Current Intelligence Bulletin 61

A Strategy for Assigning New 

NIOSH Skin Notations

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Disease Control and Prevention

National Institute for Occupational Safety and Health

Current Intelligence Bulletin 61

A Strategy for Assigning New 

NIOSH Skin Notations

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Disease Control and Prevention

National Institute for Occupational Safety and Health
ii

This document is in the public domain and may be freely copied or 

reprinted.

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DHHS (NIOSH) Publication No. 2009–147

July 2009

Safer • Healthier • PeopleTM
iii

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 
iv

and other occupational diseases where skin exposure may contribute to disease development.

Christine M. Branche, Ph.D. /s

Acting Director, National Institute for 

Occupational Safety and Health

Centers for Disease Control 

 and Prevention
v

Executive Summary

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. 

Difficulties with Assigning Current NIOSH Skin Notations 

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 [skin]. 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:

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

This document, Current Intelligence Bulletin (CIB) 61: A Strategy for Assigning New 

NIOSH Skin Notations, provides a new strategy for assigning skin notations. The 
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

Figure 1. Decision tree for assigning new NIOSH skin notations

Select candidate chemical substance (Appendix D)

Apply literature search strategy (Appendix E.1)

Identify and select critical data, studies, and information (Chapter 2.0)

Review and evaluate critical data, studies and information (Chapter 2.0, Appendix E.2)

Are there sufficient data to assign skin notations?

Are data supportive to assign skin 

notations? (Chapter 2, Appendix A, B, C)?

Assignment of 

ID(SK) notation; 

drafting of Skin 

Notation Profile Assignment 

of the [SK]

notation; 

drafting of 

Skin Notation 

Profiles No

Yes

Yes

DIR DIR 

(IRR)

DIR 

(COR)

SYS

SEN

Assignment of DIR, DIR 

(IRR), or DIR (COR) 

notations; drafting of 

Skin Notation Profile

No

No DIR, DIR (IRR), or DIR 

(COR) notations; drafting 

of Skin Notation Profile

No

No

No

Yes

Yes

Yes Yes

Yes

Assignment of the SYS 

notation or the SYS (FATAL) 

notation; drafting of Skin 

Notation Profile SYS 

 (FATAL)

No SYS or SYS (FATAL); 

drafting of Skin Notation Profile No

Assignment of SEN notation; drafting of 

Skin Notation Profile

No SEN notation; drafting of 

Skin Notation Profile

Yes

No

No
ix

Contents

Foreword. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iii

Executive Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v

Difficulties with Assigning Current NIOSH Skin Notations. . . . . . . . . . . . . v

New Strategy for Assigning NIOSH Skin Notations. . . . . . . . . . . . . . . . . . . . v

Abbreviations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xii

Glossary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv

Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvi

1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

2 Assigning Skin Notations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

2.1 Criteria for Assigning Skin Notations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

2.2 SYS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

2.3 DIR. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

2.4 SEN. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

2.5 SK. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

2.6 ID(SK). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

2.7 ND. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Appendix A: Protocols Used in Studies of Health Effects from Skin 

Exposure and the Determination of Criteria Derived for Assigning 

Skin Notations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

A.1 Experimental protocols for investigating systemic effects of skin 

exposure and derived criteria for assigning the SYS notations. . . . . . . . 15

A.1.1 Dermal absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

A.1.2 Acute toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

A.1.3 Repeat-dose toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

A.1.4 Subchronic toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

A.1.5 Chronic toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

A.1.6 Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

A.1.7 Toxic effects of exposures of the skin on organ systems or 

biologic functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

A.1.8 Assignment of the SYS notation based on alternative 

exposure pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
x

A.2 Experimental protocols for investigating direct effects of skin 

exposure and derived criteria for assigning the DIR notations. . . . . . . 18

A.2.1 In vivo animal tests for acute irritancy and corrosivity . . . . 18

A.2.2 In vitro tests for corrosivity using human or animal 

skin models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

A.2.3 Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

A.2.4 In vitro tests of skin integrity using human donor skin . . . . 20

A.3 Experimental protocols for investigating sensitization from 

skin exposure and derived criteria for assigning the SEN Notation. . . 20

A.3.1 Identifying skin sensitization or ACD with guinea 

pig test methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

A.3.2 Identifying skin sensitization potential with the murine 

local lymph node assay . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

A.3.3 Identifying skin sensitization potential with the mouse ear 

swelling test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Appendix B: Algorithm for estimating skin absorption and systemic 

toxicity and suggested application for assigning SYS notations. . . . . . . . . . . . 25

B.1 Algorithm for estimating and evaluating skin exposure hazards. . . . . . 25

B.1.1 Step 1: Determining the skin permeation coefficient . . . . . . 25

B.1.2 Step 2: Estimating chemical uptake from skin and inhalation 

exposures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

B.1.3 Step 3: Evaluating the skin exposure hazard . . . . . . . . . . . . . 27

B.2 Criterion for assigning the SYS notations. . . . . . . . . . . . . . . . . . . . . . . . . 27

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Appendix C: Identifying skin corrosives and sensitizers using physicochemical 

properties and structure activity relationship-based analysis. . . . . . . . . . . . . . 31

C.1 Using pH and acid/alkali reserve to identify skin corrosives. . . . . . . . . 31

C.2 Using structural alerts implemented in the DEREKTM expert 

system to identify sensitizers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Appendix D: Selecting and Prioritizing Candidate Chemicals. . . . . . . . . . . . . . . 35

D.1 Selecting chemicals for evaluation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

D.2 Selecting and prioritizing candidate chemicals found within the 

NIOSH Pocket Guide to Chemical Hazards. . . . . . . . . . . . . . . . . . . . . . . 35

Appendix E: Guidelines and Criteria for the Search Strategy, Evaluation, 

and Selection of Supporting Data Used for the Assignment of 

Skin Notations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

E.1 Literature search. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

E.1.1 Primary sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
xi

E.1.2 Search terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

E.2 Evaluation of data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Appendix F: Example of Assigning New NIOSH Skin Notations 

and Format of the Skin Notation Profile. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

F.1 Chemical background information and introduction. . . . . . . . . . . . . . . 43

F.2 Systemic toxicity from skin exposure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

F.3 Direct effect(s) on the skin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

F.4 Sensitization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

F.5 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

Appendix G: Supplemental information. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

G.1 Contaminants and isomers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

G.2 Globally Harmonized System of Classification and Labeling 

of Chemicals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

G.3 Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

G.4 Nanoparticles and the skin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
xii

Abbreviations

ACD allergic contact dermatitis

ACGIH American Conference of Governmental Industrial Hygienists

CIB Current Intelligence Bulletin

cm centimeter(s)

cm2 square centimeter(s)

cm/hr centimeter(s) per hour 

(COR) subnotation of SK: DIR indicating the potential for a chemical to be 

corrosive following exposure of the skin

CFR Code of Federal Regulations

DEREKTM Deductive Estimation of Risk from Existing Knowledge

DIR skin notation indicating the potential for direct effects to the skin following contact with a chemical

EC European Commission

ECETOC European Centre for Ecotoxicology and Toxicology of Chemicals

ECVAM European Centre for the Validation of Alternative Methods

(FATAL) subnotation of SK: SYS indicating chemicals are highly or extremely 

toxic and may be potentially lethal or life threatening following exposure of the skin

g gram(s)

g/kg gram(s) per kilograms of animal body weight

g/kg-day gram(s) per kilograms of animal body weight per day

GHS Globally Harmonized System of Classification and Labeling of 

Chemicals

hr hour(s)

IARC International Agency for Research on Cancer
xiii

ICCVAM Interagency Coordinating Committee on the Validation of Alternative Methods

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

K

aq

coefficient in the watery epidermal layer

kg kilogram(s)

KOW octanol-water partition coefficient

K

p

skin permeation coefficient

Kpol coefficient in the protein fraction of stratum corneum

K

psc permeation coefficient in the lipid fraction of stratum corneum

LD50 lethal dose 50% by skin, oral, and intradermal routes

LLNA local lymph node assay

LOAEL lowest-observed-adverse-effect level

LOEL lowest-observed-effect level

m meter(s)

m2 squared meter(s)

m3 cubic meter(s)

MEST mouse ear swelling test

μg/cm2 microgram of a substance/ squared centimeter

mg milligram(s)

mg/cm3 milligram(s) of a dissolved substance/cubic centimeter meter of solute

mg/cm3

/hr milligram(s) of a dissolved substance/cubic centimeter meter of solute/hour

mg/kg milligram(s) of a substance/kilograms animal body weight 

mg/kg-day milligram(s) of a substance/kilograms animal body weight as a daily 

dose
xiv

mg/m3 milligram(s) of a substance per cubic meter of air 

MW molecular weight

ND notation used to indicate that a chemical has not been evaluated by 

the strategy outlined in this CIB, and that the health risks associated 

with skin exposure are unknown. 

NIOSH National Institute for Occupational Safety and Health

NOAEL no-observed-adverse-effect level

NOEL no-observed-effect level

NTP National Toxicology Program 

OECD Organization for Economic Cooperation and Development 

OEL occupational exposure limit

OSHA Occupational Safety and Health Administration

QSAR quantitative structure-activity relationship

QSPR quantitative structure-permeability relationship

RF retention factor

RTECS Registry of Toxic Effects of Chemical Substances

R-phrases risk phrases

SAR structure-activity relationship

SI ratio ratio of the skin dose to the inhalation dose

SEN skin notation indicating the potential for immune-mediated reactions following exposure of the skin

SK skin notation

SK skin notation indicating that the reviewed data did not identify a 

health risk associated with skin exposure

SYS skin notation indicating the potential for systemic toxicity following 

exposure of the skin

SW water solubility

TER transcutaneous electrical resistance assay

U.S. EPA U.S. Environmental Protection Agency 
xv

Glossary

Absorption—The transport of a chemical from the outer surface of the skin into both 

the skin and systemic circulation (including penetration, permeation, and resorption).

Acute—Contact with a chemical that occurs once or for only a short period of time.

Cancer—Any one of a group of diseases that occurs when cells in the body become 

abnormal and grow or multiply out of control.

Contaminant—A chemical that (1) is unintentionally present within a neat substance 

or mixture in concentrations less than 1.0% or (2) is recognized as a potential carcinogen present within a neat substance or mixture in concentrations less than 0.1%.

Cutaneous (percutaneous)—Referring to the skin.

Dermal—Referring to the skin. 

Dermal contact—Contact with (touching) the skin.

Dermatosis—A disease or disorder of the skin. 

Direct effects—Localized non-immune mediated adverse health effects to the skin occurring at or near the point of contact, including corrosion, primary irritation, changes 

in skin pigmentation, and reduction/disruption of the skin barrier integrity, following 

skin exposure to chemicals. 

Immune-mediated responses—Responses mediated by the immune systems including allergic responses. 

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.

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

Acknowledgements

This document was prepared by the Education and Information Division (EID), 

Paul Schulte, Ph.D., Director. Heinz W. Alhers, J.D., Chen-Peng Chen, Ph.D., Eugene Demchuk, Ph.D., and G. Scott Dotson, Ph.D. were the principle authors. Other 

members of EID, in particular Richard Niemeier, Ph.D., were extremely helpful in 

providing technical reviews and comments.

For contributions to the technical content and review of this document, the authors 

gratefully acknowledge the following NIOSH personnel:

Education and Information Division (EID)

Vern P. Anderson, Ph.D. David Votaw, M.Sc.

Charles L. Geraci, Ph.D. Ralph Zumwalde, M.Sc. 

Thomas J. Lentz, Ph.D.

Division of Applied Research and Technology (DART)

R. Leroy Mickelsen, M.Sc., formerly with the DART

Robert Streicher, Ph.D.

Samuel Tucker, Ph.D.

Division of Respiratory Disease and Surveillance (DRDS)

Greg Day, Ph.D.

Division of Surveillance, Hazard Evaluations, and Field Studies (DSHEFS)

Boris Lushniak, M.D., M.P.H., formerly with the DSHEFS

Aaron L. Sussell, Ph.D.

Mark Boeniger, M.Sc., retired

Marie Haring Sweeney, Ph.D.

Loren Tapp, M.D. 

Health Effects Laboratory Division (HELD)

Michael Luster, Ph.D. Al Munson, Ph.D. Fred Frasch, Ph.D.

National Personal Protective Technology Laboratory (NPPTL)

Rolland Berry Ann, M.Sc. Nadia S. El-Ayouby, Ph.D. 
xvii

Office of the Director (OD)

Sid Soderholm, Ph.D.

The authors wish to thank Vanessa Becks, Gino Fazio, and Anne Hamilton for their 

editorial support and contributions to the design and layout of this document. 

