# 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 Healthii

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- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupa tional Safety and Health. It does not represent and should not be construed to represent any
agency determination or policy. 

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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 Occupationa l Safety and Health, DHHS (NIOSH)

Publication No. XXX

DHHS (NIOSH) Publication No. XXXiii

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 Occupa tional 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 system ic 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 H ealth (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 notation s (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 poten tial 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 propertie s 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

- manage ment 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 Preventioniv

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

## Content s

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 Referen ces

................................ ................................ ................................ ........................... 11v

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 Occupa tional 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

cm 2 squared 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 G lobally 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

k aq coefficient in the watery epidermal layer

k p skin permeation coefficient

k po l coefficient in the protein fraction of the stratum corneum

k psc permeation coefficient in the lipid fraction of the stratum corneum

LD 50 d ose resulting in 50% mortality in the exposed population

LD Lo dermal lethal dose

LLNA local lymph node assa y LOAEL lowest

- observed

- adverse

- effect level log K OW base

- 10 logarithm of a substance’s octanol

– water partition

M molarity

m 3 cubic meter(s)

mg milligram(s) mg/cm 2 /hr milligram(s) per square centimeter per hour mg/kg milligram(s) per kilogram body weight mg/m 3 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 Programvi

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 Occupa tional 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

exp osure of the skin

SI ratio ratio of skin dose to inhalation dose

SK skin notation

S W 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/cm 2 microgram(s) per square centimeter μg/cm 2 /hr microgram(s) per square centimeter per hour μL microliter(s) μmol micromole(s)vii

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- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupa tional 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.

Ca ncer

— 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 carcino gen 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 wit h (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, oc curring at or near t he point of contact with chemicals.

Immune

- mediated responses

— Responses mediated by the immune system, in cluding allergic

responses.

Sensitization

— A specific immune

- mediated response that develops following ex posure to a chemical, which, upon re

- exposu re, can lead to allergic contact derma titis (ACD) or other

immune

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

- exposure. Substance

— A chemical.

Systemic effects

— Systemic toxicity associated with skin absorption of chemicals aft er exposure of the skin.viii

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- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupa tional 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 contrib ution 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 Inform ation 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

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 Occupa tional 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 pr oviding 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, Clevelan d, OH1

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 Occupa tional 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: Disulfoton

CAS No: 298

- 04

- 4 Molecular weight (

MW ): 274.41

Molecular formula: C 8 H 19 O 2 PS 3 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 Inte lligence 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 effect s (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 exposur e 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: SYS2

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

rang ed 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 de rmal 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

formulat ing 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 consid ered 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 (LD Lo ) of disulfoton in humans have been identified. Howev er, LD 50 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 LD 50 value of 0.285 milliliter s 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 LD 50 values for disulfoton are lower than the critical cutoff dermal LD 50 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 chroni c exposure to disulfoton. However, one occupational exposure study evaluated effects of disulfoton. Wolfe et al. [1978] conducted a 9

- week3

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 Occupa tional Safety and Health. It does not represent and should not be construed to represent any agency determination or
policy. study in which employees in a typical fertilizer

- pesticide mixing plant were exposed to mean disulfoton

doses calcula ted 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 opera tions 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. 1 978]. 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 subst ance 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 expos ure 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 we re 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 dem onstrate 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.

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

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- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupa tional Safety and Health. It does not represent and should not be construed to represent any agency determination or
policy. 

## 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, pr edicted 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 sensitizat ion 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 se nsitization 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 p recludes 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 Chem icals, is Acute Toxicity Category 1 (Hazard statement: Fatal in contact with the skin) [ European Parliament 2008].5

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

*Date accessed6

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- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupa tional Safety and Health. It does not represent and should not be construed to represent any agency determination or
policy. 

## 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 Exist ing 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://eur

lex.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://toxn et.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://mon ographs.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 Occupa tional 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 Me d 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/disu lfoton

- ired

- addendum.pdf . Accessed: 01

- 28

- 15.

U.S. EPA (United States Environmental Protection Agency) [2015]. Disulfoton. Integrated Risk Information System. Wash ington, 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.

Wol fe 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

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 Occupa tional 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 incorpo rating 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 ( k p ) 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 operat e 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 k p for the substance to describe the transdermal penetration rate of the substance [NIOSH 2009]. T he k p , 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 K

OW ). In this example, k p 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 k

p 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 Occupa tional 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 ( k p )

where k

psc is the permeation coefficient in the lipid fraction of the stratum corneum, k pol is the coefficient in the protein fraction of the stratum corneum, and k aq is the coefficient in the watery epidermal layer. These components are individually estimated by

log k psc = −1.326 + 0.6097 × log K

ow − 0.1786 × MW 0.5

k pol = 0.0001519 × MW −0.5

k aq = 2.5 × MW

−0.5

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 k p , the water solub ility ( S

W ) 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 [cm 2 ]).

Equation 2: Determination of Skin Dose

Skin dose = k

p × S

w × Exposed skin surface area × Exposure time

= k p (cm/hr) × S

w (mg/cm 3 ) × 360 cm 2 × 8 hr

The inhalation dose (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 me ters (m 3 ) 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/m 3 ) × 10 m 3 × 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 Occupa tional Safety and Health. It does not represent and should not be construed to represent any agency determination or
policy. 

### Calculation

Table A1 s ummarizes 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 o f 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( k psc ) cm/hr 0.0147 Permeation coefficient of the protein fraction of the stratum corneum ( k

pol ) cm/hr 9.1698 × 10 - 6

Permeation coefficient of the watery epidermal layer ( k aq ) cm/hr 0.151 Molecular weight ( MW

) * amu 274.41
Base

- 10 logarithm of its octanol

– water partition coefficient (Log K

ow ) * None 4.02

Calculated skin permeation coefficient ( k p ) cm/hr 0.013

Skin dose

Water solubility ( S w ) * mg/cm 3 0.016 Calculated skin permeation coefficient ( k p ) cm/hr 0.013
Estimated skin surface area (palms of hand) cm 2 360 Exposure time hr 8

Calculated skin dose mg 0.628

Inhalation Dose
Occupational exposure limit (OEL) † mg/m 3 0.1

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 Occupa tional 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

.