Skin Notation (SK) Profile

Dimethyl sulfate (DMS)

[CAS No. 77-78-1]

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: Dimethyl sulfate. 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 dimethyl sulfate 

(DMS). 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 decisionmakers, employers, and workers in potentially hazardous workplaces—so that improved riskmanagement 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 ..........................................................................................................................1

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............................................................................................................................................................5

REFERENCES ............................................................................................................................................................6

APPENDIX: CALCULATION OF THE SI RATIO................................................................................................9

OVERVIEW.................................................................................................................................................................9

CALCULATION .........................................................................................................................................................11

APPENDIX REFERENCES...........................................................................................................................................12
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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/hour 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

DMS dimethyl sulfate

EC European Commission 

ECB European Chemicals Bureau

GHS Globally Harmonized System for Classification and Labelling of Chemicals

GPMT guinea pig maximization test

IARC International Agency for Research on Cancer

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

following exposure to the skin

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/hour 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

OEL occupational exposure limit

OSHA Occupational Safety and Health Administration
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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.

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 
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.
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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, Clayton B’Hymer, 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 

John Snawder, Ph.D.

Mark Toraason, Ph.D.

Division of Respiratory Disease Studies 

Gregory A. Day, Ph.D. 

Aleksander Stefaniak, Ph.D. 

Division of Surveillance, Hazard Evaluations, and Field Studies

Matt Dahm, M.Sc. 

Aaron Sussell, Ph.D.

Loren Tapp, M.D. 

Education and Information Division 

Devin Baker, M.Ed.

Charles L. Geraci, Ph.D.

Thomas J. Lentz, Ph.D.

Richard Niemeier, Ph.D.

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

Health Effects Laboratory Division

Stacey Anderson, Ph.D. 

H. Fredrick Frasch, Ph.D. 

Vic Johnson, Ph.D.

Michael Luster, Ph.D. 

Paul Siegel, Ph.D.

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

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

agency determination or policy.

National Personal Protection Technology Laboratory

Heinz Ahlers, JD, M.Sc.

Angie Shepherd

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

acknowledgment is given to the following CDC personnel:

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

Program Office 

Barbara Landreth, M.A.

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

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

improvement of this document:

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

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

Environmental Health Sciences, Research Triangle, NC

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

Nashville, TN 

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

 James Taylor, M.D., Industrial Dermatology, The Cleveland Clinic, Cleveland, OH
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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: Dimethyl sulfate

CAS No: 77-78-1

Molecular weight (MW): 126.1

Molecular formula: (CH3)2SO4

Structural formula:

Synonyms: DMS; Methyl sulfate; Dimethyl ester of sulfric acid; Dimethylsulfate

Uses: Dimethyl sulfate (DMS) is primarily used as a methylating and sulfonating agent during the 

manufacturing of organic compounds [ACGIH 2001]. 

1.2 Purpose 

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

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

(SK) assignment for DMS. 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 DMS. A literature search was conducted through 

February 2013 to identify information on DMS, 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 

DMS. 

1.3 Overview of SK Assignment

DMS 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 DMS: SK: SYS-DIR (COR). 

Table 1 provides an overview of the critical effects and data used to develop the SK assignment for 

DMS. 
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Table 1. Summary of the SK Assignment for DMS

Skin Notation Critical

Effect

Available

Data

SK: SYS Hematological effects; Hepatoxicity; 

central nervous system effects

Sufficient human data; 

limited animal data

SK: DIR (COR) Skin corrosion Sufficient human data; 

sufficient animal data

2.0 Systemic Toxicity from Skin Exposure (SK: SYS)

Quantitative information of absorption via the dermal route of exposure to DMS has not been identified. 

However, the chemical is considered to be rapidly absorbed through intact skin [Rippey and Stallwood 

2005]. In an occupational exposure study, Schettgen et al. [2004] observed a significant increase in 

hemoglobin adducts of DMS in a group of employees that worked in a specific building of a chemical 

plant where stationary monitoring of DMS showed only values below the limit of detection (reported as 

10 μg/m3) data collected with area samples, which are less accurate for estimating worker exposure than 

personal breathing zone samples. According to these investigators, the high exposures to DMS was 

attributed to skin contact with residues of unreacted DMS in the product [Schettgen et al. 2004]. Based 

on this qualitative information, the chemical may be considered to have the potential to be absorbed 

following dermal exposure. The potential of DMS to pose a skin absorption hazard was also 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 12.8 was calculated for DMS. An SI ratio of ≥0.1 indicates that skin absorption may 

significantly contribute to the overall body burden of a substance [NIOSH 2009]; therefore, DMS 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 dose (LDLo) for humans or dermal LD50 values (the dose resulting in 50% mortality in 

the exposed animals) in experimental animals have been identified. 

