NIOSH Skin Notation (SK) Profiles

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Disease Control and Prevention

National Institute for Occupational Safety and Health

Methyl Isocyanate

[CAS No. 624-83-9]
ii Skin Notation Profiles | Methyl isocyanate

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Suggested Citation

NIOSH [2014]. NIOSH skin notation profiles: methyl isocyanate. 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. 2014-145.

DHHS (NIOSH) Publication No. 2014-145

August 2014

Safer • Healthier • PeopleTM
Skin Notation Profiles | Methyl isocyanate iii

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 methyl isocyanate (MIC). 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

Skin Notation Profiles | Methyl isocyanate v

Contents

Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iii

Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vi

Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . viii

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

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

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

1.3 Overview of SK Assignment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

2 Systemic Toxicity from Skin Exposure (SK: SYS) . . . . . . . . . . . . . . . . . . . . . . . 1

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

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

5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

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

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

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

Calculation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Appendix References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
vi Skin Notation Profiles | Methyl isocyanate

Abbreviations

ACGIH American Conference of Governmental Industrial Hygienists 

ATSDR Agency for Toxic Substances and Disease Registry

CIB Current Intelligence Bulletin

cm2 square centimeter(s)

DEREKTM 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 

GHS Globally Harmonized System for Classification and Labelling of Chemicals

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

k

aq coefficient in the watery epidermal layer 

k

p skin permeation coefficient 

kpol coefficient in the protein fraction of the stratum corneum

k

psc permeation coefficient in the lipid fraction of the stratum corneum 

LD50 dose resulting in 50% mortality in the exposed population

LDLo dermal lethal dose

LOAEL lowest-observed-adverse-effect level 

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

M molarity

m3 cubic meter(s)

mg milligram(s)

mg/cm3 milligram(s) per cubic centimeter

mg/kg milligram(s) per kilogram body weight

MIC methyl isocyanate

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

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
Skin Notation Profiles | Methyl isocyanate vii

SW solubility 

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

the skin

TDI toluene diisocyanate 

USEPA United States Environmental Protection Agency 
viii Skin Notation Profiles | Methyl isocyanate

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.
Skin Notation Profiles | Methyl isocyanate ix

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, Stacey Anderson, Ph.D., and H. Fredrick 

Frasch, 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 

John Snawder, Ph.D.

Mark Toraason, Ph.D.

Division of Respiratory Disease Studies 

Gregory A. Day, Ph.D. 

Aleksander Stefaniak, Ph.D. 

Division of Surveillance, Hazard Evaluations, and Field Studies

Matt Dahm, M.Sc. 

Todd Niemeier, M.Sc.

Aaron Sussell, Ph.D.

Loren Tapp, M.D. 

Education and Information Division

Devin Baker, M.Ed.

Charles L. Geraci, Ph.D.

Thomas J. Lentz, Ph.D.

Richard Niemeier, Ph.D.

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

Health Effects Laboratory Division

Vic Johnson, Ph.D.

Michael Luster, Ph.D.

Anna Shvedova, Ph.D. 

Paul Siegel, Ph.D.

Berran Yucesoy, Ph.D. 

National Personal Protection Technology Laboratory

Heinz Ahlers, 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.
x Skin Notation Profiles | Methyl isocyanate

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:

Shane Stephen Que Hee, M.Sc., Ph.D., University of California at Los Angeles, School 

 of Public Health, Los Angeles, CA

Glenn Sipes, Ph.D., University of Arizona, College of Medicine, Tucson, AZ

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
Skin Notation Profiles | Methyl isocyanate 1

Methyl isocyanate

Chemical: Methyl isocyanate (MIC)

CAS No: 624-83-9

Molecular weight (MW): 57.1

Molecular formula: CH3NCO

Structural formula:

Synonyms: 

MIC; Isocyanate methane; Isocyanatomethane; Isocyanomethane; Methyl carbonyl 

amine; Methyl ester, Isocyanic acid 

Uses:

MIC is primarily used as a chemical intermediate during the manufacturing of carbamate

and other pesticides [ACGIH 2001]. 