Finally, the following individuals and organizations have earned special appreciation for serving as independent external reviewers and providing comments that 

contributed to the development of this document:

David A. Basketter, D.Sc., Safety and Environmental Assurance Centre, 

Unilever Research

Annette L. Bunge, Ph.D., Professor, Department of Chemical Engineering, 

Colorado School of Mines

John Cherrie, Ph.D., Research Director, Institute of Occupational Medicine

Julia H. Fentem, Ph.D., Head of Applied Science and Technology, Safety and 

Environmental Assurance Centre, Unilever Research

Bernard K. Gadagbui, Ph.D., M.S., D.A.B.T., Toxicologist, Toxicology 

Excellence for Risk Assessment (TERA)

G. Frank Gerberick, Ph.D., Research Fellow—Victor Mills Society, The Procter 

and Gamble Company Miami Valley Innovation Center

Dori Germolec, Ph.D., Immunology Discipline Leader, National Toxicology 

Program, National Institute for Environmental Health Sciences

Ben Hayes, M.D., Ph.D., Adjunct Clinical Instructor, Division of Dermatology

Vanderbilt School of Medicine

Youcheng Liu, M.D., Sc.D., M.P.H., Assistant Professor, Department of 

Preventive Medicine and Environmental Health, College of Public Health, 

University of Kentucky

Andrew Maier, Ph.D., D.A.B.T., C.I.H., Director, TERA

Linda A. Malley, Ph.D., D.A.B.T., Senior Research Toxicologist, DuPont 

Haskell Global Centers for Health and Environmental Sciences 

James N. McDougal, Ph.D., Professor and Director of Toxicology Research, 

Department of Pharmacology and Toxicology, Wright State University

Elaine A. Merrill, M.Sc., Air Force Research Laboratory, Wright-Patterson Air 

Force Base, GeoCenters, Inc.

John Morawetz, M.Sc., Director, Center for Worker Health and Safety 

Training, International Chemical Workers Union Council
xviii

Leena A. Nylander-French, Ph.D., C.I.H., Associate Professor, Department 

of Environmental Sciences and Engineering, University of North Carolina at 

Chapel Hill

Karin A. Pacheco, M.D., M.S.P.H., Assistant Professor, Division of 

Environmental and Occupational Health Sciences, National Jewish Health

Travis M. Parsons, M.Sc., Occupational Safety and Health Division, Laborers’ 

Health and Safety Fund of North America

Lyn Penniman, M.P.H., Acting Director, Office of Chemical Hazards, 

Occupational Safety and Health Administration (OSHA), U.S. Department of 

Labor (DOL)

William G. Perry, C.I.H., Deputy Director, Directorate of Standards and 

Guidance, OSHA, U.S. DOL

Carrie A. Redlich, M.D., M.P.H., Professor of Medicine and Acting Director, 

Occupational and Environmental Medicine Program, Department of Internal 

Medicine, School of Medicine, Yale University

Susan Ripple, M.Sc., C.I.H., Industrial Hygiene Leader for Occupational and 

Community Exposure Limits, Industrial Hygiene Technical Focal Point Coach, 

The Dow Chemical Company

Peter J. Robinson, Ph.D., Principal Scientist, Air Force Research Laboratory, 

Mantech Environmental Technology Inc. 

Jennifer Sahmel, M.Sc., C.I.H., Senior Health Scientist, ChemRisk

Scott P. Schneider, M.Sc., C.I.H., Division Director, Occupational Safety and 

Health Division, Laborers’ Health and Safety Fund of North America

James Taylor, M.D., Section Head, Industrial Dermatology, The Cleveland 

Clinic

John D. Walker, Ph.D., M.P.H., Director, Toxic Substances Control Act 

Interagency Testing Committee, U.S. Environmental Protection Agency

Steven F. Witt, Directorate of Standards and Guidance, OSHA, U.S. DOL 
1

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 [1.5–2.0 

squared meters (m2

)] 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. 

The National Institute for Occupational Safety 

and Health (NIOSH) currently uses [skin] as 

*

The terms dermal, cutaneous, and percutaneousreferto 

the skin. These terms are used interchangeably within 

this document. 

the skin notation on 142 chemicals listed in the 

NIOSH Pocket Guide to Chemical Hazards to 

alert workers and employers to the potential 

of skin absorption [NIOSH 2005]. This skin 

notation was adopted by NIOSH in its testimony on the Occupational Safety and Health 

Administration (OSHA) Proposed Rule on Air 

Contaminants (Permissible Exposure Limit 

update) on August 1, 1988 [NIOSH 1988]. Despite the usefulness of the notation [skin] 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 [54 CFR 2718 (1989)].

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. 

2. A single skin notation assigned to a 

chemical was often used to warn of serious dermal effects other than systemic 

toxicity—effects such as irritation, corrosion, and sensitization. According to its 

A Strategy for Assigning New NIOSH Skin 

Notations
2 NIOSH CIB 61 • Skin Notations

current definition, a skin notation is assigned to a chemical only when the substance has been scientifically established 

to be dermally absorbed and to potentially contribute to systemic toxicity. Use 

of the notation [skin] as an indicator for 

other health effects from skin exposure is 

inappropriate and misleading. 

3. The skin notation does not reflect the 

contemporary state of scientific knowledge or include recommendations made 

in NIOSH criteria document since the 

1988 Permissible Exposure Limit update 

project. For example, the criteria document for ethylene glycol monomethyl 

ether, ethylene glycol monoethyl ether, 

and their acetates recommends that skin 

exposures to these chemicals be avoided 

because of their ability to be readily absorbed by the skin [NIOSH 1991]. However, none of these chemicals has been assigned a skin notation.
NIOSH CIB 61 • Skin Notations 3

2 Assigning Skin Notations 

The Current Intelligence Bulletin (CIB) 61: A 

Strategy for Assigning New NIOSH Skin Notations provides an updated and formalized 

strategy for the assignment of skin notations 

capable of distinguishing among systemic, 

direct, and sensitizing effects caused by exposures of the skin to chemicals. The strategic 

framework outlined within this document is a 

form of hazard identification that has been designed to accomplish the following: 

1. Ensure that the assigned skin notations 

reflect the contemporary state of scientific knowledge

2. Provide transparency to the assignment 

process

3. Communicate the hazards of chemical 

exposures of the skin

4. Meet the needs of health professionals, 

employers, and other interested parties in 

protecting workers from chemical contact with the skin 

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. 
4 NIOSH CIB 61 • Skin Notations

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). 

The new skin notations will be included within future NIOSH publications, including the 

NIOSH Pocket Guide to Chemical Hazards. 

Future versions of the NIOSH Pocket Guide 

to Chemical Hazards will have the skin notation assignments for each evaluated substance 

[e.g., SK: SYS-DIR (COR)] and an overview 

of the new skin notations. A separate publication called a Skin Notation Profile (see Appendix F) will provide an in-depth summary of the 

relevant data used to aid in determining the 

hazards associated with skin exposures.

2.1 Criteria for Assigning Skin 

Notations 

The critical step in assigning skin notations to a 

chemical is determining its hazard potential—

that 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 [e.g., quantitative structure-activity relationships 

(QSAR)] 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, 
NIOSH CIB 61 • Skin Notations 5

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 Globally Harmonized 

System of Classification and Labeling of Chemicals (GHS) developed by the United Nations 

[UNECE 2005]. Appendix G.2 contains supplemental information on the harmonization 

of the NIOSH skin notations with GHS. 

2.2 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. The following are examples of adverse systemic effects 

that human and animal data have shown to be 

associated with skin exposures to chemicals 

with the assignment of the SYS notation or its 

subnotation (FATAL): 

• Cardiotoxicity 

• Carcinogenesis and photocarcinogenesis 

(excluding cancers of the skin) (see Appendix G.3)

• Hematotoxicity 

• Hepatotoxicity

• Histopathological changes

• Immunotoxicity

• Lethality

Human health effec st

and exposure data

In vivo x city to i udy data st

In vitro toxicity study data 

Computational techniques 

tical m eling a

redictive o

ath m o

g h

(M e a d nd

p al it mr s)

 

Figure 2. Hierarchy of evaluated scientific 

data
6 NIOSH CIB 61 • Skin Notations

• Neurotoxicity

• Nephrotoxicity

• Reproductive and developmental effects

Systemic immune-mediated responses associated with exposures of the skin to chemicals 

are not assigned the SYS notation despite being systemic effects. These immune-mediated 

responses would be assigned the SEN notation 

if supportive data are identified, and they are 

addressed within Section 2.4. 

Standardized and widely accepted research 

protocols exist for using animals to test the systemic toxicity of skin exposures to chemicals:

• Protocols for testing chemicals developed 

by the Organization for Economic Cooperation and Development (OECD) and 

European Centre for the Validation of Alternative Methods 

• Health effects testing guidelines developed by the U.S. Environmental Protection Agency (U.S. EPA) Office of Prevention, Pesticides, and Toxic Substances

• Protocols established by the National 

Toxicology Program (NTP) for determining the prechronic toxicity and 

chronic toxicity/carcinogenesis of toxic 

substances 

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:

— Investigation of the relevant 

toxicokinetics and potential 

toxic effects of metabolic 

transformation(s) of chemicals 

following skin absorption

— Examination of the adverse 

effects of chemical mixtures with 

skin absorption or potential 

systemic toxicity different from 

the level anticipated for individual 
NIOSH CIB 61 • Skin Notations 7

components of the mixture because 

of synergistic effects

— Investigation of altered skin 

permeability characteristics of toxic 

components resulting from the 

presence of a solvent or vehicle in a 

chemical preparation

• If no acceptable-quality empirical data 

exist for systemic effects from skin exposure to a chemical, systemic toxicity data 

may be extrapolated from toxicity data 

associated with other routes of exposure 

(such as oral and inhalation) when—

— Quality toxicokinetics data 

demonstrate the ability of a chemical 

to be absorbed by the skin and

— A direct link can be determined 

between the health effects caused by 

alternative routes of exposure and 

skin exposures. 

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. 

Table 2.2 provides an overview for the assignment of the SYS notation based on the criteria outlined within this section, in addition 

to Appendices A and B. Variables considered 

for the assignment of the SYS notation within 

this model include systemic toxicity associated 

with skin exposures and dermal absorption. 

Table 2.2 illustrates when the assignment of 

the SYS notation is appropriate based on the 

results of the critical review of all relevant scientific data. 

2.3 DIR

Direct effects are non-immune mediated adverse health effects resulting in damage or 

destruction of the skin localized at or near 

the point of contact. Most currently available reports on the direct effects of chemicals 

on skin (not immune-mediated) are related 

to irritation and corrosion and are qualitative 

descriptions summarized from the clinical 

observations of patients or the results of experimental animal studies. Manifestations of 

erythema and edema observed in humans and 
8 NIOSH CIB 61 • Skin Notations

in experimental animal studies are frequently 

used as indicators of skin irritation. Along with 

these reports, in vitro studies have shown that 

chemical contact with the skin may reduce 

the skin’s integrity as a barrier to penetration. 

Semiquantitative information can also be obtained from irritation/corrosion testing such as 

the Draize patch test or its modifications [NAS 

1977]. Chemicals producing a direct effect on 

the skin that is not a result of an immune-mediated response are labeled SK: DIR. Chemicals that are identified as irritants would be 

identified with the subnotation (IRR) [i.e., SK: 

DIR (IRR)]. Additionally, chemicals that cause 

necrosis of skin tissues or destruction of stratum corneum following skin exposure would 

receive the subnotation (COR) [i.e., SK: DIR 

(COR)]. The following are examples of direct 

health effects on the skin that would result in 

the assignment of the DIR notation or one of 

its subnotations:

• Carcinogenesis and photocarcinogenesis 

of the skin (see Appendix G.3) 

• Changes in pigmentation including bleaching (blanching) and staining of the skin

• Chloracne

• Compromise of the skin barrier integrity

• Corrosion

• Defatting or drying of skin

• Irritant contact dermatitis

• Phototoxicity

A chemical will be assigned the (IRR) subnotation when the reviewed data indicate that 

exposure of the skin to the substance causes 

reversible adverse effects, including inflammation, dryness, or redness with minor pain 

or discomfort, at or near the point of contact. The (COR) subnotation will be assigned 

when a chemical is known to cause irreversible 

Table 2.2. Overview for the assignment of the SYS notation

Systemic toxicity

Dermal absorption

Yes No No data

Yes SYS* SYS† SYS‡

No SYS SYS SYS

No data SYS SYS No assignment§

*Indicates categories where the SYS notation would be assigned

†

Indicates categories where the SYS notation would not be assigned

‡

Assignment of the SYS notation is based on criteria outlined in NIOSH [2009]

§

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.
NIOSH CIB 61 • Skin Notations 9

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 [OECD 1997]. 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 
10 NIOSH CIB 61 • Skin Notations

structure-activity-relationship (SAR)-based 

analysis and the physicochemical properties and reactivity of the chemical may be 

used as alternative methods for identifying 

hazards [OECD 2001]. 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.

2.4 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 

[Kimber 1996; Beck and Leung 2000; Tinkle 

et al. 2003; Day et al. 2006; Bello et al. 2007; 

Kreiss 2007; Redlich and Herrick 2008; Pauluhn 2008]. Animal studies in several species 

have shown that skin exposure to isocyanates 

followed by inhalational challenge is highly effective at inducing asthmatic lung responses. 

[Bello et al. 2007; Pauluhn 2008]. Human studies, although more limited, suggest a similar 

role following skin exposure to certain sensitizing chemicals [Beck et al. 2000; Day et al. 2006; 

Kreiss et al. 2007; Redlich et al. 2008]. Despite 
NIOSH CIB 61 • Skin Notations 11

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 [Bello et al. 2007; Kreiss et 

al. 2007; Redlich et al. 2008]. 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 [Bello et al. 2007; Kreiss et al. 

2007; Redlich et al. 2008].

