For more than 20 years, the occupational safety and health community has relied on skin notations from the National Institute for Occupational Safety and Health (NIOSH) to warn workers about the health hazards of skin exposures to chemicals. These notations have proved to be useful risk management tools for occupational health professionals concerned about protecting workers from injuries and illnesses caused by skin contact with chemicals. However, according to the definition, a NIOSH skin notation may be assigned to a chemical only if that substance has been scientifically determined to be dermally absorbed. The current, widespread practice of using a skin notation to indicate that a substance poses other health effects, such as skin irritation, following any kind of skin exposure is inaccurate and misleading.NIOSH adopted the skin notations for 142 chemicals as part of its 1988 testimony to the Occupational Safety and Health Administration's (OSHA) proposed rule on Air Contaminants (Permissible Exposure Limit update). The skin notations for these chemicals are listed in the NIOSH Pocket Guide to Chemical Hazards by the symbol . Despite the usefulness of the skin notations as a risk management tool, NIOSH has identified several conceptual difficulties with the ways in which skin notations have been assigned:#
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# Foreword
The National Institute for Occupational Safety and Health (NIOSH) has estimated that workplace skin diseases account for 15%-20% of all reported occupational diseases in the United States, with estimated total annual costs (including lost workdays and lost productivity) up to $1 billion. Skin exposures to chemicals can cause a wide array of injuries and illness including contact dermatitis, immunemediated responses, and irreversible damage to the skin. Despite the relatively high incidence of contact dermatitis and other workplace skin diseases, the impact and risk of skin contact with chemicals and other hazardous agents are not well known, hampering the recognition and prevention of these disorders. Additionally, skin contact represents a significant route of exposure for chemicals that have the potential to be percutaneously absorbed and subsequently cause systemic effects including, but not limited to, acute toxicity, cancers, neurotoxicity, and effects on the reproductive system.
NIOSH has long recognized the hazards of skin contact with chemicals in the workplace and the importance of quality research and policies to prevent such exposures. In 1999, NIOSH launched an Interdisciplinary Cross-Sectional Research Program as part of the National Occupational Research Agenda (NORA). This Dermal Exposure Research Program (DERP) was established to promote the identification and control of skin exposures to hazardous agents and conditions in the workplace. The focus of DERP was to expand the current knowledge base through laboratory and field research and to apply scientific decision-making processes for policy development. NIOSH has entered the second decade of NORA and, through its Immunological and Dermal Cross-Sector Program, continues to investigate methods for protecting workers from hazardous skin exposures and for reducing the prevalence of occupational skin diseases.
NIOSH skin notations are hazard warnings used worldwide to alert workers and employers to the health risks of skin exposures to chemicals in the workplace. This Current Intelligence Bulletin (CIB) provides the rationale for assigning new NIOSH skin notations. The new system reflects the current state of scientific knowledge and involves critical evaluation of scientific data so that scientists can assign multiple skin notations that distinguish between the systemic, direct, and sensitizing effects of skin exposures to chemicals. This new strategy is a form of hazard identification that advances our understanding of the hazards posed by skin exposures to chemicals. Such improved understanding will enable us to implement better risk management practices and controls for the prevention of workplace skin diseases 1. The current NIOSH system relies on a single skin notation that is intended to warn against the potential for a chemical to be dermally absorbed and contribute substantially to systemic toxicity. This skin notation is not intended to be applied to chemicals that would cause direct effects to the skin or to chemicals that have the potential to act as a sensitizer. 2. The NIOSH skin notation has not been assigned on the basis of a standardized methodology. As a result, chemicals have been improperly assigned a skin notation as a warning for nonsystemic effects, such as skin irritation and corrosion, thereby causing confusion about what types of risk-management practices should be undertaken to prevent skin exposure. 3. The NIOSH skin notation does not reflect the contemporary state of scientific knowledge or recommendations made in NIOSH criteria documents since the 1988 Permissible Exposure Limit update.

# New Strategy for Assigning NIOSH Skin Notations
vi strategic framework outlined within this document is a form of hazard identification that has been designed to do the following:
- Ensure that the assigned skin notations reflect the contemporary state of scientific knowledge
- Provide transparency behind the assignment process
- Communicate the hazards of chemical exposures of the skin - Meet the needs of health professionals, employers, and other interested parties in protecting workers from chemical contact with the skin This strategy involves the assignment of multiple skin notations for distinguishing systemic (SYS), direct (DIR), and sensitizing (SEN) effects caused by exposure of skin (SK) to chemicals. Chemicals that are highly or extremely toxic and may be potentially lethal or life-threatening following exposures of the skin are designated with the systemic subnotation (FATAL). Potential irritants and corrosive chemicals are indicated by the direct effects subnotations (IRR) and (COR), respectively. Thus with the new strategy, chemicals labeled as SK: SYS are recognized to contribute to systemic toxicity through dermal absorption. Chemicals assigned the notation SK: SYS (FATAL) have been identified as highly or extremely toxic and have the potential to be lethal or life-threatening following acute contact with the skin. Substances identified to cause direct effects (i.e., damage or destruction) to the skin limited to or near the point of contact are labeled SK: DIR, and those resulting in skin irritation and corrosion at the point of contact are labeled as SK: DIR (IRR) and SK: DIR (COR), respectively. The SK: SEN notation is used for substances identified as causing or contributing to allergic contact dermatitis (ACD) or other immune-mediated responses, such as airway hyper reactivity (asthma). Candidate chemicals may be assigned more than one skin notation when they are identified to cause multiple effects resulting from skin exposure. For example, if a chemical is identified as corrosive and also contributes to systemic toxicity, it will be labeled as SK: SYS-DIR (COR). When scientific data for a chemical indicate that skin exposure does not produce systemic, direct, or sensitizing effects, the compound will be assigned the notation (SK). The ID (SK) notation is assigned to indicate that insufficient data on the health hazards associated with skin exposure to a substance exist at the time of the review to determine whether the chemical has the potential to act as a systemic, direct, or sensitizing agent. The ND notation indicates that a chemical has not been evaluated by the strategy outlined in this CIB and that the health hazards associated with skin exposure are unknown.
The new skin notation strategy is a form of health hazard identification that standardizes the method for deriving skin notations. Assignment of the new NIOSH skin notations to chemicals relies on a critical assessment of the following:
- A substance's physicochemical properties
- Reports of human exposures and health effects
- Empirical data from in vivo and in vitro laboratory testing vii
- Considerations provided by computational techniques, such as predictive algorithms (e.g., QSAR) and mathematical models (e.g., skin permeation)
A weight-of-evidence approach is applied in evaluating the quality and constituency of the scientific data when conflicting findings are reported. Figure 1 illustrates an overview of the process used to assign skin notations.
The new strategy for assigning the NIOSH skin notations was designed to preserve the conventional wisdom about them and also to address the issues associated with their historic misuse-including their assignment to nonsystemic effects. This system provides a framework for assigning multiple skin notations that incorporates the current scientific database on workplace chemicals and dermal toxicity. The new system warns users about the direct, systemic, and sensitizing effects of exposures of the skin to chemicals. The labeling of a chemical with a hazard-specific skin notation (and in some cases multiple notations) will greatly enhance the quality of hazard communication and the associated risk management process. The new strategy outlined in this CIB also corresponds with the classification strategy adopted in the Globally Harmonized System of Classification and Labeling of Chemicals (GHS) developed by the United Nations (see Appendix G.2). This CIB will be updated as new scientific data becomes available.
Historically, skin notations have been published in the NIOSH Pocket Guide to Chemical Hazards. This practice will continue with the NIOSH skin notation assignments for each evaluated chemical being integrated as they become available. A support document called a Skin Notation Profile (see Appendix F) will be developed for each evaluated chemical. The Skin Notation Profile for a chemical will provide information supplemental to the skin notation, including a summary of all relevant data used to aid in determining the hazards associated with skin exposures.
viii

