Skin Notation (SK) Profile

Arsenic and inorganic arsenic containing 

compounds

[CAS No. 7440-38-2]

Department of Health and Human Services

Centers for Disease Control and Prevention

National Institute for Occupational Safety and Health 
ii

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Suggested Citation

NIOSH [20XX]. NIOSH skin notation profile: Arsenic and inorganic arsenic containing 

compounds. By Hudson NL, Dotson GS. 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. XXX

DHHS (NIOSH) Publication No. XXX
iii

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information quality guidelines. It has not been formally disseminated by the National Institute for 

Occupational Safety and Health. It does not represent and should not be construed to represent any 

agency determination or policy.

Foreword

As the largest organ of the body, the skin performs multiple critical functions, such as serving as 

the primary barrier to the external environment. For this reason, the skin is often exposed to 

potentially hazardous agents, including chemicals, which may contribute to the onset of a 

spectrum of adverse health effects ranging from localized damage (e.g., irritant contact 

dermatitis and corrosion) to induction of immune-mediated responses (e.g., allergic contact 

dermatitis and pulmonary responses), or systemic toxicity (e.g., neurotoxicity and hepatoxicity). 

Understanding the hazards related to skin contact with chemicals is a critical component of 

modern occupational safety and health programs. 

In 2009, the National Institute for Occupational Safety and Health (NIOSH) published 

Current Intelligence Bulletin (CIB) 61 – A Strategy for Assigning New NIOSH Skin Notations

[NIOSH 2009-147]. This document provides the scientific rationale and framework for the 

assignment of multiple hazard-specific skin notations (SK) that clearly distinguish between the 

systemic effects, direct (localized) effects, and immune-mediated responses caused by skin 

contact with chemicals. The key step within assignment of the hazard-specific SK is the 

determination of the hazard potential of the substance, or its potential for causing adverse health 

effects as a result of skin exposure. This determination entails a health hazard identification 

process that involves use of the following:

 Scientific data on the physicochemical properties of a chemical

 Data on human exposures and health effects

 Empirical data from in vivo and in vitro laboratory testing

 Computational techniques, including predictive algorithms and mathematical models that 

describe a selected process (e.g., skin permeation) by means of analytical or numerical 

methods. 

This Skin Notation Profile provides the SK assignments and supportive data for arsenic and 

inorganic arsenic containing compounds. In particular, this document evaluates and summarizes 

the literature describing the hazard potential of the substance and its assessment according to the 

scientific rationale and framework outlined in CIB 61. In meeting this objective, this Skin 

Notation Profile intends to inform the audience—mostly occupational health practitioners, 

researchers, policy- and decision-makers, employers, and workers in potentially hazardous 

workplaces—so that improved risk-management practices may be developed to better protect 

workers from the risks of skin contact with the chemicals of interest.

John Howard, M.D.

Director

National Institute for Occupational Safety and Health

Centers for Disease Control and Prevention
iv

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information quality guidelines. It has not been formally disseminated by the National Institute for 

Occupational Safety and Health. It does not represent and should not be construed to represent any 

agency determination or policy.

Contents

FOREWORD ............................................................................................................................................................III

ABBREVIATIONS.....................................................................................................................................................V

GLOSSARY .............................................................................................................................................................. VI

ACKNOWLEDGMENTS.......................................................................................................................................VII

1.0 INTRODUCTION .................................................................................................................................................1

1.1 GENERAL SUBSTANCE INFORMATION:.................................................................................................................1

1.2 PURPOSE..............................................................................................................................................................1

1.3 OVERVIEW OF SK ASSIGNMENT ..........................................................................................................................1

2.0 SYSTEMIC TOXICITY FROM SKIN EXPOSURE (SK: SYS) ......................................................................2

3.0 DIRECT EFFECTS ON SKIN (SK: DIR)...........................................................................................................4

4.0 IMMUNE-MEDIATED RESPONSES (SK: SEN) .............................................................................................4

5.0 SUMMARY............................................................................................................................................................5

REFERENCES ............................................................................................................................................................6
v

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information quality guidelines. It has not been formally disseminated by the National Institute for 

Occupational Safety and Health. It does not represent and should not be construed to represent any 

agency determination or policy.

