Skin Notation (SK) Profile

Disulfoton

[CAS No. 298-04-4]

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: Disulfoton. 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 disulfoton. 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..................................................................................................................................................vii

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

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............................................................................................................................................ 4

References............................................................................................................................................... 6

Appendix: Calculation of the SI Ratio for Disulfoton ................................................................................ 8

Overview................................................................................................................................................... 8

Calculation.............................................................................................................................................. 10

Appendix References ........................................................................................................................... 11
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/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
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.

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 

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.
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, John Snawder, Ph.D., and Anna Shevdova, Ph.D. 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. 

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 Niemier, Ph.D.

Ralph Zumwalde, M.Sc.

Health Effects Laboratory Division

Fredrick H. Frasch, Ph.D. 

Michael Luster, Ph.D. 

Anna Shvedova, Ph.D.

Paul Siegel, Ph.D.
ix

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

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policy.

1.0 Introduction 

1.1 General Substance Information 

Chemical: Disulfoton

CAS No: 298-04-4

Molecular weight (MW): 274.41

Molecular formula: C8H19O2PS3

Structural formula:

Synonyms: O,O-Diethyl S-2-(ethylthio)-ethyl phosphorodithioate

Uses: Disulfoton is used primarily as an organophosphate pesticide; approximately 5.5 million pounds 

(2.5 million kilograms) of disulfoton were used in 1974 [HSDB 2010].

1.2 Purpose 

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

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

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

conducted through February 2013 to identify information on disulfoton, 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 

disulfoton. 

1.3 Overview of SK Assignment

Disulfoton 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 disulfoton: SK: SYS 
2

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

assignment for disulfoton. 

Table 1. Summary of the SK Assignment for disulfoton

Skin Notation Critical Effect Available Data

SK: SYS(FATAL) Cholinesterase inhibition Sufficient animal data

2.0 Systemic Toxicity from Skin Exposure (SK: SYS)

Studies of the human health effects of disulfoton were limited to occupational exposure studies with 

potential for both dermal and inhalation exposures. Wolfe et al. [1978] calculated a potential dermal 

exposure of workers to disulfoton in fertilizer mixing plants that ranged from 0.1 milligram per hour 

(mg/hour) to 10.5 mg/hour with a mean value of 2.0 mg/hour of work activity, and respiratory values 

ranged from 0.001 to 0.036 mg/hour with a mean of 0.009 mg/hour during both wet and dry conditions. 

These data indicate that there is higher exposure by the dermal route [Wolfe et al. 1978]. At the highest 

exposure, these investigators estimated a potential dermal absorption value of around 34.4% dose per 8-

hour day, indicating that relatively high exposure can occur [Wolfe et al. 1978]. Brokopp et al. [1981] 

measured metabolites of disulfoton in urine samples from volunteers who worked in a disulfoton 

formulating plant; however, the pesticide formulators were not exposed to the same amount of 

disulfoton during the study period. While the presence of urinary disulfoton metabolites were detected in 

the workers, it is uncertain how much was absorption through the skin and how much was inhalation 

exposure [Brokopp et al. 1981]. The potential of disulfoton to pose a skin absorption hazard was also 

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. On the basis of this algorithm, a ratio of the skin dose to the 

inhalation dose (SI ratio) of 0.837 was calculated for disulfoton. An SI ratio of ≥0.1 indicates that skin 

absorption may significantly contribute to the overall body burden of a substance [NIOSH 2009]; 

therefore, disulfoton is 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 dermal lethal doses (LDLo) of disulfoton in humans have been identified. However, LD50 values (the 

dose resulting in 50% mortality in exposed animals) have been reported. These values ranged from 2.3 

to 15.9 milligrams per kilogram (mg/kg) for male and female rats [Gaines 1969; Bayer AG 1978]. A 

higher LD50 value of 0.285 milliliters per kilogram (mL/kg) [corresponding to 324.9 mg/kg] in rats was 

reported for a liquid formulation containing 65.7% disulfoton [Weil et al. 1971]. Because the reported

acute dermal LD50 values for disulfoton 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], disulfoton is considered acutely fatal following dermal exposure.