# ICSC
International Chemical Safety Cards ID (SK) skin notation indicating that a chemical has been evaluated, but insufficient data exist to accurately assess the hazards of skin exposure (IRR) subnotation of SK: DIR indicating the potential for a chemical to be a skin irritant following exposure to the skin Isomers-Molecules that exhibit unique physical structures, but consist of the same elemental composition and weight that may result in significant difference in toxic potency.
K
Photocarcinogenesis-The elicitation or increase of a carcinogenic response after skin exposure to a photo reactive chemical and subsequent exposure to sunlight.
Phototoxicity-The elicitation or increase of a toxic response after skin exposure to a photo reactive chemical and subsequent exposure to sunlight.
Sensitization-A specific immune-mediated response that develops following exposure to a chemical, which, upon re-exposure, can lead to allergic contact dermatitis (ACD) or other immune-mediated diseases such as asthma, depending on the site and route of re-exposure.

# Substance-A chemical.
Systemic effects-Systemic toxicity associated with skin absorption of chemicals after exposure of the skin.
xvi 1

# Introduction
The skin - is the largest organ of the human body and accounts for more than 10% of the body's mass. It enables the body to readily interact with the environment and also serves as a general defense system. It also represents a potentially significant exposure pathway for many chemicals because of the large surface area  available for contact to any one of the innumerable potentially toxic substances in the workplace. The health and economic impacts of such exposures are not fully understood because of the inherent difficulties in differentiating between the contribution of dermal absorption of a chemical and other routes of entry (i.e., inhalation and ingestion) to total body burden and subsequent onset of a specific disease or disorder. Additionally, less attention is often given to characterizing occupational and environmental exposures of the skin to chemicals than is given to other exposure pathways. These limitations potentially leave exposed workers susceptible to a wide spectrum of adverse health outcomes including dermatoses, systemic toxicity, and, in extreme cases, death.  August 1, 1988. Despite the usefulness of the notation  as a risk management tool, it provides little guidance about a chemical other than warning of its possible absorption through the skin.
The assignment of skin notations has several inconsistencies and limitations:
1. The skin notation is based in theory on the potential contribution a chemical makes to systemic toxicity when it is absorbed by the skin . However, the notation has not been consistently assigned according to this principle. Many skin notations are based only on the potential or reported transdermal penetration of chemicals-with no consideration of the causality between dermal absorption and overall toxicity. The system preserves the conventional wisdom for assigning skin notations to chemicals that pose a hazard from skin contact. In addition, this system attempts to prevent possible misclassifications by assigning a notation that specifies potential adverse effects. The skin notation classification scheme presented within this CIB is as follows:
- SYS indicates the potential for a chemical to contribute substantially to systemic toxicity through dermal absorption.
-(FATAL), a subnotation of SYS, indicates that a chemical is highly or extremely toxic, and may be potentially lethal or life-threatening following skin exposures.
- DIR indicates non-immune mediated direct effect(s) of a chemical on the skin at or near the point of contact, including corrosion, primary irritation, bleaching (blanching), staining, and reduction/disruption of the skin barrier integrity.
-(IRR), a subnotation of DIR, indicates that a chemical is a skin irritant.
-(COR), a subnotation of DIR, indicates that a chemical is a corrosive.
- SEN indicates that skin exposure to a chemical may cause or contribute to the onset of allergic contact dermatitis (ACD) or other immune-mediated responses, such as airway hyper reactivity (asthma).
- SK indicates that the reviewed data identified no health hazard associated with skin exposure and did not support assignment of the SYS, DIR, or SEN notation.
- ID (SK) indicates that insufficient data were available at time of evaluation to determine the hazards associated with dermal contact to a candidate chemical substance.
- ND indicates that a chemical has not been evaluated by the improved skin notation strategy, and the health hazards associated with skin exposure are unknown.
The new system also permits the assignment of several skin notations for a chemical when multiple skin hazards exist. For example, if health data indicate that the chemical causes systemic toxicity when absorbed by the skin and is also corrosive, the notation assigned to the chemical would be SK: SYS-DIR (COR).
The skin notations may be modified or additional skin notations may be added when improved scientific data on test methods and increased understanding about the toxicological mechanisms of skin injuries become available.
Also, current criteria for assigning skin notations may be revised to enhance the usefulness of the notations for selecting exposure prevention strategies. Hazard categories that are added later may follow the current scheme, which makes skin corrosives a subnotation under the DIR notation and acute lethality a subnotation under the SYS notation.
It should be noted that the strategy and skin notations outlined in this CIB are not intended to provide a risk-based exposure value for skin exposures to chemicals and should not be used to infer toxic potency for evaluated chemicals.
Other issues associated with skin notations include their application to chemical mixtures, the health effects of contaminants within neat substances, and isomeric variations of a chemical. Because of the complexity of assessing the hazards of chemical interactions associated with complex mixtures or because of the presence of contaminants, the skin notations are intended to apply to neat chemicals and may not be health protective against additional effects associated with complex mixtures (see Appendix G.1). Also, assigned skin notations are applicable only to the specified forms of an evaluated compound and may not provide adequate warnings about unique hazards of the nonspecified isomeric forms of the chemical (see Appendix G.1).

# Criteria for Assigning Skin Notations
The critical step in assigning skin notations to a chemical is determining its hazard potentialthat is, its potential for causing adverse health effects as a result of skin exposure. This determination involves a health hazard identification process that assesses the following:
- Scientific data on the physicochemical properties of a chemical
- Human exposures and health effects
- Empirical data from in vivo and in vitro laboratory testing
- The use of computational techniques, including predictive algorithms  and mathematical models that describe a selected process (e.g., skin permeation) using analytical or numerical methods.
A weight-of-evidence approach is applied when available data are inconsistent. Figure 2 illustrates the hierarchy of scientific data used for assigning skin notations.
Computational techniques, such as mathematical models and predictive algorithms, represent alternative methods to expensive in vivo and in vitro toxicity testing methods. These approaches are increasingly applied to estimate the potential of chemicals to act as skin irritants and sensitizers and their potential to be absorbed (i.e., skin permeation). The performance and reliability of these computational techniques remain unclear. For this reason, predications from computational techniques, such as QSARs and the skin dose to inhalation dose ratio (SI ratio) (see Appendix B), should not be used as the primary basis for the assignment of a skin notation. Instead, they are intended only to serve as additional supportive data sources when limited data are available for the assignment of skin notations. As the computational techniques become more reliable and validated, NIOSH will reassess their use within the assignment of skin notations. If it is determined that the computational techniques accurately predict the effects of skin exposures to chemicals, they may become a primary basis for the assignment of skin notations.
The following sections discuss the skin notation assignments in each category. Exceptions to this approach are also described. This strategy for assigning skin notations has been developed to correspond with the classification strategy adopted in the