Abbreviations

ACGIH American Conference of Governmental Industrial Hygienists 

ATSDR Agency for Toxic Substances and Disease Registry

CIB Current Intelligence Bulletin

cm2squared centimeter(s)

cm/hour centimeter(s) per hour

DIR skin notation indicating the potential for direct effects to the skin following 

contact with a chemical

DMBA 7,12-dimethylbenz(a)anthracene 

EC European Commission 

GHS Globally Harmonized System for Classification and Labelling of Chemicals

GPMT guinea pig maximization test

IARC International Agency for Research on Cancer

(IRR) subnotation of SK: DIR indicating the potential for a chemical to be a skin irritant 

following exposure to the skin

kp skin permeation coefficient 

LD50 dose resulting in 50% mortality in the exposed population

LDLo dermal lethal dose

LLNA local lymph node assay

LOAEL lowest-observed-adverse-effect level 

M molarity

mg milligram(s)

mg/hour milligram(s) per hour

mg/kg milligram(s) per kilogram body weight

mL milliliter(s)

MW molecular weight

NIOSH National Institute for Occupational Safety and Health

NOAEL no-observed-adverse-effect level

NTP National Toxicology Program

OSHA Occupational Safety and Health Administration

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

exposure of the skin

SK skin notation

SYS skin notation indicating the potential for systemic toxicity following exposure of 

the skin

USEPA United States Environmental Protection Agency 

μL microliter(s)

μg/cm2 microgram(s) per square centimeter

g/cm2-hour microgram(s) per square centimeter per hour
vi

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information quality guidelines. It has not been formally disseminated by the National Institute for 

Occupational Safety and Health. It does not represent and should not be construed to represent any 

agency determination or policy.

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 exposure—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 is (1) unintentionally present within a neat substance or mixture 

at a concentration less than 1.0% or (2) recognized as a potential carcinogen and present within a 

neat substance or mixture at a concentration less than 0.1%. 

Cutaneous (or percutaneous)—Referring to the skin (or through the skin). 

Dermal—Referring to the skin. 

Dermal contact—Contact with (touching) the skin. 

Direct effects—Localized, non-immune-mediated adverse health effects on the skin, including 

corrosion, primary irritation, changes in skin pigmentation, and reduction/disruption of the skin 

barrier integrity, occurring at or near the point of contact with chemicals. 

Immune-mediated responses—Responses mediated by the immune system, including allergic 

responses. 

Sensitization—A specific immune-mediated response that develops following exposure to a 

chemical, which, upon re-exposure, can lead to allergic contact dermatitis (ACD) or other 

immune-mediated diseases such as asthma, depending on the site and route of re-exposure. 

Substance—A chemical. 

Systemic effects—Systemic toxicity associated with skin absorption of chemicals after exposure 

of the skin.
vii

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information quality guidelines. It has not been formally disseminated by the National Institute for 

Occupational Safety and Health. It does not represent and should not be construed to represent any 

agency determination or policy.

Acknowledgments

This document was developed by the Education and Information Division (Paul Schulte, Ph.D., 

Director). G. Scott Dotson, Ph.D., was the project officer for this document, assisted in great part 

by Naomi Hudson, Dr.P.H., MPH and Eric Esswein, M.Sc.. The basis for this document was a 

report (Toxicology Excellence for Risk Assessment [TERA]) contracted by NIOSH and prepared 

by Bernard Gadagbui, Ph.D., and Andrew Maier, Ph.D. 

For their contribution to the technical content and review of this document, special 

acknowledgment is given to the following NIOSH personnel:

Division of Applied Research and Technology 

Clayton B’Hymer, Ph.D. 

John Snawder, Ph.D.

Mark Toraason, Ph.D.

Division of Respiratory Disease Studies 

Gregory A. Day, Ph.D.

Aleksander Stefaniak, Ph.D. 

Division of Surveillance, Hazard Evaluations, and Field Studies

Matt Dahm, M.Sc. 

Todd Niemeier, M.Sc.

Aaron Sussell, Ph.D.

Loren Tapp, M.D. 

Education and Information Division 

Devin Baker, M.Ed.

Charles L. Geraci, Ph.D.

Thomas J. Lentz, Ph.D.

Richard Niemeier, Ph.D

Sudha Pandalai, M.D., Ph.D. 

Health Effects Laboratory Division

Stacey Anderson, Ph.D. 

H. Fredrick Frasch, Ph.D. 

Vic Johnson, Ph.D.

Michael Luster, Ph.D. 

Paul Siegel, Ph.D.

Berran Yucesoy, Ph.D. 
viii

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information quality guidelines. It has not been formally disseminated by the National Institute for 

Occupational Safety and Health. It does not represent and should not be construed to represent any 

agency determination or policy.

