# 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.



## Disclaimer Mention of any company or product does not constitute endorsement by the Na

tional Institute for Occupational Safety and Health (NIOSH). In addition, citations to Web sites external to NIOSH do not constitute NIOSH endorsement of the spon

soring organizations or their programs or products. Furthermore, NIOSH is not responsible for the content of these Web sites. All Web addresses referenced in this document were accessible as of the publication date. 

## Ordering Information To receive documents or other information about occupational safety and health topics, contact NIOSH at Telephone: 1–800–CDC–INFO (1–800–232–4636) TTY: 1–888–232–6348 E-mail: cdcinfo@cdc.gov or visit the NIOSH Web site at www.cdc.gov/niosh. For a monthly update on news at NIOSH, subscribe to NIOSH eNews by visiting www.cdc.gov/niosh/eNews. 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 cancause 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 po

tential to be percutaneously absorbed and subsequently cause systemic effects in

cluding, 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 work

place 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 Expo

sure 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 develop

ment. NIOSH has entered the second decade of NORA and, through its Immu

nological 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 identifica

tion 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 de

velopment.

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 scientifi

cally 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 ir

ritation, 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 sym

bol [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 contrib

ute 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 standard

ized methodology. As a result, chemicals have been improperly assigned a skin notation as a warning for nonsystemic effects, such as skin irritation and cor

rosion, thereby causing confusion about what types of risk-management prac

tices 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 identifica

tion that has been designed to do the following:

• Ensure that the assigned skin notations reflect the contemporary state of sci

entific 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 par

ties 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 poten

tial 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 irrita

tion 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 caus

ing 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 cor

rosive 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 stan

dardizes 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 sys

tem 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 nota

tion (and in some cases multiple notations) will greatly enhance the quality of haz

ard 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) de

veloped 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 as

signments 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 suf fi cient 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 Pro fi le 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 Pro fi le 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 Pro fi le 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 al lergic contact dermatitis
ACGIH Am erican Conference of Governmental Industrial Hygienists
CIB Cur rent Intelligence Bulletin

cm ce ntimeter(s)

cm 2 square centimeter(s) cm/hr ce ntimeter(s) per hour (COR) su bnotation of SK: DIR indicating the potential for a chemical to be corrosive following exposure of the skin
CFR Co de of Federal Regulations
DEREKTM De ductive Estimation of Risk from Existing Knowledge
DIR sk in notation indicating the potential for direct effects to the skin fol

lowing contact with a chemical
EC Eur opean Commission
ECETOC Eur opean Centre for Ecotoxicology and Toxicology of Chemicals
ECVAM Eur opean Centre for the Validation of Alternative Methods (FATAL) su bnotation of SK: SYS indicating chemicals are highly or extremely toxic and may be potentially lethal or life threatening following expo

sure of the skin
g gra m(s) g/kg gra m(s) per kilograms of animal body weight g/kg-day gra m(s) per kilograms of animal body weight per day
GHS Gl obally Harmonized System of Classification and Labeling of Chemicals hr ho ur(s)
IARC In ternational Agency for Research on Cancer

### xiii ICCVAM In teragency Coordinating Committee on the Validation of Alterna

tive Methods
ICSC In ternational Chemical Safety Cards
ID (SK) skin notation indicating that a chemical has been evaluated, but in

sufficient data exist to accurately assess the hazards of skin exposure (IRR) su bnotation of SK: DIR indicating the potential for a chemical to be a skin irritant following exposure to the skin
K aq co efficient in the watery epidermal layer kg ki logram(s)
K

OW octanol-water partition coefficient
K

p sk in permeation coefficient
K

pol coefficient in the protein fraction of stratum corneum
K

psc permeation coefficient in the lipid fraction of stratum corneum
LD 50 lethal dose 50% by skin, oral, and intradermal routes
LLNA lo cal lymph node assay
LOAEL lo west-observed-adverse-effect level
LOEL lo west-observed-effect level

m met er(s)

m 2 squared meter(s)

m 3 cu bic meter(s)
MEST mo use ear swelling test μg/cm 2 microgram of a substance/ squared centimeter
mg mi lligram(s) mg/cm 3 milligram(s) of a dissolved substance/cubic centimeter meter of solute mg/cm 3 /hr milligram(s) of a dissolved substance/cubic centimeter meter of sol

ute/hour mg/kg mi lligram(s) of a substance/kilograms animal body weight mg/kg-day mi lligram(s) of a substance/kilograms animal body weight as a daily dose

### xiv mg/m 3 milligram(s) of a substance per cubic meter of air
MW mo lecular weight
ND no tation 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 Na tional Institute for Occupational Safety and Health
NOAEL no-o bserved-adverse-effect level
NOEL no-o bserved-effect level
NTP Na tional Toxicology Program
OECD Or ganization for Economic Cooperation and Development
OEL oc cupational exposure limit
OSHA Oc cupational Safety and Health Administration QSAR qu antitative structure-activity relationship QSPR qu antitative structure-permeability relationship
RF ret ention factor
RTECS Re gistry of Toxic Effects of Chemical Substances R-phrases ri sk phrases
SAR st ructure-activity relationship
SI ratio rat io of the skin dose to the inhalation dose
SEN sk in notation indicating the potential for immune-mediated reac

tions following exposure of the skin
SK sk in notation SK sk in notation indicating that the reviewed data did not identify a health risk associated with skin exposure
SYS sk in notation indicating the potential for systemic toxicity following exposure of the skin
S W wat er solubility
TER tra nscutaneous electrical resistance assay
U.S. EPA U.S. E nvironmental 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 carcino

gen 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 oc

curring 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 in

cluding allergic responses. Isomers— Molecules that exhibit unique physical structures, but consist of the same el

emental 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 ex

posure to a chemical, which, upon re-exposure, can lead to allergic contact derma

titis (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., Eu

gene 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. Da vid Votaw, M.Sc. Charles L. Geraci, Ph.D. Ra lph 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 M unson, Ph.D. Fr ed Frasch, Ph.D. National Personal Protective Technology Laboratory (NPPTL ) Rolland Berry Ann, M.Sc. Na dia 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 apprecia

tion 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 chemi

cals because of the large surface area [1.5–2.0 squared meters (m 2 )] 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 ful

ly understood because of the inherent difficul

ties 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 at

tention is often given to characterizing occupa

tional and environmental exposures of the skin to chemicals than is given to other exposure pathways. These limitations potentially leave ex

posed 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 percutaneous refer to 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 testi

mony on the Occupational Safety and Health Administration (OSHA) Proposed Rule on Air Contaminants (Permissible Exposure Limit update) on August 1, 1988 [NIOSH 1988]. De

spite the usefulness of the notation [skin] as a risk management tool, it provides little guid

ance 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 ab

sorbed by the skin [54 CFR 2718 (1989)]. However, the notation has not been con

sistently assigned according to this prin

ciple. Many skin notations are based only on the potential or reported transdermal penetration of chemicals—with no con

sideration of the causality between der

mal absorption and overall toxicity. 2. A single skin notation assigned to a chemical was often used to warn of se

rious dermal effects other than systemic toxicity—effects such as irritation, corro

sion, 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 as

signed to a chemical only when the sub

stance has been scientifically established to be dermally absorbed and to poten

tially 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 knowl

edge or include recommendations made in NIOSH criteria document since the 1988 Permissible Exposure Limit update project. For example, the criteria docu

ment 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 ab

sorbed by the skin [NIOSH 1991]. How

ever, none of these chemicals has been as

signed a skin notation.

