# 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 

## This document is in the public domain and may be freely copied or reprinted.



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# Suggested Citation NIOSH [2014]. NIOSH skin notation profiles: isophorone diisocyanate. By Hudson NL, Dot

son GS. Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Dis

ease 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 • PeopleTMSkin 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 contrib

ute 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 re

sponses (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 pro

grams. In 2009, the National Institute for Occupational Safety and Health (NIOSH) pub

lished 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) thatclearly distinguish between the systemic effects, direct (localized) effects, and immunemediated responses caused by skin contact with chemicals. The key step within as

signment 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 ana

lytical or numerical methods. This Skin Notation Profile provides the SK assignments and supportive data for isopho

rone 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 po

tentially 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 PreventionSkin 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

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

# Abbreviations
ACGIH American Conference of Governmental Industrial Hygienists CIB Current Intelligence Bulletin

cm 2 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 G lobally Harmonized System for Classification and Labelling of Chemicals GPMT guinea pig maximization test IARC International Agency for Research on Cancer IPDI i sophorone 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 k pol coefficient in the protein fraction of the stratum corneum k psc permeation coefficient in the lipid fraction of the stratum corneum LD 50 dose resulting in 50% mortality in the exposed population LD Lo dermal lethal dose LLNA local lymph node assay LOAEL lowest-observed-adverse-effect level log K OW base-10 logarithm of a substance’s octanol–water partition M molarity

m 3 cubic meter(s) MEST mouse ear swelling test mg milligram(s) mg/kg milligram(s) per kilogram body weight mg/m 3 milligram(s) per cubic meter mL milliliter(s) mL/kg milliliter(s) per kilogram body weight 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 AdministrationSkin 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 S W 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 expo

sure 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 acknowl

edgment 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 acknowl

edgment 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 inde

pendent, 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, OHSkin Notation Profiles | Isophorone Diisocyanate 1 

### Chemical: Isophorone Diisocyanate CAS No: 4098-71-9 Molecular weight ( MW ): 222.3 Molecular formula: C 12 

### H 18 

### N 2 

### O 2 

### Structural formula: Synonyms: Isophorone diisocyanate; 3-Isocyanato

methyl-3,5,5-trimethylcyclohexyl-isocy

anate; Isophorone diamine diisocyanate; IPDI Uses: Isophorone diisocyanate (IPDI) is pri

marily 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-spe

cific skin notation (SK) assignment for IPDI. The SK assignment is based on the scientific rationale and logic outlined in the Current In

telligence Bulletin (CIB) 61: A Strategy for As

signing 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 iden

tify 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 rel

evant to assessing the effects of dermal expo

sure to IPDI.


## 1.3 Overview of SK Assignment IPDI is potentially capable of causing nu

merous adverse health effects following skin contact. A critical review of avail

able 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 sys

temic toxicity following dermal absorption2 Skin Notation Profiles | Isophorone Diisocyanate were identified in humans. Acute dermal tox

icity studies identified also are inconclusive with regard to the potential of IPDI to be acutely toxic. Bello et al. [2008a] found poly

meric 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 (cm 2 ) to guinea pig skin. The results indicated that the poly

mer form of IPDI remained on the skin lon

ger than methyl diisocyanate [Bello 2008]. The potential of IPDI to pose a skin absorp

tion hazard was also evaluated, with use of a predictive algorithm for estimating and evalu

ating the health hazards of dermal exposure to substances [NIOSH 2009]. The evaluation method compares an estimated dose accumu

lated in the body from skin absorption and an estimated dose from respiratory absorption associated with a reference occupational ex

posure 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 includ

ed in the appendix. No dermal lethal doses (LD Lo s) of IPDI for humans have been identified. The dermal LD 50 value (the dose resulting in 50% mortal

ity 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
cm 2 of the shaved abdomens and backs of rats, and an LD 50 of 1 mL/kg [corresponding to 1062 mg/kg] was reported following 4 hours of exposure and an LD 50 of 0.5 mL/kg [corre

sponding to 531 mg/kg] was reported follwing 7 days of exposure [Farbenfabriken Bayer AG 1968]. However, a report by H ü ls A.G. [1989] reported an LD 50 of greater than 7000 mg/kg in rats. Because the conflicting reports in rats and the high dermal LD 50 value reported in rabbits is higher than the critical dermal LD 50 value of 2000 mg/kg body weight that identi

fies chemical substances with the potential for acute dermal toxicity [NIOSH 2009], IPDI is not considered acutely toxic following der

mal 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 evalu

ating biological system/function specific effects (including reproductive and developmental ef

fects) following dermal exposure to IPDI were identified. No studies evaluating the carcino

genic 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 Ap

pendix) indicates that the chemical can be ab

sorbed 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 stud

ies 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 dataSkin Notation Profiles | Isophorone Diisocyanate 3 of the potential for IPDI to cause systemic health effects. Therefore, on the basis of the data 

### for this assessment, IPDI is not as

signed the SK: SYS notation. 