1 Introduction 

1.1 General Substance Information

1.2 Purpose 

This skin notation profile presents (1) a brief 

summary of epidemiological and toxicological 

data associated with skin contact with MIC 

and (2) the rationale behind the hazard-specific skin notation (SK) assignment for MIC. 

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 MIC. A literature search 

was conducted through April 2014 to identify information on MIC, 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 MIC. 

1.3 Overview of SK Assignment

MIC 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 

MIC: SK: SYS-DIR (COR)-SEN. Table 

1 provides an overview of the critical effects 

and data used to develop the SK assignment 

for MIC.

2 Systemic Toxicity from Skin 

Exposure (SK: SYS)

There have been no documented dermal absorption studies of MIC in humans or animals. 

Table 1. Summary of the SK assignment for MIC

Skin notation Critical effect Data available

SK: SYS Acute toxicity Sufficient animal data

SK: DIR (COR) Skin corrosion Sufficient animal data

SK: SEN Skin allergy Sufficient animal data
2 Skin Notation Profiles | Methyl isocyanate

Methyl isocyanate

The potential of MIC 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 3.7 was calculated for MIC. An 

SI ratio of ≥0.1 indicates that skin absorption 

may significantly contribute to the overall 

body burden of a substance [NIOSH 2009]; 

therefore, MIC 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 estimated dermal lethal dose (LDLo) for 

humans was identified. However, dermal 

LD50 (the dose resulting in 50% mortality 

in the exposed animals) values of 1800 milligrams per kilogram body weight (mg/kg) 

and 0.22 milliliters (undiluted) per kilogram 

(mL/kg) [corresponding to 203 mg/kg] have 

been reported in rabbits [Mellon Institute 

1963, 1970; Smyth et al. 1969; Vernot et al. 

1977]. In guinea pigs, Eastman Kodak Company [1990] reported a dermal LD50 value of 

1 to 5 mL/kg [corresponding to 923 mg/kg 

to 4615 mg/kg]. Because the reported acute 

dermal LD50 values for these species are lower 

than the critical dermal LD50 value of 2000 

mg/kg body weight that identifies chemical 

substances with the potential for acute dermal 

toxicity [NIOSH 2009], MIC is considered 

systemically available and acutely toxic by the 

dermal route. 

No effects data were identified regarding dermal repeat-dose (21-day or 28-day), 

sub-chronic (90-day), or chronic (at least 

12-month) toxicity of MIC in humans or 

animals. No standard toxicity or specialty 

studies evaluating biological system/function 

specific effects (including reproductive and 

developmental effects and immunotoxicity) of 

MIC following dermal exposures were identified. No epidemiological studies or standard 

animal carcinogenicity studies were identified 

that evaluated the potential of the chemical to 

cause tumors. However, studies following the 

industrial disaster in Bhopal, India in 1984 

examined these outcomes following exposure 

to the eyes, respiratory tract and skin from the 

MIC gas cloud, which might have also included exposure to toxic byproducts and contaminants [Dhara 2002]. While researchers found 

limited evidence of carcinogenesis, there was 

evidence that exposure to MIC depressed 

phagocytic activity of lymphocytes, indicating 

a toxicological effect [Saxena 1988]. Exposure 

to MIC from the disaster was also found to 

lead to reproductive outcomes such as spontaneous abortion [Bhandari 1990]. Table 2 

summarizes carcinogenic designations of 

multiple governmental and nongovernmental 

organizations for MIC. 

No toxicokinetic studies following dermal exposure to MIC were identified. However, the 

capacity of the compound to penetrate the 

skin can be inferred from the fact that values 

for the dermal median lethal dose (LD50) have 

been reported, and is supported by a predictive 

mathematical model (see Appendix) that indicate the chemical can be absorbed through 

the skin. In addition, acute dermal toxicity 

studies showed that the MIC is acutely toxic. 

No repeat-dose or prolonged dermal toxicity 

studies were identified in humans or animals. 