No clinical human health effects data were identified for chronic exposure to disulfoton. However, one 

occupational exposure study evaluated effects of disulfoton. Wolfe et al. [1978] conducted a 9-week 
3

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study in which employees in a typical fertilizer-pesticide mixing plant were exposed to mean disulfoton 

doses calculated to be 0.11 to 2.0 mg/hour (dermal) and 0.009 to 0.325 mg/hour (inhalation) for wet and 

dry mix operations, respectively. A decrease of 22.8% of erythrocyte cholinesterase activity was 

reported from week 2 to week 9 in employees engaged in dry mix operations who were exposed 

dermally to doses as high as 0.23 mg/kg-day (dermal) and 0.04 mg/kg-day (inhalation) of disulfoton 

[Wolfe et al. 1978]. No depression of cholinesterase activity was observed in employees involved in wet 

mix operations [Wolfe et al. 1978]. Savage et al. [1971] noted signs of disulfoton toxicity evidenced by 

weakness, fatigue, cyanosis, and severe depression of cholinesterase activity, and high concentration of 

disulfoton in the serum of a farmer exposed to unspecified dose of the substance through a contaminated 

glove.

No repeat-dose, subchronic, or chronic toxicology studies were identified in animals. No studies were 

identified that evaluated the reproductive or developmental toxicity potential in humans or animals after 

dermal exposure to disulfoton. No standard toxicity or specialty studies evaluating biological 

system/function specific effects (including reproductive and developmental effects and immunotoxicity) 

following dermal exposure to disulfoton were identified. No studies were identified that evaluated the 

carcinogenic potential in humans or animals from dermal exposure to disulfoton. Table 2 summarizes 

carcinogenic designations of multiple governmental and nongovernmental organizations for disulfoton. 

Table 2. Summary of the carcinogenic designations*for disulfoton 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.

* 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.

Taken together, there is sufficient information from dermal absorption studies [Wolfe et al. 1978;

Brokopp et al. 1981]1, acute dermal toxicity studies [Gaines 1969; Bayer AG 1978], and the 

occupational exposure study [Wolfe et al. 1978] to demonstrate that disulfoton is absorbed through the 

skin, is acutely toxic and potentially fatal, and can cause cholinesterase inhibition [Savage 1971; Wolfe 

et al. 1978]. Therefore, on the basis of the data for this assessment, disulfoton is assigned the SK: SYS 

(FATAL) notation.

 

1References in bold text indicate studies that serve as the basis of the SK assignments.
4

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3.0 Direct Effects on Skin (SK: DIR)

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

human or animal skin models or in vitro tests of skin integrity using cadaver skin were identified. The 

U.S. EPA [2008] waived dermal irritation studies because disulfoton was too toxic to test in standard 

irritation assays. The structure-activity relationship model, Deductive Estimation of Risk from Existing 

Knowledge (DEREK) for Windows, predicted disulfoton to be negative for skin irritation. 

The absence of reliable standard irritation tests precludes adequate evaluation of the skin irritation 

potential of disulfoton. Therefore, on the basis of the data for this assessment, disulfoton is not assigned 

the SK: DIR (IRR) notation. 

4.0 Immune-mediated Responses (SK: SEN)

Although no studies were identified that evaluated the potential of disulfoton to cause skin sensitization 

in humans or animals, the U.S. EPA [2008] waived dermal sensitization studies because disulfoton was 

too toxic to test. The structure activity relationship model, DEREK for Windows, predicted disulfoton to 

be negative for skin sensitization. 

The absence of sensitization data precludes adequate evaluation of the skin sensitization potential of 

disulfoton. Therefore, on the basis of the data for this assessment, disulfoton is not assigned the SK: 

SEN notation.

5.0 Summary

The available data in both humans and animals indicate that disulfoton is absorbed through skin, is 

systemically available, acutely toxic and potentially fatal following acute dermal exposure [Gaines 

1969; Bayer AG 1978], and can cause cholinesterase inhibition following prolonged exposure to the 

skin [Savage 1971; Wolfe et al. 1978]. Insufficient data precludes the assessment of skin irritation and 

sensitization potential of disulfoton. Therefore, on the basis of these assessments, disulfoton is assigned 

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

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

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

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

1 (Hazard statement: Fatal in contact with the skin) [European Parliament 2008]. 
5

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policy.