# 3 Direct Effects on Skin (SK: DIR) No human or animal in v ivo studies for corrosivity of IPDI or in vitro tests for cor

rosivity 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 cm 2 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 lim

ited 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 re

ported 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 topi

cally administered 30

– 300 millimoles (mM) [corresponding to 6669

– 66690 mg] IPDI in olive oil in a volume of 30 μ L under gauze patch occlusion for 6 hours. Erythema was observed 24 hours post IPDI chemical appli

cation for the 100mM and 300 mM treatment groups [Bio/dynamics Inc. 1984]. The struc

ture 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] pre

cludes adequate evaluation of the potential of IPDI to be corrosive to the skin of rab

bits. However, data from the primary irritan

cy 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 Occu

pational 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 

# 4 Immune-mediated Responses (SK: SEN) Skin sensitization induced by dermal exposure to IPDI has been well-documented in hu

mans and animals. Over a period of 13 years, 345 people who were examined for suspected occupational skin diseases were tested for al

lergy to isocyanate monomers, and of these 9 had positive reactions to IPDI [Aalto-Korte et al. 2012]. IPDI was shown to provoke al

lergic dermatitis in four sensitized work

ers 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 re

actions 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 hyper

sensitivity was also assessed in animals. Zissu et al. [1998] reported a sensitization grade of IV in Buehler tests in guinea pigs adminis

tered 0.5 mL of 5% IPDI solution. In a study conducted by the Bio/dynamics Inc. [1984] IPDI exhibited the potential to produce der

mal 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 ery

thema 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 sig

nificant hypersensitivity was observed in mice when administered a 1.0% sensitizing concen

tration 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 as

says (LLNA) on IPDI and several other iso

cyanates. 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 report

ed that 2% IPDI provoked a stimulation index of 50, indicating IPDI is a skin sensitizer. A similar stimulation index was earlier report

ed 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 test

ing 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 ex

ist 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 I PDI to be absorbed through the skin following dermal exposure were not identified. However, predictions from a math

ematical 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; HülsSkin Notation Profiles | Isophorone Diisocyanate 5 A.G. 1989] and the lack of epidemiological studies in humans, repeat dose, sub-chronic, and chronic toxicity studies in animals pre

cludes adequate evaluation of the potential for IPDI to cause systemic health effects. Skin ir

ritation studies in rabbits and mice [Bio/ dynamics Inc. 1984; Stern 1989; Bayer AG Farbenfabriken Toxikologie 1994] in

dicate that IPDI can be irritating to the skin. Positive responses from patch testing in hu

mans [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 suf

ficient evidence that IPDI has the potential to cause sensitization of the skin. Therefore, on the basis of these assessments, IPDI is as

signed a composite skin notation of SK: DIR (IRR)-SEN

. Table 3 summarizes the skin hazard designa

tions for IPDI previously issued by NIOSH and other organizations. The equivalent dermal designations for IPDI, according to the Global Harmonization System (GHS) of Classifica

tion and Labelling of Chemicals, are Skin Ir

ritation Category 2 (Hazard statement: Causes skin irritation) and Skin Sensitization Catego

ry 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, Hen

riks-Eckerman M [2012]. Occupational con

tact allergy to monomeric isocyanates. Contact Dermatitis 67 :78–88. *ACGIH (American Conference of Governmen

tal Industrial Hygienists) [2001]. Isophorone diisocyanate. In: Documentation of threshold limit values and biological exposure indices 7th ed., Vol. 2. Cincinnati, OH: American Confer

ence of Governmental Industrial Hygienists. *Bayer AG Fachbereich Toxikologie [1994]. Isopho

rondiisocyanat: study for skin irritation/corrosion in rabbits. Bayer AG Fachbereich Toxikologie, re