# SYS
The SYS notation is assigned to chemicals that are absorbed through the skin and contribute to systemic toxicity. The (FATAL) subnotation is assigned to chemicals identified as highly or extremely toxic and potentially lethal or lifethreatening following skin exposure. Experimental toxicity studies using these protocols frequently result in quantitative data that can be used in assigning skin notations.
The SYS notation is assigned to a chemical when one or more of the following criteria are met:
- Credible evidence indicates that systemic effects in workers result from skin exposure to a chemical in the absence of significant inhalation or oral exposures.
- Data from experimental animal studies indicate--Systemic effects occurred from skin exposures.
-Fatalities or health effects in exposed animals were not associated with skin damage by the chemical or the vehicle containing the chemical.
-Skin exposure results for animals included data on acute toxicity, repeat-dose toxicity, subchronic toxicity, chronic toxicity, carcinogenicity, or biologic system/ function-specific effects.
Appendix A describes the study protocols used and the criteria selected for assigning the SYS notation and its subnotations.
- Studies of scientific merit that followed protocols other than those previously identified and demonstrated systemic effects from skin exposure to a chemical. The protocols may be modifications of the standardized protocols with variations in the evaluation procedures, or they may be designs allowing for examination of health endpoints other than those the standardized protocols allow for. Examples of the latter studies include the following:
- Both conditions must be satisfied to assign a SYS notation.
- When no acceptable-quality empirical data exist on the systemic effects of skin exposure, the potential for dermal absorption and consequent systemic toxicity of the chemical may be mathematically estimated via computational techniques.
To mathematically determine the risk for systemic toxicity (e.g., predictive algorithm), the following information is needed: (1) skin permeation rate, (2) chemical dose calculated to be absorbed through skin (skin dose), (3) reference dose representing the threshold of acceptable body accumulation (a chemical dose to be absorbed via inhalation during the same period of exposure), and (4) comparison of the skin dose to the reference dose (which indicates the significance of skin absorption and its potential contribution to systemic toxicity).
Appendix B presents an algorithm that can be used for determining the potential for systemic toxicity. When the predictive algorithm is used as the basis for identification, a positive result indicates that a chemical is capable of producing systemic toxicity from skin exposure and should be assigned the SYS notation. If the predictive algorithm indicates no potential for systemic toxicity from dermal absorption, the chemical should be further evaluated with accepted tests. The results of the predictive algorithm should not be used as the sole basis of the assignment of a SYS notation.  Indicates that insufficient data were identified to accurately assess the systemic hazards or potential for dermal absorption associated with contact of the skin with a specified chemical.
adverse effects accompanied by pain or discomfort, such as tissue lesions or blisters, and burns of varying degrees at or near the point of contact. Skin irritants that are identified to cause corrosion will be assigned only the SK: DIR (COR) notation to ensure that the most hazards endpoint is recognized.
Immune-mediated responses of the skin associated with exposures of the skin to chemicals, such as ACD and allergic urticaria, are not assigned the DIR notation. These immunemediated responses would be assigned the SEN notation if data are supportive and are addressed within Section 2.4.
An SK: DIR notation is assigned when one or more of the following criteria are met:
- Credible evidence indicates that immediate, prolonged, or repeated contact of skin with the chemical produces direct effects on the skin of exposed workers. The direct effects reported were based on incidents of worker exposures. The effects consist of the following:
-Primary irritation, including irritant contact dermatitis (macroscopically manifested as erythema and edema)
-Corrosion (manifested as ulceration, visible necrosis of epidermis/dermis, bleeding, eschar formation, and discoloration)
-Changed pigmentation -Chloracne caused by chemicals such as halogenated aromatic hydrocarbons -Defatting/drying of skin -Skin cancer at or near the point of contact
Predictive patch tests conducted on human volunteers (e.g., the acute dermal irritation study in human volunteers) may also yield information about acute or cumulative irritation of human skin . Such information will be considered when assigning skin notations.
- Data from laboratory tests indicate direct effects on skin as a result of chemical exposures. These data include in vivo animal studies reporting the acute irritancy, corrosivity, and carcinogenicity of chemicals, in vitro assays identifying corrosivity potentials, and in vitro evaluations examining alteration in the barrier properties of skin as a result of skin exposure to chemicals. Appendix A describes protocols and the criteria that can be used for deriving SK: DIR notations.
- Relevant scientific data not generated using the study protocols previously described can be used if they provide adequate qualitative data on the direct effects on skin as a result of skin exposure to a chemical. Protocols may be modifications of standardized protocols (e.g., the research protocols introduced in Appendix A) with variations in the evaluation procedures or study design that examine health endpoints other than those evaluated by the standardized protocols. Examples of the latter include reports of histopathological examinations indicating impairment of skin tissues, disintegration of skin components (e.g., defatting and discoloration), or the presence of neoplastic lesions or tumors in the epidermis and dermis in association with changes in the transdermal penetration of chemicals.
- When no acceptable-quality empirical data exist on the direct effects of skin exposure to a chemical, information from the structure-activity-relationship (SAR)-based analysis and the physicochemical properties and reactivity of the chemical may be used as alternative methods for identifying hazards . Examples of SAR analysis are the clinical and/or experimental observations of the adverse effects occurring at the site of exposure to a structurally related or similar chemical in question.
Physicochemical properties such as extreme pH and buffering capacity can be used to estimate the corrosivity potential of acidic or alkaline chemicals on the skin. See Appendix C for further discussion about using pH and acid/alkali reserves for assigning SK: DIR notations. When the algorithm is used as the basis of identification, a positive result is sufficient to classify a chemical as capable of provoking direct effects on the skin and assigning an SK: DIR notation.

