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

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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 Control 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 • PeopleTM
Skin 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 spectrum of adverse health effects ranging from localized damage (e.g., irritant contact dermatitis 

and corrosion) to induction of immune-mediated responses (e.g., allergic contact dermatitis 

and pulmonary responses), or systemic toxicity (e.g., neurotoxicity and hepatoxicity). Understanding the hazards related to skin contact with chemicals is a critical component of modern 

occupational safety and health programs. 

In 2009, the National Institute for Occupational Safety and Health (NIOSH) published Current Intelligence Bulletin (CIB) 61: A Strategy for Assigning New NIOSH Skin Notations [NIOSH 

2009-147]. This document provides the scientific rationale and framework for the assignment 

of multiple hazard-specific skin notations (SK) that clearly distinguish between the systemic 

effects, direct (localized) effects, and immune-mediated responses caused by skin contact with 

chemicals. The key step within assignment of the hazard-specific SK is the determination of the 

hazard potential of the substance, or its potential for causing adverse health effects as a result 

of skin exposure. This determination entails a health hazard identification process that involves 

use of the following:

• Scientific data on the physicochemical properties of a chemical

• Data on human exposures and health effects

• Empirical data from in vivo and in vitro laboratory testing

• Computational techniques, including predictive algorithms and mathematical 

models that describe a selected process (e.g., skin permeation) by means of analytical or numerical methods. 

This Skin Notation Profile provides the SK assignments and supportive data for nitrobenzene.

In particular, this document evaluates and summarizes the literature describing the hazard potential of the substance and its assessment according to the scientific rationale and framework 

outlined in CIB 61. In meeting this objective, this Skin Notation Profile intends to inform the 

audience—mostly occupational health practitioners, researchers, policy- and decision-makers, 

employers, and workers in potentially hazardous workplaces—so that improved risk-management practices may be developed to better protect workers from the risks of skin contact with 

the chemicals of interest.

John Howard, M.D.

Director, National Institute for 

 Occupational Safety and Health

Centers for Disease Control and Prevention

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

Abbreviations

ACGIH American Conference of Governmental Industrial Hygienists 

ATSDR Agency for Toxic Substances and Disease Registry

CIB Current Intelligence Bulletin

cm2 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 Globally Harmonized System for Classification and Labelling of Chemicals

IARC International Agency for Research on Cancer

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

irritant following exposure to the skin

k

aq coefficient in the watery epidermal layer 

k

p skin permeation coefficient 

kpol coefficient in the protein fraction of the stratum corneum

k

psc permeation coefficient in the lipid fraction of the stratum corneum 

LD50 dose resulting in 50% mortality in the exposed population

LDLo dermal lethal dose

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

M molarity

m3 cubic meter(s)

mg milligram(s)

mg/kg milligram(s) per kilogram body weight

mg/m3 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

SW solubility 
Skin 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/cm2 microgram(s) per square centimeter 
viii 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 exposure 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 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. 

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 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 | Nitrobenzene

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

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

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

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

 Environmental Health Sciences, Research Triangle, NC

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

 Nashville, TN 

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

James Taylor, M.D., Industrial Dermatology, The Cleveland Clinic, Cleveland, OH
Skin Notation Profiles | Nitrobenzene 1

Nitrobenzene

1.2 Purpose 

This skin notation profile presents (1) a brief 

summary of epidemiological and toxicological 

data associated with skin contact with nitrobenzene and (2) the rationale behind the hazard-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 Notations [NIOSH 2009]. The summarized information and health hazard assessment are limited 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 effects of dermal exposure to nitrobenzene. 

1.3 Overview of SK Assignment

Nitrobenzene 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 nitrobenzene: SK: SYS. Table 1 provides 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: C6H5NO2

Structural formula:

Synonyms: 

Nitrobenzol

Uses:

Nitrobenzene is used primarily as a chemical intermediate of aniline and similar compounds [ATSDR 1990]. Additional applications of nitrobenzene include as a solvent in 

petroleum refining, in the manufacture of 

cellulose ethers and acetate, and in the synthesis 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 data
2 Skin Notation Profiles | Nitrobenzene

Nitrobenzene

2 Systemic Toxicity from Skin 

Exposure (SK: SYS)

Several toxicokinetic studies following dermal exposure to nitrobenzene were identified. 

