka & Langeland index, an index that has 

been widely used as the basis for some of the more common severity scoring systems. This adaptation is simple and 

has been used in clinical trials and is significant because it incorporates chronicity, extent, and intensity of disease. 

The three-part score evaluates loss of sleep, clinical course, and extent of body surface affected. 31 Schachner LA et al., Pediatrics 2005 Sept; 116(3):e334-42; IGADA uses scores based on the Physician 

Assessment of Individual Signs (PAIS), which evaluates the severity (on a scale from 0 to 3) of erythema, edema, 

excoriations, oozing/weeping/crusting, scaling, and lichenification. The IGADA severity score categories are clear, 

almost clear, mild, moderate, severe, and very severe. 32 Silny W et al., Acta Dermatov Croat 2005; 3(4):219-24.
Severity Index Score = I + II33

o I = A + B

o II = (C + D)/10

Section I

A. Pruritus Points B. Loss of Sleep Points

1. No pruritus 0 1. No loss of sleep 0

2. Problems in falling asleep 3

2. Extent 3. Night awakening 6

- Single or multiple 2 4. Sleeplessness 12

- Extensive 6 

3. Frequency

- < 30 minutes 2

- Long-lasting 4

- Constant 8

4. Severity

- No scratching 2 

- Scratching 4

- Anxiety, irritation 8

Section II

C: Skin lesions D: Severity signs of inflammation

Erythema & vesicles crust lichenification

Body areas: edema score score scaling score score

Head and neck ( ) x 2 + Face and neck ( ) x 3 + ( ) x 3 + ( ) x 2 + ( ) = 

Trunk ( ) x 8 Trunk (anterior) ( ) x 3 ( ) x 3 ( ) x 2 ( ) =

Upper Appendages ( ) x 4 Right arm ( ) x 3 ( ) x 3 ( ) x 2 ( ) =

Lower Appendages ( ) x 8 Right thigh ( ) x 3 ( ) x 3 ( ) x 2 ( ) =

C: extent of skin lesions (scored from 0 to 3):

o 0 = absence of lesions

o 1 = 1%-10% of skin surface involved

o 2 = 11%-30% of skin surface involved

o 3 = 31%=100% of skin surface involved

D: severity of skin inflammation (sum of four criteria, each scored from 0 to 3):

o 0 = absent

o 1 = mild

o 2 = moderate

o 3 = severe

 33 Based on the W-AZS severity scoring system.
III.Normal Living Tissue

The allergic hypersensitivity reaction occurs in normal living tissues, including the skin 

and other organ systems, such as the respiratory or gastrointestinal tract, either 

singularly or in combination, following sensitization by contact, ingestion, or 

inhalation.34

In the future, with progress in the science, there may be a need to have a definition for 

classes of allergen (e.g., chemical, protein, respiratory, ocular, skin). At this time 

insufficient evidence exists to clearly separate the sensitization characteristics (e.g., 

different mechanisms of sensitization) of the different target organs. 

Conclusion

Multiple considerations would be used by CPSC staff before suggesting that a substance is a 

strong sensitizer. The determination of risk of hypersensitivity should follow a weight-ofevidence approach, using all available validated tools. Existing human data are preferred over 

animal data. CPSC staff, when evaluating existing data from human and/or animal studies, takes 

the quality of the data into consideration. The frequency of sensitization occurrence and the 

severity of the sensitization response will be considered. 

New data and methodologies continue to be developed; therefore, to specify particular assays 

would likely result in their replacement as new data and information become available. 

Once designated as a strong sensitizer, for a product to be considered a hazardous substance and 

to require cautionary labeling under the FHSA, the product must be capable of causing 

substantial personal injury or substantial illness during, or as a result of, customary or reasonably 

foreseeable handling or use, including reasonably foreseeable ingestion by children. This 

requires consideration of the route and the level of exposure that can be expected to be presented 

by the strong sensitizer as it exists in the particular substance. Therefore, determining whether a 

cautionary label is required must occur on a product-by-product basis and is not solely based 

upon the presence of a strong sensitizer in a product. 

 34 Updated strong sensitizer supplemental definition 16 CFR §1500.3(c)(5).