### 3 NIOSH CIB 61 • Skin Notations 

## 2 Assigning Sk in Notations
The Current Intelligence Bulletin (CIB) 61: A Strategy for Assigning New NIOSH Skin No

tations provides an updated and formalized strategy for the assignment of skin notations capable of distinguishing among systemic, direct, and sensitizing effects caused by expo

sures of the skin to chemicals. The strategic framework outlined within this document is a form of hazard identification that has been de

signed to accomplish the following:
1. Ensure that the assigned skin notations

reflect the contemporary state of scien

tific 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 con

tact with the skin The system preserves the conventional wis

dom for assigning skin notations to chemicals that pose a hazard from skin contact. In addi

tion, this system attempts to prevent possible misclassifications by assigning a notation that specifies potential adverse effects. The skin no

tation classification scheme presented within this CIB is as follows:

• SYS indicates the potential for a chemi

cal 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 di

rect effect(s) of a chemical on the skin at or near the point of contact, including corro

sion, primary irritation, bleaching (blanch

ing), 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 iden

tified no health hazard associated with skin exposure and did not support assign

ment of the SYS, DIR, or SEN notation.

• ID (SK) indicates that insufficient data were available at time of evaluation to deter

mine 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 associ

ated 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 addi

tional skin notations may be added when im

proved scientific data on test methods and in

creased understanding about the toxicological mechanisms of skin injuries become available.

### 4 NIOSH CIB 61 • Skin Notations Also, current criteria for assigning skin nota

tions may be revised to enhance the usefulness of the notations for selecting exposure preven

tion strategies. Hazard categories that are add

ed 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 in

clude their application to chemical mixtures, the health effects of contaminants within neat substances, and isomeric variations of a chemi

cal. Because of the complexity of assessing the hazards of chemical interactions associated with complex mixtures or because of the pres

ence of contaminants, the skin notations are intended to apply to neat chemicals and may not be health protective against additional ef

fects 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 ad

equate warnings about unique hazards of the nonspecified isomeric forms of the chemical (see Appendix G.1).
The new skin notations will be included with

in future NIOSH publications, including the NIOSH Pocket Guide to Chemical Hazard s. Future versions of the NIOSH Pocket Guide to Chemical Hazard s will have the skin nota

tion assignments for each evaluated substance [e.g., SK: SYS-DIR (COR)] and an overview of the new skin notations. A separate publica

tion called a Skin Notation Profile (see Appen

dix 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 deter

mination involves a health hazard identifica

tion 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, in

cluding predictive algorithms [e.g., quan

titative structure-activity relationships (QSAR)] and mathematical models that describe a selected process (e.g., skin per

meation) 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 mathemat

ical models and predictive algorithms, repre

sent alternative methods to expensive in vivo and in vitro toxicity testing methods. These ap

proaches are increasingly applied to estimate the potential of chemicals to act as skin irri

tants and sensitizers and their potential to be absorbed (i.e., skin permeation). The perfor

mance and reliability of these computational techniques remain unclear. For this reason, predications from computational techniques,

### 5 NIOSH CIB 61 • Skin Notations 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 assign

ment of a skin notation. Instead, they are in

tended only to serve as additional supportive data sources when limited data are available for the assignment of skin notations. As the com

putational 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 nota

tion assignments in each category. Exceptions to this approach are also described. This strat

egy for assigning skin notations has been de

veloped to correspond with the classification strategy adopted in the Globally Harmonized System of Classification and Labeling of Chemi

cals (GHS) developed by the United Nations [UNECE 2005]. Appendix G.2 contains sup

plemental 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 orextremely toxic and potentially lethal or lifethreatening following skin exposure. The fol

lowing 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 Ap

pendix 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 associ

ated with exposures of the skin to chemicals are not assigned the SYS notation despite be

ing 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 sys

temic toxicity of skin exposures to chemicals:

• Protocols for testing chemicals developed by the Organization for Economic Coop

eration and Development (OECD) and European Centre for the Validation of Al

ternative Methods

• Health effects testing guidelines devel

oped by the U.S. Environmental Protec

tion Agency (U.S. EPA) Office of Preven

tion, Pesticides, and Toxic Substances

• Protocols established by the National Toxicology Program (NTP) for deter

mining the prechronic toxicity and chronic toxicity/carcinogenesis of toxic substances Experimental toxicity studies using these pro

tocols 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 expo

sure to a chemical in the absence of sig

nificant 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 ef

fects from skin exposure to a chemical. The protocols may be modifications of the standardized protocols with varia

tions in the evaluation procedures, or they may be designs allowing for exami

nation 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

### 7 NIOSH CIB 61 • Skin Notations 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 expo

sure 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 ab

sorption and consequent systemic toxici

ty of the chemical may be mathematically estimated via computational techniques. To mathematically determine the risk for systemic toxicity (e.g., predictive algo

rithm), the following information is need

ed: ( 1 ) skin permeation rate, ( 2 ) chemical dose calculated to be absorbed through skin (skin dose), ( 3 ) reference dose repre

senting the threshold of acceptable body accumulation (a chemical dose to be ab

sorbed via inhalation during the same pe

riod of exposure), and ( 4 ) comparison of the skin dose to the reference dose (which indicates the significance of skin absorp

tion and its potential contribution to sys

temic 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 produc

ing 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 ac

cepted tests. The results of the predictive algo

rithm should not be used as the sole basis of the assignment of a SYS notation. Table 2.2 provides an overview for the assign

ment of the SYS notation based on the crite

ria 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 sci

entific data.



### 2.3 DIR Direct effects are non-immune mediated ad

verse health effects resulting in damage or destruction of the skin localized at or near the point of contact. Most currently avail

able 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 ex

perimental 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 ob

tained 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-me

diated response are labeled SK: DIR. Chemi

cals 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 stra

tum 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 bleach

ing (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) subno

tation when the reviewed data indicate that exposure of the skin to the substance causes reversible adverse effects, including inflam

mation, dryness, or redness with minor pain or discomfort, at or near the point of con

tact. 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 toxicityDermal 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.

