Skin Notation (SK) Profile

Dioxathion

[CAS No. 78-34-2]

Department of Health and Human Services

Centers for Disease Control and Prevention

National Institute for Occupational Safety and Health 
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Suggested Citation

NIOSH [20XX]. NIOSH skin notation profile:Dioxathion. 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
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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 dioxathion. 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
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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..................................................................................................................................................vii

Acknowledgments.................................................................................................................................viii

1.0 Introduction....................................................................................................................................... 1

1.1 General Substance Information: .......................................................................................................... 1

1.2 Purpose ................................................................................................................................................ 1

1.3 Overview of SK Assignment.................................................................................................................. 2

2.0 Systemic Toxicity from Skin Exposure (SK: SYS).................................................................................. 2

3.0 Direct Effects on Skin (SK: DIR)........................................................................................................... 3

4.0 Immune-mediated Responses (SK: SEN)............................................................................................. 4

5.0 Summary............................................................................................................................................ 4

References............................................................................................................................................... 5

Appendix: Calculation of the SI Ratio for Dioxathion ............................................................................... 7

Overview .................................................................................................................................................... 7

Calculation ................................................................................................................................................. 9

Appendix References................................................................................................................................ 10
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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/hr centimeter(s) per hour

cm/s centimeter(s) per second

DEREK Deductive Estimation of Risk from Existing Knowledge

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

contact with a chemical

EC European Commission 

g gram(s)

g/L gram(s)/liter

GHS Globally Harmonized System for Classification and Labelling of Chemicals

GPMT guinea pig maximization test

hr hour(s)

IARC International Agency for Research on Cancer

IPCS International Program for Chemical Safety 

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

following exposure to the skin

kaq coefficient in the watery epidermal layer

kp skin permeation coefficient 

kpol coefficient in the protein fraction of the stratum corneum

kpsc permeation coefficient in the lipid fraction of the stratum corneum 

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 

log KOW base-10 logarithm of a substance’s octanol–water partition

M molarity

m

3

cubic meter(s)

mg milligram(s)

mg/cm2/hr milligram(s) per square centimeter per hour

mg/kg milligram(s) per kilogram body weight

mg/m3 milligram(s) per cubic meter

mL milliliter(s)

mL/kg milliliter(s) per kilogram body weight

MW molecular weight

NIOSH National Institute for Occupational Safety and Health

NOAEL no-observed-adverse-effect level

NTP National Toxicology Program
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agency determination or policy.

OEL occupational exposure limit

OSHA Occupational Safety and Health Administration

ppm parts per million

REL recommended exposure limit

RF retention factor 

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

exposure of the skin

SI ratio ratio of skin dose to inhalation dose

SK skin notation

SW solubility in water

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

the skin

USEPA United States Environmental Protection Agency 

μg microgram(s)

μg/cm2 microgram(s) per square centimeter

μg/cm2/hr microgram(s) per square centimeter per hour

μL microliter(s)

μmol micromole(s)
vii

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

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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.
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.

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, Paul Siegel, Ph.D. and Todd Niemeier, 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:

Denver Field Office

Eric Esswein, M.Sc.

Division of Applied Research and Technology 

Clayton B’Hymer, Ph.D. 

John Snawder, 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.

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.

Ralph Zumwalde, M.Sc.

Health Effects Laboratory Division

Stacey Anderson, Ph.D.

H. Fredrick Frasch, Ph.D. 

Michael Luster, Ph.D. 

Anna Shvedova, Ph.D.

Paul Siegel, Ph.D.

Berran Yucesoy, Ph.D.
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information quality guidelines. It has not been formally disseminated by the National Institute for 

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agency determination or policy.

National Personal Protective Technology Laboratory

Heinz Ahlers, J.D., 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
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policy.