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 [ECETOC 2002]:

• 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 [ECETOC 2000]). 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 

[European Commission 1996].

• 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. 
12 NIOSH CIB 61 • Skin Notations

• 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. 

2.5 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. 

2.6 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. 

 2.7 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. 

References

Beck LA, Leung DYM [2000]. Allergen sensitization through the skin induces systemic 

allergic responses. J Allergy Clin Immunol 

106:S258–263. 
NIOSH CIB 61 • Skin Notations 13

Bello D, Herrick CA, Smith TJ, Woskie SR, 

Streicher RP, Cullen MR, Liu Y, Redlich 

CA [2007]. Skin exposures to isocyanates: 

reasons for concerns. Environ Health Perspect 

115:328–335. 

Day GA, Stefaniak AB, Weston A, Tinkle S 

[2006]. Beryllium exposure: dermal and immunological considerations. Int Arch Occup 

Environ Health 79:161–164.

ECETOC [2000]. Skin sensitisation testing 

for the purpose of hazard identification and 

risk assessment. ECETOC Monograph No.29. 

Brussels, Belgium: European Centre for 

Ecotoxicology and Toxicology of Chemicals.

ECETOC [2002]. Use of human data in hazard 

classification for irritation and sensitization. 

ECETOC Monograph No.32. Brussels, Belgium: 

European Centre for Ecotoxicology and Toxicology of Chemicals.

European Commission [1996]. Commission 

Directive 96/54/EC of 30 July 1996 adapting 

to technical progress for the twenty-second 

time; Council Directive 67/548/EEC on the 

approximation of the laws, regulations, and 

administrative provisions relating to the 

classification, packaging, and labeling of 

dangerous substances. Official J Euro Commun 

L248.

54 Fed. Reg. 2718 [1989]. Occupational Safety 

and Health Administration: air contaminants; 

final rule. VI. Health effects discussion and 

determination of final PEL. 18. Substances for 

which OSHA is adding skin designations. (To 

be codified at 29 CFR 1910.)

Kimber I [1996]. The role of the skin in the 

development of chemical respiratory hypersensitivity. Toxicol Letters 86:89–92.

Kreiss K [2007]. Beryllium: a modern industrial 

hazard. Annu Rev Public Health. 28:259–77.

NAS [1977]. Dermal and eye toxicity tests. In: 

Principles and procedures for evaluating the 

toxicity of household substances. Washington, 

DC: National Academy of Sciences, pp. 23–59. 

NIOSH [1988]. Testimony on OSHA’s proposed 

rule on air contaminants, August 1, 1988. 

Cincinnati, OH: U.S. Department of Health 

and Human Services, Centers for Disease Control, National Institute for Occupational Safety 

and Health.

NIOSH [1991]. NIOSH criteria for a recommended standard: occupational exposure to 

ethylene glycol monomethyl ether, ethylene 

glycol monoethyl ether, and their acetates. 

Cincinnati, OH: U.S. Department of Health, 

Education, and Welfare, Centers for Disease 

Control and Prevention, National Institute 

for Occupational Safety and Health, DHEW 

(NIOSH) Publication No. 78–16.

NIOSH [2005]. NIOSH pocket guide to chemical hazards. Cincinnati, OH: U.S. Department 

of Health and Human Services, Centers for 

Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS 

(NIOSH) Publication No. 2005−149.

OECD [1997]. OECD proposal for a draft new 

guideline for the testing of chemicals: acute 

dermal irritation study in human volunteers. 

Paris, France: Organization for Economic 

Cooperation and Development.

OECD [2001]. OECD series on testing and 

assessment no. 33: harmonized integrated 

classification system for human health and 

environmental hazards of chemical substances 

and mixtures. ENV/JM/MONO(2001)6. Paris, 

France: Organization for Economic Cooperation 

and Development, Environment Directorate, 
14 NIOSH CIB 61 • Skin Notations

Joint Meeting of the Chemicals Committee and 

the Working Party on Chemicals, Pesticides, 

and Biotechnology.

Pauluhn J [2008]. Brown Norway rat asthma 

model of diphenylmethane-4,4’-diisocyanate 

(MDI): analysis of the elicitation dose-response 

relationship. Toxicol Sci 104(2):320–331. 

Redlich CA, Herrick CA [2008]. Lung/skin 

connections in occupational lung disease. Curr 

Opin Allergy Clin Immunol 8:115–119.

Tinkle SS, Antonini JM, Rich BA, Roberts JR, 

Salmen R, DePree K, Adkins EJ [2003]. Skin as 

a route of exposure and sensitization in chronic 

beryllium disease. Environ Health Perspect 

111:1202–1208. 

UNECE [2005]. Globally harmonized system 

of classification and labeling of chemicals 

(GHS). ST/SG/AC.10/30. New York, USA, and 

Geneva, Switzerland: United Nations Economic 

Commission for Europe.
NIOSH CIB 61 • Skin Notations 15

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 [OECD 2004a,b,c; IPCS 2006]. 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 [OECD 2004a; OECD 2004c; 

IPCS 2006]. 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 [Bronaugh and Stewart 1985; 

U.S. EPA 2004; OECD 2004b]. 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; Riviere 

and Brooks 2005; IPCS 2006]. The predictive 

APPENDIX A • Protocols Used in Studies of 

Health Effects from SkinExposure and the 

Determination of Criteria Derived for Assigning 

SkinNotations
16 NIOSH CIB 61 • Skin Notations

algorithms use the physicochemical properties 

(i.e., molecular weight, solubility, pH) of a test 

substance to estimate the potential biologic effects or transport properties within a biologic 

system [Moss et al. 2002; Riviere and Brooks 

2005; OECD 2004a; IPCS 2006]. 

The results of dermal absorption tests are frequently presented as the estimated or predicted 

percentage (%) of the applied dose absorbed. 

To differentiate between low and high dermal 

absorption, a 10% absorption rate has been selected as the critical cutoff value. This value corresponds to OECD guidelines [OECD 2004a] 

and is based on recommendations proposed by 

the Netherlands Organization for Applied Scientific Research (TNO) [De Heer et al. 1999]. 

If the dermal absorption rate values reported 

within reviewed data are consistently higher 

than 10%, the chemical is considered to have 

a high potential for dermal absorption and to 

contribute to systemic dose. 

A.1.2 Acute toxicity

Acute toxicity testing examines the mortality 

of test animals after single, short-term exposures to a toxic chemical [OECD 1987; U.S. 

EPA 1998a]. Typically, the test chemical is 

applied to the skin and remains in place for 

24 hours. The animals are then observed for 

14 days. The results of acute toxicity tests are 

presented as the dose that is lethal to 50% of 

the exposed animals (LD50) following application of the chemical to the skin, with observations of behavioral/clinical abnormalities 

and pathologic findings from gross necropsy. 

If the LD50 values are consistently lower than 

the critical cutoff value of 2000 milligrams of a 

substance/kilograms animal body weight (mg/

kg), the chemical is considered systemically 

toxic by the dermal route and is assigned the 

SYS notation. The critical value of 2000 mg/kg 

for the dermal LD50 reflects the dose selected in 

standardized limit tests to identify chemicals 

with the potential for acute toxicity. This value 

corresponds with the upper LD50 limit for establishing a chemical as harmful in the general 

classification and labeling requirements for 

chemicals in member countries of the OECD 

[Council of the European Communities 1992] 

and by GHS [UNECE 2005]. 

If LD50 values are consistently lower than the 

critical cutoff value of 200 mg/kg of animal 

body weight, the chemical is potentially lethal 

or life-threatening following acute exposures 

of the skin and is assigned the (FATAL) notation. This value is consistent with the numeric 

cutoff value used by GHS to identify chemicals 

capable of causing death following contact with 

the skin (see Appendix G.2.). 

A.1.3 Repeat-dose toxicity

Repeat-dose toxicity testing examines the toxic 

effect(s) of repeated exposure of the skin to 

a chemical for 21 or 28 days [OECD 1981a; 

U.S. EPA 1998b]. The animals are observed 

for behavioral and clinical abnormalities during the study. At the end of the study, they are 

examined for gross organ lesions, hematology, 

clinical chemistry, ophthalmology, and histopathology. Test results often include the reporting of a no-observed-adverse-effect level 

(NOAEL) as the most sensitive endpoint(s) 

selected from all evaluated health effects. If 

the NOAEL for a selected endpoint is lower 

than the critical cutoff value of 1000 mg/kg as 

a daily dose (mg/kg-day), the chemical is considered systemically toxic by the dermal route 

and is assigned the SYS notation. The critical 

NOAEL value of 1000 mg/kg-day reflects the 

dose selected in the standardized limit tests 

to identify chemicals with the potential for 

repeat-dose toxicity following contact with the 
NIOSH CIB 61 • Skin Notations 17

skin. If a creditable NOAEL is not identified 

within the reviewed toxicological data, other 

toxicity threshold measurements, such as the 

lowest-observed-adverse-effect level (LOAEL), 

lowest-observed-effect level (LOEL), or noobserved-effect level (NOEL), may be substituted for comparison with the critical cutoff 

value of 1000 mg/kg-day. 

A.1.4 Subchronic toxicity 

Subchronic toxicity testing examines the cumulative toxic effect(s) from continuous or 

repeated exposure of the skin to a chemical 

for at least 90 days [OECD 1981b; U.S. EPA 

1998c]. The animals are observed for behavioral/clinical abnormalities during the study. 

At the end of the study, they are examined for 

gross organ lesions, hematology, clinical chemistry, ophthalmology, and histopathology. Test 

results often include the NOAEL for the most 

sensitive endpoint(s) selected from all evaluated health effects. If the NOAEL for a selected 

endpoint is lower than the critical cutoff value 

of 1000 mg/kg-day, the chemical is considered 

systemically toxic by the dermal route and is 

assigned the SYS notation. The critical NOAEL 

value of 1000 mg/kg-day reflects the dose selected in the standardized limit tests to identify 

chemicals with the potential for subchronic 

toxicity following contact with the skin. If a 

creditable NOAEL is not identified within the 

reviewed toxicological data, a LOAEL, LOEL, 

or NOEL may be substituted when available 

for comparison to the critical cutoff value of 

1000 mg/kg-day. 

A.1.5 Chronic toxicity 

Chronic toxicity testing examines the cumulative toxic effect(s) of continuous or repeated 

exposure of a chemical to the skin for at least 12 

months [OECD 1981c; U.S. EPA 1998d]. The 

animals are observed for behavioral/clinical 

abnormalities during the study. They are evaluated using hematology, clinical chemistry, urinalysis, and ophthalmology during and at the 

end of the study. At necropsy, they are examined for gross organ lesions and tissue histopathology. Test results often include the NOAEL 

for the most sensitive endpoint(s) selected 

from all evaluated health effects. If the NOAEL 

for a selected endpoint is lower than the critical 

cutoff value of 1000 mg/kg-day, the chemical is 

considered systemically toxic following skin 

exposure and is assigned the SYS notation. The 

critical cutoff value of 1000 mg/kg-day reflects 

the dose selected in the standardized limit tests 

to identify chemicals with the potential for 

chronic toxicity following contact of the skin. 

If a creditable NOAEL is not identified within the reviewed toxicological data, a LOAEL, 

LOEL, or NOEL may be substituted when available for comparison to the selected cutoff value 

of 1000 mg/kg-day. 

A.1.6 Carcinogenicity

Carcinogenicity testing examines the development of neoplastic lesions or tumors in organs 

and tissues—excluding the skin (see Section 

A.2.3)—as a result of long-term exposure of the 

skin to a chemical for 18–24 months [OECD 

1981d; U.S. EPA 1998e]. The test period constitutes a substantial portion of the lifespan 

of test animals. The animals are observed for 

behavioral/clinical abnormalities during the 

study. They are investigated for clinical pathology during and at the end of the study and for 

gross organ lesions and tissue histopathology 

at necropsy. Carcinogenicity from skin exposure to a chemical may be studied and reported 

jointly with chronic toxicity following exposures of the skin [OECD 1981e; U.S. EPA 1998f; 

NTP 2001a]. Other systemic toxicants in this 
18 NIOSH CIB 61 • Skin Notations

category are chemicals reported to cause photocarcinogenesis (the elicitation or increase 

of a toxic and/or carcinogenic response after 

dermal absorption and subsequent exposure 

to sunlight) [NIH 2002a; OECD 2004d]. If a 

candidate chemical is determined to produce 

a statistically significant increase in the incidence of neoplastic lesions or tumors in test 

animals, it is considered to be carcinogenic and 

assigned the SYS notation.

A.1.7 Toxic effects of exposures of 

the skin on organ systems or 

biologic functions 

Several types of tests allow for the examination of the destruction or disruption of target 

organ systems and/or biologic functions from 

skin exposure to chemicals. Examples include 

(1) prenatal development toxicity (maternal 

and fetal toxicity) testing [U.S. EPA 1998g; 

NTP 2001b; OECD 2001a], (2) two-generation 

reproduction and fertility effects testing [U.S. 

EPA 1998h; OECD 2001b], and (3) immunotoxicity (suppression of the immune system) 

testing [U.S. EPA 1998i]. Ideally, a NOAEL is 

identified and reported for the studied effect(s). 