# SEN
Skin exposure to a chemical may cause or contribute to the onset of ACD or other immunemediated responses, such as airway hyper reactivity (asthma). Occupationally, the most commonly recognized immune-mediated responses following skin exposure is ACD. For ACD, the skin-sensitizing potential of the chemical is typically evaluated by two endpoints-the immunologic induction of sensitization and the elicitation of ACD. The SEN notation may be assigned to the following types of immunemediated responses caused by or contributed to exposures of the skin:
- ACD
- Systemic allergic reactions
- Immune-mediated respiratory diseases Immune-mediated responses are commonly associated with two immune mechanisms: the immediate hypersensitivity response (which, in a previously sensitized person, normally occurs within minutes of exposure) and the delayed hypersensitivity response (which occurs 24-72 hours following exposure). Immediate responses are primarily mediated by immunoglobulin E antibodies when the chemical-specific antibodies in systemic circulation contact antigens such as exogenous proteinaceous molecules.
In the immediate hypersensitivity reaction, the respiratory tract, in addition to the skin, may respond after dermal exposure to the causative agent. Delayed hypersensitivity response is a T-cell-mediated immune response that requires a procession of cellular events within the body (the induction phase) leading up to the inflammatory response (the elicitation phase). This procession includes (1) association of antigens (haptens) with proteins, (2) presentation of the protein-hapten conjugates to the regional lymph nodes, (3) recognition of the conjugates by specific T cells, and (4) proliferation of the specific T cells in draining lymph nodes.
Results of animal and human studies support a link between exposures of the skin to certain chemical allergens, systemic sensitization, and the subsequent development of lung allergic responses following inhalational exposures . Animal studies in several species have shown that skin exposure to isocyanates followed by inhalational challenge is highly effective at inducing asthmatic lung responses.
. Human studies, although more limited, suggest a similar role following skin exposure to certain sensitizing chemicals . Despite decreased inhalation exposures to isocyanates and beryllium within various occupational settings, immune-mediated respiratory diseases associated with these compounds continue to occur, frequently in settings with opportunities for skin exposure . Together, the human and animal data suggest that skin contact with certain chemical allergens may contribute to the development of immune-mediated respiratory diseases, such as asthma or chronic beryllium disease .
In laboratory testing, chemical allergens are largely identified in vivo using the conventional guinea pig sensitization test or the more innovative murine local lymph node assay (LLNA). Data relevant for determining whether the chemical may cause an immune-mediated response include the following :
- Analytical or descriptive epidemiologic studies
- Observational case reports from health surveillance programs and/or poison control centers - Clinical studies Note-The main purpose of clinical tests with human volunteers is to confirm the safety of test materials or preparations rather than to identify skin sensitization hazards.
The SEN notation is assigned when one or more of the following criteria are met:
- Credible evidence indicates the occurrence of ACD or sensitization as a result of chemical exposure of the skin. Skin sensitization among workers is often characterized clinically by immunologically mediated cutaneous reactions such as pruritus, erythema, edema, papules, vesicles, bullae, or a combination of these findings. Information about human immune-mediated reactions from skin exposure may also be used from the results of predictive patch tests conducted on human volunteers (e.g., the human repeat insult patch test ). Such information will be considered when assigning skin notations.
- When human data are used as the basis of identification, one of the following types of evidence is sufficient to classify a substance as a sensitizer:
-Studies in which sensitization is evident from valid clinical investigations (e.g., patch testing or antigen-specific immune responses, such as antibody responses or lymphocyte proliferation)
-Confirmed case reports describing several subjects in more than one independent study -Epidemiologic evidence establishing a causal relationship between exposure and sensitization When only isolated episodes of ACD are observed, supporting evidence should be obtained (including data available from animal tests and an appropriate SAR) before the chemical is recognized as a contact allergen .
- Animal data indicate the potential for ACD or other immune-mediated responses associated with skin exposure. Such animal data include the guinea pig sensitization tests identifying sensitization or ACD, LLNA, mouse ear swelling test, and relevant animal models of asthma. Appendix A describes protocols and criteria that can be used in assigning the SEN notation.
- Scientific data other than those previously described may be used to demonstrate sensitization as a result of skin exposure to a chemical. Such protocols include those that may be modifications of the standardized protocols (e.g., the research protocols introduced in Appendix A) with variations in the evaluation procedures or study designs that examine health endpoints other than those evaluated by the standardized protocols. An example is studies that evaluate the induction of antigen-mediated responses following skin exposure.
- When no empirical data of acceptable quality exist, the occurrence of ACD or other immune-mediated responses as a result of skin exposure to a chemical, information from the SAR-based analysis, and other computational techniques can be used as alternative methods for identifying hazards. An example of a SAR analysis is the use of the knowledge-based expert system Deductive Estimation of Risk from Existing Knowledge (DEREKTM) to evaluate the relationship between the molecular structure of the chemical and its allergenic properties. Appendix C describes the DEREKTM expert system for identifying sensitizers. When the algorithm is used as the basis of identification, a positive result is sufficient to classify a chemical as an agent capable of provoking ACD or sensitization from skin exposure and assigning the SEN notation.

# SK
The SK notation is assigned to indicate that a chemical underwent a critical assessment, based on the criteria described above, of the scientific data and was not identified as a systemic, direct, or sensitizing health risk from skin exposure. It should be noted that for a chemical to be assigned the SK notation, the scientific data must be classified as sufficient based on the criteria outlined in Appendix E.

# ID (SK)
The ID (SK) notation indicates that insufficient data exist on the health hazards associated with skin exposures to a substance to determine if the chemical has the potential to act as a systemic, direct, or sensitizing agent. Assignment of this notation will be determined through an assessment of a chemical's creditable scientific data identified during an extensive search of published literature (see Appendix E). Chemicals designated with the ID (SK) notation may represent a significant health hazard following contact with the skin, and proper controls should be applied to prevent or minimize occupational exposures. Despite the absence of sufficient data to assign the SYS, DIR, or SEN notation, a Skin Notation Profile (see Appendix F) will be drafted for all chemicals assigned ID (SK) to document that the substance has been previously evaluated.

# ND
The ND notation signifies that a chemical has not been evaluated by the strategy outlined in this CIB, and the associated health hazards of skin exposure are unknown. The ND notation will be included within future NIOSH publications, including the NIOSH Pocket Guide to Chemical Hazards. This appendix presents the experimental protocols used in laboratory studies of the systemic effects, direct effects on skin, and sensitization potentials of chemicals resulting from skin exposure using animal models or alternative methods (e.g., in vitro bioassays). The protocols included have generally been standardized and validated by various regulatory agencies and research institutes in the United States and Europe. For each protocol, the introduction contains (1) concise discussions of the underlying principles and methods and
(2) criteria for assigning skin notations based on results of studies that followed the protocol.
As the investigative methods are developed or improved, other protocols with scientific merit may become available. Depending on their status, additional protocols may be selected to develop criteria for assigning skin notations.

# A.1 Experimental protocols for investigating systemic effects of skin exposure and derived criteria for assigning the SYS notations

# A.1.1 Dermal absorption
Dermal absorption is the transport of chemicals from the outer surface of the skin both into the skin and into systemic circulation. This process is often described using the terms penetration, permeation, and resorption. Experimental techniques used to estimate the potential for absorption include in vivo and in vitro toxicity studies and computational techniques.
In vivo and in vitro test methods have been developed to estimate both the rate and percentage of an applied dose of a substance absorbed (i.e., penetration or permeation) through the skin . In vivo studies use a physiologically and metabolically active system in the form of human volunteers or test animals, such as rats, to assess the skin penetration, permeation, and resorption of test chemicals . In vitro dermal absorption tests generally rely on the application of a radiolabelled test substance to a sample of nonviable or metabolically active excised skin suspended between two chambers of a diffusion cell and are used to measure the rates of penetration and permeation . In both in vivo and in vitro experimental studies, the applied dose and the vehicle may directly influence the absorption of the substance across the skin.
Computational techniques, such as QSARs and QSPR, have been developed to offer a relatively inexpensive method for determining skin penetration of chemicals [Moss et al. 2002

# A.1.8 Assignment of the SYS notation based on alternative exposure pathways
Toxicity data associated with alternative exposure pathways (i.e., ingestion, inhalation, and injection) may be considered during the assignment of the SYS notation. The primary criteria applied for determining the appropriateness of the use of toxicity data associated from alternative exposure pathways are as follows:
1. No quality dermal toxicity data were identified.
2. Toxicokinetics data clearly demonstrate that the chemical has a high potential to be dermally absorbed and contributes significantly to systemic dose (see Section A.1.1).
3. The critical health endpoint(s) being investigated must be systemic in nature.
4. The critical systemic endpoint(s) is independent of the route of exposure.

# A.2 Experimental protocols for investigating direct effects of skin exposure and derived criteria for assigning the DIR notations

# A.2.1 In vivo animal tests for acute irritancy and corrosivity
Most research protocols available for in vivo testing for skin irritation and corrosion follow the Draize procedure, with modifications in exposure duration, test animal species and number, and intervals between observations. In the standardized protocols [U.S. EPA 1998j;
OECD 2002a], a single dose of the test chemical is applied to the skin of albino rabbits, normally for 4 hours unless corrosion is observed. The animals are examined for signs of erythema and edema, and the responses are scored at intervals over 72 hours. These procedures are also used to examine and grade any persistent or delayed effects that may occur within 14 days after exposure and to fully evaluate the reversibility of observed effects. A chemical that induces reversible inflammation, dryness, or redness with minor pain or discom fort of the skin is considered an irritant and is assigned the (IRR) notation. The (COR) subnotation will be assigned when a chemical is known to cause irreversible adverse effects accompanied by pain or discomfort, such as tissue lesions or blisters, and burns of varying degrees at or near the point of contact.