Based primarily on observed acute toxicity 

following dermal exposure [Mellon Institute 1963, 1970; Smyth et al. 1969; Vernot et 

al. 1977; Eastman Kodak Company 1990] *, 

there are sufficient data in animals to conclude 

that MIC is systemically absorbed and acutely 

toxic. Therefore, on the basis of the data for 

this assessment, MIC is assigned the SK: SYS 

notation. 

*References in bold text indicate studies that serve 

as the basis of the SK assignments.
Skin Notation Profiles | Methyl isocyanate 3

Methyl isocyanate

3 Direct Effects on Skin 

(SK: DIR)

No human data on direct effects (corrosivity 

or irritancy) of MIC were identified. Several 

experimental animal studies were identified 

that investigated the direct effects of MIC on 

skin. Necrosis of the skin occurred at the site 

of application when undiluted MIC was applied to intact rabbit skin [Mellon Institute 

1963, 1970; Smyth et al. 1969], and moderate erythema and marked capillary injection 

occurred when a 10% solution of MIC was 

applied to intact rabbit skin [Mellon Institute 1963]. Guinea pigs receiving undiluted 

applications of 1.0-10.0 mL/kg MIC exhibited gross edema, necrosis, and hemorrhaging 

[Eastman Kodak Company 1990]. In another 

study in guinea pigs, single administrations of 

10% or less of MIC produced no irritation to 

the intact skin, whereas 25% to 100% solutions 

produced mild, moderate or strong erythema 

and severity of erythema and edema varied 

depending on the concentration [E.I. du Pont 

de Nemours and Company 1968]. E.I. du 

Pont de Nemours and Company [1968] also 

reported that a second application of MIC 

to the intact skin of the guinea pigs resulted 

in increased skin irritation. Dow Chemical 

Company [1990] reported slight to extensive 

hyperemia, edema and slight necrosis when 

the undiluted material was applied twice to 

the intact or abraded belly of rabbits, whereas 

no irritation was observed following 10 applications of a 2% solution to the intact belly or 

ear or three applications of the same solution 

to abraded belly of rabbits. Predictions using 

structure activity relationship models provide 

some additional information regarding this 

endpoint. The structure activity relationship 

model, Deductive Estimation of Risk from 

Existing Knowledge (DEREK) for Windows, 

predicted MIC to be negative for skin irritation, indicating that the substance does not 

have structural alerts for skin irritation.

Although no case reports of skin effects resulting from dermal exposure to MIC were 

identified and the DEREK model predicted 

MIC to be negative for skin irritation, there 

was evidence of skin irritation and corrosion 

in animals. Animal studies [Mellon Institute 1963, 1970; E.I. du Pont de Nemours 

and Company 1968; Smyth et al. 1969; Dow 

Chemical Company 1990; Eastman Kodak 

1990] showed that the undiluted material or 

concentrated solutions are corrosive, while 

weaker dilutions tend to be non-irritating or 

slightly irritating to the skin. Therefore, on the 

Table 2. Summary of the carcinogenic designations* for MIC by numerous 

governmental and nongovernmental organizations

Organization Carcinogenic designation

NIOSH [2005] No designation

NTP [2011] No designation

USEPA [2012] No designation

European Parliament [2008] No designation

IARC [2007] No designation

EC [2014]† No designation

ACGIH [2001] No designation

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

Health and Consumer Protection; 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 rather than 

dermal exposure.

†

Date accessed.
4 Skin Notation Profiles | Methyl isocyanate

Methyl isocyanate

basis of the data for this assessment, MIC is 

assigned the SK: DIR (COR) notation. 

4 Immune-mediated 

Responses (SK: SEN)

No human reports were identified that suggest that MIC is a skin sensitizer. However, 

skin sensitization studies in guinea pigs demonstrate that the chemical is a skin sensitizer. 