Table 3. Summary of previous skin hazard designations for disulfoton

Organization Skin hazard designation 

NIOSH [2005] [skin]: Based on potential for skin absorption

OSHA [2015]* No designation

ACGIH [2002] [skin]: Disulftoton was highly toxic by the dermal route in animals 

nad produced organophosphate poisoning in workers

EC [2013]* R27: Very 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
6

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References

ACGIH (American Conference of Governmental Industrial Hygienists) [2002]. Disulfoton. In: 

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

American Conference of Governmental Industrial Hygienists.

Bayer AG [1978]. S 276 (disyston active ingredient) acute toxicity studies. Wuppertal-Elberfeld, West 

Germany: Bayer AG, Report #7602.

EC (European Commission) [ND]. Disulfoton. In: EINICS (European Inventory of Existing Commercial 

Chemical Substances), http://esis.jrc.ec.europa.eu/. Accessed 07-25-13.

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: 01-28-15. 

Gaines TB [1969]. Acute toxicity of pesticides. Toxicol Appl Pharmacol 14:515-534. 

HSDB (Hazardous Substances Data Bank) [2010]. Disulfoton. In: HSDB (Hazardous Substances Data 

Bank), http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/f?./temp/~iU9Z0A:1. Accessed: 01-28-15.

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: 01-28-15.

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/npgd0211.html. Accessed: 01-28-15.

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: 01-28-15.

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: 01-28-15.

OSHA [ND]. Disulfoton. In: OSHA occupational chemical database, 

https://www.osha.gov/chemicaldata/chemResult.html?recNo=343. Accessed: 01-28-15.
7

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.

Savage EP, Bagby JR, Jr., Mounce L, Williams, LP, Jr., Cholas G [1971]. Pesticide poisonings in rural 

Cp\Colorado. Rocky Mountain Med J. 68(4): 29-33.

U.S. EPA (United Stated Environmental Protection Agency) [2008]. Interim Reregistration Eligibility 

Decision for Disulfoton. List A, Case 102. Washington, DC: USEPA, Off Pest Prog., 

http://www.epa.gov/pesticides/reregistration/REDs/disulfoton-ired-addendum.pdf. Accessed: 01-28-15.

U.S. EPA (United States Environmental Protection Agency) [2015]. Disulfoton. Integrated Risk 

Information System. Washington, DC., http://www.epa.gov/iris/subst/0154.htm. Accessed: 01-28-15.

Weil, CS, Condra NI, Carpenter CP [1971]. Correlation of 4-hour vs. 24-hour contact skin penetration 

toxicity in the rat and rabbit and use of the former for predictions of relative hazard of pesticide 

formulations. Toxicol Appl Pharmacol 18: 734-742.

Wolfe HR, Staiff DC, Armstrong JF, Davis JE [1978]. Exposure of fertilizer mixing plant workers to 

disulfoton. Bull Environ Contam Toxicol 20(1): 79-86.
8

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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: Calculation of the SI Ratio for Disulfoton

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

disulfoton. 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].
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.

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.
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.

Calculation 

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

disulfoton. The calculated SI ratio was 0.837. On the basis of these results, disulfoton is predicted to 

represent a skin absorption hazard.

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

Variables Used in Calculation Units Value 

Skin permeation coefficient

Permeation coefficient of stratum corneum lipid path(kpsc) cm/hr 0.0147

Permeation coefficient of the protein fraction of the stratum 

corneum (kpol) cm/hr 9.1698 × 10-6

Permeation coefficient of the watery epidermal layer (kaq) cm/hr 0.151

Molecular weight (MW)

*

amu 274.41

Base-10 logarithm of its octanol–water partition coefficient 

(Log Kow)

* None 4.02

Calculated skin permeation coefficient (kp) cm/hr 0.013

Skin dose

Water solubility (Sw)

* mg/cm3

0.016

Calculated skin permeation coefficient (kp) cm/hr 0.013

Estimated skin surface area (palms of hand) cm2360

Exposure time hr 8

Calculated skin dose mg 0.628

Inhalation Dose

Occupational exposure limit (OEL)† mg/m30.1

Inhalation volume m

3

10

Retention factor (RF) None 0.75

Inhalation dose mg 0.75

Skin dose–to–inhalation dose (SI) ratio None 0.837

*

Variables identified from SRC [ND].

†

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

[NIOSH 2005].
11

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: 01-28-15. 

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: 01-28-15.

SRC [2015]. Interactive PhysProp database demo, 

http://esc.syrres.com/fatepointer/webprop.asp?CAS=298044. Accessed: 01-28-15.