Feldman and Maibach [1970] reported dermal absorption of 1.5% of the applied dose 

after 4 micrograms per square centimeter (μg/

cm2), a total of 52 micrograms (μg), of nitrobenzene in acetone solvent was applied to an 

unoccluded 13-cm2 circular area of the forearm of a human volunteer for 24 hours. Bronaugh and Maibach [1985] reported dermal 

absorption of 4.2% of the applied dose following a single application to the monkey abdominal skin in vivo. The limited absorption 

observed in these studies could be attributed 

to the small amounts applied in acetone solvent to an unoccluded site. Piotrowski [1967] 

investigated the uptake of nitrobenzene vapors 

via multiple exposure routes in human volunteers. Test subjects were repeatedly exposed 

via the inhalation or dermal routes to concentrations of nitrobenzene vapors ranging 

from 5 to 30 micrograms per liter (μg/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 μg/L would have an estimated dermal absorption 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 dermal 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 humans under open conditions and evaporationprevented conditions, respectively [Bronaugh 

and Maibach 1985]. The potential of nitrobenzene 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 

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 (LDLo) 

for humans has been identified, the reported 

dermal LD50 values (the dose resulting in 50% 

mortality in the exposed animals) for rabbits was 760 milligrams per kilogram body 

weight (mg/kg) [Harton and Rawl 1976]. 

Because the reported acute dermal LD50 value for rabbits is lower than the critical dermal LD50 value of 2000 mg/kg body weight 

that identifies chemical substances with the 

potential for acute dermal toxicity [NIOSH 

2009], nitrobenzene is acutely toxic following 

dermal exposure. 

No epidemiology studies were identified that 

evaluated toxic effects of nitrobenzene in exposed workers. In a case report by Ikeda and 

Kita [1964], a worker who was exposed to 

nitrobenzene for 17 months developed severe methemoglobinemia with hepatic and 

neurological effects. No quantitative estimate 

of the dermal dose or the contribution of inhalation 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 nitrobenzene applied, and the use of only one animal 

per group precludes use of information from 
Skin Notation Profiles | Nitrobenzene 3

Nitrobenzene

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 developmental effects and immunotoxicity) following 

dermal exposure to nitrobenzene were identified in humans. There is insufficient data available to evaluate the carcinogenicity potential 

of nitrobenzene following dermal exposure. 

Table 2 summarizes carcinogenic designations of multiple governmental and nongovernmental 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; Bronaugh and Maibach 1985], acute dermal toxicity 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 corrosivity for nitrobenzene or in vitro tests for 

corrosivity using human or animal skin models or in vitro tests for skin integrity using cadaver skin were identified. In a study by E.I. 

du Pont de Nemours and Company [1977], 

rabbits administered 0.5 milliliter (mL) nitrobenzene to 1.5 square inches of skin under occlusion exhibited no corrosivity. No information is available to suggest that nitrobenzene 

is a skin irritant based on occupational exposure experience. No controlled exposure studies 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 irritation 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 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 | Nitrobenzene

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, nitrobenzene 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 supporting in vitro studies [Feldmann and Maibach 1970; Bronaugh and Maibach 1985], 

acute dermal toxicity studies in animals [Harton 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 methemoglobinemia 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 assigned a composite skin notation of SK: SYS. 

Table 3 summarizes the skin hazard designations for nitrobenzene previously issued by 

NIOSH and other organizations. The equivalent dermal designation for nitrobenzene, according to the Global Harmonization System (GHS) of Classification and Labelling 

of Chemicals, is Acute Toxicity Category 3 

(Hazard statement: Toxic in contact with the 

skin) [European Parliament 2008]. In addition, 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. Cincinnati, OH: American Conference of Governmental Industrial Hygienists.

*ATSDR [1990]. Toxicological profile for nitrobenzene. Atlanta, GA: U.S. Department of Health 

and Human Services, Public Health Service, 

Agency for Toxic Substance and Disease Registry (ATSDR), http://www.atsdr.cdc.gov/toxprofiles/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

Nitrobenzene

*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, 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:2008:353

: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 materials. 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-Nitrophenol 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/. 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 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]. Nitrobenzene (14-day and 90-day skin paint studies) in Fischer 344 rats and B6C3F1

 mice. Conducting 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 Human 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/chemicaldata/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, Wirnsberger T, Krauser K, Kreiling R, Kreuzer H, 

Lüpke N-P, Miltenburger HG, Müller N, Mürmann P, Pape W, Siegemund B, Spengler J, Steiling W, Wiebel FJ [1991]. Interlaboratory assessment 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 Chemicals. Br J Ind Med 24:189–202.