# A.2.2 In vitro tests for corrosivity using human or animal skin models
In vitro methods using human or animal skin models are used as alternatives to conventional in vivo tests for assessing the corrosivity of chemicals. - The rat skin transcutaneous electrical resistance (TER) assay  The Corrositex assay evaluates the pH-sensitive destruction of a reconstituted, collagen-based biobarrier and determines the corrosivity potential by measuring the time required for the test material to pass through the biobarrier membrane (i.e., the breakthrough time) and produce a visually detectable change in the Chemical Detection System. Chemicals of high acid/alkaline reserves (Category I materials) and those of low acid/alkaline reserves (Category II materials) are considered corrosive when their breakthrough times are less than 4 hours and 1 hour, respectively . The EPISKINTM and EpiDermTM models evaluate the corrosivity potential of a test substance by measuring the decreased viability of human skin cells in reconstructed epidermis/dermis after exposure. In EPISKINTM, a test substance is identified as potentially corrosive when it induces at least a 35% decrease in cell viability. In EpiDermTM, the substance is classified as corrosive if it induces at least a 50% decrease in relative cell viability after 3 minutes of exposure or at least an 85% decrease after 60 minutes. The TER assay measures the reduction of inherent TER on the skin of young rats caused by the loss of normal stratum corneum integrity and barrier function. A test substance is considered potentially corrosive and assigned the (COR) notation if it reduces the TER to a threshold below 5 kilohms.

# A.2.3 Carcinogenicity

# A.2.4 In vitro tests of skin integrity using human donor skin
Examples of in vitro methods for evaluating skin integrity include those for measuring the movement of a standard compound such as tritiated water through the stratum corneum, the transepidermal water loss from the stratum corneum, and the electrical resistance of skin to an alternating current at up to 2 volts .

# A.3 Experimental protocols for investigating sensitization from skin exposure and derived criteria for assigning the SEN Notation

# A.3.1 Identifying skin sensitization or ACD with guinea pig test methods
Standardized guinea pig test methods include the guinea pig maximization test and the Buehler test . In these tests, the animals are initially exposed to the test substance by intradermal injection and/or epidermal application to induce an immune response. After 10-14 days, the animals receive a challenge exposure to the test substance to establish whether a hypersensitive state has been induced. The disease-analogous skin reactions (e.g., local irritation in the forms of erythema/ edema) following the challenge exposure are measured and graded (usually 24 and 48 hours post challenge) to determine the degree of skin sensitization or ACD. A chemical that induces allergic skin reactions is considered a sensitizer and is assigned the SEN notation.

# A.3.2 Identifying skin sensitization potential with the murine local lymph node assay
The murine LLNA has been peer-reviewed by ICCVAM and the NICEATM panel and recommended for regulatory acceptance . OECD  and U.S. EPA  have adopted this assay as a standard test method for evaluating the skin sensitization potential for chemicals. The LLNA determines the induction of skin sensitization by identifying cell proliferation in the lymph node that drains the site of chemical application. The LLNA also provides quantitative data for assessing the dose-response relationship. In the test, cellular proliferation is measured as a function of in vivo radioisotope incorporation into the deoxyribonucleic acid (DNA) of dividing lymphocytes. The ratio of lymphocyte proliferation in treated groups to that in vehicular controls (stimulation index) is determined to serve as a quantitative criterion. A substance is considered a sensitizer and assigned the SEN notation if it has a statistically significant stimulation index greater than or equal to 3 and is supported by a fitting dose-response relationship.

# A.3.3 Identifying skin sensitization potential with the mouse ear swelling test
The mouse ear swelling test (MEST) 

# B.1 Algorithm for estimating and evaluating skin exposure hazards
Appendix B presents a predictive algorithm for estimating and evaluating the health hazards of skin exposure to chemicals. The algorithm is designed to evaluate the potential for a chemical agent to penetrate the skin and induce systemic toxicity. The goals for incorporating this algorithm into the proposed strategy for assigning SYS notation are as follows:
- Provide an alternative method to evaluate chemicals for which no clinical reports or animal toxicity studies exist or for which empirical data are insufficient to determine systemic effects
- Use the algorithm evaluation results to determine whether a chemical poses a skin absorption hazard and should be labeled with the SYS notation
The algorithm evaluation includes three steps:
1. Determining a skin permeation coefficient for the chemical 2. Estimating chemical uptake by the dermal and respiratory absorption routes 3. Evaluating whether the chemical poses a skin exposure hazard.
The algorithm is flexible in the data requirement and can operate entirely on the basis of the physicochemical properties of a chemical and the relevant exposure parameters. Thus, the algorithm is independent of the need for biologic data. Or, it can function using both the physicochemical properties and the experimentally determined permeation coefficients when the latter data are available and appropriate to use.

# B.1.1 Step 1: Determining the skin permeation coefficient
The first step in the evaluation is to determine the skin permeation coefficient (K p ) for the chemical to describe the transdermal penetration rate of the substance. The K p determined for a chemical is expressed in cm/hr and represents the overall diffusion of the substance through the stratum corneum and into the blood capillaries of the dermis. This value may be determined from laboratory tests or by QSPR or QSAR.
Experimentally, the permeation of chemicals through human skin can be determined in vitro using diffusion cell techniques such as those described in the protocols standardized by OECD   Exercising caution is important when a QSPR is used in the derivation of K p . Many of the empirical QSPRs, which are constrained by the experimental data used in the development and validation, are subject to limitations in the types of chemicals to which the models may apply. These QSPRs may not provide reliable K p estimates for inorganic substances, ionized substances, very high-MW chemicals, small hydrophilic molecules, or highly volatile substances. Chemicals in the first three categories are not readily absorbed through the skin, and their experimental K p values are often not readily available for model validation. Hydrophilic substances of small MW tend to penetrate hair follicles and sweat glands and, therefore, are not sufficiently covered in the assumed pathway of penetration by many models. Also, with a few exceptions, the QSPRs typically do not account for the evaporation of chemicals from the skin; as a result, the predicted K p for volatile substances could be overstated.

# B.1.2 Step 2: Estimating chemical uptake from skin and inhalation exposures
Step 2 in the evaluation (as initially proposed by the Toxic Substances Control Act Interagency
Testing Committee ) is to calculate the biologic uptake of the chemical from skin absorption (skin dose) and inhalation (inhalation dose) during the same period of exposure. The inhalation dose represents a critical presence of the examined substance in the body. Beyond this dose, bioaccumulation of the substance is a cause for concern for health effects. The skin and inhalation doses provide quantifiable measures for absorption of the chemical by different routes. These doses serve as the basis for determining whether the substance constitutes a skin absorption hazard.
The skin dose is calculated as a mathematical product of the K p acquired in Step 1, the water solubility (S W ) of the chemical, the exposed skin surface area, and the duration of exposure. In the calculation, the transdermal flux of the substance is assumed to originate from a saturated aqueous solution. Assuming that the skin exposure continues for 8 hours to unprotected skin on both palms (a surface area of 360 cm 2 ), The inhalation dose is derived on the basis of the occupational exposure limit (OEL) of the substance-if the OEL is developed to prevent the occurrence of systemic effects rather than sensory/irritant effects or direct effects on the respiratory tract. Assuming a continuous exposure of 8 hours, an inhalation volume of 10 m 3 in 8 hours, and a factor of 75% for the retention of the airborne substance in the lungs during respiration (retention factor, RF),

# Inhalation dose = OEL  Inhalation volume  RF
= OEL (mg/m 3 )  10 m 3  0.75
In the above equation, a default value of 0.75 is used for the RF to represent the respiratory retention of chemicals. The percentage value for the absorption of xenobiotics via the lungs is commonly assumed to be 75%-100% , and the default RF of 0.75 is selected to avoid underestimating skin absorption as a significant route of biologic uptake because complete absorption is unlikely to occur for most chemicals inhaled into the lungs. When scientifically justified, chemical-specific RFs may be used in place of the default value, especially for chemicals with systemic bioavailability lower than the default value (e.g., because of the extensive metabolism of substances in the lungs or accumulation in the blood leading to absorption that is no longer perfusion limited).

