NIOSH Skin Notation (SK) Profiles

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Disease Control and Prevention

National Institute for Occupational Safety and Health

Isophorone Diisocyanate

[CAS No. 4098-71-9]
ii Skin Notation Profiles | Isophorone Diisocyanate

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Suggested Citation

NIOSH [2014]. NIOSH skin notation profiles: isophorone diisocyanate. 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. 2014-148.

DHHS (NIOSH) Publication No. 2014-148

August 2014

Safer • Healthier • PeopleTM
Skin Notation Profiles | Isophorone Diisocyanate 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 immunemediated 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 isophorone diisocyanate (IPDI). 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 

interest.

John Howard, M.D.

Director, National Institute for 

 Occupational Safety and Health

Centers for Disease Control and Prevention
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Skin Notation Profiles | Isophorone Diisocyanate 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 IPDI . . . . . . . . . . . . . . . . . . . . . . . . . . 8

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

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

Appendix References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
vi Skin Notation Profiles | Isophorone Diisocyanate

Abbreviations

ACGIH American Conference of Governmental Industrial Hygienists 

CIB Current Intelligence Bulletin

cm2 square centimeter(s)

cm/hour centimeter(s) per hour

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 

FCAT Freund’s complete adjuvant 

GHS Globally Harmonized System for Classification and Labelling of Chemicals

GPMT guinea pig maximization test

IARC International Agency for Research on Cancer

IPDI isophorone diisocyanate

(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

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

m3 cubic meter(s)

MEST mouse ear swelling test 

mg milligram(s)

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

mM millimole(s)

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
Skin Notation Profiles | Isophorone Diisocyanate vii

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

SYS skin notation indicating the potential for systemic toxicity following

 exposure of the skin

USEPA United States Environmental Protection Agency 

μL microliter(s) 
viii Skin Notation Profiles | Isophorone Diisocyanate

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 | Isophorone Diisocyanate 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 Vic Johnson, 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

H. Fredrick Frasch, 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 | Isophorone Diisocyanate

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:

Frank A Barile, Ph.D., St. John’s University, College of Pharmacy, Queens, NY

Phillip L. Williams, Ph.D., CIH, The University of Georgia, College of Public Health, 

Athens, GA

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 | Isophorone Diisocyanate 1

Isophorone Diisocyanate

Chemical: Isophorone Diisocyanate

CAS No: 4098-71-9

Molecular weight (MW): 222.3

Molecular formula: C12H18N2O2

Structural formula:

Synonyms:

Isophorone diisocyanate; 3-Isocyanatomethyl-3,5,5-trimethylcyclohexyl-isocyanate; Isophorone diamine diisocyanate; 

IPDI

Uses:

Isophorone diisocyanate (IPDI) is primarily used as a chemical intermediate 

during the production of polyurethanes 

paints and varnishes [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 IPDI 

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

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 IPDI. A literature search 

was conducted through May 2014 to identify information on IPDI, 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 IPDI. 

1.3 Overview of SK Assignment

IPDI 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 IPDI: SK: DIR (IRR)-

SEN. Table 1 provides an overview of the 

critical effects and data used to develop 

the SK assignment for IPDI. 

2 Systemic Toxicity from Skin 

Exposure (SK: SYS)

No toxicokinetic studies following dermal 

exposure to IPDI in humans or animals were 

identified. No reports of death or other systemic toxicity following dermal absorption 
2 Skin Notation Profiles | Isophorone Diisocyanate

Isophorone Diisocyanate

were identified in humans. Acute dermal toxicity studies identified also are inconclusive 

with regard to the potential of IPDI to be 

acutely toxic. Bello et al. [2008a] found polymeric IPDI was detectable in 89% of people 

wearing gloves (most typically latex gloves) 

during spraying with a maximum value of 

12.2 nanograms polymeric IPDI that was 

collected under gloves. In another study, Bello 

et al. [2008b] applied 30 microliters (μL) of 

isocyanates diluted in ethyl acetate over an 

area of 5 square centimeters (cm2) to guinea 

pig skin. The results indicated that the polymer form of IPDI remained on the skin longer than methyl diisocyanate [Bello 2008].