National Personal Protection Technology Laboratory

Heinz Ahlers, JD, M.Sc.

Angie Shepherd

For their contribution to the technical content and review of this document, special 

acknowledgment is given to the following CDC personnel:

Office of Surveillance, Epidemiology and Laboratory Services/Epidemiology and Analysis 

Program Office 

Barbara Landreth, M.A.

In addition, special appreciation is expressed to the following individuals for serving as 

independent, external reviewers and providing comments that contributed to the development or 

improvement of this document:

 G. Frank Gerberick, Ph.D., The Procter and Gamble Company, Cincinnati, OH

 Dori Germolec, Ph.D., National Toxicology Program, National Institute for 

Environmental Health Sciences, Research Triangle, NC

 Ben Hayes, M.D., Ph.D., Division of Dermatology, Vanderbilt School of Medicine, 

Nashville, TN 

 Jennifer Sahmel, M.Sc., CIH, ChemRisk, Boulder, CO

 James Taylor, M.D., Industrial Dermatology, The Cleveland Clinic, Cleveland, OH
1

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information quality guidelines. It has not been formally disseminated by the National Institute for Occupational 

Safety and Health. It does not represent and should not be construed to represent any agency determination or 

policy.

1.0 Introduction 

1.1 General Substance Information: 

Chemical: (Elemental) Arsenic and inorganic arsenic containing compounds1

CAS No: 7440-38-2 (elemental arsenic)

Molecular weight (MW): 74.9 (elemental arsenic)

Molecular formula: As (elemental arsenic)

Structural formula: As (elemental arsenic)

Synonyms: Arsenic metal; arsenia

Uses: Arsenic is used as a wood preservative and pesticide [ATSDR 2007]. 

1.2 Purpose 

This skin notation profile presents (1) a brief summary of epidemiological and toxicological data 

associated with skin contact with arsenic and (2) the rationale behind the hazard-specific skin notation 

(SK) assignment for arsenic. The SK assignment is based on the scientific rationale and logic outlined in 

the Current Intelligence Bulletin (CIB) 61: A Strategy for Assigning New NIOSH Skin Notations

[NIOSH 2009]. The summarized information and health hazard assessment are limited to an evaluation 

of the potential health effects of dermal exposure to arsenic. A literature search was conducted through 

February 2013 to identify information on arsenic, including but not limited to data relating to its 

toxicokinetics, acute toxicity, repeated-dose systemic toxicity, carcinogenicity, biological 

system/function–specific effects (including reproductive and developmental effects and 

immunotoxicity), irritation, and sensitization. Information was considered from studies of humans, 

animals, or appropriate modeling systems that are relevant to assessing the effects of dermal exposure to 

arsenic. 

1.3 Overview of SK Assignment

Arsenic is potentially capable of causing skin irritation following skin contact. A critical review of 

available data has resulted in the following SK assignment for arsenic: SK: DIR (IRR). Table 1 

provides an overview of the critical effects and data used to develop the SK assignment for arsenic. 

Table 1. Summary of the SK Assignment for arsenic

 

1

This document summarizes the health risks associated with skin contact with inorganic arsenic and other 

substances that contain inorganic arsenic, including, but not limited to, arsenic metal; arsenic acid (CAS No. 

7778-39-4), arsenic trioxide (CAS No. 1327-53-3), arsenite (i.e., potassium), and arsenates (i.e, calcium, lead, 

magnesium, sodium). 
2

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information quality guidelines. It has not been formally disseminated by the National Institute for Occupational 

Safety and Health. It does not represent and should not be construed to represent any agency determination or 

policy.

Skin Notation Critical

Effect

Available

Data

SK: DIR (IRR) Skin irritation Sufficient human data; limited animal data

2.0 Systemic Toxicity from Skin Exposure (SK: SYS)

Toxicokinetic studies following dermal exposure to arsenic and its inorganic compounds were 

identified. Although no in vivo studies in humans were identified, in vivo toxicokinetic studies in 

monkeys and rats demonstrate that arsenic is absorbed following dermal exposure. Wester et al. [1993] 

reported that 6.4% and 2.0% of the applied arsenic dose were absorbed through the skin when 

radioactive water solutions of arsenic-73 as arsenic acid at a low (trace) level of 0.000024 micrograms 

per square centimeter (μg/cm2), and a higher dose of 2.1 μg/cm2, respectively, were applied in a volume 

of 5 microliters (μL)/cm2 to the skin of Rhesus monkey for 24 hours. In rats, skin application of sodium 

arsenate aqueous solutions for one hour caused the initial accumulation of arsenic in the skin, with the 

absorption rate of 1.14-33.1 g/cm2-hour for 0.01 to 0.2 molar (M) concentrations, followed by a slow 

and continuous distribution to the blood stream and to other tissues [Dutkiewicz 1977]. Thirty percent of 

the absorbed dose was eliminated in the urine and feces at 10 days after the skin application. Dutkiewicz 