# B.1.3 Step 3: Evaluating the skin exposure hazard
The final step is to compare the calculated skin and inhalation doses and to present the result as a ratio of skin dose to inhalation dose (the SI ratio). This ratio quantitatively indicates (1) the significance of dermal absorption as a route of occupational exposure to the substance and (2) the contribution of dermal uptake to systemic toxicity. If a chemical has an SI ratio greater than or equal to 0.1, it is considered a skin absorption hazard.

# B.2 Criterion for assigning the SYS notations
The SYS notation will be assigned to a chemical when the mathematical evaluation indicates an SI ratio of at least 0.1 and when no data of scientific merit suggest that the potential health effects exclude systemic effect(s). An SI ratio of 0.1 is selected as the reference level based on a recent examination of chemicals recognized as skin absorption hazards by NIOSH. In this examination, SI ratios were calculated for 108 chemicals; all chemicals had assigned NIOSH skin notations, and the literature suggested them to be agents of systemic toxicity following skin exposure. Approximately 76% of the examined substances had SI ratios greater than 0.1. This result suggests that a chemical be treated as a skin absorption hazard when its dermal uptake exceeds 10% of its uptake by inhalation. The result also supports an SI ratio of 0.1 as the threshold value for assigning SYS notation. For the 24% of examined substances predicted to have an SI ratio less than 0.1, the preliminary analysis indicates that two factors may have contributed significantly to the low ratio:
- The OELs used to calculate inhalation dose were initially developed with a small safety margin compared with the OELs for substances having an SI ratio greater than 0.1.
- The health effects basis for skin notations may not be adequate.
These factors are being further investigated as a part of the ongoing NIOSH effort to reevaluate the health effects of skin exposure to these chemicals using scientifically up-to-date data. Results of these analyses will be used to improve the NIOSH skin notations.
This criterion agrees with the findings from similar research conducted by other international occupational safety and health organizations. One example is the proposal of the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) to recommend skin notations based on a semiquantitative approach . The algorithm proposed by ECETOC is similar to the one intended for assigning NIOSH SK: SYS notations. The ECETOC algorithm determines the skin exposure hazard posed by a chemical agent by comparing its dermal uptake to its systemic absorption from inhalation. ECETOC concluded that a skin notation should be assigned to a chemical when the amount of chemical absorbed by both hands and forearms in 1 hour could exceed 10% of the amount absorbed by inhalation when airborne concentrations are at the OEL for 8 hours. This comparison shows that for any chemical where the modeling approach may be applied, the SI ratio determined using the algorithm for assigning the SYS notation is approximately the same as the SI ratio generated by following the assumptions made in the algorithm proposed by ECETOC. Similarly, in both methods, the criteria for determining the health hazard of a skin exposure are based on essentially the same level of skin absorption.
In view of these findings, dermal absorption of a chemical is considered a systemic toxicity hazard if the substance is evaluated by the algorithm as demonstrated in this appendix and is shown to have an SI ratio greater than 0.1. The SYS notation will be assigned accordingly. For these substances, additional toxicological evaluations are recommended to clinically or experimentally verify the adverse systemic effect(s).
Note that in the context of Appendix B, the predictive algorithm is intended to serve as a hazard identification tool for determining whether skin exposure to a chemical agent is inherently capable of provoking systemic toxicity and is supportive of assigning the SYS notation. The SI ratio of 0.1 was determined as the threshold level by modeling chemicals that currently carry NIOSH skin notations. To provide a consistent basis for comparing modeling results, the following exposure parameters were treated as constants during the investigation (with assumptions made for reasonably representing the conditions of skin exposures):
(1) concentration of the chemical on the skin surface, (2) surface area of exposed skin, and
(3) exposure duration. If exposure conditions are not known, these parameters will remain as constants when the algorithm is used to estimate the SI ratio for assigning the SYS notation. Note that in actual workplace situations, these exposure parameters are likely to vary from the values assumed here, depending on the chemicals and the industrial processes or tasks involved. Before using the predictive algorithm to assess the risk of a given chemical exposure during a specific task, an exposure assessment should be conducted to sufficiently characterize all relevant information. The mathematical model described here may be improved and updated as more dermal absorption data become available and other facets of dermal penetration are incorporated into the model.

# C.1 Using pH and acid/alkali reserve to identify skin corrosives
In A Sequential Testing Strategy for Dermal Irritation and Corrosion, the supplement to the OECD Guideline for Testing of Chemicals 404 , the OECD recommends using a weight-of-evidence analysis on existing relevant data before undertaking in vivo testing to evaluate skin corrosion. Relevant data encompass data generated from methods alternative to biologic testing, including "evidence of corrosivity/irritation of one or more structurally related substances or mixtures of such substance" and "data demonstrating strong acidity or alkalinity of the substance. " The OECD Guideline also specifies that the acid/alkali reserve (or buffering capacity) be considered if a chemical is recognized as a skin corrosive on the basis of its extreme pH. Using pH and acid/ alkali reserve to identify potential skin corrosives is in accordance with the approach adopted in the GHS . In this system, the appropriate evaluation of extreme pH values ( 2.0 or  11.5) (including acid/alkaline reserve capacity) is accepted as a decision logic for recognizing corrosive agents.
When a chemical is evaluated for potential skin corrosivity based on pH and buffering capacity, the substance is to be recognized as corrosive following the outlined predictive models :
- pH  2.0 or  11.5
- pH  (acid reserve  6)  1 or - pH + (alkali reserve  12)  14.5
where the acid reserve of a substance is the amount in grams of sodium hydroxide required to bring 100 g of a test substance (in a 10% solution or suspension) to a pH of 4, and the alkali reserve is the amount in grams of sulfuric acid required to bring 100 g of a test substance to a pH of 10. (See Young et al.  for details about the generation and use of acid/alkali reserve measurements.)

