# NIOSH Skin Notation (SK) Profiles

DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention National Institute for Occupational Safety and Health 

# Nitrobenzene [CAS No. 98-95-3]ii Skin Notation Profiles | Nitrobenzene 

## 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: nitrobenzene. By Hudson NL, Dotson GS. Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Con

trol and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2014-146. DHHS (NIOSH) Publication No. 2014-146 August 2014



### Safer • Healthier • PeopleTMSkin Notation Profiles | Nitrobenzene 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 spec

trum 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). Under

standing 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 Cur

rent 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 ana

lytical or numerical methods. This Skin Notation Profile provides the SK assignments and supportive data for nitrobenzene. In particular, this document evaluates and summarizes the literature describing the hazard po

tential of the substance and its assessment according to the scientific rationale and framework outlined in CIB 61. In meeting this objective, this Skin Notation Profile intends to inform the audience—mostly occupational health practitioners, researchers, policy- and decision-makers, employers, and workers in potentially hazardous workplaces—so that improved risk-manage

ment practices may be developed to better protect workers from the risks of skin contact with the chemicals of interest.



### John Howard, M.D. Director, National Institute for Occupational Safety and Health Centers for Disease Control and PreventionSkin Notation Profiles | Nitrobenzene v 

# Contents Foreword

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iii Abbreviations

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vi Glossary

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . viii Acknowledgments

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix 1 Introduction

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

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

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

. . . . . . . . . . . . . . . . . . . . . . . 2 3 Direct Effects on Skin (SK: DIR)

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 4 Immune-mediated Responses (SK: SEN)

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

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 References

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Appendix: Calculation of the SI Ratio for Nitrobenzene

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

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Calculation

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Appendix References

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8vi Skin Notation Profiles | Nitrobenzene 

# Abbreviations
ACGIH American Conference of Governmental Industrial Hygienists ATSDR Agency for Toxic Substances and Disease Registry CIB Current Intelligence Bulletin

cm 2 squared centimeter(s) cm/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 GHS G lobally 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 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 log K OW base-10 logarithm of a substance’s octanol–water partition M molarity

m 3 cubic meter(s) mg milligram(s) mg/kg milligram(s) per kilogram body weight mg/m 3 milligram(s) per cubic meter mL milliliter(s) MW molecular weight NIOSH National Institute for Occupational Safety and Health 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 ratioratio of skin dose to inhalation dose SK skin notation S W solubilitySkin Notation Profiles | Nitrobenzene vii SYS skin notation indicating the potential for systemic toxicity following exposure of the skin USEPA United States Environmental Protection Agency μg microgram (s) μg /cm 2 microgram(s) per square centimeterviii Skin Notation Profiles | Nitrobenzene 

# 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 expo

sure of the skin.Skin Notation Profiles | Nitrobenzene 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, Paul Siegel, Ph.D., and John Snawder, 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. 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 Stacey Anderson, Ph.D. H. Fredrick Frasch, Ph.D. Vic Johnson, Ph.D. Michael Luster, Ph.D. Anna Shvedova, 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 | Nitrobenzene 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 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, OHSkin Notation Profiles | Nitrobenzene 1 

## 1.2 Purpose This skin notation profile presents (1) a brief summary of epidemiological and toxicological data associated with skin contact with nitro

benzene and (2) the rationale behind the haz

ard-specific skin notation (SK) assignment for nitrobenzene. 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 Nota

tions [NIOSH 2009]. The summarized infor

mation and health hazard assessment are lim

ited to an evaluation of the potential health effects of dermal exposure to nitrobenzene. A literature search was conducted through May 2014 to identify information on nitrobenzene, 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 ef

fects of dermal exposure to nitrobenzene.


## 1.3 Overview of SK Assignment Nitrobenzene is potentially capable of caus

ing numerous adverse health effects follow

ing skin contact. A critical review of available data has resulted in the following SK assign

ment for nitrobenzene: SK: SYS . Table 1 pro

vides an overview of the critical effects and data used to develop the SK assignment for nitrobenzene. 