The Mellon Institute [1963, 1970] reported 

that MIC was a confirmed sensitizing agent 

in 16 of 16 guinea pigs following an intradermal sensitization test that involved injection 

of 0.05 mL of a 0.01% solution in peanut oil 

followed by a series of seven 0.1 mL sensitizing injections. E.I. du Pont de Nemours and 

Company [1968] reported allergic dermatitis 

in 9 of 10 guinea pigs challenged with 5-25% 

MIC in a 1:1 solution of acetone and dioxane containing 13% guinea pig fat on intact 

and abraded skin. Five animals received nine 

applications of 5% to 25% MIC in guinea 

pig fat on abraded skin during a three-week 

period and the remaining five received two 

intradermal dermal injections of 1% MIC 

in dimethyl phthalate seven days apart [E.I. 

du Pont de Nemours and Company 1968]. 

Although the Mellon Institute [1963, 1970] 

observed no cross-sensitization in guinea pigs 

that were previously sensitized with toluene 

diisocyanate (TDI), Union Carbide Corporation [1987] reported that 7 of 20 guinea pigs 

produced positive reactions when the animals 

were previously sensitized intradermally with 

8 applications of MIC followed by a challenge 

with intradermal injections of TDI. In a similar study, cross-sensitization was observed in 

15 of 16 guinea pigs that received intradermal 

injections of TDI followed by an intradermal 

challenge with MIC [Union Carbide Corporation 1987]. Supplemental support for the 

occurrence of cross-sensitization was noted 

for both TDI and MIC following repeated 

intranasal instillations of TDI only [Svesson 

et al. 2009]. DEREK predicted MIC to be a 

plausible skin sensitizer.

Although no diagnostic human patch tests 

were identified that assessed the potential of 

MIC to be a skin sensitizer in humans, isocyanates are known to cause occupation-related 

allergic contact dermatitis and respiratory 

sensitization. Sufficient data were identified 

from predictive tests in guinea pigs [Mellon Institute 1963, 1970; E.I. du Pont de 

Nemours and Company 1968; Union Carbide Corporation 1987], supported by results 

from a modeling prediction, to conclude that 

MIC induces skin sensitization and can crossreact with other isocyanates. Therefore, on the 

basis of the data for this assessment, MIC is 

assigned the SK: SEN notation. 

5 Summary

Toxicokinetic studies that evaluated the potential of MIC to be absorbed through the 

skin following dermal exposure were not 

identified. However, predictions from a mathematical model indicate that MIC has the potential to be absorbed through the skin. The 

dermal absorption potential of the chemical 

is supported by several acute dermal toxicity 

studies in animals [Mellon Institute 1963, 

1970; Smyth et al. 1969; Vernot et al. 1977; 

Eastman Kodak Company 1990] that show 

that the chemical is acutely toxic. No case 

reports of skin effects resulting from dermal 

exposure to MIC were identified. However, 

several skin irritation studies in rabbits and 

guinea pigs [Mellon Institute 1963; E.I. 

du Pont de Nemours and Company 1968; 

Smyth et al. 1969; Dow Chemical Company 

1990; Eastman Kodak 1990] demonstrate 

that MIC produces skin damage and is corrosive in undiluted or very concentrated form, 

while weaker concentrations produce skin irritation. No diagnostic human patch tests 

were identified that assessed the potential of 

MIC to be a skin sensitizer in humans. However, isocyanates generally are known to cause 

occupation-related allergic contact dermatitis 

and respiratory sensitization. The potential 

to cause skin sensitization and to cross-react 

with related isocyanates is demonstrated by 
Skin Notation Profiles | Methyl isocyanate 5

Methyl isocyanate

several predictive tests in guinea pigs [Mellon Institute 1963; E.I. du Pont de Nemours 

and Company 1968; Union Carbide Corporation 1987], supported by results from a 

modeling prediction. Based on the available 

data, this assessment concludes that there 

are sufficient data in animals to demonstrate 

that MIC is absorbed through the skin, is 

acutely toxic, is corrosive to the skin and can 

cause skin sensitization and cross-reactivity 

with other isocyanates. Therefore, on the basis of these assessments, MIC is assigned a 

composite skin notation of SK: SYS-DIR 

(COR)-SEN. 