# C.2 Using structural alerts implemented in the DEREKTM expert system to identify sensitizers
The knowledge-based DEREKTM expert system contains algorithms to predict the toxicity of chemical mixtures based on a series of structure-activity rules (also known as structural rules or structural alerts). These rules describe the substructures of chemical molecules potentially responsible for adverse health effects . As part of the DEREKTM expert system architecture, a rule base for APPENDIX C - Identifying skin corrosives and sensitizers using physicochemical properties and structure activity relationship-based analysis identifying potential contact allergens was derived using results of the guinea pig maximization test conducted for 294 substances classified as strong or moderate sensitizers . The rule base initially consisted of 40 structural rules and has been continuously updated since its inception. Workshop 19 of the European Centre for the Validation of Alternative Methods discussed the DEREKTM skin sensitization rule base as an alternative to skin sensitization testing. The Workshop recommended that QSAR predictions and expert systems serve as screens for identifying positive substances .
Zinke et al.  assessed the effectiveness of these structural alerts for identifying the skinsensitizing properties of chemicals. The researchers evaluated the 40 originally published structural alerts against a database developed in the German Federal Institute for Health Protection of Consumers and Veterinary Medicine (BgVV). The BgVV database contained data submitted under its procedure for notification about new chemicals within the European Union and data on the skin-sensitization potentials of 1,039 substances . Zinke et al.  reported that among the structural alerts examined, eight could be used to identify contact allergens without further refinement. These alerts are for acid halides, acid anhydrides, isocyanates, isothiocyanates, -lactams, aldehydes, epoxides, and quaternary ammonium cation.
These structural alerts will be used to evaluate substances for their potential as skin sensitizers when no human or biologic testing data are available. As the DEREKTM structural rules continue to be refined, it is anticipated that additional alerts will be validated and available to identify hazards and facilitate the assignment of SK: SEN notations.
Zinke S, Gerner I, Schlede E . Evaluation of a rule base for identifying contact allergens by using a regulatory database: comparison of data on chemicals notified in the European Union with "structural alerts" used in the DEREKTM expert system. Altern Lab Animals 30:285-298.
NIOSH CIB 61 - Skin Notations

# D.1 Selecting chemicals for evaluation
Chemicals can be identified and selected for evaluation based on the strategic framework outlined in this CIB through three primary pathways:

# D.2 Selecting and prioritizing candidate chemicals found within the NIOSH Pocket Guide to Chemical Hazards
The NIOSH Pocket Guide to Chemical Hazards lists 142 chemicals assigned the skin notation
, which indicates the potential for dermal absorption. These substances have been selected to be the first evaluated through the strategic framework outlined in this CIB. As part of this process, a hierarchal ranking scheme that applies a binominal hazard-ranking approach has been developed to aid in the ranking of the many candidate chemicals. Parameters addressed within the hierarchal scheme of prioritizing the candidate chemicals include the following:
- Potential health hazards
- Potential for occupational exposure
- Annual production volume - OELs recommended by both governmental and nongovernmental organizations.
An array of information resources containing data related to the outlined parameters were assessed to aid in ranking the chemicals to be classified according to the new strategy. The following information resources were applied within this scheme:

# F.2 Systemic toxicity from skin exposure
Toxicokinetic studies of phenol have been identified. Dermal absorption of phenol by human subjects has been reported to range from 4%-23% of the applied dose, depending on the period of exposure and the concentration of phenol . In male volunteers, the rate of absorption of an aqueous phenol solution (2.5, 5.0, or 10.0 g/L from a 2 mL reservoir) applied directly to the forearm (15.6 cm 2 ) was found to be concentration-dependent, with the rate ranging from 0.079 mg/ cm 2 /hr at the low concentration to 0.301 mg/ cm 2 /hr at the high concentration . In this study, the total amount of phenol absorbed-but not the rate of absorption-at the low concentration increased with time, with 12.6% and 22.7% of the applied dose absorbed in 30 and 60 minutes, respectively. Feldman and Maibach  reported the degree of dermal absorption as 4.4% of the administered dose following a single topical application of 4 g/cm 2 phenol on 13 cm 2 of the unprotected ventral forearm of human adults. Phenol vapors are also reported to readily penetrate the skin with absorption efficiency equal to that of inhalation, thus contributing to the total skin exposure . In a whole-body skin exposure study in which unclothed and lightly clothed volunteers were exposed to phenol vapors at concentrations from 1.3-6.5 ppm for 6 hours, but were breathing clean air by mask, reported that absorption increased proportionately with air concentration . These studies generally demonstrated that phenol can be absorbed through the human skin.
The potential of phenol to be absorbed through the skin has also been evaluated in laboratory animals. Hughes and Hall  reported a 120-hour cumulative dermal absorption of 66%-80% in young rats (29-day-old female rat).
In an earlier study, the same authors  reported that approximately 85% of the dose of phenol was absorbed in 72 hours in 90-day-old female rats after dermal administration of phenol. In vitro studies using laboratory animal tissues also indicate that phenol is absorbed through the skin. For example, in an in vitro system using dermatomed rat skin, Hughes et al.  reported a 72-hour dermal absorption of phenol of 95% of the applied dose. Brooks and Riviere  considered a recent study that evaluated dermal absorption of phenol in acetone and water under nonoccluded and occluded applications using isolated perfused porcine skin. The authors reported absorption, penetration into tissues, and total recoveries of phenol to be greater under occluded than nonoccluded conditions and that for each solvent, the absorption percentage was higher with the low-dose (4 g/cm 2 ) compared to the high-dose (40 g/cm 2 ), suggesting saturation of absorption or other nonlinear kinetics under some conditions of exposure. Depending on the solvent and dose, Brooks and Riviere  reported that dermal absorption ranged from 9.24%-14.62% under occluded conditions at the low dose and 2.90%-5.45% under nonoccluded condition. In vitro permeability coefficients for phenol were found to increase with increasing concentration of aqueous phenol applied to mouse skin , with a 12-fold increase in mean coefficient (0.007-0.085 cm / hour) resulting from doubling the concentration from 20 g/L to 40 g/L, and a value of 0.169 cm/hr noted when 60 g/L was applied . The authors concluded that phenol concentrations exceeding 20 g/L may destroy a diffusion barrier normally provided by the intact stratum corneum, permitting increased dermal absorption. Results from animal studies in vivo and studies using animal skin in vitro also demonstrated that phenol is absorbed through the skin of animals. The potential of phenol to pose a skin absorption hazard was also evaluated using the NIOSH  predictive algorithm for estimating and evaluating the health hazards of skin exposure to substances.
Based on this algorithm, the ratio of the skin dose to the inhalation dose (SI ratio) of 11 was calculated for phenol. This ratio is significantly higher than the SI ratio of greater than or equal to 0.1 indicating that skin absorption may substantially contribute to the overall body burden of a chemical. For this reason, phenol is considered to be absorbed through the skin following dermal contact. The result from the predictive algorithm supports the results from human and animal studies in vivo and from in vitro studies.
- Application of Appendix A.1.1: Dermal absorption. The results of studies using human subjects have reported that dermal absorption of phenol range from 4%-23% of the applied dose. The studies indicate that phenol may be readily absorbed in liquid or vapor forms. Animal studies using different protocols report dermal absorption range from 9%-85% of the applied dose in multiple species. For this reason, phenol is identified as having a high potential to be absorbed following contact with the skin in liquid and vapor forms.
Several case reports of humans dermally exposed to varying doses of phenol have been identified . In these reports, accidental exposure of phenol to intact skin or intentional (therapeutic) application of phenol to the skin has resulted in fatalities (from, e.g., respiratory depression and cardiac arrest), but the doses were not known with any accuracy, precluding estimation of a lethal dermal dose for humans. In animals, the dermal LD 50 values (the dose resulting in 50% mortality in the exposed animals) range from 0.5 mL/kg body weight to 0.68 mL/kg (corresponding to 669-1,500 mL / kg body weight)  in rats under both occlusive and nonocclusive conditions and 1400 mg/kg in rabbits . The Conning and Hayes  study reported severe muscular tremors, twitching, generalized convulsions with loss of consciousness, and prostration occurring within 10 minutes of skin exposure to phenol in water; subjects developed severe hemoglobinuria from 45-90 minutes. Brown et al.  reported hematuria and convulsions as clinical signs of phenol toxicity. Because the reported acute dermal LD 50 values for the rat and rabbit are both lower than the critical dermal LD 50 value of 2 g / kg body weight that identifies substances with the potential for acute dermal toxicity , phenol is considered systemically toxic by the acute dermal route. No standard toxicity or specialty studies evaluating biologic-system/function-specific effects (including reproductive and developmental effects and immunotoxicity) following skin exposure to phenol were identified in humans or animals.
- Application of Appendix A.1.7: Toxic effects of exposures of the skin on organ systems or biologic functions. No evidence was identified that evaluated the effects of phenol on organ systems or biologic functions. The SYS notation would not be assigned to phenol based on the criteria outlined in this section.
Although a literature search identified no epidemiologic studies that allowed for evaluation of the carcinogenic potential of phenol, a limited number of studies in animals involving repeated application of phenol in benzene  or in acetone  in two-stage carcinogenicity protocols in mice indicated that phenol has promoting activity. Studies conducted by Boutwell and Bosch  in several strains of mice also suggested that phenol in benzene or dioxane is a tumor promoter and possibly a complete carcinogen (i.e., having both promoting and initiating activity). In the latter study, phenol elicited skin tumors in mice even in the absence of a tumor-initiating agent (i.e., 9,10-dimethyl-1,2-benzanthracene). These studies are inadequate for the evaluation of the carcinogenic potential of phenol because of the following:
- The short duration of exposures applied in the studies 
- The lack of appropriate controls , and/or