# 1 Introduction
1.1 General Substance Information

Chemical: Nitrobenzene CAS No: 98-95-3 Molecular weight ( MW ): 123.1 Molecular formula: C 6 H 5 NO 2 Structural formula: Synonyms: Nitrobenzol Uses: Nitrobenzene is used primarily as a chemi

cal intermediate of aniline and similar com

pounds [ATSDR 1990]. Additional applica

tions of nitrobenzene include as a solvent in petroleum refining, in the manufacture of cellulose ethers and acetate, and in the syn

thesis of other organic compounds including acetaminophen [ATSDR 1990].



### Table 1. Summary of the SK assignment for nitrobenzene
Skin notation Critical effect Data available SK: SYS Hepatic, and neurological effects Sufficient human and animal data2 Skin Notation Profiles | Nitrobenzene 

# 2 Systemic Toxicity from Skin Exposure (SK: SYS) Several toxicokinetic studies following der

mal exposure to nitrobenzene were identified. Feldman and Maibach [1970] reported der

mal absorption of 1.5% of the applied dose after 4 micrograms per square centimeter ( μg /
cm 2 ), a total of 52 micrograms ( μg ), of nitro

benzene in acetone solvent was applied to an unoccluded 13-cm 2 circular area of the fore

arm of a human volunteer for 24 hours. Bro

naugh and Maibach [1985] reported dermal absorption of 4.2% of the applied dose fol

lowing a single application to the monkey ab

dominal skin in vivo . The limited absorption observed in these studies could be attributed to the small amounts applied in acetone sol

vent to an unoccluded site. Piotrowski [1967] investigated the uptake of nitrobenzene vapors via multiple exposure routes in human volun

teers. Test subjects were repeatedly exposed via the inhalation or dermal routes to con

centrations of nitrobenzene vapors ranging from 5 to 30 micrograms per liter ( μ g/L). The magnitude of exposure was determined via urinary p-nitrophenol, a primary metabolite of nitrobenzene. Piotrowski [1967] reported that a dressed worker exposed for 6-hours (hr) to nitrobenzene vapors at a concentration of 5 μ g/L would have an estimated dermal ab

sorption of 7 milligrams (mg)/day, whereas the18 mg/day is estimated via the inhalation route. The findings of this study indicate that the dermal absorption of nitrobenzene vapors was approximately half of the absorption via the lungs, but still contributes substantially to total dose. Bronaugh and Maibach [1985] reported der

mal absorption in vitro of 7.8% (human skin) and 6.2% (monkey skin) of the applied dose. In vitro skin penetration studies indicated that approximately 8 and 41% of the applied dose penetrated the abdominal skin of hu

mans under open conditions and evaporationprevented conditions, respectively [Bronaugh and Maibach 1985]. The potential of nitro

benzene to pose a skin absorption hazard was also evaluated, with use of a predictive algo

rithm for estimating and evaluating the health hazards of dermal exposure to substances [NIOSH 2009]. The evaluation method com

pares 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 1.03 was calculated for nitrobenzene. An SI ratio of ≥0.1 indicates that skin absorption may significantly contribute to the overall body burden of a substance [NIOSH 2009]; therefore, nitrobenzene 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. While no dermal lethal concentration (LD Lo ) for humans has been identified, the reported dermal LD 50 values (the dose resulting in 50% mortality in the exposed animals) for rab

bits was 760 milligrams per kilogram body weight (mg/kg) [Harton and Rawl 1976]. Because the reported acute dermal LD 50 val

ue for rabbits is lower than the critical der

mal LD 50 value of 2000 mg/kg body weight that identifies chemical substances with the potential for acute dermal toxicity [NIOSH 2009], nitrobenzene is acutely toxic following dermal exposure. No epidemiology studies were identified that evaluated toxic effects of nitrobenzene in ex

posed workers. In a case report by Ikeda and Kita [1964], a worker who was exposed to nitrobenzene for 17 months developed se

vere methemoglobinemia with hepatic and neurological effects. No quantitative estimate of the dermal dose or the contribution of in

halation exposure was provided. Matsumaru and Yoshida [1959] reported that prolonged application of nitrobenzene (15 to 89 days) to the skin of rabbits caused damage to the liver and brain. However, the experimental design, lack of information on the dose of nitroben

zene applied, and the use of only one animal per group precludes use of information fromSkin Notation Profiles | Nitrobenzene 3 this study in assessing the dermal effects of the substance. No standard toxicity or specialty studies evaluating biological system/function specific effects (including reproductive and develop