[1977] calculated that this absorption rate would result in an overall absorption rate of 0.8 to 23.2 

milligrams (mg)/hour in humans, assuming the surface area of the hands to be 700 cm2. Wester et al. 

[1993] reported a percutaneous absorption of 1.9% of the applied dose (when receptor fluid and skin 

concentrations were added) when the low level radioactive water solution of arsenic-73 of 0.000024 

μg/cm2, as used in the Rhesus monkey study, was applied to human skin in vitro for 24 hours. The value 

from the in vitro study was less than the in vivo percutaneous absorption of 6.4% in the Rhesus monkey. 

When arsenic-73 was applied to 0.64 cm2dermatosed pig skin samples for 16 hours, Turkall [2003] 

reported total penetration (sum of the radioactivity of the initial dose in the receptor fluid of 0.4% and 

the remaining dose of 44.2% bound to skin) as 44.6% of the initial dose recovered at the end of the 16-

hour study. This study indicated that more arsenic bound to the skin following topical application than 

penetrated into receptor fluid. The potential of arsenic to pose a skin absorption hazard was not 

evaluated with a predictive algorithm for estimating and evaluating the health hazards of dermal 

exposure to substances [NIOSH 2009]. The evaluation method compares an estimated dose accumulated 

in the body from skin absorption and an estimated dose from respiratory absorption associated with a 

reference occupational exposure limit (OEL). The ratio of the skin dose to the inhalation dose (SI ratio) 

could not be calculated because this method is not validated to determine skin absorption for inorganic 

compounds. More information about the SI ratio can be found in the appendix.

Wester et al. [1993] demonstrated that the presence of other chemicals significantly enhanced the dermal 

bioavailability of arsenic. The partition coefficient (kp) of arsenic chloride from water to powdered 

human stratum corneum was reported as 1.1 x 104[Wester et al. 1993]. It is important to note that lead 

arsenate compounds have low solubility in water [Liu et al. 2009], and would not be as hazardous as 

some of the other inorganic compounds of arsenic described in this document. Based on the available 

toxicokinetic studies in both humans and animals, arsenic has limited potential to be absorbed through 

human skin compared to animal skin. 
3

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policy.

No estimated dermal lethal doses (LDLo) of arsenic for humans have been identified. However, a dermal 

LD50 (the dose resulting in 50% mortality in the exposed animals) value of greater than 2,400 milligrams 

per kilogram body weight (mg/kg) was reported for female rats for arsenic as lead or calcium arsenate 

[Gaines 1960]. Because the reported acute dermal LD50 value for the rat is greater than the critical 

dermal LD50 value of 2000 mg/kg that identifies chemical substances with the potential for acute dermal 

toxicity [NIOSH 2009], arsenic and its inorganic compounds are not considered acutely toxicity 

following dermal exposure.

No epidemiological or occupational exposure studies or repeat-dose, sub-chronic or chronic toxicity 

studies in animals were identified that evaluated system effects following dermal exposure to arsenic or 

its inorganic compounds. No specialty studies were identified that evaluated biological system/function 

specific effects (including reproductive effects and immunotoxicity) following dermal exposure to 

arsenic. A case report by Robinson [1975] described peripheral neuropathy in a man who was dermally 

treated with arsenic; however detailed information was not provided.

No studies that evaluated the carcinogenic potential of arsenic or its inorganic compounds following the 

dermal exposure route were identified. The classification of carcinogenicity of arsenic following dermal 

exposure has not been done, but several organizations have developed such classifications based on data 

from other exposure routes. It should be noted that skin cancers in the form of Bowen’s disease, a 

squamous cell carcinoma in situ, and basal cell carcinomas, are commonly associated with the chronic 

ingestion and inhalation of arsenic [ATSDR 2007]. The relationship between skin contact with arseniccontaining compounds and these diseases could not be determined because of the absence of quality data 

on the subject. Table 2 summarizes carcinogenic designations of multiple governmental and 

nongovernmental organizations for arsenic.