Although no epidemiological studies or dermal repeated-dose studies using DMS have been identified, 

several reports in the literature demonstrate systemic and pulmonary toxicity resulting from skin 

contamination through spills, though, in such cases, there might have been some contribution by 

inhalation exposure [Littler and McConnell 1955; Wang et al. 1988; Schettgen et al 2004; Yagami et al. 

2009]. Although no quantitative information on the exposure dose was provided, these case reports 

demonstrate that dermal exposure to DMS can result in systemic effects (e.g., albuminuria, hematuria, 

hypoglycemia) indicating involvement of the liver and nausea, headache and irritability, indicating 

central nervous system effects. 

No repeat-dose or subchronic standard toxicity or specialty studies evaluating biological system/function 

specific effects (including reproductive and developmental effects and immunotoxicity) or standard 
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cancer bioassays following dermal exposure to DMS were identified in animals. Hoffman [1980] 

indicated that DMS is a methylating material that can act as a mutagenic substance for nucleic acids. 

However, in animal studies, van Duuren et al. [1974] observed no carcinogenic effects when 0.1 mL 

(corresponding to 133 mg) solution of DMS in 0.1 mL acetone was applied to the skin of 20 mice three 

times per week for a period of 385 or 475 days. The authors also observed no cancers when the chemical 

was combined with the tumor promotor phorbol myristate acetate and did not report any findings on the 

non-neoplastic changes in this study [van Duuren et al. 1974]. Although no studies were identified that 

demonstrate the potential of DMS to be carcinogenic, the chemical has been evaluated for 

carcinogenicity via other routes of exposure. Table 2 summarizes carcinogenic designations of multiple 

governmental and nongovernmental organizations for DMS. 

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

nongovernmental organizations

Organization Carcinogenic designation 

NIOSH [2005] Potential occupational carcinogen

NTP [2014] Reasonably anticipated to be human carcinogen

European Parliament [2008] GHS Category 1B: May cause cancer

USEPA [2014] Group B2: Probable human carcinogen

IARC [2012] Group 2A: Probably carcinogenic to humans

EC [2013]† R45: May cause cancer

ACGIH [2001] Group A3: Confirmed animal carcinogen with unknown 

relevance to humans

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.

Based on the limited information from occupational case reports [Littler and McConnell 1955; Wang 

et al. 1988; Schettgen et al 2004; Yagami et al. 2009]1and supported by a mathematical model, DMS 

is systemically available and toxic following dermal exposure. Therefore, on the basis of the data for this 

assessment, DMS is assigned the SK: SYS notation. 

3.0 Direct Effects on Skin (SK: DIR)

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

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

reports were identified that indicate varying skin changes from simple redness to skin burns depending 

on the length of contact. For example, Littler and McConnell [1955] reported burns from a direct spill 

on the skin of a student, who dropped and broke a 2.5 L bottle that was almost full of DMS. The liquid 

 

1References in bold text indicate studies that serve as the basis of the SK assignments.
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soaked through his pants to involve the genitalia and left thigh, Littler and McConnel [1955] also 

reported a worker whose job duties included working on an analgesic drug to which dimethyl sulfate 

was added. The worker whose work clothing was likely splashed with dimethyl sulfate, experienced 

disturbances in vision, breathing difficulties, and swollen and vesicated skin [Littler and McConnel 

1955]. Wang et al. [1988] reported that within 1-2 hours of skin exposure to DMS, redness, swelling, 

pain, bleb formation, and burns were present. Yagami et al. [2009] reported a patient that spilled 100% 

DMS in his lap; the patient developed severe irritation, redness, swelling, and blisters at the exposure 

site. In the cases reported by Littler and McConnell [1955],Wang et al. [1988] and Yagami et al. [2009], 

there was a delay in onset but symptoms were still occurring. DMS has anesthetic effects; thus, the 

sensation of skin contact may not be noticed until the onset of significant tissue damage. 