### 9 NIOSH CIB 61 • Skin Notations adverse effects accompanied by pain or dis

comfort, 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 as

sociated with exposures of the skin to chemi

cals, such as ACD and allergic urticaria, arenot assigned the DIR notation. These immunemediated responses would be assigned the SEN notation if data are supportive and are ad

dressed within Section 2.4. An SK: DIR notation is assigned when one or more of the following criteria are met:

• Credible evidence indicates that imme

diate, 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 in

formation about acute or cumulative irritation of human skin [OECD 1997]. Such informa

tion will be considered when assigning skin notations.

• Data from laboratory tests indicate direct effects on skin as a result of chemical ex

posures. These data include in vivo ani

mal studies reporting the acute irritancy, corrosivity, and carcinogenicity of chemi

cals, in vitro assays identifying corrosivity potentials, and in vitro evaluations exam

ining alteration in the barrier properties of skin as a result of skin exposure to chemicals. Appendix A describes proto

cols 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 quali

tative data on the direct effects on skin as a result of skin exposure to a chemical. Proto

cols may be modifications of standardized protocols (e.g., the research protocols in

troduced in Appendix A) with variations in the evaluation procedures or study design that examine health endpoints other than those evaluated by the standardized proto

cols. Examples of the latter include reports of histopathological examinations indicat

ing impairment of skin tissues, disintegra

tion of skin components (e.g., defatting and discoloration), or the presence of neoplas

tic 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 expo

sure to a chemical, information from the

### 10 NIOSH CIB 61 • Skin Notations structure-activity-relationship (S AR)-based analysis and the physicochemical proper

ties 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 experimen

tal observations of the adverse effects oc

curring at the site of exposure to a structur

ally 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 Ap

pendix 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 con

tribute to the onset of ACD or other immunemediated responses, such as airway hyper re

activity (asthma). Occupationally, the most commonly recognized immune-mediated re

sponses following skin exposure is ACD. For ACD, the skin-sensitizing potential of the chem

ical is typically evaluated by two endpoints—the immunologic induction of sensitization and the elicitation of ACD. The SEN notation maybe 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 respons

es are primarily mediated by immunoglobulin E antibodies when the chemical-specific anti

bodies 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 inflam

matory 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 spe

cific 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; Pau

luhn 2008]. Animal studies in several species have shown that skin exposure to isocyanates followed by inhalational challenge is highly ef

fective at inducing asthmatic lung responses. [Bello et al. 2007; Pauluhn 2008]. Human stud

ies, although more limited, suggest a similar role following skin exposure to certain sensitiz

ing chemicals [Beck et al. 2000; Day et al. 2006; Kreiss et al. 2007; Redlich et al. 2008]. Despite

### 11 NIOSH CIB 61 • Skin Notations decreased inhalation exposures to isocyanates and beryllium within various occupational set

tings, 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 hu

man and animal data suggest that skin contact with certain chemical allergens may contribute to the development of immune-mediated re

spiratory 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 inno

vative murine local lymph node assay (LLNA). Data relevant for determining whether the chemical may cause an immune-mediated re

sponse 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 occur

rence of ACD or sensitization as a result of chemical exposure of the skin. Skin sensi

tization among workers is often character

ized clinically by immunologically medi

ated cutaneous reactions such as pruritus, erythema, edema, papules, vesicles, bullae, or a combination of these findings. Infor

mation about human im mune-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 [ECE

TOC 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 sub

stance 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 ob

served, supporting evidence should be ob

tained (including data available from ani

mal 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 respons

es associated with skin exposure. Such animal data include the guinea pig sensi

tization tests identifying sensitization or ACD, LLNA, mouse ear swelling test, and relevant animal models of asthma. Appen

dix 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 standard

ized protocols (e.g., the research protocols introduced in Appendix A) with variations in the evaluation procedures or study de

signs that examine health endpoints other than those evaluated by the standardized protocols. An example is studies that eval

uate 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, in

formation from the SAR-based analysis, and other computational techniques can be used as alternative methods for identi

fying hazards. An example of a SAR anal

ysis is the use of the knowledge-based ex

pert 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 de

scribes the DEREKTM expert system for identifying sensitizers. When the algo

rithm is used as the basis of identification, a positive result is sufficient to classify a chemical as an agent capable of provok

ing ACD or sensitization from skin expo

sure 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 sys

temic, 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, di

rect, or sensitizing agent. Assignment of this no

tation 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 as

signed 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 publi

cations, including the NIOSH Pocket Guide to Chemical Hazards

. 

## References Beck LA, Leung DYM [2000]. Allergen sen

sitization through the skin induces systemic allergic responses. J Allergy Clin Immunol 106 :S258–263.

### 13 NIOSH CIB 61 • Skin Notations 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 im

munological 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 Tox

icology 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 hyper

sensitivity. 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 Con

trol, National Institute for Occupational Safety and Health. NIOSH [1991]. NIOSH criteria for a recom

mended 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 che

mical hazards. Cincinnati, OH: U.S. De pa rtment of Health and Human Services, Centers for Disease Control and Prevention, National Inst

itute 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 class ification 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.

### 15 NIOSH CIB 61 • Skin Notations This appendix presents the experimental pro

tocols used in laboratory studies of the sys

temic effects, direct effects on skin, and sensi

tization potentials of chemicals resulting from skin exposure using animal models or alter

native methods (e.g., in vitro bioassays). The protocols included have generally been stan

dardized and validated by various regulatory agencies and research institutes in the United States and Europe. For each protocol, the in

troduction 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 sta

tus, additional protocols may be selected to de

velop 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 tech

niques used to estimate the potential for absorp

tion include in vivo and in vitro toxicity studies and computational techniques.
In vivo and in vitro test methods have been de

veloped to estimate both the rate and percent

age 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 radiola

belled 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 pen

etration of chemicals [Moss et al. 2002; Riviere and Brooks 2005; IPCS 2006]. The predictive 

# APPENDIX A • Protocols Used in Studies of Health Effects from Skin Exposure and the Determination of Criteria Derived for Assigning Skin Notations

### 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 ef

fects 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 fre

quently 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 se

lected as the critical cutoff value. This value cor

responds to OECD guidelines [OECD 2004a] and is based on recommendations proposed by the Netherlands Organization for Applied Sci

entific 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 expo

sures 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 (LD 50 ) following applica

tion of the chemical to the skin, with obser

vations of behavioral/clinical abnormalities and pathologic findings from gross necropsy. If the LD 50 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 LD 50 reflects the dose selected in standardized limit tests to identify chemicals with the potential for acute toxicity. This value corresponds with the upper LD 50 limit for es

tablishing 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 LD 50 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) nota

tion. 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 dur

ing the study. At the end of the study, they are examined for gross organ lesions, hematology, clinical chemistry, ophthalmology, and his

topathology. Test results often include the re

porting of a no-o bserved-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-da y), the chemical is con

sidered systemically toxic by the dermal route and is assigned the SYS notation. The critical NOAEL value of 1000 mg / kg-da y reflects the dose selected in the standardized limit tests to identify chemicals with the potential for repeat-dose toxicity following contact with the

### 17 NIOSH CIB 61 • Skin Notations 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 substi

tuted for comparison with the critical cutoff value of 1000 mg/kg-day.