Table 2. Summary of the carcinogenic designations* for arsenic by numerous governmental and 

nongovernmental organizations

Organization Carcinogenic designation 

NIOSH [2005] Potential occupational carcinogen 

NTP [2014] Known human carcinogen

USEPA [2014] Group A: Human carcinogen 

European Parliament [2008] No GHS designation

IARC [2012] Group 1: Carcinogenic to humans

EC [2013]† No designation 

ACGIH [2001] Group A1 : Confirmed human carcinogen 

ACGIH = American Conference of Governmental Industrial Hygienists; EC = European Commission, Joint Research, 

Institute for Health and Consumer Protection; GHS = Globally Harmonized System for Classification and Labelling of 

Chemicals; IARC = International Agency for Research on Cancer; NIOSH = National Institute for Occupational Safety and 

Health; NTP = National Toxicology Program; USEPA = United States Environmental Protection Agency.

* The listed cancer designations were based on data from nondermal (such as oral or inhalation) exposure since studies using 

the dermal route of exposure were unavailable.

†Date accessed.
4

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policy.

There is some indication from toxicokinetic studies that arsenic has measurable but limited potential to 

be absorbed through the skin of humans and animals [Dutkiewicz 1977; Wester et al. 1993; Turkall 

2003]. The limited availability by the dermal route is consistent with the results of the acute dermal 

toxicity study identified in animals [Gaines 1960] that indicates that arsenic is not acutely toxic despite 

its known acute toxicity via other routes. In addition, the lack of case reports, epidemiological studies, 

prolonged or repeat-dose studies in animals precludes adequate evaluation of the potential of arsenic to 

cause systemic effects following dermal exposure. Therefore, on the basis of the data for this 

assessment, arsenic is not assigned the SK: SYS notation. 

3.0 Direct Effects on Skin (SK: DIR)

No human or animal in vivo studies on corrosivity of arsenic or in vitro tests for corrosivity using human 

or animal skin models or in vitro tests of skin integrity using cadaver skin were identified. However, 

several occupational cases or human studies have reported irritant contact dermatitis or cutaneous effects 

in patients or workers exposed to arsenic [Pinto and McGill 1953; Bourrain 1998; Mohamed 1998]. Skin 

reactions were mostly in the form of itching, dryness, hyperpigmentation, folliculitis, superficial 

ulceration, erythema, swelling, and papules, with vesicle formation in severe cases. In mice treated twice 

daily with 50 μL of 0.4% potassium arsenite solution in 80% ethanol extensive ulceration was observed 

[Boutwell 1963].

Boutwell [1963] evaluated the tumor initiation and promotion potential of topical applications of 

potassium arsenite in ethanol. In an 18-week initiation study, mice received a total of 1.24 mg of 

potassium arsenite divided into 8 applications over 5 days. The tumor-promoting agent, croton oil (25 

μL of 2.0% concentration in benzene) was then applied twice weekly to the skin beginning 2 days after 

application of the test material. No increase in tumorigenicity was observed [Boutwell 1963]. In a 30-

week tumor-promotion study, 20 mice were given a single application of 75 μg of 7,12-

dimethylbenz(a)anthracene (DMBA) in 25 μL of acetone to a shaved area on the skin, followed by twice 

daily (11 times a week) application with 50 μL of 0.4% potassium arsenite solution in 80% ethanol. The 

exposure resulted in a weekly cumulative dose of 2.2 mg potassium arsenite [Boutwell 1963]. Although 

hyperplasia and external ulceration were observed, no tumors were identified. Boutwell [1963] 

concluded potassium arsenite was neither a tumor initiator nor promoter.

Case reports and human studies [Pinto and McGill 1953; Bourrain 1998; Mohamed 1998] 2

demonstrate that chronic or high-dose dermal exposure to arsenic can result in irritant contact dermatitis. 

Some of the irritant symptoms observed could possibly reflect other ingredients. Moreover, some of the 

observed skin effects could arise from arsenic uptake via other routes of exposure (e.g., oral, inhalation) 

in the occupational setting. However, the effects are consistent with irritation and are supported by the 

finding that prolonged exposure to arsenic following dermal application resulted in extensive ulceration 

at the site of application in mice [Boutwell 1963]. Therefore, on the basis of the data for this assessment, 

arsenic is assigned the SK: DIR (IRR) notation. 

4.0 Immune-mediated Responses (SK: SEN)

 

2References in bold text indicate studies that serve as the basis of the SK assignments.
5

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policy.