port #22961. On file with the U.S. Environmen

tal 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 polyiso

cyanates 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 absorp

tion using in vitro guinea pig skin. J Enviorn Monit 8 :523–529. *Bio/dynamics Inc. [1984]. A closed-patch re

peated 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 #4971-84, report to American Cyanamid Com

pany. On file with the U.S. Environmental Pro

tection Agency under TSCA Section 8D. OTS #0515234. Document #86-870000795. *Ciba-Geigy Limited [1984]. Report on skin sen

sitizing (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 se

rum concentration in mice. Preliminary evalu

ation of a novel approach to the identifica

tion 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 Phar

macol 112 (2):190–197. *EC (European Commission) [ND]. 3-isocyana

tomethyl-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, label

ing and packaging of substances and mixtures, amending and repealing Directives 67/548/ EEC and 1999/45/EC, and amending Regu

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hexylmethane-4,4’-diisocyanate. Contact Dermatitis 48 (6):305–309. *H Ü ls 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 Protec

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stitute 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 Hu

man 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 sensi

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ous sensitization to some polyisocyanate pre

polymers in guinea pigs. Contact Dermatitis 39 :248–251.8 Skin Notation Profiles | 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 sub

stance’s hazard potential following skin con

tact, 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 Bul

letin (CIB) 61: A Strategy for Assigning New NIOSH Skin Notations [NIOSH 2009].


## Overview The SI ratio is a predictive algorithm for esti

mating and evaluating the health hazards of skin exposure to substances. The algorithm is designed to evaluate the potential for a sub

stance to penetrate the skin and induce sys

temic toxicity [NIOSH 2009]. The goals for incorporating this algorithm into the pro

posed 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 la

beled with the SYS notation. The algorithm evaluation includes three steps: 1. determining a skin permeation coeffi

cient ( 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 require

ment 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 deter

mine 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 capil

laries of the dermis, is estimated from the compound’s molecular weight ( MW ) and base-10 logarithm of its octanol–water par

tition coefficient (log K OW

). In this example, k p is determined for a substance with use of Equation 1. A self-consistent set of units must be used, such as 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 

### )

aq pol psc 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 K
ow − 0.1786 × MW 0.5
k pol

= 0.0001519 × MW −0.5
k aq = 2.5 × MW −0.5 The second step is to calculate the biologic mass uptake of the substance from skin ab

sorption (skin dose) and inhalation (inhalationSkin Notation Profiles | Isophorone Diisocyanate 9 dose) during the same period of exposure. The skin dose is calculated as a mathematical product of the k p , the water solubility ( S W ) of the substance, the exposed skin surface area, and the duration of exposure. Its units are milligrams (mg). Assume that the skin expo

sure continues for 8 hours to unprotected skin on the palms of both hands (a surface area of 360 cm 2 ).


### Equation 2: Determination of Skin Dose Skin dose

= k p × S
w × Exposed skin surface area × Exposure time

= k p (cm/hour) × S
w (mg/cm 3 ) × 360 cm 2 × 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 de

veloped 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 inhala

tion volume of 10 cubic meters (m 3 ) inhaled air in 8 hours, and a factor of 75% for reten

tion of the airborne substance in the lungs during respiration (retention factor, or RF).


### Equation 3: Determination of Inhalation Dose Inhalation dose = OEL × Inhalation volume × RF = OEL (mg/m 3 ) × 10 m 3 × 0.75 The final step is to compare the calculated skin and inhalation doses and to present the result as a ratio of skin dose to inhalation dose (the SI ratio). This ratio quantitatively indi

cates (1) the significance of dermal absorp

tion 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 Dis

ease 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 In

stitute 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 ( k pol

) cm/hr 1.1019 × 10 -5 Permeation coefficient of the watery epidermal layer ( k aq ) cm/hr 0.1677 Molecular weight ( MW ) * amu 222.29 Base-10 logarithm of its octanol–water partition coefficient

(Log K
ow ) * None 4.75 Calculated skin permeation coefficient ( k p ) cm/hr 5.452 × 10 -2 Skin dose

Water solubility ( S w 

### ) * mg/cm 3 2.93 × 10 -3 Calculated skin permeation coefficient ( k p ) cm/hr Estimated skin surface area (palms of hand) cm 2 360 Exposure time hr 8 Calculated skin dose mg 0.4601 Inhalation dose

Occupational exposure limit (OEL) † mg/m 3 0.005 Inhalation volume m 3 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].