### A.1.4 Subchronic t oxicity Subchronic toxicity testing examines the cu

mulative 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 behav

ioral/clinical abnormalities during the study. At the end of the study, they are examined for gross organ lesions, hematology, clinical chem

istry, ophthalmology, and histopathology. Test results often include the NOAEL for the most sensitive endpoint(s) selected from all evalu

ated health effects. If the NOAEL for a selected endpoint is lower than the critical cutoff value of 1000 mg / kg-da y, 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 se

lected 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 cumula

tive 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 evalu

ated using hematology, clinical chemistry, uri

nalysis, and ophthalmology during and at the end of the study. At necropsy, they are exam

ined for gross organ lesions and tissue histopa

thology. 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-da y, the chemical is considered systemically toxic following skin exposure and is assigned the SYS notation. The critical cutoff value of 1000 mg / kg-da y 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 with

in the reviewed toxicological data, a LOAEL, LOEL, or NOEL may be substituted when avail

able for comparison to the selected cutoff value of 1000 mg/kg-day.



### A.1.6 Carcinogenicity Carcinogenicity testing examines the develop

ment 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 con

stitutes 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 pathol

ogy during and at the end of the study and for gross organ lesions and tissue histopathology at necropsy. Carcinogenicity from skin expo

sure to a chemical may be studied and reported jointly with chronic toxicity following expo

sures 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 pho

tocarcinogenesis (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 inci

dence 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 examina

tion 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 ) immuno

toxicity (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 consid

ered systemically toxic by the dermal route and assigned the SYS notation. The critical cutoff value of 1000 mg/kg-day reflects the dose se

lected 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 can

not be identified within reviewed toxicological data, a LOAEL, LOEL, or NOEL may be sub

stituted 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 expo

sure pathways (i.e., ingestion, inhalation, and injection) may be considered during the as

signment of the SYS notation. The primary cri

teria applied for determining the appropriate

ness of the use of toxicity data associated from alternative exposure pathways are as follows:
1. No quality dermal toxicity data were iden

tified. 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 in

vestigated must be systemic in nature. 4. The critical systemic endpoint(s) is inde

pendent 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 fol

low 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

### 19 NIOSH CIB 61 • Skin Notations 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 expo

sure and to fully evaluate the reversibility of ob

served 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 co ntact.


### 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 convention

al 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 (ICC

VAM) and the NTP Interagency Center for the Evaluation of Alternative Toxicological Meth

ods (NICEATM):

• Corrositex ® [NIH 1999a]

• The human skin models [OECD 2004e], including EPISKINTM and EpiDermTM [NIH 2002b]

• The rat skin transcutaneous electrical re

sistance (TER) assay [NIH 2002b; OECD 2004f] The Corrositex ® assay evaluates the pH-sensitive destruction of a reconstituted, collagen-based biobarrier and determines the corrosivity poten

tial by measuring the time required for the test material to pass through the biobarrier mem

brane (i.e., the breakthrough time) and produce a visually detectable change in the Chemical De

tection 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, respec

tively [Fentem et al. 1998; U.S. EPA 1996]. The EPISKINTM and EpiDermTM models evaluate the corrosivity potential of a test substance by mea

suring the decreased viability of human skin cells in reconstructed epidermis/dermis after expo

sure. 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 re

duction 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 thresh

old below 5 kilohms.



### A.2.3 Carcinogenicity Carcinogenicity testing examines the develop

ment 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 clini

cal 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. Carcino

genicity 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 chemi

cal 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 nota

tion. 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 stra

tum 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 Bue

hler 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 re

sponse. After 10–14 days, the animals receive a challenge exposure to the test substance to es

tablish 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 rec

ommended for regulatory acceptance [NIH 1999b]. OECD [2002b] and U.S. EPA [2003] have adopted this assay as a standard test meth

od for evaluating the skin sensitization poten

tial 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, cel

lular proliferation is measured as a function of in vivo radioisotope incorporation into the deoxyribonucleic acid (DNA) of dividing lym

phocytes. 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 consid

ered a sensitizer and assigned the SEN notation if it has a statistically significant stimulation in

dex greater than or equal to 3 and is supported by a fitting dose-response relationship.

### 21 NIOSH CIB 61 • Skin Notations 

### 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 screen

ing test for detecting chemicals with sensitiza

tion potential. In the noninvasive MEST, the an

imals are initially exposed to the test substance by topical application on the abdomen to in

duce 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 sen

sitizer 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 sensitiza

tion test or the LLNA [U.S. EPA 2003] before the substance is considered a nonsensitizer.


## References Bronaugh RL, Stewart RF [1985]. Methods for in vitro percutaneous absorption studies IV: the flow-through diffusion cell. J Pharm Sci 74 (1):64–67. Council of the European Communities [1992]. Council Directive 92/32/EEC of 30 April 1992 amending for the seventh time 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 L154 (5.6.92). De Heer C, Wilschut A, Stevenson H, Hackkert BC [1999]. Guidance document on the estimation of dermal absorption according to a tiered approach: an update. Zeist, The Netherlands: TNO Report V98 1237, p. 27. Fentem JH, Archer GEB, Balls M, Botham PA, Curren RD, Earl LK, Esdaile DJ, Holzhütter H-G, Liebsch M [1998]. The ECVAM international validation study on in vitro tests for skin corrosivity. 2. Results and evaluation by the management team. Toxicol in Vitro 12 :483–524. Gad SC, Dunn BJ, Dobbs DW, Reilly C, Walsh RD [1986]. Development and validation of an alternative dermal sensitization test: the mouse ear swelling test (MEST). Toxicol Appl Pharmacol 84 :93–114. IPCS [2006]. Environmental health criteria 235: dermal absorption. Geneva, Switzerland: World Health Organisation, International Pro

gramme on Chemical Safety. [www.inchem.org/ documents/ehc/ehc/ehc235.pdf]. Moss GP, Dearden JC, Patel H, Cronin MTD [2002]. Quantitative structure permeability relationships (QSPRs). Toxicol in Vitro 26 :299–317. NIH [1999a]. Corrositex®: an in vitro test method for assessing dermal corrosivity potential of chemicals. Research Triangle Park, NC: U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program, National Institutes of Health, DHHS (NIH) Publication No. 99–4495. NIH [1999b]. The murine local lymph node assay: a test method for assessing the allergic contact dermatitis potential of chemicals/ compounds. Research Triangle Park, NC: U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program, National Institutes of Health, DHHS (NIH) Publication No. 99–4494.