# F.3 Direct effect(s) on the skin
The available information indicates that phenol is corrosive to the skin. For example, skin Other effects, such as erythema, inflammation, discoloration, eczema, redness, and severe edema have been reported on contact of the skin with solid or liquid phenol . The effects of phenol on the skin have been attributed to its ability to impair the barrier function of the stratum corneum and produce coagulation necrosis by denaturing and precipitating proteins. Although the structure-activity-relationship model, DEREKTM, predicts that phenol is nonirritating to the skin, which indicates that the chemical does not have structural alerts for skin irritation, several studies in humans and animals show that phenol is corrosive to the skin or is a skin irritant depending on the concentration.

# F.4 Sensitization
Few studies have been identified that evaluated the potential of phenol to cause skin sensitization in both humans and animals. In one study using 24 volunteers, phenol produced negative results in skin sensitization tests . The Magnussen and Kligman skin sensitization test in guinea pigs also gave negative results for phenol . Predictions using structure-activity-relationship models provide some information regarding this endpoint. Based on the chemical structure, phenol is predicted by DEREKTM as negative for sensitization, indicating that the chemical does not have structural alerts for skin sensitization. This prediction of negative sensitization potential is consistent with the absence of published reports of sensitization in workers handling phenol and the limited empirical evidence.
The limited information available indicates that phenol is not likely to be a skin sensitizer. Therefore, this assessment does not assign a SK: SEN notation for phenol.
- Application of Appendix A.3: Experimental protocols for investigating sensitization from skin exposure and derived criteria for assigning the SK: SEN Notations and Appendix C.2: Using structural alerts implemented in the DEREKTM expert system to identify sensitizers. This section reviews the assembled data set for phenol to assess the potential for sensitization following skin exposures. The identified data set provided insufficient information to assign the SEN notation. This decision is supported by the inclusion of the DEREKTM negative prediction for phenol to cause sensitization.

# F.5 Summary
There is sufficient information from toxicokinetics , acute dermal toxicity studies , and repeatdose dermal toxicity studies  to indicate that phenol is absorbed through the skin and is acutely toxic and induces systemic effects (e.g., central nervous system effects, effects on body weight and survival) following skin exposure. Information from human experience  and animal studies  is sufficient to demonstrate that phenol is corrosive and that more dilute solutions are irritating to the skin. The limited information available indicates that phenol is not a skin sensitizer. Therefore, this assessment recommends the composite skin notation of SK: SYS-DIR (COR) for phenol.
Phenol has also been classified as being harmful and toxic upon contact with the skin and corrosive by the European Commission (EC) . ACGIH , NIOSH

# G.1 Contaminants and isomers
Skin notations are intended to provide warnings and salient facts about the adverse health effects associated with skin exposures to a neat chemical or mixture. Commercial-grade chemicals may contain a contaminant, which has been defined as the following:
1. A chemical that is unintentionally present within a neat substance or mixture having a concentration less than 1.0% or 2. A chemical that is recognized as a potential carcinogen present within a neat substance or mixture having a concentration less than 0.1% 
Contaminants may be discussed within the supporting documentation for a specific compound, but the skin notations apply solely to the neat substance or mixture because of the potential for the contaminant to represent a unique occupational hazard. If a contaminant is deemed to represent a substantial health hazard for workers following contact of the skin, it may be independently evaluated to determine whether assignment of skin notations is appropriate.
Isomers are molecules that exhibit unique physical structures, despite having the same elementary composition and weight. Variations within the chemical properties of isomers of a molecule may result in substantial differences in toxic potency. Unless otherwise noted, skin notations derived for a chemical that displays isomerism apply strictly to the structural arrangements specified within the supporting documentation of the compound.

# G.2 Globally Harmonized System of Classification and Labeling of Chemicals
GHS is an international classification and labeling system for chemicals adopted by the U.N.

# G.3 Cancer
Cancer refers to any one of a group of diseases that occurs when cells in the body become abnormal and grow or multiply out of control.
Exposure of the skin to some chemicals has been demonstrated to contribute to the development of (1) cancers within internal organ systems beyond the point of contact and
(2) cancers of the skin at or near the point of contact. To ensure consistency in the assignment of the skin notations, the following paradigm has been developed:
- Cancers occurring within an internal organ system or tissue beyond the point of contact are defined as systemic effects and warrant the assignment of the SYS notation.
- Cancers occurring at or near the point of contact on the skin are defined as direct effects and warrant the assignment of the DIR notation.
The weight-of-evidence approach described within this CIB will be applied to assess the potential for a chemical to act as a carcinogen following exposures of the skin and the subsequent assignment of the SYS and DIR notations when appropriate. In addition, the Skin Notation Profiles (see Appendix F) will summarize the data associated with carcinogenic potential of a chemical, including cancer designations provided by NIOSH, NTP, U.S. EPA, IARC, and ACGIH.

# G.4 Nanoparticles and the skin
Nanotechnology is a system of innovative methods to control and manipulate matter at nearatomic scale (1-100 nanometers) to produce new materials, structures, and devices. Examples of nanoparticles include carbon-based materials (i.e., nanotubes and fullerenes), metal-based materials (i.e., quantum dots, metal oxides, nanogold, and nanosilver), nanocomposites, and dendrimers. Because of their small size and relatively large surface area, engineered nanoparticles may have chemical, physical, and biologic properties distinctly different from and greater than fine particles of similar chemical composition . These variations may result in unique health hazards for workers employed to manufacture or use products containing nanomaterials.
Limited information is currently available to accurately assess the health hazards of skin exposures to nanoparticles. The results from in vitro studies using primary or cultured human skin cells show that single-walled and multi-walled carbon nanotubes are able to enter cells and cause the release of proinflammatory cytokines, oxidative stress, and decreased viability .
More recent studies have reported the ability of quantum dots and fullerenes to penetrate the stratum corneum by passive diffusion and to induce inflammatory response and cytotoxicity within skin fibroblasts and keratinocytes . Factors including size, shape, water solubility, and surface coating may directly affect a nanoparticle's potential to penetrate the skin .
The occupational health hazards of exposing skin to the different forms of nanoparticles are unclear. For this reason, skin notations derived from neat substances or mixtures with similar chemical composition to a specific form of nanoparticles may not be applicable because of the different physicochemical properties and toxic potential. As new data become available, the skin notations and supporting documentation will address the toxic potential of 57