*USEPA [2013]. Integrated risk information 

system: nitrobenzene. In: Integrated Risk Information System, http://www.epa.gov/iris/

subst/0079.htm. Accessed: 05-02-14.
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Skin Notation Profiles | Nitrobenzene 7

Nitrobenzene

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 supportive data during the assignment of the NIOSH 

SK. An in-depth discussion on the rationale 

and calculation of the SI ratio can be found 

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

NIOSH Skin Notations [NIOSH 2009]. 

Overview 

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

skin exposure to substances. The algorithm is 

designed to evaluate the potential for a substance to penetrate the skin and induce systemic toxicity [NIOSH 2009]. The goals for 

incorporating this algorithm into the proposed strategy for assigning SYS notation are 

as follows:

1. Provide an alternative method to evaluate substances for which no clinical 

reports or animal toxicity studies exist 

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

2. Use the algorithm evaluation results to 

determine whether a substance poses a 

skin absorption hazard and should be 

labeled with the SYS notation.

The algorithm evaluation includes three steps:

1. determining a skin permeation coefficient (k

p

) for the substance of interest,

2. estimating substance uptake by the skin 

and respiratory absorption routes, and 

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

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

the physicochemical properties of a substance 

and the relevant exposure parameters. Thus, 

the algorithm is independent of the need for 

biologic data. Alternatively, it can function 

with both the physicochemical properties and 

the experimentally determined permeation 

coefficient when such data are available and 

appropriate for use.

The first step in the evaluation is to determine the k

p

 for the substance to describe the 

transdermal penetration rate of the substance 

[NIOSH 2009]. The k

p

, which represents the 

overall diffusion of the substance through the 

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

compound’s molecular weight (MW) and 

base-10 logarithm of its octanol–water partition coefficient (log KOW). In this example, 

k

p

is determined for a substance with use of 

Equation 1. A self-consistent set of units must 

be used, such as outlined in Table A1. Other 

model-based estimates of k

p

 may also be used 

[NIOSH 2009].

Equation 1: Calculation of Skin Permeation 

Coefficient (k

p

)

psc pol aq

p

k k k

k 1 1

1

+

+

=

where k

psc is the permeation coefficient in the 

lipid fraction of the stratum corneum, kpol is 

the coefficient in the protein fraction of the 

stratum corneum, and kaq is the coefficient in 

the watery epidermal layer. These components 

are individually estimated by

log kpsc = −1.326 + 0.6097 × log Kow

− 0.1786 × MW 0.5

kpol = 0.0001519 × MW −0.5

k

aq

 = 2.5 × MW−0.5
8 Skin Notation Profiles | Nitrobenzene

Nitrobenzene

The second step is to calculate the biologic 

mass uptake of the substance from skin absorption (skin dose) and inhalation (inhalation dose) during the same period of exposure. 

The skin dose is calculated as a mathematical 

product of the kp, the water solubility (SW) of 

the substance, the exposed skin surface area, 

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

continues for 8 hours to unprotected skin on 

the palms of both hands (a surface area of 360 

squared centimeters [cm2]). 

Equation 2: Determination of Skin Dose 

Skin dose 

= 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 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 Disease Control and Prevention, National Institute 

for Occupational Safety and Health, DHHS 

(NIOSH) Publication No. 2005–149 [http://

www.cdc.gov/niosh/npg/]. Accessed: 05-02-14.

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 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.

SRC [2009]. Interactive PhysProp database demo 

[http://www.srcinc.com/what-we-do/databaseforms.aspx?id=386.]. Accessed: 05-02-14.
Skin Notation Profiles | Nitrobenzene 9

Nitrobenzene

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

psc

) cm/hr 6.611 × 10-3

Permeation coefficient of the protein fraction of the stratum 

corneum (kpol)

cm/hr 1.3690 × 10-5

Permeation coefficient of the watery epidermal layer (kaq) cm/hr 0.2532

Molecular weight (MW)* amu 123.1

Base-10 logarithm of its octanol–water partition coefficient 

(Log Kow)

*

None 1.85

Calculated skin permeation coefficient (k

p

) cm/hr 6.4358 × 10-3

Skin dose

Water solubility (Sw)

* mg/cm3 2.09

Calculated skin permeation coefficient (k

p

) cm/hr 6.4358 × 10-3

Estimated skin surface area (palms of hand) cm2 360

Exposure time hr 8

Calculated skin dose mg 38.78

Inhalation Dose

Occupational exposure limit (OEL)† mg/m3 5

Inhalation volume m3 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].
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