Several studies were identified that evaluated the potential of arsenic to cause skin sensitization in 

humans and animals. Wahlberg and Boman [1986] reported two out of 379 (0.5%) eczema patients 

patch tested with arsenic compounds [0.1% sodium arsenate in distilled water (pH 8.5) and 0.05% 

sodium arsenite in distilled water (pH 10.0)] that showed positive test results. The patients had no 

known previous exposure to arsenic compounds and the positive response might have been due to a 

cross reactivity with nickel. In a guinea pig maximization test (GPMT), arsenic compounds (1.0% 

sodium arsenate and 0.1% sodium arsenite) were not sensitizing to the skin, and were not rated as Grade 

I Allergens [Wahlberg and Boman 1986].

An in vivo animal study using the GPMT did not support the weak skin sensitization data in humans 

[Wahlberg and Boman 1986]. This assessment concludes that data are too limited to conclude that 

arsenic and its inorganic compounds have the potential to cause skin sensitization in humans. Therefore, 

on the basis of the data for this assessment, arsenic is not assigned the SK: SEN notation. 

5.0 Summary

There is some indication from toxicokinetic studies that arsenic and its inorganic compounds have 

measurable, but limited potential to be absorbed through the skin of humans and animals [Dutkiewicz 

1977; Wester et al. 1993; Turkall 2003]. The limited availability by the dermal route is consistent with 

the results of the acute dermal toxicity study identified in animals [Gaines 1960] that indicates that 

arsenic is not acutely toxic despite its known acute toxicity via other routes. These data are insufficient 

to adequately evaluate the potential of arsenic and its inorganic compounds to cause systemic effects, 

including skin cancers, following dermal exposure. Case reports and human studies [Pinto and McGill 

1953; Bourrain 1998; Mohamed 1998] and data from animals [Boutwell 1963] indicate that chronic or 

high-dose dermal exposure to arsenic can result in irritant contact dermatitis. An in vivo animal study 

using the GPMT did not support the weak skin sensitization data in humans [Wahlberg and Boman 

1986]. Therefore, on the basis of these assessments, arsenic is assigned a composite skin notation of SK: 

DIR (IRR). 

Table 3 summarizes the skin hazard designations for arsenic previously issued by NIOSH and other 

organizations. There is not an equivalent dermal designation by the Globally Harmonized System (GHS) 

[European Parliament 2008]. 

Table 3. Summary of previous skin hazard designations for arsenic

Organization Skin hazard designation 

NIOSH [2005] No designation

OSHA [2015]* No designation

ACGIH [2001] No designation

EC [2013]* No designation

ACGIH = American Conference of Governmental Industrial Hygienists; EC = European Commission, Joint Research, 

Institute for Health and Consumer Protection; NIOSH = National Institute for Occupational Safety and Health; OSHA = 

Occupational Safety and Health Administration.

*Date accessed.
6

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policy.

References

Note: Asterisks (*) denote sources cited in text; daggers (†) denote additional resources.

*ACGIH (American Conference of Governmental Industrial Hygienists) [2001]. Arsenic. In: 

Documentation of threshold limit values and biological exposure indices 7th ed., Vol. 1. Cincinnati, OH: 

American Conference of Governmental Industrial Hygienists.

*ATSDR [2007]. Toxicological profile for arsenic. Atlanta, GA: U.S. Department of Health and Human 

Services, Public Health Service, Agency for Toxic Substance and Disease Registry (ATSDR), 

http://www.atsdr.cdc.gov/toxprofiles/tp.asp?id=22&tid=3. Accessed: 03-08-11.

*Bourrain JL, Morin C, Béani JC, et al. [1998]. Airborne contact dermatitis from cacodylic acid. 

Contact Dermatitis 38(6):364-365.

*Boutwell RK [1963]. A carcinogenicity evaluation of potassium arsenite and arsanilic acid. Agric Food 

Chem 11:381-385.

*Dutkiewicz T [1977]. Experimental studies on arsenic absorption routes in rats. Environ Health 

Perspect 19:173-177.

*EC (European Commission) [2011]. Arsenic. In: EINICS (European Inventory of Existing Commercial 

Chemical Substances), http://esis.jrc.ec.europa.eu/. Accessed: 03-26-13.

*European Parliament, Council of the European Union [2008]. Regulation (EC) No 1272/2008

of the European Parliament and of the Council of 16 December 2008 on classification, labeling and 

packaging of substances and mixtures, amending and repealing Directives 67/548/

EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006. OJEU, Off J Eur Union L353:1–

1355, http://eurex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2008:353:0001:1355:EN:PDF. 