### 22 NIOSH CIB 61 • Skin Notations NIH [2002a]. National Toxicology Program annual plan for fiscal year 2002. Research Triangle Park, NC: U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program, National Insti tu tes of Health, DHHS (NIH) Publication No. 03–5309. [ http://ntp.niehs.nih.gov/index.cfm?objectid=EF56AEB7-F1F6-975E76F005930F80E9EA ]. NIH [2002b]. ICCVAM evaluation of EPISKINTM, EpiDermTM (EPI-200), and the rat skin transcutaneous electrical resistance (TER) assay: in vitro test methods for assessing dermal corrosivity potential of chemicals. Research Triangle Park, NC: U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program, National Insti

tutes of Health, DHHS (NIH) Publication No. 02–4502. NTP [2001a]. Objectives and procedures of NTP studies: 2-year study. In: NTP testing information and study results. Research Tri

angle Park, NC: U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program. NTP [2001b]. Objectives and procedures of 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 Coop

eration and Development. OECD [1981d]. OECD guideline for testing of chemicals 451: carcinogenicity studies. Paris, France: Organization for Economic Coop

eration and Development. OECD [1981e]. OECD guideline for testing of chemicals 453: combined chronic toxicity/ carcinogenicity studies. Paris, France: Organ

ization for Economic Cooperation and Devel

opment. 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.

### 23 NIOSH CIB 61 • Skin Notations 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 swell ing 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. Wash

ington, 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. Wash

ington, 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. En

vironmental Protection Agency, Office of Pre

vention, 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. Envi

ronmental Protection Agency, Office of Pre

vention, 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, Pes ticides, 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 Re

mediation and Technology Innovation, U.S. EPA/540/R/99/005.

### 25 NIOSH CIB 61 • Skin Notations 

## 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 chemi

cal agent to penetrate the skin and induce sys

temic toxicity. The goals for incorporating this algorithm into the proposed strategy for as

signing 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 deter

mine systemic effects

• Use the algorithm evaluation results to determine whether a chemical poses a skin absorption hazard and should be la

beled with the SYS notation The algorithm evaluation includes three steps:
1. Determining a skin permeation coeffi

cient for the chemical 2. Estimating chemical uptake by the der

mal and respiratory absorption routes 3. Evaluating whether the chemical poses a skin exposure hazard. The algorithm is flexible in the data require

ment and can operate entirely on the basis of the physicochemical properties of a chemical and the relevant exposure parameters. Thus, the al

gorithm is independent of the need for biologic data. Or, it can function using both the physi

cochemical properties and the experimentally determined permeation coefficients when the latter data are available and appropriate to use.



### B.1.1 Step 1: Determining the skin permeation coefficient The first step in the evaluation is to determine the skin permeation coefficient (K p ) for the chemical to describe the transdermal penetra

tion rate of the substance. The K p determined for a chemical is expressed in cm/hr and rep

resents 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 de

scribed in the protocols standardized by OECD [2004a,b] and U.S. EPA [69 Fed. Reg. † 22402 (2004)]. These methods typically me asure 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 K p 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 ex

perimentally determined K p values are not al

ways available or generated following standard

ized protocols. An alternative approach is to use the QSPRs that predict the K p of chemicals based on the physicochemical properties relevant to their transport behavior in the stratum cor

neum, 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 determi

nation of K p by predictive QSPRs, the revised Robinson model is presented here for its math

ematical descriptors and operation. The revised Robinson model has been shown to be among the QSPRs that provide reasonable K p esti

mates 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 K OW , 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, K pol is the coefficient in the protein fraction of the stratum corneum, and K aq is the coefficient in the watery epidermal layer. These components are individually estimated by log K psc = −1.326 + 0.6097 × log K OW − 0.1786 × MW 0.5
K pol = 0.0001519 × MW −0.5
K aq = 2.5 × MW −0.5 Exercising caution is important when a QSPR is used in the derivation of K p . Many of the em

pirical 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 sub

stances. Chemicals in the first three categories are not readily absorbed through the skin, and their experimental K p values are often not read

ily 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 path

way of penetration by many models. Also, with a few exceptions, the QSPRs typically do not account for the evaporation of chemicals from the skin; as a result, the predicted K p for vola

tile 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

### 27 NIOSH CIB 61 • Skin Notations Testing Committee [Walker et al. 1996]) is to calculate the biologic uptake of the chemical from skin absorption (skin dose) and inhala

tion (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, bioaccumula

tion of the substance is a cause for concern for health effects. The skin and inhalation doses provide quantifiable measures for absorption of the chemical by different routes. These doses serve as the basis for determining whether the substance constitutes a skin absorption hazard. The skin dose is calculated as a mathematical product of the K p acquired in Step 1, the water solubility (S W ) of the chemical, the exposed skin surface area, and the duration of exposure. In the calculation, the transdermal flux of the sub

stance is assumed to originate from a saturated aqueous solution. Assuming that the skin expo

sure continues for 8 hours to unprotected skin on both palms (a surface area of 360 cm 2 ),
Skin dose = K p × S W × Exposed skin surface area × Exposure time = K p (cm/hr) × S W (mg/cm 3 ) × 360 cm 2 × 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 expo

sure of 8 hours, an inhalation volume of 10 m 3 in 8 hours, and a factor of 75% for the retention of the airborne substance in the lungs during respiration (retention factor, RF),
Inhalation dose = OEL × Inhala tion volume × RF = OEL (mg/m 3 ) × 10 m 3 × 0.75 In the above equation, a default value of 0.75 is used for the RF to represent the respiratory retention of chemicals. The percentage value for the absorption of xenobiotics via the lungs is commonly assumed to be 75%–100% [Euro

pean Chemicals Bureau 2003], and the default RF of 0.75 is selected to avoid underestimating skin absorption as a significant route of bio

logic 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 metabo

lism of substances in the lungs or accumula

tion 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 sub

stance and ( 2 ) the contribution of dermal up

take to systemic toxicity. If a chemical has an SI ratio greater than or equal to 0.1, it is consid

ered a skin absorption hazard.