1.0 Introduction 

1.1 General Substance Information: 

Chemical: Dioxathion

CAS No: 78-34-2

Molecular weight (MW): 456.6

Molecular formula: C4H6O2[SPS(OC2H5)2]2

Structural formula:

Synonyms: Delnav®, p-Dioxane-2,3-diyl ethyl phosphorodithioate, Dioxane phosphate, 2,3-pDioxanethiol-S,S-bis(O,O-diethyl phosphorodithioate), Navadel

Uses: Dioxathion is an organophosphate pesticide [HSDB 2009]. No data were identified to determine 

the volume of the pesticide currently or historically produced in the United States.

1.2 Purpose 

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

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

notation (SK) assignment for dioxathion. 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 dioxathion. A literature search was 

conducted through February 2013 to identify information on dioxathion, 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 

dioxathion. 
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1.3 Overview of SK Assignment

Dioxathion is potentially capable of causing numerous adverse health effects following skin contact. A 

critical review of available data has resulted in the following SK assignment for dioxathion: SK: SYS 

(FATAL). Table 1 provides an overview of the critical effects and data used to develop the SK 

assignment for dioxathion. 

Table 1. Summary of the SK Assignment for dioxathion

Skin Notation Critical Effect Available Data

SK: SYS (FATAL) Acute toxicity; Acutely 

fatal 

Sufficient animal data

2.0 Systemic Toxicity from Skin Exposure (SK: SYS)

No toxicokinetic studies were identified in humans or in animals that estimated the degree of absorption 

of dioxathion through the skin following dermal exposure. The potential of dioxathion to pose a skin 

absorption hazard was evaluated, with use of 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. On the basis of this algorithm, a 

ratio of the skin dose to the inhalation dose (SI ratio) of 0.0027 was calculated for dioxathion. An SI 

ratio of ≥0.1 indicates that a chemical is capable of producing systemic toxicity from skin exposure 

[NIOSH 2009]; therefore, dioxathion is not considered to be absorbed through the skin following dermal 

exposure. Additional information on the SI ratio and the variables used in its calculation are included in 

the appendix.

No estimates of the dermal lethal dose (LDLo) of dioxathion for humans were identified. However, acute 

dermal LD50 values (the dose resulting in 50% mortality in the exposed animals) of 63 and 235 

milligrams per kilogram body weight (mg/kg) were reported in female and male rats, respectively, when 

dioxathion was applied in xylene [Gaines 1969]. The dermal LD50 value for m-xylene, for which data 

were available, is 14.1 millilitres per kilogram body weight (mL/kg, corresponding to 12,126 mg/kg) in 

rabbits [Smyth et al. 1960], indicating that the observed value for dioxathion was not due to xylene 

toxicity. In rabbits, dermal LD50 values for a commercial preparation of dioxathion containing 70% cis

and trans isomers (present in the ratio of 1:2, respectively) were reported as 106 mg/kg in the absence of 

a solvent and 100 mg/kg applied in xylene as a solvent in rabbits and 63 and 235 mg/kg of the 

commercial preparation of dioxathion applied in xylene in female and male rats, respectively [Frawley 

et al. 1963]. Because the reported acute dermal LD50 values for female rats and for rabbits are lower than 

the critical cutoff dermal LD50 value of 200 mg/kg body weight that identifies chemical substances with 

the potential to be fatal at low doses [NIOSH 2009], dioxathion is considered acutely fatal following 

dermal exposure.

No case reports or epidemiological studies or animal repeated dose, subchronic or chronic toxicity 

studies were identified that evaluated the potential of dioxathion to cause systemic effects following 
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dermal exposure. No specialty studies were identified that evaluated the potential of dioxathion to cause 

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

immunotoxicity) following dermal exposure. No epidemiological studies or animal bioassays were 

identified that evaluated the potential of dioxathion to be carcinogenic or co-carcinogenic following 

dermal exposure. However, agencies or organizations have evaluated the carcinogenic potential of 

dioxathion following other routes of exposure. Table 2 summarizes carcinogenic designations of 

multiple governmental and nongovernmental organizations for dioxathion. 

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

nongovernmental organizations

Organization Carcinogenic designation 

NIOSH [2005] No designation

NTP [2014] No designation

USEPA [2015] No designation 

European Parliament [2008] No GHS designation 

IARC [2012] No designation

EC [2013]* No designation

ACGIH [2002] A4: Not classifiable as a 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.