mental effects and immunotoxicity) following dermal exposure to nitrobenzene were identi

fied in humans. There is insufficient data avail

able to evaluate the carcinogenicity potential of nitrobenzene following dermal exposure. Table 2 summarizes carcinogenic designa

tions of multiple governmental and nongov

ernmental organizations for nitrobenzene. Taken together, data from the toxicokinetic studies in humans in vivo [Piotrowski 1967; Feldman and Maibach 1970] * and in vitro studies [Feldmann and Maibach 1970; Bro

naugh and Maibach 1985] , acute dermal tox

icity studies [Harton and Rawl 1976] , and human case reports [Ikeda and Kita 1964 ] demonstrate that nitrobenzene is absorbed through the skin, is systemically available and is toxic. Therefore, on the basis of the data for this assessment, nitrobenzene is assigned the SK: SYS notation.

*References in bold text indicate studies that serve

as the basis of the SK assignments. 

# 3 Direct Effects on Skin (SK: DIR)
No human or animal in vivo studies for cor

rosivity for nitrobenzene or in vitro tests for corrosivity using human or animal skin mod

els or in vitro tests for skin integrity using ca

daver skin were identified. In a study by E.I. du Pont de Nemours and Company [1977], rabbits administered 0.5 milliliter (mL) nitro

benzene to 1.5 square inches of skin under oc

clusion exhibited no corrosivity. No informa

tion is available to suggest that nitrobenzene is a skin irritant based on occupational expo

sure experience. No controlled exposure stud

ies in humans were identified that assessed skin irritation. In animals, nitrobenzene was reported not to irritate rabbit skin [Spielman et al. 1991]. The structure activity relationship model, Deductive Estimation of Risk from Existing Knowledge ( DEREK ) for Windows, predicted nitrobenzene to be negative for skin irritation, indicating that the substance does not have structural alerts for skin irritation. There is limited information upon which to base the potential of nitrobenzene to cause skin irritation in humans. Acute dermal irrita

tion studies in animals [Spielman et al. 1991] show that nitrobenzene is not a significant 

### Table 2. Summary of the carcinogenic designations * 

### for nitrobenzene by numerous governmental and nongovernmental organizations Organization Carcinogenic designation NIOSH [2005] No designation NTP [2011] Reasonably anticipated to be a human carcinogen US EPA [2013] Likely to be carcinogenic to humans European Parliament [2008] Carcinogenicity Category 2: Suspected of causing cancer IARC [2012] Group 2B: Probably carcinogenic to humans EC [2014] † R40: Limited evidence of a carcinogenic effect ACGIH [2001] Confirmed animal carcinogen with unknown relevance to humans
ACGIH = American Conference of Governmental Industrial Hygienists; EC = European Commission, Joint Research, Institute for

Health and Consumer Protection; 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 | Nitrobenzene skin irritant. Therefore, on the basis of the data for this assessment, nitrobenzene is not assigned the SK: DIR notation. 

# 4 Immune-mediated Responses (SK: SEN) No epidemiological or human studies were identified for skin sensitization potential of nitrobenzene. In a standard ear-flank skin sensitization test in guinea pigs, nitrobenzene dissolved in dimethyl formamide failed to cause sensitization when applied daily to the outer surface of the ears (0.1 mL per ear per day; 10%) for three days, followed by a range of concentrations of solutions (0.2 mL) of the test material on the clipped flank [Stevens 1967]. DEREK predicted nitrobenzene to be negative as a skin sensitizer. Therefore, on the basis of the data for this assessment, nitroben

zene is not assigned the SK: SEN notation. 

# 5 Summary
The available data in human in vivo studies [Piotrowski 1967; Feldman and Maibach 1970; Bronaugh and Maibach 1985] and sup

porting in vitro studies [Feldmann and Mai

bach 1970; Bronaugh and Maibach 1985] , acute dermal toxicity studies in animals [Har

ton and Rawl 1976] , and human case reports [e.g., Ikeda and Kita 1964 ] demonstrate that nitrobenzene is absorbed through the skin, is systemically available and can cause methe

moglobinemia and hepatic and neurological effects in humans [Ikeda and Kita 1964] . The available studies show that nitrobenzene is not a skin irritant or a skin sensitizer. Therefore, this assessment assigns the skin notations of SK: SYS for nitrobenzene. Therefore, on the basis of these assessments, nitrobenzene is as