Table 3 summarizes the skin hazard designations for MIC previously issued by NIOSH 

and other organizations. The equivalent dermal designations for MIC, according to the 

Global Harmonization System (GHS) of 

Classification and Labelling of Chemicals, are 

Acute Toxicity Category 3 (Hazard statement: 

Toxic in contact with the skin), Skin Irritation 

Category 2 (Hazard statement: Causes skin 

irritation), and Skin Sensitization Category 

1 (Hazard statement: May cause an allergic 

skin reaction) [European Parliament 2008]. 

In addition, MIC is identified as a Category 

2 Reproductive Toxicant (Hazard statement: 

Suspected of damaging the unborn child.) 

[European Parliament 2008]. 

References

ACGIH (American Conference of Governmental Industrial Hygienists) [2001]. Methyl isocyanate. In: Documentation of threshold limit 

values and biological exposure indices. 7th ed., 

Vol. 1. Cincinnati, OH: American Conference 

of Governmental Industrial Hygienists.

Bhandari NR, Syal AK, Kambo I, nair A, Beohar 

V, Sexena NC, Dabke AT, Agarwal, SS, Saxena BN [1990]. Pregnancy outcome survey in 

women exposed to toxic gas at Bhopal. Indian J 

Med Res 92:28–33.

Dhara VR, Dhara R [2002]. The Union Carbide 

disaster in Bhopal: A review of health effects. 

Arch Environ Health 57(5):391–404.

Dow Chemical Company [1990]. Results of range 

finding toxicological tests on methyl isocyanate. 

Midland, MI: Dow Chemical Company, Biochemical Research Laboratory. On file with the 

U.S. Environmental Protection Agency under 

TSCA Section 8D. OTS #0530132. Document 

# 86-910000361S.

E.I. du Pont de Nemours and Company [1968]. 

Dermal irritation and sensitization tests of 

methyl isocyanate in guinea pigs. E.I. du Pont 

de Nemours and Company. On file with the 

U.S. Environmental Protection Agency under 

TSCA Section 8D. OTS #0571239. Document 

# 88-920009582.

Eastman Kodak Company [1990]. Health and 

safety study on methyl isocyanate. Rochester, 

NY: Eastman Kodak Company. On file with the 

U.S. Environmental Protection Agency under 

Table 3. Summary of previous skin hazard designations for MIC

Organization Skin hazard designation

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

OSHA [2014]* [skin]: Potential for dermal absorption

ACGIH [2001] [skin]: Based on the reported mortality in rabbits following topical 

application and absorption of MIC.

EC [2014]* R24: Toxic in contact with skin

R38: Irritating to skin

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.
6 Skin Notation Profiles | Methyl isocyanate

Methyl isocyanate

TSCA Section 8D. OTS #0528350. Document 

# 86-910000056.

EC (European Commission) [ND]. Methyl isocyanate. In: EINICS (European Inventory of 

Existing Commercial Chemical Substances), 

http://esis.jrc.ec.europa.eu/. Accessed: 05-01-14. 

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: 05-01-14. 

IARC (International Agency for Research on 

Cancer) [2007]. Agents reviewed by the 

IARC monographs. In: IARC monographs 

on the evaluation of carcinogenic risks to humans, http://monographs.iarc.fr/ENG/Classification/Listagentsalphorder.pdf. Accessed: 

05-01-14.

Mellon Institute [1963]. Range finding tests on 

methyl isocyanate. Pittsburgh: Mellon Institute 

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U.S. Environmental Protection Agency under 

TSCA Section 8D. OTS #0529151. Document 

#86-910000658D.

Mellon Institute [1970]. Methyl isocyanate: acute 

inhalation toxicity, human response to low concentrations, guinea pig sensitization, and cross 

sensitization to other isocyanates. Pittsburgh: 

Mellon Institute Confidential Special Report 

33-19 for Union Carbide Corporation. On file 

with the U.S. Environmental Protection Agency under TSCA Section 8D. OTS #0528500. 

Document #86-910000268.

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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: 05-01-14.

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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: 05-01-14.