*Date accessed.

No toxicokinetic data in humans or animals were identified that evaluated the potential of dioxathion to 

be absorbed through the skin following dermal exposure. Although a predictive model indicates that 

dioxathion has low potential to be absorbed through the skin and be systemically available, acute dermal 

toxicity studies in rats and rabbits [Frawley et al. 1963; Gaines 1969]1indicate dioxathion is absorbed 

through the skin, is systemically available, and can be fatal at low doses. Therefore, on the basis of the 

data for this assessment, dioxathion is assigned the SK: SYS (FATAL) notation. 

3.0 Direct Effects on Skin (SK: DIR)

No human or animal in vivo studies that evaluated the corrosivity of dioxathion or in vitro tests for 

corrosivity using human or animal skin models or in vitro tests of skin integrity using cadaver skin were 

identified. No case reports or clinical studies or standard skin irritation tests were identified that 

evaluated the potential of dioxathion to cause skin irritation. The lack of in vitro tests, case reports or 

standard skin irritation tests precludes adequate evaluation of the potential of dioxathion to produce 

direct effects on the skin. Therefore, on the basis of the data for this assessment, dioxathion is not 

assigned the SK: DIR (IRR) notation.

 

1References in bold text indicate studies that serve as the basis of the SK assignments.
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4.0 Immune-mediated Responses (SK: SEN)

Studies that evaluated skin sensitization following dermal exposure to dioxathion were not identified. 

No reports of sensitization in humans or predictive tests (for example, guinea pig maximization tests, 

Buehler tests, murine local lymph node assays, mouse ear swelling tests) or other tests that evaluated the 

potential of dioxathion to cause skin sensitization in animals were identified. The lack of diagnostic tests 

in humans and predictive tests in animals precludes adequate evaluation of the potential of dioxathion to 

cause skin sensitization. Therefore, on the basis of the data for this assessment, dioxathion is not 

assigned the SK: SEN notation.

5.0 Summary

No toxicokinetic data in humans or animals, or case reports, epidemiological studies or repeated dose, 

subchronic or chronic toxicity studies in animals were identified that evaluated the potential of 

dioxathion to be absorbed through the skin or to cause systemic effects following dermal exposure. 

Although a predictive model indicates that dioxathion has low potential to be absorbed through the skin 

and be systemically available, acute dermal toxicity studies in rats and rabbits [Frawley et al. 1963; 

Gaines 1969] indicate that dioxathion is absorbed through the skin, is systemically available, and can be 

fatal at low doses following dermal exposure. No in vitro tests, case reports or standard skin irritation 

tests were identified that evaluated the potential of dioxathion to produce direct effects on the skin. No 

diagnostic tests in humans or predictive tests in animals were identified to adequately evaluate the 

potential of dioxathion to cause skin sensitization. Therefore, on the basis of these assessments, 

dioxathion is assigned a composite skin notation of SK: SYS (FATAL). 

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

organizations. The equivalent dermal designations for dioxathion, according to the Global 

Harmonization System (GHS) of Classification and Labelling of Chemicals, is Acute Toxicity Category 

3 (Hazard statement: Toxic in contact with the skin) [European Parliament 2008]. 

Table 3. Summary of previous skin hazard designations for dioxathion

Organization Skin hazard designation 

NIOSH [2005] [skin]: Potential for dermal absorption; prevent skin contact

OSHA [2015]* No designation

ACGIH [2002] [skin]: Based on severe symptoms of organophosphate poisoning 

produced in animals following relatively small dermal doses

EC [2013]* R21: Toxic in contact with skin

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.
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References

ACGIH [2002]. Dioxathion. In: Documentation of threshold limit values and biological exposure indices 

7th ed., Vol. 1. Cincinnati, OH: American Conference of Governmental Industrial Hygienists.