In animals, Dow [1938] reported necrosis, blistering and deep ulceration when 0.001 cubic centimeters 

per square centimeter (cc/cm2) was applied to the ear and abdomen (species unspecified). A review by 

Browning [1965] reported that the chemical caused secondary and tertiary burns when applied directly 

to animal skin, although no further detailed information was provided. No irritation was observed when 

0.01 ml undiluted DMS were applied to the skin of guinea pigs, but 0.1 ml was sufficient to produced 

moderate to severe skin irritation [E.I. du Pont de Nemours and Company 1972]. The structure activity 

relationship model, Deductive Estimation of Risk from Existing Knowledge (DEREK) for Windows, 

predicted DMS to be a plausible skin irritant. 

Taken together, human [Littler and McConnell 1955; Wang et al. 1988; Yagami et al. 2009] and 

animal data [Dow 1938; Browning 1965; E.I. du Pont de Nemours and Company 1972] demonstrate 

that DMS is corrosive at high doses and prolonged dermal exposure, and irritating at low concentrations. 

Therefore, on the basis of the data for this assessment, DMS is assigned the SK: DIR (COR) notation. 

4.0 Immune-mediated Responses (SK: SEN)

There is limited information identified from occupational exposures. Yagami et al. [2009] reported a 

patient that spilled 100% DMS in his lap; the patient developed severe irritation, redness, swelling, and 

blisters at the exposure site. The authors suspected that the patient developed allergic contact dermatitis 

to DMS, and patch tested him using 0.1% pet. DMS and noted a positive skin reaction [Yagami et al. 

2009]. In guinea pigs, 0.05 ml (67 mg) of 0.5% and 1% DMS solution was sufficient to cause positive 

responses upon the challenge dose, although no guinea pigs were sensitized [E.I. du Pont de Nemours 

and Company 1972]. Ashby et al. [1995] suggested that DMS is a potential skin sensitizer based on the 

results of their murine local lymph node assay (LLNA). In this assay, topical application of 0.25, 0.5 and 

1% DMS in acetone/olive oil (80/20 v/v) resulted in greater than a 3-fold increase in thymidine isotope 

incorporation in the lymph nodes of exposed mice compared with vehicle controls [Ashby et al. 1995]. 

Ashby et al. [1995] considered a 3-fold increase to be determinant of sensitizing activity. The ECB 

[2002] review of the Ashby et al. [1995] study noted that the positive response observed may be due to 

the corrosive properties of the chemical. A non-standard, Ear-Flank Test was also conducted, and which 

the authors [Stevens 1967] concluded that the chemical was not a skin sensitizer. In guinea pigs, 0.05 ml 

(67 mg) of 0.5% DMS solution was not sufficient to cause sensitization when applied to the intact skin 

of guinea pigs [E.I. du Pont de Nemours and Company 1972]. 
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Although positive responses were observed in the murine LLNA test [Ashby et al. 1995] and in a single 

human patch test [Yagami et al. 2009], conflicting evidence in animal studies [Stevens 1967; E.I. du 

Pont de Nemours and Company 1972] suggest that DMS is not capable of causing immune-mediated 

responses (i.e., sensitization) following skin contact and that the positive responses may be attributable 

to corrosive properties of the chemical. Therefore, on the basis of the data for this assessment, DMS is 

not assigned the SK: SEN notation. 

5.0 Summary

Although limited information was identified on the toxicokinetics and systemic toxicity of DMS, 

occupational case reports [Littler and McConnell 1955; Wang et al. 1988; Schettgen et al 2004; 

Yagami et al. 2009] supported by the mathematical model prediction demonstrates that DMS is 

systemically available and toxic following dermal exposure. DMS is corrosive at high doses and 

following prolonged dermal exposure and irritating at lower concentrations based on human [Littler 

and McConnell 1955; Wang et al. 1988; Yagami et al. 2009] and animal [Dow 1938; Browning 

1965; E.I. du Pont de Nemours and Company 1972] studies. Although positive responses were 

observed in the murine LLNA test [Ashby et al. 1995] and in a single human patch test [Yagami et al. 