The potential of IPDI 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 12.3 was calculated for IPDI. An 

SI ratio of ≥0.1 indicates that skin absorption 

may significantly contribute to the overall 

body burden of a substance [NIOSH 2009]; 

therefore, IPDI is considered to be absorbed 

through the skin following dermal exposure. 

Additional information on the SI ratio and 

the variables used in its calculation are included in the appendix. 

No dermal lethal doses (LDLos) of IPDI for 

humans have been identified. The dermal 

LD50 value (the dose resulting in 50% mortality in the exposed animals) was 4.52 milliliters 

per kilogram (mL/kg) [corresponding to 4800 

mg/kg] in rabbits [Mellon Institute 1967]. 

IPDI was applied as a 50% solution to 2-3 

cm2 of the shaved abdomens and backs of rats, 

and an LD50 of 1 mL/kg [corresponding to 

1062 mg/kg] was reported following 4 hours 

of exposure and an LD50 of 0.5 mL/kg [corresponding to 531 mg/kg] was reported follwing 

7 days of exposure [Farbenfabriken Bayer AG 

1968]. However, a report by Hüls A.G. [1989] 

reported an LD50 of greater than 7000 mg/kg 

in rats. Because the conflicting reports in rats 

and the high dermal LD50 value reported in 

rabbits is higher 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], IPDI 

is not considered acutely toxic following dermal exposure.

No epidemiological studies or case reports of 

systemic effects produced by dermal exposure 

were identified. No repeat-dose, sub-chronic, 

or chronic studies following dermal exposure 

to IPDI were identified in humans or animals. 

No standard toxicity or specialty studies evaluating biological system/function specific effects 

(including reproductive and developmental effects) following dermal exposure to IPDI were 

identified. No studies evaluating the carcinogenic potential dermal exposure to IPDI were 

identified. Table 2 summarizes carcinogenic 

designations of multiple governmental and 

nongovernmental organizations for IPDI. 

No toxicokinetic studies following dermal 

exposure to IPDI were identified. However, 

a predictive mathematical model (see Appendix) indicates that the chemical can be absorbed through the skin. Conflicting data in 

acute toxicity studies [Farbenfabriken Bayer 

AG 1968; Hüls A.G. 1989] and the lack of 

epidemiological studies in humans, repeat 

dose, sub-chronic, and chronic toxicity studies in animals precludes adequate evaluation 

Table 1. Summary of the SK assignment for IPDI

Skin notation Critical effect Data available

SK: DIR (IRR) Skin irritation Sufficient animal data

SK: SEN Skin allergy Sufficient human and animal data
Skin Notation Profiles | Isophorone Diisocyanate 3

Isophorone Diisocyanate

of the potential for IPDI to cause systemic 

health effects. Therefore, on the basis of the 

data for this assessment, IPDI is not assigned the SK: SYS notation.

3 Direct Effects on Skin

(SK: DIR)

No human or animal in vivo studies for 

corrosivity of IPDI or in vitro tests for corrosivity using human skin models or in vitro

tests of skin integrity using cadaver skin were 

identified. Evidence of the corrosivity of IPDI 

is limited to a single study involving a single 

rabbit in which 500 μL IPDI (99% pure) was 

corrosive when applied to 1 cm2 of the skin 

under occlusion [Bayer AG Farbenfabriken 

Toxikologie 1994]. No studies evaluating 

the skin irritating potential of the substance 

were identified in humans. However, a limited number of animal studies were identified. 

Stem [1989] conducted a primary irritancy 

study using mice and concentrations of IPDI 

ranging from 0.1 to 30.0%. Following being 

shaved and abraded, the back was treated for 

5 consecutive days with IPDI. The author reported that that 1.0% IPDI was the minimum 

concentration necessary to produce irritation 

in mice and that treatment with 3.0% IPDI 

resulted in an irritation response nearly twice 

as severe [Stern 1989]. Guinea pigs were topically administered 30–300 millimoles (mM) 

[corresponding to 6669–66690 mg] IPDI in 

olive oil in a volume of 30μL under gauze 

patch occlusion for 6 hours. Erythema was 

observed 24 hours post IPDI chemical application for the 100mM and 300 mM treatment 

groups [Bio/dynamics Inc. 1984]. The structure activity relationship model, Deductive 

Estimation of Risk from Existing Knowledge 

(DEREK), predicted IPDI to be negative for 

skin irritation.