EC (European Commission) [2011]. Dioxathion. In: EINICS (European Inventory of Exisiting 

Commerical Chemical Substances), 

http://ecb.jrc.ec.europa.eu/esis/index.php?GENRE=CASNO&ENTREE=78-34-2. Accessed: 08-29-13.

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, labelling 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://eurlex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2008:353:0001:1355:EN:PDF. Accessed: 01-29-15. 

Frawley JP, Weir R, Tusing T, DuBois KP, Calandra JC [1963]. Toxicologic Investigations on Delnav. 

Toxicology and Applied Pharmacology 5(5):605-624. 

Gaines T [1969]. Acute Toxicity of Pesticides. Toxicology and Applied Pharmacology, 14: 515-534.

HSDB (Hazardous Substances Data Bank) [2009]. Dioxathion. In: HSDB (Hazardous Substances Data 

Bank), http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/f?./temp/~6pP4H6:1. Accessed: 01-29-15.

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: 01-29-15.

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

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

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

Accessed: 01-29-15. 

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: 01-29-15. 

NTP [2014]. Report on Carcinogens. Thirteenth Edition; U.S. Department of Health and Human 

Services, Public Health Service. National Toxicology Program, 

http://ntp.niehs.nih.gov/pubhealth/roc/roc13/index.html. Accessed: 01-29-15.

OSHA (Occupatonal Safety and Health Administration) [ND]. Dioxathion. In: OSHA Occupational 

Chemical Database, https://www.osha.gov/chemicaldata/chemResult.html?recNo=672. Accessed: 01-

29-15.
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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.

Smyth HF, Carpenter CP, Weil CS, Pozzani UC, Striegel JA [1962]. Range-finding toxicity data: List 

VI. Ind Hyg J 23: 95-107. 

USEPA [2015]. Dioxathion. In: Integrated risk information system, http://www.epa.gov/iris. Accessed: 

01-29-15.
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Appendix: Calculation of the SI Ratio for Dioxathion

This appendix presents an overview of the SI ratio and a summary of the calculation of the SI ratio for 

dioxathion. 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 centimeters per hour (cm/hr), outlined in Table A1. Other model-based 

estimates of kp may also be used [NIOSH 2009].
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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/hr) × Sw (mg/cm3) × 360 cm2× 8 hr

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.
9

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.

Calculation 

Table A1 summarizes the data applied in the previously described equations to determine the SI ratio for 

dioxathion. The calculated SI ratio was 0.0027. On the basis of these results, dioxathion is not predicted 

to represent a skin absorption hazard.

Table A1. Summary of Data used to Calculate the SI Ratio for Dioxathion 

Variables Used in Calculation Units Value 

Skin permeation coefficient

Permeation coefficient of stratum corneum lipid path(kpsc) cm/hr 0.00092

Permeation coefficient of the protein fraction of the stratum 

corneum (kpol) cm/hr 7.1092× 10-6

Permeation coefficient of the watery epidermal layer (kaq) cm/hr 0.117

Molecular weight (MW)

*

amu 456.54

Base-10 logarithm of its octanol–water partition coefficient 

(Log Kow)

* None 3.45

Calculated skin permeation coefficient (kp) cm/hr 0.0009

Skin dose

Water solubility (Sw)

* mg/cm3

0.00155

Calculated skin permeation coefficient (kp) cm/hr 0.0009

Estimated skin surface area (palms of hand) cm2360

Exposure time hr 8

Calculated skin dose mg 0.00408

Inhalation Dose

Occupational exposure limit (OEL)† mg/m30.2

Inhalation volume m

3

10

Retention factor (RF) None 0.75

Inhalation dose mg 1.5

Skin dose–to–inhalation dose (SI) ratio None 0.0027

*

Variables identified from SRC [ND].

†

The OEL used in calculation of the SI ratio for dioxathion was the NIOSH recommended exposure limit (REL) 

[NIOSH 2005].
10

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 References 

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

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

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

Accessed: 01-29-15. 

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: 01-29-15.

SRC [2009]. Interactive PhysProp database demo, 

http://esc.syrres.com/fatepointer/webprop.asp?CAS=78342. Accessed: 01-29-15.