If the NOAEL for selected endpoint(s) is lower 

than 1000 mg/kg-day, the chemical is considered systemically toxic by the dermal route and 

assigned the SYS notation. The critical cutoff 

value of 1000 mg/kg-day reflects the dose selected in the standardized limit tests used to 

identify chemicals that are potentially toxic to 

organs or biologic functions following contact 

with the skin. In the event that a NOAEL cannot be identified within reviewed toxicological 

data, a LOAEL, LOEL, or NOEL may be substituted when available for comparison to the 

critical cutoff value of 1000 mg/kg-day. 

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 
NIOSH CIB 61 • Skin Notations 19

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 following methods have been 

standardized by the OECD as guidelines for 

testing of chemicals and peer-reviewed and 

recommended for regulatory acceptance by 

the Interagency Coordinating Committee on 

the Validation of Alternative Methods (ICCVAM) and the NTP Interagency Center for the 

Evaluation of Alternative Toxicological Methods (NICEATM):

• Corrositex® [NIH 1999a]

• The human skin models [OECD 2004e], 

including EPISKINTMand EpiDermTM [NIH 

2002b]

• The rat skin transcutaneous electrical resistance (TER) assay [NIH 2002b; OECD 

2004f]

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 [Fentem et al. 1998; U.S. EPA 1996]. 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

Carcinogenicity testing examines the development of neoplastic lesions on skin as a result of 

long-term exposure of the skin to a chemical for 

18–24 months [OECD 1981d; U.S. EPA 1998e]. 

The test period constitutes a major portion of 

the life span of test animals. The animals are 

observed for behavioral/clinical abnormalities 

during the study. They are investigated for clinical pathology during and at the end of the study. 
20 NIOSH CIB 61 • Skin Notations

They are also examined for gross organ lesions 

and tissue histopathology at necropsy. Carcinogenicity from skin exposure to a chemical may 

be studied and reported jointly with chronic 

toxicity of the skin [OECD 1981e; U.S. EPA 

1998f; NTP 2001a]. If skin exposure to a chemical induces a statistically significant increase in 

the incidence of neoplastic lesions or tumors in 

test animals, it is considered to be a potential 

skin carcinogen and is assigned the DIR notation. Additionally, chemicals identified as being 

capable of causing photocarcinogenesis when 

topically applied in conjunction with exposure 

to sunlight will be included within this category 

[NIH 2002a; OECD 2004d].

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 

[OECD 2004a,b]. 

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 [OECD 1992; U.S. EPA 2003]. 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 [NIH 

1999b]. OECD [2002b] and U.S. EPA [2003] 

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.
NIOSH CIB 61 • Skin Notations 21

A.3.3 Identifying skin sensitization 

potential with the mouse ear 

swelling test 

The mouse ear swelling test (MEST) [Gad et 

al. 1986; Thorne et al. 1991a,b] is accepted by 

OECD [1992] and U.S. EPA [2003] as a screening test for detecting chemicals with sensitization potential. In the noninvasive MEST, the animals are initially exposed to the test substance 

by topical application on the abdomen to induce an immune response. After the induction 

period, the test substance is applied topically to 

the ears of animals (challenge exposure). Ear 

thickness as a function of swelling is measured 

at 24-hour intervals for 2–3 days post challenge 

to determine whether a delayed hypersensitivity 

has occurred. A chemical is considered a sensitizer if it yields a positive result in the MEST. 

If this test indicates no sensitization potential, 

the chemical should be further examined with 

an accepted test such as the guinea pig sensitization test or the LLNA [U.S. EPA 2003] before the 

substance is considered a nonsensitizer. 

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NTP studies: development toxicity. In: NTP 

testing information and study results. Research 

Triangle Park, NC: U.S. Department of Health 

and Human Services, Public Health Service, 

National Toxicology Program.

OECD [1981a]. OECD guideline for testing of 

chemicals 410: repeated dose dermal toxicity—

21/28-day study. Paris, France: Organization 

for Economic Cooperation and Development.

OECD [1981b]. OECD guideline for testing of 

chemicals 411: subchronic dermal toxicity—

90-day study. Paris, France: Organization for 

Economic Cooperation and Development.

OECD [1981c]. OECD guideline for testing of 

chemicals 452: chronic toxicity studies. Paris, 

France: Organization for Economic Cooperation and Development.

OECD [1981d]. OECD guideline for testing of 

chemicals 451: carcinogenicity studies. Paris, 

France: Organization for Economic Cooperation and Development.

OECD [1981e]. OECD guideline for testing 

of chemicals 453: combined chronic toxicity/

carcinogenicity studies. Paris, France: Organization for Economic Cooperation and Development.

OECD [1987]. OECD guideline for testing of 

chemicals 402: acute dermal toxicity. Paris, 

France: Organization for Economic Cooperation 

and Development.

OECD [1992]. OECD guideline for testing of 

chemicals 406: skin sensitization. Paris, France: 

Organization for Economic Cooperation and 

Development.

OECD [2001a]. OECD guideline for testing of 

chemicals 414: prenatal developmental toxicity 

study. Paris, France: Organization for Economic 

Cooperation and Development.

OECD [2001b]. OECD guideline for testing of 

chemicals 416: two-generation reproduction 

toxicity study. Paris, France: Organization for 

Economic Cooperation and Development.

OECD [2002a]. OECD guideline for testing 

of chemicals 404: acute dermal irritation/

corrosion. Paris, France: Organization for 

Economic Cooperation and Development.

OECD [2002b]. OECD guideline for testing of 

chemicals 429: skin sensitization—local lymph 

node assay. Paris, France: Organization for 

Economic Cooperation and Development.
NIOSH CIB 61 • Skin Notations 23

OECD [2004a]. Guidance document for the 

conduct of skin absorption studies. Paris, France: 

Organization for Economic Cooperation and 

Development, Environment Directorate.

OECD [2004b]. OECD guideline for the testing 

of chemicals. Skin absorption: in vitro method. 

428. Adopted: 13 April 2004. Paris, France: 

Organization for Economic Cooperation and 

Development.

OECD [2004c]. OECD guideline for the testing 

of chemicals. Skin absorption: in vivo method. 

427. Adopted: 13 April 2004. Paris, France: 

Organization for Economic Cooperation and 

Development.

OECD [2004d]. OECD guideline for testing of 

chemicals 432: in vitro 3T3 NRU phototoxicity 

test. Paris, France: Organization for Economic 

Cooperation and Development.

OECD [2004e]. OECD guideline for testing of 

chemicals 431: in vitro skin corrosion—human 

skin model test. Paris, France: Organization for 

Economic Cooperation and Development.

OECD [2004f]. OECD guideline for testing 

of chemicals 430: in vitro skin corrosion—

transcutaneous electrical resistance test (TER). 

Paris, France: Organization for Economic 

Cooperation and Development.

Riviere JE, Brooks JD [2005]. Predicting skin 

permeability from complex chemical mixtures. 

Toxicol Appl Pharmacol 208:99–110.

Thorne PS, Hawk C, Kaliszewski SD, Guiney 

PD [1991a]. The noninvasive mouse ear 

swelling assay. I. Refinements for detecting 

weak contact sensitizers. Fund Appl Toxicol 

17:790–806.

Thorne PS, Hawk C, Kaliszewski SD, Guiney PD 

[1991b]. The noninvasive mouse ear swelling 

assay. II. Testing the contact sensitizing potency 

of fragrances. Fund Appl Toxicol 17:807–820.

UNECE [2005]. Globally harmonized system 

of classification and labeling of chemicals 

(GHS). ST/SG/AC.10/30. New York, USA, and 

Geneva, Switzerland: United Nations Economic 

Commission for Europe. 

U.S. EPA [1996]. Test methods for evaluating 

solid waste, physical/chemical methods, SW–846 

Method 1120: dermal corrosion. Washington, 

DC: U.S. Environmental Protection Agency, 

Office of Solid Waste, U.S. EPA Publication 

SW–846 Manual, 3rd ed. 

U.S. EPA [1998a]. Health effects test guidelines 

OPPTS 870.1200: acute dermal toxicity. Washington, DC: U.S. Environmental Protection 

Agency, Office of Prevention, Pesticides, and 

Toxic Substances, U.S. EPA 712–C–98–192.

U.S. EPA [1998b]. Health effects test guidelines 

OPPTS 870.3200: 21/28-day dermal toxicity. 

Washington, DC: U.S. Environmental Protection 

Agency, Office of Prevention, Pesticides, and 

Toxic Substances, U.S. EPA 712–C–98–201.

U.S. EPA [1998c]. Health effects test guidelines 

OPPTS 870.3250: 90-day dermal toxicity. Washington, DC: U.S. Environmental Protection 

Agency, Office of Prevention, Pesticides, and 

Toxic Substances, U.S. EPA 712–C–98–202.

U.S. EPA [1998d]. Health effects test guidelines 

OPPTS 870.4100: chronic toxicity. Washington, 

DC: U.S. Environmental Protection Agency, 

Office of Prevention, Pesticides, and Toxic 

Substances, U.S. EPA 712–C–98–210.

U.S. EPA [1998e]. Health effects test guidelines 

OPPTS 870.4200: carcinogenicity. Washington, 

DC: U.S. Environmental Protection Agency, 

Office of Prevention, Pesticides, and Toxic 

Substances, U.S. EPA 712–C–98–211.
24 NIOSH CIB 61 • Skin Notations

U.S. EPA [1998f]. Health effects test guidelines 

OPPTS 870.4300: combined chronic toxicity/

carcinogenicity. Washington, DC: U.S. Environmental Protection Agency, Office of Prevention, Pesticides, and Toxic Substances, U.S. 

EPA 712–C–98–212.

U.S. EPA [1998g]. Health effects test guidelines 

OPPTS 870.3700: prenatal developmental 

toxicity study. Washington, DC: U.S. Environmental Protection Agency, Office of Prevention, Pesticides, and Toxic Substances, U.S. 

EPA 712–C–98–207.

U.S. EPA [1998h]. Health effects test guidelines 

OPPTS 870.3800: reproduction and fertility 

effects. Washington, DC: U.S. Environmental 

Protection Agency, Office of Prevention, 

Pesticides, and Toxic Substances, U.S. EPA 

712–C–98–208.

U.S. EPA [1998i]. Health effects test guidelines 

OPPTS 870.7800: immunotoxicity. Washington, 

DC: U.S. Environmental Protection Agency, 

Office of Prevention, Pesticides, and Toxic 

Substances, U.S. EPA 712–C–98–351.

U.S. EPA [1998j]. Health effects test guidelines 

OPPTS 870.2500: acute dermal irritation. 

Washington, DC: U.S. Environmental Protection 

Agency, Office of Prevention, Pesticides, and 

Toxic Substances, U.S. EPA 712–C–98–196.

U.S. EPA [2003]. Health effects test guidelines 

OPPTS 870.2600: skin sensitization. Washington, 

DC: U.S. Environmental Protection Agency, 

Office of Prevention, Pesticides, and Toxic 

Substances, U.S. EPA 712–C–03–197.

U.S. EPA [2004]. Risk assessment guidance for 

superfund. Vol. I: Human health evaluation 

manual. Washington, DC: U.S. Environmental 

Protection Agency, Office of Superfund Remediation and Technology Innovation, U.S. 

EPA/540/R/99/005.
NIOSH CIB 61 • Skin Notations 25

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 (Kp

) 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 

[2004a,b] and U.S. EPA [69 Fed. Reg.†

 22402 

(2004)]. These methods typically measure the 

†

Federal Register. See Fed. Reg. in references.

APPENDIX B • Algorithm for estimating skin 

absorption and systemic toxicity and suggested 

application for assigning SYS notations
26 NIOSH CIB 61 • Skin Notations

diffusion of a test substance into and across 

the excised skin (which consists of epidermal 

membranes or split-thickness skin) to a fluid 

reservoir; they report the Kp as a quantitative 

measurement of the rate of skin diffusion at the 

steady state when an infinite dose is employed. 

Measured K

p

 values from the actual workplace 

vehicle should be used when available. The experimentally determined Kp

 values are not always available or generated following standardized protocols. An alternative approach is to use 

the QSPRs that predict the Kp of chemicals based 

on the physicochemical properties relevant to 

their transport behavior in the stratum corneum, such as the molecular size and solubility 

in the lipids of the stratum corneum. Vigorous 

research in the modeling of skin permeation 

has led to the development of various validated 

QSPRs—for example, the refined Potts and Guy 

equation [U.S. EPA 2004], the revised Robinson 

model [Wilschut et al. 1995], and the Random 

Walk model [Frasch 2002]. 