2009], conflicting evidence in animal studies [Stevens 1967; E.I. du Pont de Nemours and Company 

1972] suggests that DMS is not capable of causing immune-mediated responses (i.e., sensitization) 

following skin contact and that the positive responses may be attributable to corrosive properties of the 

chemical. Therefore, on the basis of these assessments, DMS is assigned a composite skin notation of 

SK: SYS-DIR (COR). 

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

organizations. The equivalent dermal designations for DMS, according to the Globally Harmonized 

System (GHS) of classification and labeling of chemicals, the equivalent GHS classification for DMS 

are Skin Corrosion Category 1B (Causes severe skin burns and eye damage) and Skin Sensitization 

Category 1 (May cause an allergic skin reaction) [European Parliament 2008]. 

Table 3. Summary of previous skin hazard designations for DMS

Organization Skin hazard designation 

NIOSH [2005] [skin]: Potential for dermal absorption

OSHA [2015]*[skin]: Potential for dermal absorption

ACGIH [2001] [skin]: Based on systemic toxicity reported for workers from

dermal contact with DMS

EC [2013]* R34: Causes burns 

R43: May cause sensitization by skin contact

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

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

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

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

OH: American Conference of Governmental Industrial Hygienists.

*Ashby J, Basketter DA, Paton D, Kimber I [1995]. Structure activity relationships in a skin 

sensitization using the murine local lymph node assay. Toxicology 103:177-194. 

*Browning E [1965]. Toxicity and metabolism of industrial solvents. Amsterdam, Netherlands pp. 713-

721.

*Dow Chemical Company [1938]. The skin irritating action of dimethylsulfate. Midland, MI: Dow 

Chemical Company. On file with the U.S. Environmental Protection Agency under TSCA Section 8D. 

OTS #0557225. 

†E.I. du Pont de Nemours and Company [1943]. Preliminary tests on the toxicology of diethyl sulfate 

and diethyl peroxide. By Fleming AJ. Wilmington, DE: E.I. du Pont de Nemours and Company, Haskell 

Laboratory for Toxicology and Industrial Medicial Research Project No. MR-119. On file with the U.S. 

Environmental Protection Agency under TSCA Section 8D. OTS #0557105.

*E.I. du Pont de Nemours and Company [1972]. Primary skin irritation and sensitization tests on guinea 

pigs. By McDonnell ME. Newark, DE: E.I. du Pont de Nemours and Company, Haskell Laboratory for 

Toxicology and Industrial Medicine Report No. 22-72. On file with the U.S. Environmental Protection 

Agency under TSCA Section 8D. OTS #0557106.

*EC (European Commission) [ND]. Dimethyl sulfate. In: EINICS (European Inventory of Existing 

Commercial Chemical Substances), http://esis.jrc.ec.europa.eu/. Accessed: 03-21-13.

*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: 01-27-15.

*Hoffman GK [1980]. Genetic effects of DMS, diethyl sulfate and related compounds. Mutat. Res. 

75:63-109. 

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

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

http://monographs.iarc.fr/ENG/Monographs/PDFs/index.php. Accessed: 01-27-15.
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This information is distributed solely for the purpose of pre-dissemination peer review under applicable 

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

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

policy.

*Littler TR, McConnell RB [1955]. Dimethyl sulphate poisoning. Br. J. Ind. Med 12: 54-56.

*NIOSH [2005]. NIOSH pocket guide to chemical hazards. By Barsan ME. 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. Date accessed: 

01-27-15.

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

By Alhers HW, Chen-Peng C, Demchuk E, 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. 2009-147. Date accessed: 01-27-15.

*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: 01-27-15.

*OSHA [ND]. Dimethyl sulfate. In: OSHA Occupational chemical database, 

http://www.osha.gov/chemicaldata/chemResult.html?recNo=644. Accessed: 01-27-14.

*Rippey JCR, Stallwood MI [2005]. Nine cases of accidental exposure to dimethyl sulphate – a potential 

chemical weapon. Emerg Med J 22:878-879.

*Schettgen T, Broding HC, Angerer J, Drexler H [2004]. Dimethyl sulphate; a hidden problem in

occupational medicine. Occup. Environ. Med 61:73-75.