Accessed: 01-27-15.

.

*Gaines TB [1960]. The acute toxicity of pesticides to rats. Toxicol Appl Pharmacol 2:88-99.

†Garb LG, Hine CH [1977]. Arsenical neuropathy: residual effects following acute industrial exposure. 

J.O.M. 19(8):567-568.

†Holmqvist I [1951]. Occupational arsenical dermatitis: A study among employees at a copper ore 

smelting work including investigations of skin reactions to contact with arsenic compounds. Acta Derm 

Venerol 31(suppl 26):26-29, 44-45, 110-112, 195-204.

†Hostynek J, hinz RS, Lorence CR, Price M, Guy RH [1993]. Metals and the skin. Crit Rev Toxicol 

23(2): 171-125.
7

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information quality guidelines. It has not been formally disseminated by the National Institute for Occupational 

Safety and Health. It does not represent and should not be construed to represent any agency determination or 

policy.

*IARC (International Agency for Research on Cancer) [2012]. Agents reviewed by the IARC 

monographs. In: IARC monographs on the evaluation of carcinogenic risks to humans, 

http://monographs.iarc.fr/ENG/Monographs/PDFs/index.php. Accessed: 01-27-13.

†Jaghabir MTW, Abdelghani A, Anderson AC [1988]. Oral and dermal toxicity of MSMA to New 

Zealand white rabbits, Oryctalagus cuniculus. Bull Environ Contam Toxicol 40:119-122.

†Kjedsberg CR, Ward HP [1972]. Leukemia in arsenic poisoning. Ann. Intern Med. 77: 935-937.

*Liu HL, Zhu YN, Yu HX [2009]. Solubility and stability of lead arsenates at 25 degrees C. J Environ 

Sci Helath A Tox Hazard Subst Environ Eng 44(13): 1465-1475.

†Miki Y, Kawatsu T, Matsuda K, Machino H, Kubo K [1982]. Cutaneous and pulmonary cancers 

associated with Bowen's disease. J Am Acad Dermatol 6(1): 26-31.

*Mohamed KB [1998]. Occupational contact dermatitis from arsenic in a tin-smelting factory. Contact 

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

Safety and Health, DHHS (NIOSH) Publication No. 2005-149, http://www.cdc.gov/niosh/npg/. 

Accessed: 01-27-15.

*NIOSH [2009]. Current intelligence bulletin 61: a strategy for assigning new NIOSH skin notations. 

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Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 

2009-147, http://www.cdc.gov/niosh/docs/2009-147/pdfs/2009-147.pdf. Accessed: 01-27-15.

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http://ntp.niehs.nih.gov/pubhealth/roc/roc13/index.html. Accessed: 01-27-15.

*OSHA [ND]. Arsenic: metal and inorganic compounds. In: OSHA Occupational chemical database, 

http://www.osha.gov/chemicaldata/. Accessed: 01-27-15.

†Perry K, Bowler RG, Buckell HM, et al. [1948]. Studies in the incidence of cancer in a factory 

handling inorganic compounds of arsenic II: Clinical and environmental investigations. Br J Ind Med 

5:6-15.

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*Robinson TJ [1975]. Arsenical polyneuropathy due to caustic arsenical paste. Br Med J 

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Safety and Health. It does not represent and should not be construed to represent any agency determination or 

policy.

penetration of arsenic and nickel in male pig in vitro. Journal of Toxicology and Environmental Health, 

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absorption and skin decontamination of arsenic from water and soil. Fundmental and Applied 

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Feng-e Z [1985]. Endemic chronic arsenism in Xinjiang. Chinese Med J 98: 219-222.

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hepatic haemangio-endothelioma after environmental and occupational exposure. Arch Toxicol 47: 145-

154.
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This information is distributed solely for the purpose of pre-dissemination peer review under applicable 

information quality guidelines. It has not been formally disseminated by the National Institute for Occupational 

Safety and Health. It does not represent and should not be construed to represent any agency determination or 

policy.

Appendix: Calculation of the SI Ratio 

This appendix presents an overview of the SI ratio. Although the SI ratio is considered in the 

determination of a substance’s hazard potential following skin contact, it is intended only to serve as 

supportive data during the assignment of the NIOSH SK. An in-depth discussion on the rationale and 

calculation of the SI ratio can be found in Appendix B of the Current Intelligence Bulletin (CIB) 61: A 

Strategy for Assigning New NIOSH Skin Notations [NIOSH 2009]. 