As an example to demonstrate the determination of K

p

 by predictive QSPRs, the revised 

Robinson model is presented here for its mathematical descriptors and operation. The revised 

Robinson model has been shown to be among 

the QSPRs that provide reasonable Kp estimates when compared with the experimentally 

derived values [Wilschut et al. 1995; Vecchia 

and Bunge 2003]. The revised Robinson model 

estimates K

p

 based on the molecular weight of 

a chemical (MW, representing the molecular 

size) and the logarithm of its octanol-water 

partition coefficient (log KOW, representing the 

hydrophobicity). This model is mathematically 

expressed as follows:

where K

psc is the permeation coefficient in the 

lipid fraction of the stratum corneum, Kpol is 

the coefficient in the protein fraction of the 

stratum corneum, and Kaq 

is the coefficient in 

the watery epidermal layer. These components 

are individually estimated by 

log Kpsc = −1.326 + 0.6097 × log KOW − 

0.1786 × MW0.5

Kpol = 0.0001519 × MW−0.5

Kaq = 2.5 × MW−0.5

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 Kp

 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 Kp

 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 
NIOSH CIB 61 • Skin Notations 27

Testing Committee [Walker et al. 1996]) 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 Kp

 acquired in Step 1, the water 

solubility (SW) 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 cm2

), 

Skin dose = Kp × SW × Exposed skin 

surface area × Exposure time

= Kp (cm/hr) × SW (mg/cm3) × 

360 cm2 × 8 hr

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 m3

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/m3) × 10 m3 × 

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% [European Chemicals Bureau 2003], 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 
28 NIOSH CIB 61 • Skin Notations

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 [ECETOC 1998]. 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. The defaults of the 

exposed skin surface area, the air volume inhaled in 8 hours, and the respiratory RF in the 

ECETOC algorithm are 2000 cm2, 10 m3, and 

50%, respectively. The SI ratio calculated in 

the algorithm proposed for recommending the 

NIOSH SK: SYS notations (SI ratioNIOSH) can be 

modified to derive an SI ratio according to the 

method proposed by the ECETOC (SI ratioECETOC). A comparison between the SI ratioNIOSH

and the SI ratioECETOC reveals that

SI ratioECETOC = SI ratioNIOSH × [2000 cm2 (hands

and arms) ÷ 360 cm2 (palms)] × 

(1 hr ÷ 8 hr) × [75% (default 

RF in NIOSH algorithm) ÷ 50% 

(default RF in ECETOC 

 algorithm)] = SI ratioNIOSH × 1.04

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 
NIOSH CIB 61 • Skin Notations 29

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. 

References

ECETOC [1998]. Examination of a proposed 

skin notation strategy. ECETOC Special Report 

No.15. Brussels, Belgium: European Centre for 

Ecotoxicology and Toxicology of Chemicals.

European Chemicals Bureau [2003]. Technical 

guidance document on risk assessment in 

support of Commission Directive 93/67/EEC 

on risk assessment for new notified substances 

and Commission Regulation (EC) No. 1488/94 

on risk assessment for existing substances and 

Directive 98/8/EC of the European Parliament 

and of the Council concerning the placing of 

biocidal products on the market. 2nd ed. Ispra, 

Italy: European Commission, Joint Research 

Centre, Institute for Health and Consumer 

Protection, European Chemicals Bureau.

69 Fed. Reg. 22402 [2004]. Environmental Protection Agency: in vitro dermal absorption rate 

testing of certain chemicals of interest to the 

Occupational Safety and Health Administration; 

final rule.

Frasch HF [2002]. A random walk model of 

skin permeation. Risk Anal 22:265–276.

OECD [2004a]. Guidance document for 

the conduct of skin absorption studies. 

Paris, France: Organization for Economic 

Cooperation and Development, Environment 

Directorate, Joint Meeting of the Chemicals 

Committee and the Working Party on 

Chemicals, Pesticides, and Biotechnology. 

OECD Series on Testing and Assessment, 

Number 28. 

OECD [2004b]. OECD guideline for the testing 

of chemicals. Skin absorption: in vitro method. 

428. Adopted: 13 April 2004. Paris, France: 

Organization for Economic Cooperation and 

Development.
30 NIOSH CIB 61 • Skin Notations

U.S. EPA [2004]. Risk assessment guidance for 

superfund. Vol. I: Human health evaluation 

manual. Washington, DC: U.S. Environmental 

Protection Agency, Office of Superfund 

Remediation and Technology Innovation, U.S. 

EPA/540/R/99/005.

Vecchia BE, Bunge AL [2003]. Evaluating the 

transdermal permeability of chemicals. In: Guy 

RH, Hadgraft J, eds. Transdermal drug delivery. 

2nd ed. New York, NY: Marcel Dekker, Inc., pp. 

25–55.

Walker JD, Whittaker C, McDougal JN 

[1996]. Role of the TSCA Interagency Testing 

Committee in meeting the U.S. government data 

needs: designating chemicals for percutaneous 

absorption rate testing. In: Marzulli FN, Maibach 

HI, eds. Dermatotoxicology. 5th ed. Washington, 

DC: Taylor and Francis, pp. 371–381.

Wilschut A, ten Berge WF, Robinson PJ, McKone 

TE [1995]. Estimating skin permeation. The 

validation of five mathematical skin permeation 

models. Chemosphere 30(1):1275–1296.
NIOSH CIB 61 • Skin Notations 31

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

[OECD 2002], 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 [UNECE 2005]. 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 [Worth et al. 1998]:

• 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. 

[1988] 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 

[Ridings et al. 1996]. 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 
32 NIOSH CIB 61 • Skin Notations

identifying potential contact allergens was derived using results of the guinea pig maximization test conducted for 294 substances classified as strong or moderate sensitizers [Barratt 

et al. 1994]. 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 [de Silva et al. 1996].

Zinke et al. [2002] 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. 2002]. 

Zinke et al. [2002] 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, 

β-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.

References

Barratt MD, Basketter DA, Chamberlain 

M, Admans GD, Langowski JJ [1994]. An 

expert system rulebase for identifying contact 

allergens. Toxicol in Vitro 8(5):1053–1060.

de Silva O, Basketter DA, Barratt MD, Corsini 

E, Cronin MTD, Das PK, Degwert J, Enk A, 

Garrigue JL, Hauser C, Kimber I, Lepoittevin J-P, 

Peguet J, Ponec M [1996]. Alternative methods 

for skin sensitization testing. The report and 

recommendations of ECVAM Workshop 19. 

Altern Lab Animals 24:683–705.

OECD [2002]. OECD guideline for the testing 

of chemicals. Acute dermal irritation/corrosion. 

404. Adopted: 24 April 2002. Paris, France: 

Organization for Economic Cooperation and 

Development.

Ridings JE, Barratt MD, Cary R, Earnshaw CG, 

Eggington CE, Ellis MK, Judson PN, Langowski 

JJ, Marchant CA, Payne MP, Watson WP, Yih 

TD [1996]. Computer prediction of possible 

toxic action from chemical structure: an update 

on the DEREKTM system. Toxicol 106:267–279.

UNECE [2005]. Globally harmonized system 

of classification and labeling of chemicals 

(GHS). ST/SG/AC.10/30. New York, USA, and 

Geneva, Switzerland: United Nations Economic 

Commission for Europe. 

Worth AP, Fentem JH, Balls M, Botham PA, 

Curren RD, Earl LK, Esdaile DJ, Liebsch M 

[1998]. An evaluation of the proposed OECD 

testing strategy for skin corrosion. Altern Lab 

Animals 26:709–720. 

Young JR, How MJ, Walker AP, Worth WMH 

[1988]. Classification as corrosive or irritant to 

skin of preparations containing acid or alkaline 

substances, without testing on animals. Toxic 

in Vitro 2(1):19–26.
NIOSH CIB 61 • Skin Notations 33

Zinke S, Gerner I, Schlede E [2002]. 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 35

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: 

1. When recognized as existing occupational hazards or associated with potential 

emerging issues

2. When nominated by interested parties, 

including NIOSH stakeholders, other 

governmental agencies, and the public

3. When listed in the NIOSH Pocket Guide 

to Chemical Hazards. 

Chemicals identified as emerging issues, existing as occupational hazards, or nominated for 

evaluation will be assessed by NIOSH based on 

the availability of quality data that clearly outline the hazards posed by the candidate chemical. For chemicals listed within the NIOSH 

Pocket Guide to Chemical Hazards, a hierarchal 

ranking scheme has been developed to prioritize candidate chemicals (see Appendix D.2). 

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 

[skin], 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:

ATSDR Toxicological Profiles 

(ToxProfiles)

www.atsdr.cdc.gov/toxpro2.html

European Inventory of Existing Commercial chemical Substances (EINICS)

http://ecb.jrc.it/esis/index.php?PGM=ein

National Occupational Exposure Survey 

(NOES)

www.cdc.gov/noes/

APPENDIX D • Selecting and Prioritizing 

Candidate Chemicals
36 NIOSH CIB 61 • Skin Notations

NIOSHTIC-2 

www2a.cdc.gov/nioshtic-2/advsearch2.asp

NIOSH Immediately Dangerous to Life 

and Health (IDLH) Values 

www.cdc.gov/niosh/idlh/idlh-1.html

NIOSH International Chemical Safety 

Card (ICSC)

www.cdc.gov/niosh/ipcs/nicstart.html

NIOSH Pocket Guide to Chemical 

Hazards

www.cdc.gov/niosh/npg/

NIOSH Registry of Toxic Effects of 

Chemical Substances (RTECS) 

www.cdc.gov/niosh/rtecs/rteccas1.html

NIOSH Recommendations for 

Occupational Safety and Health, 

Compendium of Policy Documents and 

Statements

www.cdc.gov/niosh/pubs/all_date_desc_

nopubnumbers.html

NIOSH Skin Exposures and Effects 

Topic Page

www.cdc.gov/niosh/topics/skin/

OSHA Permissible Exposure Limits

www.osha.gov/SLTC/pel/

U.S. EPA High Production Volume 

Information System (HPV)

www.epa.gov/hpvis/

The 142 chemicals previously assigned the 

notation [skin] by NIOSH were systematically assigned a score from 0–7 to determine 

which substances posed the greatest potential 

occupational health hazard based on the parameters outlined in Table D.1. The scores for 

15 chemicals are illustrated within Table D.2. 

The hierarchal ranking scheme may be modified in the future to aid NIOSH in prioritizing 

(1) chemicals listed within the NIOSH Pocket 

Guide to Chemical Hazards that do not have 

the notation [skin] and (2) chemicals nominated for evaluation from stakeholders, governmental agencies, and public interest groups.

Table D.1. Definition scoring of parameters applied with hierarchal ranking scheme

Parameter Definition and scoring

OEL potency If OEL is < 1 mg/m3, assign score of 1; 

if not, assign score of 0.

Carcinogen If identified as a carcinogen, assign score of 0.5; 

if not, assign score of 0.

Reproductive/development 

toxicant

If identified as a reproductive or development toxicant, assign score of 0.5; 

if not, assign score of 0.

Irritant/corrosive If identified as a corrosive, assign score of 1; 

if identified as an irritant only, assign score of 0.5; 

if identified as neither, assign score of 0.

(Continued)
NIOSH CIB 61 • Skin Notations 37

Table D.1 (Continued). Definition scoring of parameters applied 

with hierarchal ranking scheme

Parameter Definition and scoring

Sensitizer If identified as a sensitizer, assign score of 1; 

if not, assign score of 0.

HPV chemical If identified as a HPV chemical, assign score of 1; 

if not, assign score of 0.

Exposure potential If identified within NOES data as having potential to expose > 75,000 workers, assign score of 1; 

if not, assign score of 0.

RTECS or 

risk phrases (R-phrases) 

If identified within RTECS as either extremely or highly hazardous or within the 

R-phrases as either highly toxic or toxic, assign score of 1, 

if not assign 0. 

Table D.2. Example of the application of the hierarchal ranking scheme 

ranking of 15 candidate chemicals 

Chemical

CAS 

no.

OEL*

Potency CAN† R/DT‡

IRR/

COR§ SEN¶ HPV**

Exposure potential

Skin 

hazard††

Overall

score

Epichlorohydrin 106–89–8 0 0.5 0.5 1 1 1 1 1 6

Acrylonitrile 107–13–1 0 0.5 0.5 0.5 1 1 1 1 5.5

Dichlorvos 62–73–7 1 0.5 0.5 0.5 1 1 0 1 5.5

Hydrazine 302–01–2 1 0.5 0.5 1 1 0 0 1 5

p-Phenylene 

diamine

106–50–3 1 0.5 0 0.5 1 1 0 1 5

Acrylamide 79–06–1 1 0.5 0.5 0.5 1 1 0 0 4.5

Phenol 108–95–2 0 0 0.5 1 0 1 1 1 4.5

Acrylic Acid 79–10–7 0 0 0 1 1 1 1 0 4

(Continued)
38 NIOSH CIB 61 • Skin Notations

Table D.2 (Continued). Example of the application of the hierarchal ranking 

scheme ranking of 15 candidate chemicals 

Chemical

CAS 

no.

OEL*

potency CAN† R/DT‡

IRR/

COR§ SEN¶ HPV**

Exposure potential

Skin 

hazard††

Overall

score

Diethylenetriamine111–40–0 0 0 0 1 1 1 1 0 4

Heptachlor 76–44–8 1 0.5 0.5 0 0 1 0 1 4

o-Cresol 95–48–7 1 0 0 1 0 1 0 1 4

Phenylhydrazine 100–63–0 1 0.5 0 0.5 1 0 0 1 4

1,3-Dichloropropene542–75–6 0 0.5 0.5 0.5 1 1 0 0 3.5

2-Ethoxyethanol 110–80–5 0 0 0.5 0 0 1 1 1 3.5

Aniline 62–53–3 0 0.5 0 0 1 1 0 1 3.5

*OEL = Occupational Exposure Limits

†

CAN = Carcinogen

‡

R/DT = Reproductive and Development Toxicant

§

IRR/COR = Irritant/Corrosive

¶

SEN = sensitizer

**HPV = High Production Volume Chemical

††Skin Hazard = Based on information provided by RTECS and EU risk phrases
NIOSH CIB 61 • Skin Notations 39

E.1 Literature search

The literature search strategy has been developed to identify critical scientific data on 

(1) physical and chemical properties of candidate substances, (2) human health effects associated with exposures to substances, (3) reported results of in vivo and in vitro toxicity 

testing, and (4) estimates of chemical toxicokinetics and toxicity based on computational 

techniques. The primary sources of information reviewed during the literature search are 

peer-reviewed journals, domestic and international governmental agencies reports, reference 

books, private industry reports, and scientific 

evaluations from public interest organizations. 