## B.2 Criterion for assigning the SYS notations The SYS notation will be assigned to a chemi

cal 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 re

sult also supports an SI ratio of 0.1 as the thresh

old 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 investigatedas 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 interna

tional occupational safety and health organi

zations. One example is the proposal of the European Centre for Ecotoxicology and Toxi

cology of Chemicals (ECETOC) to recom

mend skin notations based on a semiquantita

tive approach [ECETOC 1998]. The algorithm proposed by ECETOC is similar to the one intended for assigning NIOSH SK: SYS nota

tions. 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 con

cluded that a skin notation should be assigned to a chemical when the amount of chemical ab

sorbed 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 in

haled in 8 hours, and the respiratory RF in the ECETOC algorithm are 2000 cm 2 , 10 m 3 , and 50%, respectively. The SI ratio calculated in the algorithm proposed for recommending the NIOSH SK: SYS notations (SI ratio NIOSH ) can be modified to derive an SI ratio according to the method proposed by the ECETOC (SI ratio ECE

TOC ). A comparison between the SI ratio NIOSH and the SI ratio ECETOC reveals that

SI ratio ECETOC = SI ratio NIOSH × [2000 cm 2 (hands and arms) ÷ 360 cm 2 (palms)] × (1 hr ÷ 8 hr) × [75% (default RF in NIOSH algorithm) ÷ 50% (default RF in ECET OC algorithm)] = SI ratio NIOSH × 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 toxic

ity hazard if the substance is evaluated by the

### 29 NIOSH CIB 61 • Skin Notations algorithm as demonstrated in this appendix and is shown to have an SI ratio greater than 0.1. The SYS notation will be assigned ac

cordingly. 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 tox

icity and is supportive of assigning the SYS no

tation. The SI ratio of 0.1 was determined as the threshold level by modeling chemicals that currently carry NIOSH skin notations. To pro

vide a consistent basis for comparing model

ing results, the following exposure parameters were treated as constants during the investiga

tion (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 es

timate the SI ratio for assigning the SYS nota

tion. 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 al

gorithm to assess the risk of a given chemical exposure during a specific task, an exposure assessment should be conducted to sufficient

ly characterize all relevant information. The mathematical model described here may be improved and updated as more dermal absorp

tion 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 Pro

tection 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.

### 31 NIOSH CIB 61 • Skin Notations 

## C.1 Using pH and acid/alkali reserve to identify skin corrosives
In A Sequential Testing Strategy for Dermal Ir

ritation and Corrosio n, the supplement to the OECD Guideline for Testing of Chemicals 404 [OECD 2002], the OECD recommends using a weight-of-evidence analysis on existing rel

evant data before undertaking in vivo testing to evaluate skin corrosion. Relevant data en

compass data generated from methods alterna

tive to biologic testing, including “evidence of corrosivity/irritation of one or more structur

ally related substances or mixtures of such sub

stance” and “data demonstrating strong acid

ity or alkalinity of the substance.” The OECD Guideline also specifies that the acid/alkali re

serve (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 corro

sives is in accordance with the approach adopt

ed in the GHS [UNECE 2005]. In this system, the appropriate evaluation of extreme pH val

ues (≤ 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 re

quired 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 struc

ture-activity rules (also known as structural rules or structural alerts). These rules describe the substructures of chemical molecules po

tentially 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 de

rived using results of the guinea pig maximiza

tion test conducted for 294 substances classi

fied as strong or moderate sensitizers [Barratt et al. 1994]. The rule base initially consisted of 40 structural rules and has been continu

ously 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 rec

ommended that QSAR predictions and expert systems serve as screens for identifying posi

tive substances [de Silva et al. 1996]. Zinke et al. [2002] assessed the effectiveness ofthese structural alerts for identifying the skinsensitizing properties of chemicals. The re

searchers evaluated the 40 originally published structural alerts against a database developed in the German Federal Institute for Health Pro

tection of Consumers and Veterinary Medicine (BgVV). The BgVV database contained data submitted under its procedure for notifica

tion about new chemicals within the European Union and data on the skin-sensitization po

tentials 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 quaterna

ry ammonium cation. These structural alerts will be used to evaluate substances for their potential as skin sensitiz

ers when no human or biologic testing data are available. As the DEREKTM structural rules continue to be refined, it is anticipated that ad

ditional 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.

### 33 NIOSH CIB 61 • Skin Notations 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.

### 35 NIOSH CIB 61 • Skin Notations 

## D.1 Selecting chemicals for evaluation
Chemicals can be identified and selected for eval

uation based on the strategic framework outlined in this CIB through three primary pathways:
1. When recognized as existing occupation

al 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, exist

ing as occupational hazards, or nominated for evaluation will be assessed by NIOSH based on the availability of quality data that clearly out

line the hazards posed by the candidate chemi

cal. For chemicals listed within the NIOSH Pocket Guide to Chemical Hazards, a hierarchal ranking scheme has been developed to priori

tize 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 can

didate chemicals. Parameters addressed within the hierarchal scheme of prioritizing the candi

date chemicals include the following:

• Potential health hazards

• Potential for occupational exposure

• Annual production volume

• OELs recommended by both govern

mental and nongovernmental organiza

tions. 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 Com

mercial 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 systemati

cally assigned a score from 0–7 to determine which substances posed the greatest potential occupational health hazard based on the pa

rameters outlined in Table D.1. The scores for 15 chemicals are illustrated within Table D.2. The hierarchal ranking scheme may be modi

fied 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 nomi

nated for evaluation from stakeholders, gov

ernmental 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/m 3 , 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)

### 37 NIOSH CIB 61 • Skin Notations 

### 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, as

sign 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 ** Expo

sure po tential 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 ** Expo

sure po tential Skin hazard †† Overall score Diethylenetri

amine 111–40–0 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-Dichloropro

pene 542–75–6 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

### 39 NIOSH CIB 61 • Skin Notations 

## E.1 Literature search The literature search strategy has been de

veloped to identify critical scientific data on ( 1 ) physical and chemical properties of candi

date substances, ( 2 ) human health effects as

sociated with exposures to substances, ( 3 ) re

ported results of in vivo and in vitro toxicity testing, and ( 4 ) estimates of chemical toxico

kinetics and toxicity based on computational techniques. The primary sources of informa

tion reviewed during the literature search are peer-reviewed journals, domestic and interna

tional 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 Electr onic 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 docu

ments, and Web sites represent common sourc

es 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

### 41 NIOSH CIB 61 • Skin Notations 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 candi

date chemical based on the substance’s Chemical Abstract Services Number (CAS No.), chemical nomenclature, common names, and synonyms. Additional terminology used during the litera

ture 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 ap

proach. Other general considerations used to evaluate the assembled data include:

• How many studies were identified?

• Were the identified studies peer- re viewed?

• Were the identified data generated using standardized protocols (e.g., guidelines established by OECD, European Centre for the Validation of Alternative Meth

ods, 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 classi

fication scheme, the data sets are classified as sufficient, limited, or insufficient. These rank

ings are intended to aid in assessing the over

all quality and completeness of the assembled data sets. Data sets classified as sufficient are those that include human and/or animal tox

icity studies conducted according to stan

dardized 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 ei

ther human and/or animal studies conducted by nonstandardized protocols or contain in

complete descriptions of the exposure condi

tions 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 ex

posure 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

### 43 NIOSH CIB 61 • Skin Notations This appendix documents the assignment of skin notations based on the scientific criteria outlined in this document. This profile con

tains 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 con

tact 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 assign

ing or not assigning the various skin notations. References that are bold indicate primary studies. 

## F.1 Chemical back ground information and introduction Skin Notation for Phenol: SK: SYS-DIR (COR) This documentation for skin notation assign

ments is limited to an assessment of the po

tential 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 toxicoki

netics, 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 documen

tation of the rationale in support of the SK as

signments 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 as

signed skin notations for phenol, and data sup

porting these notations are summarized below.