Use of a single rabbit in the skin corrosivity 

study conducted by Bayer Corp. [1994] precludes adequate evaluation of the potential 

of IPDI to be corrosive to the skin of rabbits. However, data from the primary irritancy studies [Bio/dynamics Inc. 1984; Stern 

1989; Bayer AG Farbenfabriken Toxikologie 

1994]* sufficiently demonstrate that IPDI is a 

skin irritant. Therefore, on the basis of the data 

for this assessment, IPDI is assigned the SK: 

DIR (IRR) notation. 

* References in bold text indicate studies that serve 

as the basis of the SK assignments.

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

governmental and nongovernmental organizations

Organization Carcinogenic designation

NIOSH [2005] No designation

NTP [2011] No designation

US EPA [2014] No designation

European Parliament [2008] No designation

IARC [2012] 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 | Isophorone Diisocyanate

Isophorone Diisocyanate

4 Immune-mediated 

Responses (SK: SEN)

Skin sensitization induced by dermal exposure 

to IPDI has been well-documented in humans and animals. Over a period of 13 years, 

345 people who were examined for suspected 

occupational skin diseases were tested for allergy to isocyanate monomers, and of these 9 

had positive reactions to IPDI [Aalto-Korte 

et al. 2012]. IPDI was shown to provoke allergic dermatitis in four sensitized workers patch tested with 1% of the substance in 

ethanol [Lachapelle and Lachapelle-Ketelaer 

1979]. Militello et al. [2004] described two 

sculptors who presented with allergic contact 

dermatitis, both of whom showed positive reactions when patch tested with 1% IPDI in 

petroleum. In another study, positive reactions 

were reported in 4 of 17 factory workers that 

presented with eczema and were patch tested 

with IPDI [Frick et al. 2003]. 

The potential of IPDI to elicit contact hypersensitivity was also assessed in animals. Zissu 

et al. [1998] reported a sensitization grade of 

IV in Buehler tests in guinea pigs administered 0.5 mL of 5% IPDI solution. In a study 

conducted by the Bio/dynamics Inc. [1984] 

IPDI exhibited the potential to produce dermal sensitization in guinea pigs. Ciba Geigy 

Limited [1984] conducted a challenge test in 

which two intradermal induction of 0.1 mL 

were followed by application of 0.4g of a 3% 

IPDI solution to the skin of guinea pigs in 

vaseline. The authors observed positive erythema and edema reactions in 95% of the 

animals. In a mouse ear swelling test (MEST) 

[NTP 1987; Stern et al 1989], female mice 

were sensitized dermally to either 0, 0.1%, 

0.3%, or 1.0% solutions of IPDI daily for 5 

consecutive days and challenged 7 days later 

with a 3.0% solution. Some mice received an 

additional intradermal injection of Freund’s 

complete adjuvant (FCAT). Statistically significant hypersensitivity was observed in mice 

when administered a 1.0% sensitizing concentration and a challenge concentration of 3.0%, 

with or without pretreatment with FCAT 

[Stern et al. 1989]. Plitnick et al. [2005] used 

the ribonuclease protection assay (RPA) to 

detect increases in the Th2 cytokine mRNA 

and conducted murine local lymph node assays (LLNA) on IPDI and several other isocyanates. Mice exposed to IPDI had elevated 

Th2 cytokines indicating that IPDI could be 

a respiratory sensitizer, and results from the 

LLNA indicate that 2% IPDI provoked a 

stimulation index of 50 [Plitnick et al. 2005]. 