The literature search strategy includes search 

terms within electronic databases to ensure the 

identification of relevant scientific data. 

E.1.1 Primary sources 

E.1.1.1 Electronic databases 

The following databases are searched:

European Inventory of Existing 

Commercial chemical Substances 

(EINICS) 

http://ecb.jrc.it/esis/index.php?PGM=ein

EMBASE

www.embase.com/

 Extension Toxicology Network 

(EXTOXNET) 

http://extoxnet.orst.edu/pips/ghindex.html

Haz-Map: Occupational Exposure to 

Hazardous Agents (Haz-Map)

www.nlm.nih.gov/pubs/factsheets/

hazmap.html

Hazardous Substances Data Bank (HSDB)

http://toxnet.nlm.nih.gov/cgi-bin/sis/

htmlgen?HSDB

Integrated Risk Information System (IRIS)

http://toxnet.nlm.nih.gov/cgi-bin/sis/

htmlgen?IRIS

International Toxicity Estimates for Risk 

(ITER)

http://toxnet.nlm.nih.gov/cgi-bin/sis/

htmlgen?iter

NIOSH Registry of Toxic Effects of 

Chemical Substances (RTECS) 

www.cdc.gov/niosh/rtecs/

NIOSHTIC-2 

www2a.cdc.gov/nioshtic-2/advsearch2.asp

National Toxicology Program Report on 

Carcinogens (NTP)

http://ehis.niehs.nih.gov/roc/

OSH References Collection 

http://ccinfoweb.ccohs.ca/bibliographic/

search.html

PubMed

www.ncbi.nlm.nih.gov/sites/

entrez?db=pubmed

Toxicology Literature Online 

(TOXLINE) database from the U.S. 

National Library of Medicine’s TOXNET 

APPENDIX E • Guidelines and Criteria for the 

Search Strategy, Evaluation, and Selection of 

Supporting Data Used for the Assignment of 

Skin Notations
40 NIOSH CIB 61 • Skin Notations

http://toxnet.nlm.nih.gov/cgi-bin/sis/

htmlgen?TOXLINE

U.S. Environmental Protection Agency 

(U.S. EPA) Substance Registry Services

www.epa.gov/srs/

Web of Science

http://thomsonreuters.com/products_

services/scientific/Web_of_Science

E.1.1.2 Published books, technical 

documents, and Web sites

The following published books, technical documents, and Web sites represent common sources used during the derivation of the new NIOSH 

skin notations:

Agency for Toxic Substances and 

Disease Registry (ATSDR) Public Health 

Statements (PHS) Web site

www.atsdr.cdc.gov/phshome.html

ATSDR TOXFAQS Web site

www.atsdr.cdc.gov/toxfaq.html

ATSDR Toxicological Profiles Web site

www.atsdr.cdc.gov/toxpro2.html 

American Conference of Governmental 

Industrial Hygienists (ACGIH)

Documentation of the Threshold Limit 

Values (TLV) for Chemical Substances 

and Physical Agents

American Industrial Hygiene Association 

(AIHA) Workplace Environmental 

Exposure Levels Guide (WEEL) Web site

www.aiha.org/webapps/taxonomy/

documentrepository/erpgweels/7d11ed78-

37da-4ce1-99f2-763603376151.pdf

California Environmental Protection 

Agency (CalEPA) Health Reports Web site 

www.calepa.ca.gov/Publications/

Cassarett and Doull’s Toxicology: The 

Basic Science of Poisons

European Commission Risk Assessment 

Reports Web site

http://ec.europa.eu/health/ph_risk/risk_

en.htm

Hamilton and Hardy’s Industrial 

Toxicology

Health and Safety Executive (HSE) 

Publications Web site

www.hse.gov.uk/pubns/index.htm

International Agency for Research on 

Cancer (IARC) Monographs on the 

Evaluation of Carcinogenic Risks to 

Humans Web site

http://monographs.iarc.fr

International Programme on Chemical 

Safety (IPCS) Web site 

www.inchem.org/

Merck Index

National Industrial Chemicals 

Notification and Assessment Scheme 

(NICNAS) Scientific Reports Web site

www.nicnas.gov.au/

NIOSH International Chemical Safety 

Cards (ICSC)

www.cdc.gov/niosh/ipcs/nicstart.html

NIOSH Pocket Guide to Chemical 

Hazards

www.cdc.gov/niosh/npg/

NIOSH Publications Web site

www.cdc.gov/niosh/pubs/all_date_desc_

nopubnumbers.html

NIOSH Registry of Toxic Effects of 

Chemical Substances (RTECS) 

www.cdc.gov/niosh/rtecs/rteccas1.html
NIOSH CIB 61 • Skin Notations 41

New Jersey Right to Know Hazardous 

Substances Fact Sheets Web site web.

doh.state.nj.us/rtkhsfs/indexfs.aspx

Occupational and Exposure Exposures 

of the Skin to Chemicals (OEESC) 

Conference Abstracts 

http://inside.mines.edu/outreach/cont_ed/

oeesc/

www.cdc.gov/niosh/topics/skin/OEESC2/

index.html

www.oeesc2009.pwp.blueyonder.co.uk/

OEESC/Abstracts.html

Patty’s Industrial Hygiene and 

Toxicology

Proctor and Hughes’ Chemical Hazards 

of the Workplace

OSHA Publications Web site 

www.osha.gov/

U.S. EPA Web site

www.epa.gov/

U.S. National Technical Information 

Service (NTIS) Web site 

www.ntis.gov/

U.S. National Toxicology Program 

(NTP) Study Reports 

http://ntp.niehs.nih.gov/ntpweb/index.

cfm?objectid=7DA86165-BDB5-82F8-

F7E4FB36737253D5

E.1.2 Search terms

Literature searches are conducted by NIOSH 

technical informational specialist for a candidate chemical based on the substance’s Chemical 

Abstract Services Number (CAS No.), chemical 

nomenclature, common names, and synonyms. 

Additional terminology used during the literature search can be located in Table E.1.

E.2 Evaluation of data

A qualitative classification scheme has been 

developed to aid in the evaluation of data sets 

identified through the literature search. This 

Table E.1. Terminology applied during the search for critical scientific data on 

each candidate chemical substance

Acne* Epicutaneous* Keratoacanthoma QSAR 

Allerg* Epiderm* Keratoderma QSPR

Apocrine Episkin Keratosis Radiodermatitis 

Argyria Erythema Leukoderma Rash*

Atopic Exanthema Lichenoid Redness

Blister* Exfoliat* Miliaria Sebaceous 

Burn Fingernail* Mucocutaneous Sensitizer

Callosity Follicle* Neurodermat* Skin 

Cancer* Gangren* Onychomyco* Skin Diseases

Corrosion Granuloma Pain Skin Irritancy Tests

Crositex* Hirsut* Pallor Skin Physiology 

(Continued)
42 NIOSH CIB 61 • Skin Notations

scheme relies on a case-by-case analysis of the 

assembled data using a weight-of-evidence approach. Other general considerations used to 

evaluate the assembled data include:

• How many studies were identified? 

• Were the identified studies peer-reviewed?

• Were the identified data generated using 

standardized protocols (e.g., guidelines 

established by OECD, European Centre 

for the Validation of Alternative Methods, U.S. EPA, or NTP?

• Were the exposure conditions and the 

studies’ reported findings described in 

detail? 

• Should any other available information 

be considered?

Based on the results of this qualitative classification scheme, the data sets are classified as 

sufficient, limited, or insufficient. These rankings are intended to aid in assessing the overall quality and completeness of the assembled 

data sets. Data sets classified as sufficient are 

those that include human and/or animal toxicity studies conducted according to standardized protocols and that provide in-depth 

descriptions of the exposure conditions and 

study findings. Data sets classified as limited 

via the qualitative ranking scheme contain either human and/or animal studies conducted 

by nonstandardized protocols or contain incomplete descriptions of the exposure conditions and study findings. Data sets classified 

as insufficient include studies that primarily 

either did not apply standard protocols or did 

not provide an in-depth description of the exposure conditions or study findings. Data sets 

that receive the insufficient ranking will not be 

used as the basis for the NIOSH skin notation.

Table E.1 (Continued). Terminology applied during the search for critical 

scientific data on each candidate chemical substance

Cutaneous Hyperhidrosis* Panniculitis Skin Tests 

Cutis Hyperpigment* Papulosquamous Stratum Corneum 

Cyst Hypertricho* Paronychia Structure Activity Relationship 

Cystic Hypopigment* Patch Test* Sunburn 

Cysts Hypotricho* Photoallerg Sweat 

Skin* Inflammation Photosensitiv* Ulcer*

Dermatitis Immune Phototoxic* Urticaria 

Dermato* Intertrigo Porphyria* Vacciniforme 

Dermis Intraskin* Prurigo Vesiculobullous 

Eccrine Irritat* Prurit* Xeroderma 

Ectoderm* Jaundice Psoriasis 

Eczema* Keloid Purpura 

*Indicates truncated terms used within the literature search
NIOSH CIB 61 • Skin Notations 43

This appendix documents the assignment of 

skin notations based on the scientific criteria 

outlined in this document. This profile contains a proposed skin notation assignment 

and supporting documentation for phenol 

(CAS No.108–95–2). It should be noted that 

the presented information is intended to serve 

only as in illustration of the strategy outlined 

in this CIB to assess the hazards of skin contact with phenol. The proposed skin notation 

assignment should not be construed as official 

NIOSH policy.

Each section of this appendix contains a brief 

summary highlighting the rationale for assigning or not assigning the various skin notations. 

References that are bold indicate primary studies. 

F.1 Chemical background 

information and 

introduction

Skin Notation for Phenol: 

SK: SYS-DIR (COR)

This documentation for skin notation assignments is limited to an assessment of the potential health effects following skin exposure 

or the potential for direct skin injuries from 

phenol. A literature search was conducted 

through November 2006 to identify potential 

health effects information on phenol toxicokinetics, acute, repeat-dose, and chronic toxicity, 

carcinogenicity, and biologic-system/functionspecific effects (including reproductive and 

developmental effects and immunotoxicity), 

irritation, and sensitization. Information was 

considered from studies in humans, animals, or 

appropriate modeling systems that are relevant 

to skin exposure to phenol. This toxicological 

review is intended to provide brief documentation of the rationale in support of the SK assignments for this chemical, which were based 

on the logic outlined in CIB #61: A Strategy for 

Assigning New NIOSH Skin Notations [NIOSH 

2009]. Table F.1 provides a summary of the assigned skin notations for phenol, and data supporting these notations are summarized below. 

• This section outlines (1) background information on phenol, (2) briefly discusses 

the application of the literature search 

(Appendix E.1), and (3) summarizes the 

skin notations assigned to phenol. Table 

F.1 includes the identification of critical 

effects associated with each assigned skin 

notation, and a description of the quality 

APPENDIX F • Example of Assigning New NIOSH 

Skin Notations and Format of the Skin Notation 

Profile 

Skin Notation Profile for Phenol 

(CAS No. 108–95–2)

Synonyms: Structure:

Carbolic acid, 

monohydroxybenzene, 

hydroxybenzene, 

benzenol, phenylic 

acid, phenyl hydroxide, 

benzophenol, phenyl 

hydrate, phenylic alcohol, 

monophenol, phenic 

acid, oxybenzene

HO
44 NIOSH CIB 61 • Skin Notations

and type of data used to determine the 

skin notation assignment for phenol (Appendix E.2). 

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 [Feldman and Maibach 

1970; Piotrowski 1971; Roberts et al. 1977; 

Baranowska-Dutkiewicz 1981]. 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 cm2) was found to be concentration-dependent, with the rate ranging from 0.079 mg/

cm2/hr at the low concentration to 0.301 mg/

cm2/hr at the high concentration [BaranowskaDutkiewicz 1981]. 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 [1970] 

reported the degree of dermal absorption as 

4.4% of the administered dose following a single topical application of 4 μg/cm2

 phenol on 

13 cm2 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 [Piotrowski 

1971]. 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 [Piotrowski 1971]. 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 [1997] 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 [Hughes 

and Hall 1995] 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 

Table F.1. Skin notation for phenol

Supporting data for phenol skin notation

Skin notations Critical effects Available data

SK: SYS Central nervous system effects, Respiratory depression, cardiac arrest, body 

weight changes, decreased 

survival.