• This section outlines ( 1 ) background in

formation 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 (Ap

pendix 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, depend

ing on the period of exposure and the con

centration of phenol [ Feldman and Maibach 1970; Piotrowski 1971 ; Roberts et al. 1977; Baranowska-Dutkiewicz 1981 ]. In male vol

unteers, the rate of absorption of an aqueous phenol solution (2.5, 5.0, or 10.0 g/L from a 2 mL reservoir) applied directly to the forearm (15.6 cm 2 ) was found to be concentration-de

pendent, with the rate ranging from 0.079 mg/
cm 2 /hr at the low concentration to 0.301 mg/
cm 2 /hr at the high concentration [BaranowskaDutkiewicz 1981]. In this study, the total amount of phenol absorbed—but not the rate of absorption—at the low concentration in

creased 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 sin

gle topical application of 4 μg/cm 2 phenol on 13 cm 2 of the unprotected ventral forearm of human adults. Phenol vapors are also reported to readily penetrate the skin with absorption efficiency equal to that of inhalation, thus con

tributing to the total skin exposure [Piotrowski 1971]. In a whole-body skin exposure study in which unclothed and lightly clothed volun

teers were exposed to phenol vapors at con

centrations 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 stud

ies 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 ef

fects, Respiratory depres

sion, cardiac arrest, body weight changes, decreased survival. Sufficient human and animal data

SK: DIR (COR) Skin corrosivity Sufficient human and animal data

### 45 NIOSH CIB 61 • Skin Notations laboratory animal tissues also indicate that phe

nol 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 ap

plied dose. Brooks and Riviere [1996] consid

ered a recent study that evaluated dermal ab

sorption of phenol in acetone and water under nonoccluded and occluded applications using isolated perfused porcine skin. The authors re

ported 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/cm 2 ) compared to the high-dose (40 μg/cm 2 ), suggesting satu

ration of absorption or other nonlinear kinetics under some conditions of exposure. Depend

ing 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 non

occluded condition. In vitro permeability coef

ficients 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 in

creased 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] predic

tive 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 sub

stantially contribute to the overall body burden of a chemical. For this reason, phenol is consid

ered 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 liq

uid or vapor forms. Animal studies using different protocols report dermal absorp

tion range from 9%–85% of the applied dose in multiple species. For this reason, phenol is identified as having a high po

tential to be absorbed following contact with the skin in liquid and vapor forms. Several case reports of humans dermally ex

posed 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, ac

cidental exposure of phenol to intact skin or intentional (therapeutic) application of phe

nol to the skin has resulted in fatalities (from, e.g., respiratory depression and cardiac arrest), but the doses were not known with any accu

racy, precluding estimation of a lethal dermal dose for humans. In animals, the dermal LD 50 values ( the dose resulting in 50% mortality in the exposed animals) range from 0.5 mL/kg body weight to 0.68 mL/kg (corresponding to 669–1,500 mL / kg b ody 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, general

ized 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 hema

turia and convulsions as clinical signs of phe

nol toxicity. Because the reported acute dermal LD 50 values for the rat and rabbit are both low

er than the critical dermal LD 50 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: Evalu

ation of acute toxicity of exposures of the skin

. The reported LD 50 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 as

signed 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 neuro

logic damage [Merliss 1972]. A number of re

peat-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 microli

ter (μL) of a 5% [1.25 milligram (mg)] phenol or a 10% (2.5 mg phenol) in benzene per ap

plication, 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 m g/kg/treatment [ATSDR 2006]. The potential skin and systemic effects of the benzene solvent were not inves

tigated 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 ef

fects at doses significantly lower than the criticaldermal NOAEL value of 1000 mg/kg for repeatdose toxicity. This NOAEL identifies substances with the potential for subchronic dermal toxic

ity [NIOSH 2009]. Therefore, phenol is consid

ered to be systemically toxic following repeated dermal exposure.

• Application of Appendix A.1.3: Evalu

ation 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 evaluat

ing biologic-system/function-specific effects (in

cluding reproductive and developmental effects and immunotoxicity) following skin exposure to phenol were identified in humans or animals.

### 47 NIOSH CIB 61 • Skin Notations • Application of Appendix A.1.7: Toxic effects of exposures of the skin on or

gan systems or biologic functions . No evidence was identified that evaluated the effects of phenol on organ systems or bio

logic functions. The SYS notation would not be assigned to phenol based on the criteria outlined in this section. Although a literature search identified no epide

miologic 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 Glen

denning 1957; Wynder and Hoffman 1961] in two-stage carcinogenicity protocols in mice in

dicated that phenol has promoting activity. Stud

ies conducted by Boutwell and Bosch [1959] in several strains of mice also suggested that phe

nol 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 we eks (Salaman and Glen

denning 1957), 12 mo nths or 52 we eks (Salaman and Glendenning 1957; Bout

well 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 eval

uated 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 carcino

genicity of phenol through the ingestion, in

halation, and dermal routes are inadequate for an assessment of human carcinogenic potential [U.S. EPA 2002]

. The American Conference of Governmental Industrial Hygienists (AC

GIH) has assigned an A4 (not classifiable as a human carcinogen) notation to phenol [AC

GIH 2001]. IARC has classified phenol as not classifiable as to its carcinogenicity to humans (Group 3) [IARC 2007].

• Application of Appendix A.1.6: Evalu

ation of carcinogenicity of phenol. No evidence was identified that would sup

port identifying phenol as a carcinogen or the subsequent assignment of the SYS notation. Identified human [ Feldman and Maibach 1970; Piotrowski 1971; Baranowska- Du tkiewicz 1981 ] and animal [ Behl et al. 1983; Hughes and Hall 1995; Brooks and Riviere 1996 ] toxi

cokinetic 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 system

ically toxic. Systemic toxicity includes effects on the central nervous system, body weight changes, and decreased survival. Therefore, this assessment concludes that su fficient 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 phe

nol is corrosive to the skin. For example, skin

### 48 NIOSH CIB 61 • Skin Notations exposure to liquid phenol or concentrated phe

nol vapor caused corrosive effects including tis

sue death (necrosis) in humans [ Schmidt and Maibach 1981; Horch et al. 1994 ], rats [ Con

ning 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 ede

ma 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 corne

um and produce coagulation necrosis by dena

turing and precipitating proteins. Although the structure-activity-relationship model, DE REKTM, predicts that phenol is nonirritating to the skin, which indicates that the chemical does not have structural alerts for skin irritation, several stud

ies in humans and animals show that phenol is corrosive to the skin or is a skin irritant depend

ing on the concentration. Reports of necrosis and chemical burns in hu

mans [ 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 phe

nol. 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: Experi

mental protocols for investigating di

rect effects of skin exposure and derived criteria for assigning the SK: DIR nota