A substance with a stimulation index greater 

than or equal to 3 is considered a sensitizer 

[NIOSH 2009]. In a later study, Selgrade et 

al. [2006] conducted a LLNA and also reported that 2% IPDI provoked a stimulation index 

of 50, indicating IPDI is a skin sensitizer. A 

similar stimulation index was earlier reported in mice by Dearman et al. [1992a]. Skin 

sensitization was also seen in mice topically 

treated with 0.05 to 2.5% IPDI administered 

in acetone:olive oil (4:1, weight/volume basis) 

[Dearman et al. 1992b]. DEREK predicted 

IPDI to be a plausible skin sensitizer.

Based on positive responses from patch testing in humans [Lachapelle and LachapelleKetelaer 1979; Frick et al. 2003; Militello et 

al. 2004; Aalto-Korte et al. 2012] and results 

from sensitization tests in guinea pigs [Bio/

dynamics Inc. 1984; Ciba Geigy Limited 

1984], Buehler test [Zissu et al. 1998],MEST

[NTP 1987; Stern et al 1989] and LLNA 

[Dearman et al. 1992a, 1992b; Plitnick et al. 

2005; Selgrade et al. 2006], sufficient data exist to conclude that IPDI is a skin sensitizer 

in both humans and animals. Therefore, on the 

basis of the data for this assessment, IPDI is 

assigned the SK: SEN notation. 

5 Summary

Toxicokinetic studies that evaluated the 

potential of IPDI to be absorbed through 

the skin following dermal exposure were not 

identified. However, predictions from a mathematical model indicate that IPDI has the 

potential to be absorbed through the skin (see 

Appendix). Conflicting data in acute toxicity 

studies [Farbenfabriken Bayer AG 1968; Hüls 
Skin Notation Profiles | Isophorone Diisocyanate 5

Isophorone Diisocyanate

A.G. 1989] and the lack of epidemiological 

studies in humans, repeat dose, sub-chronic, 

and chronic toxicity studies in animals precludes adequate evaluation of the potential for 

IPDI to cause systemic health effects. Skin irritation studies in rabbits and mice [Bio/

dynamics Inc. 1984; Stern 1989; Bayer 

AG Farbenfabriken Toxikologie 1994] indicate that IPDI can be irritating to the skin. 

Positive responses from patch testing in humans [Lachapelle and Lachapelle-Ketelaer 

1979; Frick et al. 2003; Militello et al. 2004; 

Aalto-Korte et al. 2012] and results from 

the Buehler test [Zissu et al. 1998], MEST

[NTP 1987; Stern et al 1989] and LLNA 

[Dearman et al. 1992a, 1992b; Plitnick et 

al. 2005; Selgrade et al. 2006], provide sufficient evidence that IPDI has the potential 

to cause sensitization of the skin. Therefore, 

on the basis of these assessments, IPDI is assigned a composite skin notation of SK: DIR 

(IRR)-SEN. 

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

and other organizations. The equivalent dermal 

designations for IPDI, according to the Global 

Harmonization System (GHS) of Classification and Labelling of Chemicals, are 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]. 

References

Note: Asterisks (*) denote sources cited in 

text; daggers (†) denote additional resources.

*Aalto-Korte K, Suuronen K, Kuuliala O, Henriks-Eckerman M [2012]. Occupational contact allergy to monomeric isocyanates. Contact 

Dermatitis 67:78–88.

*ACGIH (American Conference of Governmental Industrial Hygienists) [2001]. Isophorone 

diisocyanate. In: Documentation of threshold 

limit values and biological exposure indices 7th 

ed., Vol. 2. Cincinnati, OH: American Conference of Governmental Industrial Hygienists.

*Bayer AG Fachbereich Toxikologie [1994]. Isophorondiisocyanat: study for skin irritation/corrosion 

in rabbits. Bayer AG Fachbereich Toxikologie, report #22961. On file with the U.S. Environmental Protection Agency under TSCA Section 8D. 

OTS #0558207. Document #86960000067.

*Bello D, Redlich CA, Stowe MH, Sparer J, 

Woskie SR, Streicher RP, Hosgood HD, Liu 

Y [2008a]. Skin exposure to aliphatic polyisocyanates in the auto body repair and refinishing 

industry: II. A quantitative assessment. Ann 

Occup Hyg 52(2):117–124.