Sufficient human and animal data 

SK: DIR (COR) Skin corrosivity Sufficient human and animal data
NIOSH CIB 61 • Skin Notations 45

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. [1993] reported a 72-hour 

dermal absorption of phenol of 95% of the applied dose. Brooks and Riviere [1996] 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 μg/cm2

) compared 

to the high-dose (40 μg/cm2

), suggesting saturation of absorption or other nonlinear kinetics 

under some conditions of exposure. Depending on the solvent and dose, Brooks and Riviere 

[1996] 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 [Behl et al. 1983], 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 

[Behl et al. 1983]. 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 [2009] 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 [Griffiths 1973; Soares and Tift 1982; 

Lewin and Cleary 1982; Turtle and Dolan 

1922; Foxall et al. 1989]. 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 LD50

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) [Conning and 

Hayes 1970; Brown et al. 1975] in rats under 
46 NIOSH CIB 61 • Skin Notations

both occlusive and nonocclusive conditions 

and 1400 mg/kg in rabbits [Vernot et al. 1977]. 

The Conning and Hayes [1970] 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. [1975] reported hematuria and convulsions as clinical signs of phenol toxicity. Because the reported acute dermal 

LD50 values for the rat and rabbit are both lower than the critical dermal LD50 value of 2 g/kg 

body weight that identifies substances with the 

potential for acute dermal toxicity [NIOSH 

2009], phenol is considered systemically toxic 

by the acute dermal route. 

• Application of Appendix A.1.2: Evaluation of acute toxicity of exposures 

of the skin. The reported LD50 of 414–

1400 mg/kg body weight did not exceed 

the critical cutoff value of 2000 mg/kg 

body weight. For this reason, phenol is assigned the SYS notation.

Quantitative information on doses that cause 

systemic effects during repeated occupational 

exposures is lacking. However, doses chronic 

to humans (unspecified) may result in neurologic damage [Merliss 1972]. A number of repeat-dose animal studies have been identified 

in which show systemic effects following skin 

exposure to phenol. Deichmann et al. [1950] 

exposed the tail of rabbits to aqueous phenol 

solutions of 1.18%–7.12% in water (reported 

as 64–380 mg/kg by the International Program 

for Chemical Safety IPCS [1994]) for 5 hr/day, 

5 days/week, for a total of 18 days. Dose-related 

systemic effects (tremors, death) were observed 

at 130 mg phenol/kg and above. Identified in 

this study were a NOAEL of 64 mg/kg-day and 

a LOAEL of 130 mg/kg-day to protect against 

occasional mild tremors and skin irritation. 

Boutwell and Bosch [1959] conducted a study 

in mice involving skin painting of 25 microliter (μL) of a 5% [1.25 milligram (mg)] phenol 

or a 10% (2.5 mg phenol) in benzene per application, twice weekly for 52 weeks. The high 

dose (10%) caused decreased body weight 

(average body weight at the 20th week for the 

group dosed 10% was 35.0 g compared with 

38.9 g at the 5% level of phenol) and decreased 

survival (24/30 mice survived at the end of 52 

weeks compared with 30/30 at the 5% level of 

phenol at the 20th week). The resulting doses 

were reported as 41.7 and 83.3 mg/kg/treatment 

[ATSDR 2006]. The potential skin and systemic 

effects of the benzene solvent were not investigated in this study; however, the effect levels 

of 18 mg/kg-day from the Boutwell and Bosch 

study [1959] and 130 mg/kg-day identified in 

the shorter-duration study by Deichmann et 

al. [1950] together indicate the potential for effects at doses significantly lower than the critical 

dermal NOAEL value of 1000 mg/kg for repeatdose toxicity. This NOAEL identifies substances 

with the potential for subchronic dermal toxicity [NIOSH 2009]. Therefore, phenol is considered to be systemically toxic following repeated 

dermal exposure. 

• Application of Appendix A.1.3: Evaluation of repeat-dose toxicity. The doses 

reported in the reviewed studies ranging 

from 18–130 mg/kg-day did not exceed 

the cutoff value of 1000 mg/kg-day body 

weight. For this reason, phenol would be 

assigned the SYS notation.

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. 
NIOSH CIB 61 • Skin Notations 47

• 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 [Boutwell and 

Bosch 1959] or in acetone [Salaman and Glendenning 1957; Wynder and Hoffman 1961] in 

two-stage carcinogenicity protocols in mice indicated that phenol has promoting activity. Studies conducted by Boutwell and Bosch [1959] 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 [32 weeks (Salaman and Glendenning 1957), 12 months or 52 weeks 

(Salaman and Glendenning 1957; Boutwell and Bosch 1959)]

• The lack of appropriate controls [Salaman 

and Glendenning 1957], and/or

• The use of vehicles (dioxane, benzene) that 

are skin irritants and/or defatting agents 

Other agencies or organizations have also evaluated the potential of phenol to be a carcinogen 

following exposure pathways alternative to the 

skin. NIOSH [2006] does not classify phenol as 

a potential occupational carcinogen. The U.S. 

EPA states that the data regarding the carcinogenicity of phenol through the ingestion, inhalation, and dermal routes are inadequate for 

an assessment of human carcinogenic potential 

[U.S. EPA 2002]. The American Conference 

of Governmental Industrial Hygienists (ACGIH) has assigned an A4 (not classifiable as a 

human carcinogen) notation to phenol [ACGIH 2001]. IARC has classified phenol as not 

classifiable as to its carcinogenicity to humans 

(Group 3) [IARC 2007].

• Application of Appendix A.1.6: Evaluation of carcinogenicity of phenol. No 

evidence was identified that would support identifying phenol as a carcinogen 

or the subsequent assignment of the SYS 

notation.

Identified human [Feldman and Maibach 1970; 

Piotrowski 1971; Baranowska-Dutkiewicz 

1981] and animal [Behl et al. 1983; Hughes 

and Hall 1995; Brooks and Riviere 1996] toxicokinetic data, acute dermal toxicity studies 

[Conning and Hayes 1970; Brown et al. 1975; 

Vernot et al. 1977], and repeat-dose studies 

[Deichmann et al. 1950; Boutwell and Bosch 

1959] are sufficient to demonstrate the potential 

for phenol to be dermally absorbed and systemically toxic. Systemic toxicity includes effects 

on the central nervous system, body weight 

changes, and decreased survival. Therefore, this 

assessment concludes that sufficient human and 

animal data exist to assign the SK: SYS notation 

for phenol.

F.3 Direct effect(s) on the skin

The available information indicates that phenol is corrosive to the skin. For example, skin 
48 NIOSH CIB 61 • Skin Notations

exposure to liquid phenol or concentrated phenol vapor caused corrosive effects including tissue death (necrosis) in humans [Schmidt and 

Maibach 1981; Horch et al. 1994], rats [Conning and Hayes 1970], mice [Patrick et al. 1985], 

and pigs [Pullin et al. 1978; Hunter et al.1992]. 

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 [Brown et al. 1975; 

Conning and Hayes 1970]. 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.

Reports of necrosis and chemical burns in humans [Schmidt and Maibach 1981; Horch et al. 

1994] and animals [Conning and Hayes 1970; 

Pullin et al. 1978; Patrick et al. 1985; Hunter 

et al. 1992] following direct skin contact with

undiluted phenol or concentrated solutions are 

sufficient to demonstrate the corrosivity of phenol. More diluted solutions are more likely to be 

irritating to the skin. Therefore, this assessment 

assigns an SK: DIR (COR) notation for phenol. 

• Application of Appendix A.2: Experimental protocols for investigating direct effects of skin exposure and derived 

criteria for assigning the SK: DIR notations. Sufficient evidence in the forms of 

numerous human and animal studies was 

identified that clearly demonstrated phenol’s ability to cause direct effects including inflammation, discoloration, eczema, 

redness, edema, and necrosis of the skin 

and underlying tissues. Based upon this 

evidence, phenol has been assigned both 

the DIR and (COR) subnotations.

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 [Kligman 

1966]. The Magnussen and Kligman skin sensitization test in guinea pigs also gave negative results for phenol [Itoh 1982]. 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 
NIOSH CIB 61 • Skin Notations 49

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 [Feldman and Maibach 1970; Piotrowski 

1971; Baranowska-Dutkiewicz 1981], acute dermal toxicity studies [Conning and Hayes 1970; 

Brown et al. 1975; Vernot et al. 1977], and repeatdose dermal toxicity studies [Deichmann et al. 

1950; Boutwell and Bosch 1959] 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 [Merliss 1972; 

Schmidt and Maibach 1981; Horch et al. 1994] 

and animal studies [Conning et al. 1970; Pullin 

et al. 1978; Patrick et al. 1985; Hunter et al. 1992] 

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) [2007]. 

ACGIH [2001], NIOSH [2006], and OSHA 

[2007] have also assigned a skin notation to the 

chemical. The classifications assigned by these 

organizations are indicated in Table F.2. Based 

on the scheme developed by NIOSH [2009] to 

coordinate the skin notations with the GHS, the 

equivalent GHS classification for phenol would 

most likely be Dermal Category 3 acute toxicant 

(200 mg/kg body weight < LD50 < 1000 mg/kg 

body weight) and Category 1 Skin Corrosive. 

Table F.2. Summary of skin hazard designations beyond NIOSH

Organization Skin hazard designations

NIOSH‡ [2006] Skin notation—potential for skin and eye irritation and dermal absorption

OSHA§

 [2007] Skin notation—indicates that the cutaneous route of exposure (including mucous 

membranes and eyes) contributes to overall exposure

ACGIH†

 [2001] Skin notation—phenol, as a vapor, liquid, or solid, can penetrate the intact skin 

causing systemic effects

EC* [2007] R21—Harmful: danger of serious damage to health by prolonged contact with skin

R24—Toxic in contact with skin

R34—Corrosive: causes burns

C—Corrosive

‡

NIOSH = National Institute for Occupational Safety and Health

§

OSHA = Occupational Safety and Health Administration.

†

ACGIH = American Conference of Governmental Industrial Hygienists

*EC = European Commission, Joint Research Center, Institute for Health and Consumer Protection
50 NIOSH CIB 61 • Skin Notations

References

Note—(*) citied in text; (†) represent additional 

resources of interest not citied within text

*ACGIH [2001]. Documentation of the threshold 

limit values and biological exposure indices. 

Phenol. 7th ed. Cincinnati, OH: American 

Conference of Governmental Industrial Hygienists.

*ATSDR [2006]. Toxicological profile for phenol 

(draft for public comment). U.S. Department of 

Health and Human Services, Agency for Toxic 

Substances and Disease Registry. [www.atsdr.

cdc.gov/toxprofiles/tp115.html]. 

*Baranowska-Dutkiewicz B [1981]. Skin absorption of phenol from aqueous solutions in 

men. Int Arch Occup Environ Health 49:99–104.

*Behl CR, Linn EE, Flynn GL, Ho NF, Higuchi 

WI, Pierson CL [1983]. Permeation of skin and 

eschar by antiseptics. I: Baseline studies with 

phenol. J Pharm Sci 72:391–397. 

*Boutwell RK, Bosch DK [1959]. The tumorpromoting action of phenol and related compounds for mouse skin. Cancer Res 19:413–424. 

*Brooks JD, Riviere JE [1996]. Quantitative 

percutaneous absorption and cutaneous distribution of binary mixtures of phenol and 

para-nitrophenol in isolated perfused porcine 

skin. Fund Appl Toxicol 32:233–243. 

*Brown VKH, Box VL, Simpson BJ [1975]. 

Decontamination procedures for skin exposed 

to phenolic substances. Arch Environ Health 

30:1–6. 

*Conning DM, Hayes MJ [1970]. The dermal 

toxicity of phenol: an investigation of the most 

effective first-aid measures. Br J Ind Med. 

27:155–159. 

†

Deichmann WB [1949]. Local and systemic 

effects following skin contact with phenol: 

a review of the literature. J Ind Hyg Toxicol 

31:146–154. 

*Deichmann WB, Miller T, Roberts JB [1950]. 

Local and systemic effects following application 

of dilute solutions of phenol in water and in 

camphor-liquid petrolatum on the skin of animals. Arch Ind Hyg Occup Med 2:454–461. 

†

Dow Chemical Company [1944]. Toxicity of 

Phenol. OTS 0517006.

†

Dow Chemical Company [1977]. Skin irritation 

potential of six chemicals: H2

SO4, HCl, NaOH, 

phenol, Dowtherm A, and HCBD. OTS 

86-870002208.

†

Duverneuil G, Ravier E [1962]. Toxicité suraiguë 

du phénol par voie transcutanée. Arch Mal Prof 

23:830–833. 

*Feldman RJ, Maibach HI [1970]. Absorption 

of some organic compounds through the skin 

in man. J Invest Dermatol 54:399–404. 

*Foxall PJD, Bending MR, Gartland KPR, 

Nicholson JK [1989]. Acute renal failure 

following accidental cutaneous absorption 

of phenol: application of NMR urinalysis to 

monitor the disease process. Human Toxicol 

9:491–496.

*Griffiths GJ [1973]. Fatal acute poisoning by 

intradermal absorption of phenol. Med Sci 

Law 13:46–48. 

†

Hinkel GK, Kintzel HW [1968]. Phenol poisoning of a newborn through skin resorption. 

Dtsch Gesundh 23:2420–2422.

*Horch R, Spilker G, Stark GB [1994]. Phenol 

burns and intoxication. Burns 20:45–50. 