signed a composite skin notation of SK: SYS

. Table 3 summarizes the skin hazard designa

tions for nitrobenzene previously issued by NIOSH and other organizations. The equiva

lent dermal designation for nitrobenzene, ac

cording to the Global Harmonization Sys

tem (GHS) of Classification and Labelling of Chemicals, is Acute Toxicity C ategory 3 (Hazard statement: Toxic in contact with the skin) [ European Parliament 2008]. In ad

dition, nitrobenzene has been classified as a Reproductive Toxicity Category 2 (Hazard Statement: Suspected of damaging fertility) [ European Parliament 2008]. 

# References
Note : Asterisks (*) denote sources cited in text; daggers (†) denote additional resources. *ACGIH (American Conference of Governmental Industrial Hygienists) [2001]. Nitrobenzene. In: Documentation of threshold limit values and biological exposure indices 7th ed., Vol. 2. Cin

cinnati, OH: American Conference of Govern

mental Industrial Hygienists. *ATSDR [1990]. Toxicological profile for nitroben

zene. 

### Atlanta , GA: U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substance and Disease Regis

try (ATSDR), http://www.atsdr.cdc.gov/toxpro

files/tp140.pdf. Accessed: 05-02-14. 

### Table 3. Summary of previous skin hazard designations for nitrobenzene Organization Skin hazard designation NIOSH [2005] [skin]: Potential for dermal absorption; prevent skin contact OSHA [2014] * [skin]: Prevent skin contact. ACGIH [2001] [skin]: Based on the acute and chronic systemic toxicity of topical nitrobenzene in air. EC [2014] * R24: Toxic in contact with skin ACGIH = American Conference of Governmental Industrial Hygienists; EC = European Commission, Joint Research, Institute

for Health and Consumer Protection; NIOSH = National Institute for Occupational Safety and Health; OSHA = Occupational Safety and Health Administration.

* Date accessed.Skin Notation Profiles | Nitrobenzene 5 *Bronough RL, Maibach HI [1985]. Percutaneous absorption of nitroaromatic compounds: In vivo and in vitro studies in the human and monkery. J Invest.Dermatol. 84 (3): 180–183. *E.I. du Pont de Nemours and Company [1977]. Department of Transportation skin corrosion test on rabbit skin. Newark, DE: E.I. du Pont de Nemours and Company. On file with the U.S. Environmental Protection Agency under TSCA Section 8D. OTS #0215211. Document #878221381. *EC (European Commission) [ND]. Nitrobenzene. In: EINICS (European Inventory of Existing Commercial Chemical Substances), http://esis. jrc.ec.europa.eu/. Accessed: 05-02-14. *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

lation (EC) No 1907/2006. OJEU, Off J Eur Union L353:1–1355, http://eurex.europa.eu/ LexUriServ/LexUriServ.do?uri=OJ:L:2008:353 :0001:1355:EN:PDF. Accessed: 05-02-14. *Feldmann RJ, Maibach HI [1970]. Absorption of some organic compounds through the skin of man. J Invest Dermatol 54 :399–404. *Harton E, Rawl RR [1976]. Toxicological and skin corrosion testing of selected hazardous materi

als. Final report 1973–1974. US Department of Transportation, Office of Hazardous Materials Operations, April (Report No. DOT/MTB/ OHMO-76/2; NTIS No. PB-264 975). *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: 05-02-14. *Ikeda M, Kita A [1964]. Excretion of p-Nitrophe

nol and p-Aminophenol in the urine of a patient exposed to Nitrobenzene. Brit J Ind Med. 21 :210 *Matsumara H, Yoshida T [1959]. Experimental studies of nitrobenzol poisoning. Kyushu J Med Sci 10 :259–264. *NIOSH [2005]. Nitrobenzene. 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/. Ac

cessed: 05-02-14. *NIOSH [2009]. Current intelligence bulletin 61: a strategy for assigning new NIOSH skin no

tations. 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. 2009-147, http:// www.cdc.gov/niosh/docs/2009-147/pdfs/2009- 147.pdf. Accessed: 05-02-14. †NTP (National Toxicology Program) [1983]. Ni