Overview 

The SI ratio is a predictive algorithm for estimating and evaluating the health hazards of skin exposure 

to substances. The algorithm is designed to evaluate the potential for a substance to penetrate the skin 

and induce systemic toxicity [NIOSH 2009]. The goals for incorporating this algorithm into the 

proposed strategy for assigning SYS notation are as follows:

(1) Provide an alternative method to evaluate substances for which no clinical reports or animal 

toxicity studies exist or for which empirical data are insufficient to determine systemic effects.

(2) Use the algorithm evaluation results to determine whether a substance poses a skin absorption 

hazard and should be labeled with the SYS notation.

The algorithm evaluation includes three steps:

(1) determining a skin permeation coefficient (kp) for the substance of interest,

(2) estimating substance uptake by the skin and respiratory absorption routes, and 

(3) evaluating whether the substance poses a skin exposure hazard.

The algorithm is flexible in the data requirement and can operate entirely on the basis of the 

physicochemical properties of a substance and the relevant exposure parameters. Thus, the algorithm is 

independent of the need for biologic data. Alternatively, it can function with both the physicochemical 

properties and the experimentally determined permeation coefficient when such data are available and 

appropriate for use.

The first step in the evaluation is to determine the kp for the substance to describe the transdermal 

penetration rate of the substance [NIOSH 2009]. The kp, which represents the overall diffusion of the 

substance through the stratum corneum and into the blood capillaries of the dermis, is estimated from 

the compound’s molecular weight (MW) and base-10 logarithm of its octanol–water partition coefficient 

(log KOW). In this example, kp is determined for a substance with use of Equation 1. A self-consistent set 

of units must be used, such as outlined in Table A1. Other model-based estimates of kp may also be used 

[NIOSH 2009].
10

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information quality guidelines. It has not been formally disseminated by the National Institute for Occupational 

Safety and Health. It does not represent and should not be construed to represent any agency determination or 

policy.

Equation 1: Calculation of Skin Permeation Coefficient (kp)

psc pol aq

p

k k k

k

1 1

1







where kpsc is the permeation coefficient in the lipid fraction of the stratum corneum, kpol is the coefficient 

in the protein fraction of the stratum corneum, and kaq is the coefficient in the watery epidermal layer. 

These components are individually estimated by

log kpsc = −1.326 + 0.6097 × log Kow − 0.1786 × MW0.5

kpol = 0.0001519 × MW−0.5

kaq = 2.5 × MW−0.5

The second step is to calculate the biologic mass uptake of the substance from skin absorption (skin 

dose) and inhalation (inhalation dose) during the same period of exposure. The skin dose is calculated as 

a mathematical product of the kp, the water solubility (SW) of the substance, the exposed skin surface 

area, and the duration of exposure. Its units are milligrams (mg). Assume that the skin exposure 

continues for 8 hours to unprotected skin on the palms of both hands (a surface area of 360 squared 

centimeters [cm2]). 

Equation 2: Determination of Skin Dose

Skin dose = kp × Sw × Exposed skin surface area × Exposure time

 = kp(cm/hour) × Sw (mg/cm3) × 360 cm2× 8 hours

The inhalation dose (in mg) 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. Assume a continuous exposure of 8 

hours, an inhalation volume of 10 cubic meters (m3) inhaled air in 8 hours, and a factor of 75% for 

retention of the airborne substance in the lungs during respiration (retention factor, or RF).

Equation 3: Determination of Inhalation Dose

Inhalation dose = OEL × Inhalation volume × RF

 = OEL (mg/m3) × 10 m3× 0.75

The final step is to compare the calculated skin and inhalation doses and to present the result as a ratio of 

skin dose to inhalation dose (the SI ratio). This ratio quantitatively indicates (1) the significance of 

dermal absorption as a route of occupational exposure to the substance and (2) the contribution of 

dermal uptake to systemic toxicity. If a substance has an SI ratio greater than or equal to 0.1, it is 

considered a skin absorption hazard.
11

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information quality guidelines. It has not been formally disseminated by the National Institute for Occupational 

Safety and Health. It does not represent and should not be construed to represent any agency determination or 

policy.

Appendix References 

NIOSH [2009]. Current intelligence bulletin 61: a strategy for assigning new NIOSH skin notations. 

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. 

2009-147, http://www.cdc.gov/niosh/docs/2009-147/pdfs/2009-147.pdf. Accessed: 01-27-15.