†

Hotchkiss SA, Hewitt P, Caldwell J, Chen 

WL, Rowe RR [1991]. In: Scott RC, Guy RH, 
NIOSH CIB 61 • Skin Notations 51

Hadgraft J, Boddé HE, eds. Prediction of 

percutaneous penetration. London, England: 

IBC Technical Services Ltd., pp. 472–482.

*Hughes MF, Hall LL [1995]. Disposition of 

phenol in rat after oral, dermal, intravenous, 

and intratracheal administration. Xenobiotica 

25:873–883.

*Hughes MF, Hall LL [1997]. In vivo disposition 

of p-substituted phenols in the young rat after 

intraperitoneal and dermal administration. 

Food Chem Toxicol 35:697–704. 

*Hughes MF, Shrivastava SP, Fisher HL, Hall 

LL [1993]. Comparative in vitro percutaneous 

absorption of p-substituted phenol through rat 

skin using static and flow-through diffusion 

systems. Toxicol in Vitro 7:221–227.

*Hunter DM, Timerding BL, Leonard RB, 

McCalmoat TH, Schwartz E [1992]. Effects of 

isopropyl alcohol, ethanol, and polyethylene 

glycol/industrial methylated spirits in the 

treatment of acute phenol burns. Ann Emerg 

Med 21:1303–1307.

*IARC (International Agency for Research on 

Cancer) [2007]. List of all agents evaluated to 

date. Overall evaluations of carcinogenicity 

to humans. Agents reviewed by the IARC 

Monographs, Volumes 1–97. Lyon, France: 

International Agency for Research on Cancer. 

[http://monographs.iarc.fr/ENG/Classification/

Listagentsalphorder.pdf].

*IPCS [1994]. Environmental health criteria 

161. Phenol. Geneva, Switzerland: World Health 

Organisation, International Programme on 

Chemical Safety. [www.inchem.org/documents/

ehc/ehc/ehc161.htm].

†

Itoh M [1982]. Sensitisation potency of some 

phenolic compounds. J Dermatol 9(3):223–283. 

*Kligman AM [1966]. The identification of 

contact allergens by human assays. III. The 

maximum test: a procedure for screening and 

rating contact sensitizers. J Invest Dermatol 

47:393–409. 

*Lewin JF, Cleary WT [1982]. An accidental 

death caused by the absorption of phenol 

through skin. A case report. Forensic Sci Int 

19:177–179. 

*Merliss RR [1972]. Case Report: Phenol 

marasmus. J Occup Med 14:55–56. 

†

Monsanto Company [1986]. Acute oral, eye, 

skin, inhalation toxicity. Study No. BF73XX01. 

OTS0515378. Doc No. 86–870000940.

*NIOSH [2006]. NIOSH pocket guide 

to chemical hazards. Cincinnati, OH: 

Department of Health and Human Services, 

Centers for Disease Control, National Institute 

for Occupational Safety and Health, DHHS 

(NIOSH) Publication No. 2005–149.

*NIOSH [2009]. Current Intelligence Bulletin 

(CIB) 61: a strategy for assigning new NIOSH 

skin notations. Cincinnati, OH: Department 

of Health and Human Services, Centers 

for Disease Control, National Institute for 

Occupational Safety and Health, DHHS 

(NIOSH) Publication No 2009–147. 

*OSHA [2007]. Occupational Safety and Health 

guidelines for phenol. [www.osha.gov/SLTC/

healthguidelines/phenol/recognition.html].

*Patrick E, Maibach HI, Burkhalter A [1985]. 

Mechanisms of chemically induced skin 

irritation. I. Studies of time course, doseresponse, and components of inflammation in 

the laboratory mouse. Toxicol Appl Pharmacol 

81:476–490. 

*Piotrowski JK [1971]. Evaluation of exposure 

to phenol: absorption of phenol vapor in the 
52 NIOSH CIB 61 • Skin Notations

lungs through the skin and excretion of phenol 

in urine. Br J Ind Med 28:172–178. 

*Pullin TG, Pinkerton MN, Johnston RV, 

Kilian DJ [1978]. Decontamination of the 

skin of swine following phenol exposure: 

a comparison of the relative efficiency of 

water versus polyethylene glycol/industrial 

methylated spirits. Toxicol Appl Pharmacol 

43:199–206. 

*Roberts MS, Anderson RA, Swarlrich J [1977]. 

Permeability of human epidermis to phenolic 

compounds. J Pharm Pharmacol 29(11):677–

683. 

*Salaman MH, Glendenning OM [1957]. 

Tumor promotion in mouse skin by sclerosing 

agents. Br J Cancer 11:434–444. 

*Schmidt R, Maibach H [1981]. Immediate and 

delayed onset “skip area” dermatitis presumed 

secondary to topical phenol exposure. Contact 

Dermatitis 7(4):199–202. 

*Soares ER, Tift JP [1982]. Phenol poisoning: 

three fatal cases. J Forensic Sci 27(3):729–731. 

*Turtle WRM, Dolan T [1922]. A case of rapid 

and fatal absorption of carbolic acid through 

the skin. Lancet 2:1273–1274. 

†

Union Carbide Corporation [1948]. 

Skin adsorption and irritation—phenol. 

OTS0515564. Doc No. 86–870001402.

†

Union Carbide Corporation [1949]. Acute 

toxicity of phenol. OTS0515567. Doc No. 86–

870001405. 

*U.S. EPA [2002]. Toxicological review of 

phenol. Integrated risk information system 

(IRIS). Washington, DC: U.S. Environmental 

Protection Agency. [www.epa.gov/iris]. 

*Vernot EH, MacEwen JD, Haun CC, 

Kinkead ER [1977]. Acute toxicity and skin 

corrosion data for some organic and inorganic 

compounds and aqueous solutions. Toxicol 

Appl Pharmacol 42:417–424.

*Wynder E, Hoffman D [1961]. A study of 

tobacco carcinogenesis. VIII. The role of acidic 

fractios as promoters. Cancer 14:1306–1315.
NIOSH CIB 61 • Skin Notations 53

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% [29 CFR 1910.1200 (2005)]

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. in 2003 to ensure their safe use, transport, 

and disposal [UNECE 2005]. The GHS criteria for the classification of chemicals is based 

on health (toxicological), physical (flammability), and environmental hazards and specifying what information should be included on 

labels of hazardous chemicals and material 

safety data sheets. The GHS criteria outlines 

a similar strategy as presented in this CIB for 

the classification and labeling of chemicals to 

warn against the health risks of skin exposures, 

including systemic toxicity, skin irritation or 

corrosivity, and sensitization [UNECE 2005]. 

The strategy outlined in this CIB has been purposely designed to correspond with GHS to 

encourage harmonization between the two systems. Table G.2 has been included to illustrate 

the harmonization of the GHS classification 

system and the new NIOSH skin notations for 

acute systemic toxicity (lethality), direct effects 

of the skin, and sensitization. The GHS assignment will be included within the skin notation 

APPENDIX G • Supplemental information
54 NIOSH CIB 61 • Skin Notations

profiles to support the assignment of the new 

NIOSH skin notations.

It should be noted that in some cases the 

NIOSH skin notation assignments and hazard 

statements found on labels and material safety 

data sheets prepared in accordance with the 

GHS may vary because of differences associated with (1) professional judgment and interruption of reviewed data and (2) deviations between the criteria outlined in the NIOSH and 

GHS strategies. The classification of hazards 

associated with skin exposures to chemicals 

under the NIOSH and GHS strategies relies 

heavily on the use of professional judgment 

during the evaluation of the scientific data and 

subsequent assignment of the hazard designations. For this reason, differences in the interruption of the reviewed data may result in 

discrepancies for a particular substance. An 

additional reason that potential differences 

may occur is because of variations in the criteria outlined in this CIB and the GHS, such 

as the numeric cutoff values applied to assess 

critical effects in animal studies. Although the 

strategy outlined in this CIB has been designed 

to harmonize with GHS, differences between 

the NIOSH skin notation assignment and hazard statements developed using the GHS strategy can be reasonably anticipated. 

Table G.2 Coordination of the GHS classification system and the 

new NIOSH skin notations

Health hazard

GHS assignment 

(mg/kg body weight)

NIOSH assignment

(mg/kg body weight)

Acute systemic toxicity

(lethality)

Dermal Category 1:

Symbol: Skull and Crossbones

Signal word: Danger

Hazard Statement: Fatal in contact with skin

(Criteria: LD50 < 50)

 OR

Dermal Category 2:

Symbol: Skull and Crossbones

Signal word: Danger

Hazard Statement: Fatal in contact with skin

(Criteria: 50 < LD50 < 200)

SK: SYS (FATAL)

(Criteria: LD50 < 200)

(Continued)
NIOSH CIB 61 • Skin Notations 55

Table G.2 (Continued). Coordination of the GHS classification system and the 

new NIOSH skin notations

Health hazard

GHS assignment 

(mg/kg body weight)

NIOSH assignment

(mg/kg body weight)

 Acute systemic toxicity

(lethality)

(Continued)

Dermal Category 3:

Symbol: Skull and Crossbones

Signal word: Danger

Hazard Statement: Toxic in contact with skin

(Criteria: 200 < LD50 < 1000)

 OR

Dermal Category 4:

Symbol: Exclamation mark

Signal word: Warning

Hazard Statement: Harmful in contact with skin

(Criteria: 1000 < LD50 < 2000)

SK: SYS

(Criteria: 200 < LD50 < 

2000)

Dermal Category 5:

Symbol: No symbol

Signal word: Warning

Hazard Statement: May be harmful in contact 

with skin 

(Criteria: 2000 < LD50 < 5000)

No equivalent assignment

Direct effects of the skin Skin Corrosion Category 1:

Symbol: Corrosion

Signal word: Danger

Hazard Statement: Causes severe skin burns 

and eye damage

SK: DIR (COR)

Skin Irritation Category 2:

Symbol: Exclamation mark

Signal word: Warning

Hazard Statement: Causes skin irritation

SK: DIR (IRR)

Skin Irritation Category 3:

Symbol: No symbol

Signal word: Warning

Hazard Statement: May be harmful in contact 

with skin

SK: DIR

Skin Sensitization Skin Sensitization Category 1:

Symbol: Exclamation mark

Signal word: Warning

Hazard Statement: May cause an allergic skin 

reaction

SK: SEN
56 NIOSH CIB 61 • Skin Notations

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 [NIOSH 2009]. 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 [Shvedova et al. 2003; Monteiro-Riviere et al. 2005]. 

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 [Sayes 

et al. 2005; Ryman-Rasmussen et al. 2006]. Factors including size, shape, water solubility, and 

surface coating may directly affect a nanoparticle’s potential to penetrate the skin [Sayes et al. 

2004; Ryman-Rasmussen et al. 2006].

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 
NIOSH CIB 61 • Skin Notations 57

nanoparticles when warranted. Additional information and guidance on safe work practices 

associated with nanoparticles can be found 

within the NIOSH document, Approaches to 

Safe Nanotechnology: Managing the Health and 

Safety Concerns with Engineered Nanomaterials [NIOSH 2009]. 

References

CFR. Code of Federal Regulations. Washington, DC: U.S Government Printing Office, Office of the Federal Register.

Monteiro-Riviere NA, Nemanich RJ, Inman AO, 

Wang YY, Riveria JE [2005]. Multi-walled carbon 

nanotubes interaction with human epidermal 

keratinocytes. Toxicol Lett 155(3):377–384.

NIOSH [2009]. Approaches to safe nanotechnology: managing the health and safety concerns associated with engineered nanomaterials. Cincinnati, OH: U.S. Department 

of Health and Human Services, Centers for 

Disease Control and Prevention, National 

Institute for Occupational Safety and Health, 

DHHS (NIOSH) Publication No. 2009–125.

Ryman-Rasmussen JP, Riviere JE, MonteiroRiviere NA [2006]. Penetration of intact skin 

by quantum dots with diverse physicochemical 

properties. Toxicol Sci 91(1):159–65.

Sayes C, Fortner J, Lyon D, Boyd AM, Ausman 

KD, Tao YJ, Sitharaman B, Wilson LJ, Hughes 

JB, West JL, Colvin VL [2004]. The differential 

cytotoxicity of water soluble fullerenes. Nano 

Let 4:1881–1887.

Sayes CM, Gobin AM, Ausman KD, Mendez 

J, West JL, Colvin VL [2005]. Nano-C60

cytotoxicity is due to lipid peroxidation. Biomaterials 26(36):7587–7595.

Shvedova AA, Kisin ER, Murray AR, Gandelsman VZ, Maynard AD, Baron PA, Castranova V 

[2003]. Exposure to carbon nanotube material: 

assessment of the biological effects of nanotube 

materials using human keratinocyte cells. 

J Toxicol Environ Health 66(20):1909–1926. 

UNECE [2005]. Globally harmonized system 

of classification and labeling of chemicals 

(GHS). ST/SG/AC.10/30. New York, USA, and 

Geneva, Switzerland: United Nations Economic 

Commission for Europe. 
58 NIOSH CIB 61 • Skin Notations

Notes
NIOSH CIB 61 • Skin Notations 59

Notes
Telephone:

occupational safety and health topics, contact NIOSH atTo receive NIOSH documents or more information about 

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Delivering on the Nation’s promise:

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www.cdc.gov/niosh.

NIOSH eNewsFor a monthly update on news at NIOSH, subscribe to 

 by visiting www.cdc.gov/niosh/eNews.

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