trobenzene (14-day and 90-day skin paint stud

ies) in Fischer 344 rats and B6C3F 1 mice. Con

ducting Laboratory: EG & G Mason Research Institute. Reviewed by the Pathology Working Group, National Toxicology Program, Public Health Service, National Institutes of Health, 15 July 1983 (unpublished). *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 05-02-14.*OSHA [ND]. Nitrobenzene. In: Chemical sampling information, http://www.osha.gov/chemi

caldata/chemResult.html?recNo=779. Accessed: 05-02-14. *Piotrowski J [1967]. Further investigations on the evaluation of exposure to nitrobenzene. Br J Ind Med 24 :60–65. *Spielmann H, Gerner I, Kalweit S, Moog R, Wirn

sberger T, Krauser K, Kreiling R, Kreuzer H, Lüpke N-P, Miltenburger HG, Müller N, Mür

mann P, Pape W, Siegemund B, Spengler J, Steil

ing W, Wiebel FJ [1991]. Interlaboratory assess

ment of alternatives to the Draize eye irritation test in Germany. Toxic In Vitro 5 :539–542. *Stevens AM [1967]. Use of the Albino Guinea-pig to Detect the Skin-sensitizing Ability of Chem

icals. Br J Ind Med 24 :189–202. *USEPA [2013]. Integrated risk information system: nitrobenzene. In: Integrated Risk In

formation System, http://www.epa.gov/iris/ subst/0079.htm. Accessed: 05-02-14.Skin Notation Profiles | Nitrobenzene 7 

# Appendix: Calculation of the SI Ratio for Nitrobenzene This appendix presents an overview of the SI ratio and a summary of the calculation of the SI ratio for nitrobenzene. 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 support

ive 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 eval

uate substances for which no clinical reports or animal toxicity studies exist or for which empirical data are insuf

ficient 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 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 pos

es 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, k pol is the coefficient in the protein fraction of the stratum corneum, and k aq is the coefficient in the watery epidermal layer. These components are individually estimated by log k psc = −1.326 + 0.6097 × log K
ow − 0.1786 × MW 0.5
k pol

= 0.0001519 × MW −0.5
k aq = 2.5 × MW −0.58 Skin Notation Profiles | Nitrobenzene The second step is to calculate the biologic mass uptake of the substance from skin ab

sorption (skin dose) and inhalation (inhala

tion 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 mil

ligrams (mg). Assume that the skin exposure continues for 8 hours to unprotected skin on the palms of both hands (a surface area of 360 squared centimeters [cm 2 ]).


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

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

= k p (cm/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 nitrobenzene. The calculated SI ratio was 1.03. On the basis of these results, nitrobenzene 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: 05-02-14. 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: 05-02-14. SRC [2009]. Interactive PhysProp database demo [ http://www.srcinc.com/what-we-do/databas

eforms.aspx?id=386 .]. Accessed: 05-02-14.Skin Notation Profiles | Nitrobenzene 9 

### Table A1. Summary of data used to calculate the SI ratio for nitrobenzene
Variables used in calculation Units Value Skin permeation coefficient

Permeation coefficient of stratum corneum lipid path( k ps c ) cm/hr 6.611 × 10-3 Permeation coefficient of the protein fraction of the stratum

corneum ( k pol

) cm/hr 1.3690 × 10 -5 Permeation coefficient of the watery epidermal layer ( k aq ) cm/hr 0.2532 Molecular weight (MW) * amu 123.1 Base-10 logarithm of its octanol–water partition coefficient

(Log K
ow ) * None 1.85 Calculated skin permeation coefficient ( k p ) cm/hr 6.4358 × 10 -3 Skin dose

Water solubility ( S w ) * mg/cm 3 2.09 Calculated skin permeation coefficient ( k p ) cm/hr 6.4358 × 10 -3 Estimated skin surface area (palms of hand) cm 2 360 Exposure time hr 8 Calculated skin dose mg 38.78 Inhalation Dose

Occupational exposure limit (OEL) † mg/m 3 5 Inhalation volume m 3 10 Retention factor (RF) None 0.75 Inhalation dose mg 37.5 Skin dose–to–inhalation dose (SI) ratio None 1.03

* Variables identified from SRC [2009]. † The OEL used in calculation of the SI ratio for nitrobenzene was the NIOSH recommended exposure limit (REL) [NIOSH 2005].