tions. Sufficient evidence in the forms of numerous human and animal studies was identified that clearly demonstrated phe

nol’s ability to cause direct effects includ

ing 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 sensitiza

tion in both humans and animals. In one study using 24 volunteers, phenol produced nega

tive results in skin sensitization tests [Kligman 1966]. The Magnussen and Kligman skin sen

sitization test in guinea pigs also gave nega

tive results for phenol [Itoh 1982]. Predictions using structure-activity-relationship models provide some information regarding this end

point. Based on the chemical structure, phenol is predicted by DEREKTM as negative for sensi

tization, indicating that the chemical does not have structural alerts for skin sensitization. This prediction of negative sensitization poten

tial 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: Experi

mental protocols for investigating sensitization from skin exposure and derived criteria for assigning the SK: SEN Notations and Appendix C.2: Us

ing structural alerts implemented in the DEREKTM expert system to identify sensitizers. This section reviews the as

sembled data set for phenol to assess the potential for sensitization following skin exposures. The identified data set pro

vided insufficient information to assign

### 49 NIOSH CIB 61 • Skin Notations the SEN notation. This decision is sup

ported by the inc lusion of the DEREKTM negative prediction for phenol to cause sensitization. 

## F.5 Summary
There is sufficient information from toxicoki

netics [Feldman and Maibach 1970; Piotrowski 1971; Baranowska-Dutkiewicz 1981], acute der

mal 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 acute

ly toxic and induces systemic effects (e.g., central nervous system effects, effects on body weight and survival) following skin exposure. Infor

mation 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 corro

sive and that more dilute solutions are irritating to the skin. The limited information available in

dicates that phenol is not a skin sensitizer. There

fore, 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 corro

sive 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 < LD 50 < 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 Hy

gienists. *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 ab

sorption 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 com

pounds for mouse skin. Cancer Res 19 :413–424. *Brooks JD, Riviere JE [1996]. Quantitative percutaneous absorption and cutaneous dis

tribution 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 ani

mals. 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: H 2 SO 4 , 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 poi

soning 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,

### 51 NIOSH CIB 61 • Skin Notations 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 Mono graphs, 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 Che mical 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 skinirritation. 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.

### 53 NIOSH CIB 61 • Skin Notations 

## G.1 Contaminants and isomers Skin notations are intended to provide warn

ings 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 pres

ent within a neat substance or mixture having a concentration less than 1.0% or 2. A chemical that is recognized as a poten

tial carcinogen present within a neat sub

stance 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 com

pound, 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 de

termine whether assignment of skin notations is appropriate. Isomers are molecules that exhibit unique physical structures, despite having the same el

ementary 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 ar

rangements 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 la

beling system for chemicals adopted by the U.N. in 2003 to ensure their safe use, transport, and disposal [UNECE 2005]. The GHS crite

ria for the classification of chemicals is based on health (toxicological), physical (flammabil

ity), and environmental hazards and specify

ing 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 pur

posely designed to correspond with GHS to encourage harmonization between the two sys

tems. 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 assign

ment 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 associ

ated with ( 1 ) professional judgment and inter

ruption of reviewed data and ( 2 ) deviations be

tween 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 designa

tions. For this reason, differences in the in

terruption 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 cri

teria 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 haz

ard statements developed using the GHS strat

egy 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: LD 50 < 50) OR Dermal Category 2:

Symbol: Skull and Crossbones Signal word: Danger Hazard Statement: Fatal in contact with skin (Criteria: 50 < LD 50 < 200) SK: SYS (FATAL) (Criteria: LD 50 < 200)

(Continued)

### 55 NIOSH CIB 61 • Skin Notations 

### 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 < LD 50 < 1000) OR Dermal Category 4:

Symbol: Exclamation mark Signal word: Warning Hazard Statement: Harmful in contact with skin (Criteria: 1000 < LD 50 < 2000) SK: SYS (Criteria: 200 < LD 50 < 2000)

Dermal Category 5:

Symbol: No symbol Signal word: Warning Hazard Statement: May be harmful in contact with skin (Criteria: 2000 < LD 50 < 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 ab

normal and grow or multiply out of control. Exposure of the skin to some chemicals has been demonstrated to contribute to the de

velopment of ( 1 ) cancers within internal or

gan systems beyond the point of contact and ( 2 ) cancers of the skin at or near the point of contact. To ensure consistency in the assign

ment of the skin notations, the following para

digm 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 sub

sequent assignment of the SYS and DIR nota

tions when appropriate. In addition, the Skin Notation Profiles (see Appendix F) will sum

marize the data associated with carcinogenic potential of a chemical, including cancer des

ignations provided by NIOSH, NTP, U.S. EPA, IARC, and ACGIH.


## G.4 Nanoparticles and the sk in Nanotechnology is a system of innovative meth

ods 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), me tal-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 nanopar

ticles may have chemical, physical, and biologic properties distinctly different from and greater than fine particles of similar chemical composi

tion [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 ac

curately assess the health hazards of skin expo

sures 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 [Shve

dova 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]. Fac

tors including size, shape, water solubility, and surface coating may directly affect a nanopar

ticle’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 simi

lar 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 avail

able, the skin notations and supporting docu

mentation will address the toxic potential of

### 57 NIOSH CIB 61 • Skin Notations nanoparticles when warranted. Additional in

formation 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 Nanomateri

als [NIOSH 2009].


## References CFR. Code of Federal Regulations. Washing

ton, DC: U.S Government Printing Office, Of

fice 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 nanotech

nology: managing the health and safety con

cerns associated with engineered nano

materials. 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, Co lvin VL [2 005]. Na no-C60 cytotoxicity is du e to li pid pe roxidation. Bio

materials 26 (36):7587–7595. Shvedova AA, Kisin ER, Murray AR, Gandels

man VZ, Maynard AD, Baron PA, Castranova V [2003]. Exposure to carbon nanotube ma te rial: assessment of the biological effects of nanotube materials using human keratino cyt e 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

### 59 NIOSH CIB 61 • Skin Notations 

# NotesDelivering on the Nation’s promise:Safety and health at work for all peoplethrough research and preventionTo receive NIOSH documents or more information aboutoccupational safety and health topics, contact NIOSH atTelephone:1–800–CDC–INFO(1–800–232–4636)TTY: 1–888–232–6348E-mail: cdcinfo@cdc.govor visit the NIOSH Web site atwww.cdc.gov/niosh.For a monthly update on news at NIOSH, subscribe toNIOSH eNewsby visitingwww.cdc.gov/niosh/eNews.DHHS (NIOSH) Publication No.2009–147SAFER • HEALTHIER • PEOPLETM

DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention National Institute for Occupational Safety and Health 4676 Columbia Parkway Cincinnati, OH 45226–1998
Official Business Penalty for Private Use $300