*Bello D, Smith TJ, Woskie SR, Streicher RP, 

Boeniger MF, Redlich CA, Liu Y [2008b]. An 

FTIR investigation of isocyanate skin absorption using in vitro guinea pig skin. J Enviorn 

Monit 8:523–529.

*Bio/dynamics Inc. [1984]. A closed-patch repeated insult dermal sensitization study in 

guinea pigs with TDI, MDI, p-TMXDI, IPDI, 

m-TMXDI, HMDI, and m-TMI (modified 

Buehler method). Bio/Dynamics Inc., Project 

 Table 3. Summary of previous skin hazard designations for IPDI

Organization Skin hazard designation

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

OSHA [2014]* No designation

ACGIH [2001] No designation

EC [2014]* 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 | Isophorone Diisocyanate

Isophorone Diisocyanate

#4971-84, report to American Cyanamid Company. On file with the U.S. Environmental Protection Agency under TSCA Section 8D. OTS 

#0515234. Document #86-870000795.

*Ciba-Geigy Limited [1984]. Report on skin sensitizing (contact allergenic) effect in guinea pigs: 

maximization test. Ciba-Geigy Limited, test 

#840461. On file with the U.S. Environmental 

Protection Agency under TSCA Section 8D. 

OTS #0555059. Document #88-920008241. 

*Dearman RJ, Basketter DA, Kimber I [1992a]. 

Variable effects of chemical allergens on serum concentration in mice. Preliminary evaluation of a novel approach to the identification of respiratory sensitizer. J Appl Toxicol 

12(5):317–323.

*Dearman RJ, Spence LM, Kimber I [1992b]. 

Characterization of murine immune responses 

to allergenic diisocyanates. Toxicol Appl Pharmacol 112(2):190–197. 

*EC (European Commission) [ND]. 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl 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, labeling 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://eurex.europa.eu/

LexUriServ/LexUriServ.do?uri=OJ:L:2008:35

3:0001:1355:EN:PDF. Accessed: 05-01-14. 

*Farbenfabriken Bayer AG [1968]. Isophorone 

diisocyannate toxicological studies. Farbenfabriken Bayer AG, Report #908. On file with the 

U.S. Environmental Protection Agency under 

TSCA Section 8D. OTS #0528418. Document 

#86-910000186.

*Frick M, Björkner B, Hamnerius N, Zimerson E 

[2003]. Allergic contact dermatitis from dicyclohexylmethane-4,4’-diisocyanate. Contact Dermatitis 48(6):305–309.

*HÜls AG [1989]. Letter from Hüls America 

Inc. to US EPA submitting German study 

on isophorone diisocyanate with attachment. 

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

#0530238. Document # 86-910000492.

*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: 05-01-14.

*Lachapelle JM, Lachapelle-Ketelaer MJ [1979]. 

Cross-sensitivity between isophorone diamine 

(IDP) and isophorone diisocyanate (IPDI). 

Contact Dermatitis 5:55. 

*Mellon Institute [1967]. Range finding toxicity 

studies of isophorone diisocyanate. Mellon Institute, report for Union Carbide Corporation. 

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

#0515604. Document #86-870001442.

*Militello G, Sasseville D, Ditre C, Brod BA 

[2004]. Allergic contact dermatitis from isocyanates among sculptors. Dermatitis 15:150–153.

*NIOSH [2005]. Isophorone Diisocyanate. In: 

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.

*NTP [2011]. Report on Carcinogens. Twelfth 

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 05-01-14.

*OSHA [ND]. Isophorone diisocyanate. In: 

OSHA occupational chemical database, http://

www.osha.gov/chemicaldata/chemResult.

html?recNo=369. Accessed: 05-01-14.

*Plitnick LM, Loveless SE, Ladics GS, Holsapple 

MP, Smialowicz RJ, Woolhiser MR, Anderson 

PK, Smith C, Selgrade MJ [2005]. Cytokine 

mRNA profiles for isocyanates with known and 

unknown potential to induce respiratory sensitization. Toxicology 207(3):487–499.