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Edition; U.S. Department of Health and Human Services, Public Health Service. National Toxicology Program, http://ntp.niehs.

nih.gov/ntp/roc/twelfth/roc12.pdf. Accessed 

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Skin Notation Profiles | Methyl isocyanate 7

Methyl isocyanate

Appendix: Calculation of the SI Ratio for MIC

This appendix presents an overview of the 

SI ratio and a summary of the calculation of 

the SI ratio for MIC. 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 (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 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 k

p

 for the substance to describe the 

transdermal penetration rate of the substance 

[NIOSH 2009]. The 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 KOW). 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 outlined in Table A1. Other 

model-based estimates of k

p

 may also be used 

[NIOSH 2009].

Equation 1: Calculation of Skin Permeation 

Coefficient (k

p

)

psc pol aq

p

k k k

k 1 1

1

+

+

=

Where K

psc 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

× MW 0.5

kpol = 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. 
8 Skin Notation Profiles | Methyl isocyanate

Methyl isocyanate

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 

square centimeters [cm2]). 

Equation 2: Determination of Skin Dose 

Skin dose 

= k

p

 × Sw × Exposed skin surface area × 

Exposure time

= k

p

(cm/hour) × Sw (mg/cm3) × 360 cm2

× 8 hours

The inhalation dose (in mg) is derived on 

the basis of the occupational exposure limit 

(OEL) of the substance—if the OEL is developed to prevent the occurrence of systemic 

effects rather than sensory/irritant effects or 

direct effects on the respiratory tract. Assume 

a continuous exposure of 8 hours, an inhalation volume of 10 cubic meters (m3

) inhaled 

air in 8 hours, and a factor of 75% for retention of the airborne substance in the lungs 

during respiration (retention factor, or RF).

Equation 3: Determination of Inhalation Dose

Inhalation dose = OEL × Inhalation 

volume × RF

= OEL (mg/m3) × 10 m3

× 0.75

The final step is to compare the calculated 

skin and inhalation doses and to present the 

result as a ratio of skin dose to inhalation dose 

(the SI ratio). This ratio quantitatively indicates (1) the significance of dermal absorption as a route of occupational exposure to the 

substance and (2) the contribution of dermal 

uptake to systemic toxicity. If a substance has 

an SI ratio greater than or equal to 0.1, it is 

considered a skin absorption hazard.

Calculation 

Table A1 summarizes the data applied in the 

previously described equations to determine 

the SI ratio for MIC. The calculated SI ratio 

was ~3.7. On the basis of these results, MIC is 

predicted to represent a skin absorption hazard.

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: 05-01-14. 

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: 05-01-14.

SRC [2009]. Interactive PhysProp database demo, 

http://www.srcinc.com/what-we-do/databaseforms.aspx?id=386. Accessed: 05-01-14.
Skin Notation Profiles | Methyl isocyanate 9

Methyl isocyanate

Table A1. Summary of data used to calculate the SI ratio for MIC 

Variables used in calculation Units Value

Skin permeation coefficient

Permeation coefficient of stratum corneum lipid path(kpsc) cm/hr 6.4072 × 10-3

Permeation coefficient of the protein fraction of the stratum corneum (kpol)cm/hr 2.0111 × 10-5

Permeation coefficient of the watery epidermal layer (kaq) cm/hr 0.331

Molecular weight (MW)* amu 57.1

Base-10 logarithm of its octanol–water partition coefficient (Log 

Kow)

*

None 0.79

Calculated skin permeation coefficient (kp) cm/hr 6.3049 × 10-3

Skin dose

Water solubility (Sw)

* mg/cm3 29.2

Calculated skin permeation coefficient (kp) cm/hr 6.3049 × 10-3

Estimated skin surface area (palms of hand) cm2 360

Exposure time hr 8

Calculated skin dose mg 530.22

Inhalation dose

Occupational exposure limit (OEL)† mg/m3 0.05

Inhalation volume m3 10

Retention factor (RF) None 0.75

Inhalation dose mg 144

Skin dose–to–inhalation dose (SI) ratio None 3.68

*Variables identified from SRC [2009].

†

The OEL used in calculation of the SI ratio for MIC was the NIOSH recommended exposure limit (REL) of 1 part per million 

(5 mg/m3) [NIOSH 2005].
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