*Stevens MA [1967]. Use of the albino guinea-pig to detect the skin-sensitizing ability of chemicals. 

Brit J Industr Med 24:189-202.

*UNECE (United Nations Economic Commission for Europe) [2007]. Part 3: health hazards. In: 

Globally harmonized system of classification and labeling of chemical (GHS): third revised edition, 

http://www.unece.org/trans/danger/publi/ghs/ghs_rev02/English/03e_part3.pdf. Accessed: 01-27-15.

†USEPA [2005]. Guidelines for carcinogen risk assessment. Washington, DC: U.S. Environmental 

Protection Agency, EPA/630/P-03/001F.

*USEPA [2014]. Integrated Risk Information System: dimethyl sulfate. In: Integrated Risk Information 

System, http://www.epa.gov/iris/subst/0365.htm. Accessed: 01-27-15.

*van Duuren; Goldschmidt BM; Katz C; Seidman I; Paul JS. [1974]. J Natl Cancer Inst 53:695-700. 

*Wang Y, Xia J, Wang, Q [1988]. Clinical Report of 62 Cases of Acute Dimethyl Sulfate Intoxication. 

American Journal of Industrial Medicine. 13:455-462.
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 Occupational 

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

policy.

*Yagami A, Kawai N, Kosai N, Inoue T, Suzuki K, Matsunaga K [2009]. Occupational allergic contact 

dermatitis due to dimethyl sulfate following sensitization from a severe acute irritant reaction to the 

reagent. Contact Dermatitis 60(3): 183-184.
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.

Appendix: Calculation of the SI Ratio

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

DMS. Although the SI ratio is considered in the determination of a substance’s hazard potential 

following skin contact, it is intended only to serve as supportive data during the assignment of the 

NIOSH SK. An in-depth discussion on the rationale and calculation of the SI ratio can be found in 

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

Notations [NIOSH 2009]. 

Overview 

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

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

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

proposed strategy for assigning SYS notation are as follows:

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

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

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

hazard and should be labeled with the SYS notation.

The algorithm evaluation includes three steps:

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

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

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

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

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

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

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

appropriate for use.

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

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

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

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

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

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

[NIOSH 2009].
10

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

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

policy.

Equation 1: Calculation of Skin Permeation Coefficient (kp)

psc pol aq

p

k k k

k

1 1

1







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

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

These components are individually estimated by

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

kpol = 0.0001519 × MW−0.5

kaq = 2.5 × MW−0.5

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

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

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

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

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

centimeters [cm2]). 

Equation 2: Determination of Skin Dose

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

 = kp(cm/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
11

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

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

policy.

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.

Calculation 

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

DMS. The calculated SI ratio was 12.8. On the basis of these results, DMS is predicted to represent a 

skin absorption hazard.

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

Variables Used in Calculation Units Value 

Skin permeation coefficient

Permeation coefficient of stratum corneum lipid path(kpsc) cm/hr 5.8309 × 10-4

Permeation coefficient of the protein fraction of the stratum 

corneum (kpol) cm/hr 1.3525 × 10-5

Permeation coefficient of the watery epidermal layer (kaq) cm/hr 0.2226

Molecular weight (MW)

*

amu 126.13

Base-10 logarithm of its octanol–water partition coefficient 

(Log Kow)

* None 0.16

Calculated skin permeation coefficient (kp) cm/hr 5.9502 × 10-4

Skin dose

Water solubility (Sw)

* mg/cm3

28

Calculated skin permeation coefficient (kp) cm/hr 5.9502 × 10-4

Estimated skin surface area (palms of hand) cm2360

Exposure time hr 8

Calculated skin dose mg 47.98

Inhalation Dose

Occupational exposure limit (OEL)† mg/m30.5

Inhalation volume m

3

10

Retention factor (RF) None 0.75

Inhalation dose mg 3.75

Skin dose–to–inhalation dose (SI) ratio None 12.8

*

Variables identified from SRC [ND].

†

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

2005].
12

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

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

policy.

Appendix References 

NIOSH [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: 01-27-15.

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: 01-27-15.

SRC [2009]. Interactive PhysProp database demo, 

http://esc.syrres.com/fatepointer/webprop.asp?CAS=77781. Accessed: 01-27-15.