*Selgrade MK, Boykin EH, Haykal-Coates N, Woolhiser MR, Wiescinski C, Andrews DL, Farraj AK, 

Doerfler DL, Gavett SH [2006]. Inconsistencies 

between cytokine profiles, antibody responses, and 

respiratory hyperresponsiveness following dermal 
Skin Notation Profiles | Isophorone Diisocyanate 7

Isophorone Diisocyanate

exposure to isocyanates. Toxicological Sciences 

94:108–117.

*Stern ML, Brown TA, Brown RD, Munson AE 

[1989]. Contact hypersensitivity response to 

isophorone diisocyanate in mice. Drug Chem 

Toxicol 12(3–4):287–296.

†USEPA (United States Environmental Protection 

Agency) [1981]. The evaluation of isophorone 

diisocyanate for primary skin irritation in rabbits with cover letter dated 07/29/87, Doc-No. 

86-870001244. Washington DC: US Environmental Protection Agency. 11 S.

†USEPA [1987]. A closed-patch repeated insult 

dermal sensitization in guinea pigs with TDI, 

MDI, P-TMXDI, IPDI, m-TMXDI, HMDI 

and m-TMI (modified Buehler method) with 

cover letter (08/03/87), Project No. 4971-84, 

Doc-No. 86-870000795. Washington DC.

†USEPA [1987]. Range finding toxicity studies of isophorone diisocyanate, Doc-No. 86-

870001442. Washington DC: US Environmental Protection Agency, 922–926.

*USEPA [2014]. Integrated Risk Information 

System (IRIS). http://www.epa.gov/ncea/iris/. 

Accessed: 05-01-14.

*Zissu D, Binet S, Limasset JC [1998]. Cutaneous sensitization to some polyisocyanate prepolymers in guinea pigs. Contact Dermatitis 

39:248–251.
8 Skin Notation Profiles | Isophorone Diisocyanate

Isophorone Diisocyanate

Appendix: Calculation of the SI Ratio for IPDI

This appendix presents an overview of the 

SI ratio and a summary of the calculation of 

the SI ratio for IPDI. 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 k

psc = −1.326 + 0.6097 × log Kow − 

0.1786 × MW0.5

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 
Skin Notation Profiles | Isophorone Diisocyanate 9

Isophorone Diisocyanate

dose) during the same period of exposure. 

The skin dose is calculated as a mathematical 

product of the k

p

, 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 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 IPDI. The calculated SI ratio 

was 12.3. On the basis of these results, IPDI 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.
Table A1. Summary of data used to calculate the SI ratio for IPDI 

Variables used in calculation Units Value

Skin permeation coefficient

Permeation coefficient of stratum corneum lipid path(k

psc) cm/hr 8.077 × 10-2

Permeation coefficient of the protein fraction of the stratum 

corneum (kpol)

cm/hr 1.1019 × 10-5

Permeation coefficient of the watery epidermal layer (kaq) cm/hr 0.1677 

Molecular weight (MW)

* amu 222.29

Base-10 logarithm of its octanol–water partition coefficient 

(Log Kow)

*

None 4.75

Calculated skin permeation coefficient (k

p

) cm/hr 5.452 × 10-2

Skin dose

Water solubility (Sw)* mg/cm3 2.93 × 10-3

Calculated skin permeation coefficient (k

p

) cm/hr

Estimated skin surface area (palms of hand) cm2 360

Exposure time hr 8

Calculated skin dose mg 0.4601

Inhalation dose

Occupational exposure limit (OEL)† mg/m3 0.005

Inhalation volume m3 10

Retention factor (RF) None 0.75

Inhalation dose mg 3.75 × 10-2

Skin dose–to–inhalation dose (SI) ratio None 12.3

*

Variables identified from SRC [2009].

†

The OEL used in calculation of the SI ratio for IPDI was the NIOSH recommended exposure limit (REL) [NIOSH 2005].
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