NIOSH Skin Notation Profiles

Dinitrobenzene (DNB)
m-Dinitrobenzene (m-DNB)

SK
o-Dinitrobenzene (o-DNB)
p-Dinitrobenzene (p-DNB)

IDSK

[SK]

SYS

SYS (FATAL)

DIR

DIR (IRR)

DIR (COR)

SEN

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Disease Control and Prevention
National Institute for Occupational Safety and Health
NIOSH Skin Notation (SK) Profile

Dinitrobenzene (DNB)
[CAS No. 25154–54–5]
m-Dinitrobenzene (m-DNB)
[CAS No. 99–65–0]
o-Dinitrobenzene (o-DNB)
[CAS No. 528–29–0]
p-Dinitrobenzene (p-DNB)
[CAS No. 100–25–4]

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Disease Control and Prevention
National Institute for Occupational Safety and Health
 This document is in the public domain and may be freely
copied or reprinted.

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DHHS (NIOSH) Publication No. 2011–141
April 2011

Safer • Healthier • PeopleTM

ii Skin Notation Profiles | DNB

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) published
Current Intelligence Bulletin (CIB) 61: A Strategy for Assigning New NIOSH Skin Nota-
tions [NIOSH 2009–147]. This document provides the scientific rationale and frame-
work 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 a substance’s hazard potential, or its poten-
tial 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 assignment and supportive data for dinitro-
benzene (DNB) and its isomers. In particular, this document evaluates and summarizes
the literature describing the substance’s hazard potential 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 chemical of
interest.

John Howard, M.D.

Director, National Institute for Occupational
Safety and Health
Centers for Disease Control and Prevention

Skin Notation Profiles | DNB iii

Contents
Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iv
Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vi
Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . viii
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1 General Substance Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 Purpose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.3 Overview of SK Assignment for DNB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2 Systemic Toxicity from Skin Exposure (SK: SYS) . . . . . . . . . . . . . . . . . . . . . . . . 2
3 Direct Effect(s) on the Skin (SK: DIR) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
4 Immune-mediated Responses (SK: SEN) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Appendix: Calculation of the SI Ratio for DNB . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Calculation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Appendix References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Skin Notation Profiles | DNB v

Abbreviations
ACGIH American Conference of Governmental Industrial Hygienists
CIB Current Intelligence Bulletin
cm2 square centimeter(s)
cm/hr centimeter(s) per hour
DEREKTM Deductive Estimation of Risk from Existing Knowledge
DIR skin notation indicating the potential for direct effects to the skin
following contact with a chemical
DNB dinitrobenzene
EC European Commission
GHS Globally Harmonized System of Classification and Labeling of Chemicals
IARC International Agency for Research on Cancer
Kaq coefficient in the watery epidermal layer
Kp skin permeation coefficient
Kpol coefficient in the protein fraction of the stratum corneum
Kpsc 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 3
cubic meter(s)
m-DNB m-dinitrobenzene
MET minimum elicitation threshold
metHb methemoglobin
mg milligram(s)
MW molecular weight
NIOSH National Institute for Occupational Safety and Health
NTP National Toxicology Program
o-DNB o-dinitrobenzene
OE occupational exposure limit
OSHA Occupational Safety and Health Administration
p-DNB p-dinitrobenzene
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

vi Skin Notation Profiles | DNB

SK skin notation
SW solubility
SYS skin notation indicating the potential for systemic toxicity following
exposure of the skin
USEPA United States Environmental Protection Agency
w/w weight by weight

Skin Notation Profiles | DNB vii

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.

viii Skin Notation Profiles | DNB

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.
Other NIOSH personnel, in particular Geraci, Ph.D., Thomas J. Lentz, Ph.D., Michael
Luster, Ph.D., Richard Niemeier, Ph.D., and Aaron Sussell, Ph.D., contributed to its
development by providing technical reviews and comments. The basis for this docu-
ment was a report contracted by NIOSH and prepared by Bernard Gadagbui, Ph.D.,
and Andrew Maier, Ph.D. (Toxicology Excellence for Risk Assessment [TERA]).
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.
Division of Respiratory Disease Studies
Gregory A. Day, Ph.D.
Division of Surveillance, Hazard Evaluations, and Field Studies
Todd Niemeier, M.Sc.
Loren Tapp, M.D.
Education and Information Division
Ralph Zumwalde, M.Sc.
Health Effects Laboratory Division
Fredrick H. Frasch, Ph.D.
Anna Shvedova, Ph.D.
Paul Siegel, Ph.D.
National Personal Protective Technology Laboratory
Heinz Ahlers, J.D.
Angie Shepherd
The authors thank Seleen Collins, Gino Fazio, and Vanessa Becks Williams for their
editorial support and contributions to the design and layout of this document. Clerical
and information resources support in preparing this document was provided by Devin
Baker, Daniel Echt, and Barbara Landreth.
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:
John Cherrie, Ph.D., Institute of Occupational Medicine, Edinburgh, Scotland,
United Kingdom
G. Frank Gerberick, Ph.D., The Procter and Gamble Company, Cincinnati, Ohio

Skin Notation Profiles | DNB ix

 Dori Germolec, Ph.D., National Toxicology Program, National Institute for Envi-
ronmental Health Sciences, Research Triangle, North Carolina
Ben Hayes, M.D., Ph.D., Division of Dermatology, Vanderbilt School of Medicine,
Nashville, Tennessee
Hasan Mukhtar, Ph.D., Department of Dermatology, School of Medicine and Pub-
lic Health, University of Wisconsin-Madison, Madison, Wisconsin
Jennifer Sahmel, M.Sc., CIH, ChemRisk, Boulder, Colorado
James Taylor, M.D., Industrial Dermatology, The Cleveland Clinic, Cleveland, Ohio

x Skin Notation Profiles | DNB

 DNB
1 Introduction
1.1 General Substance Information

Chemical: Dinitrobenzene (DNB); DNB; meta-Dinitrobenzene; 1,3-Di-

m-dinitrobenzene (m-DNB); o-dini- nitrobenzene; ortho-Dinitrobenzene;
trobenzene (o-DNB); p-dinitrobenzene 1,2-Dinitrobenzene; para-Dinitroben-
(p-DNB) zene; 1,4-Dinitrobenzene
CAS No: 25154–54–5; 99–65–0; 528– Uses:
29–0; 100–25–4 Dinitrobenzene (DNB) is primarily
Molecular weight (MW): 168.11 manufactured as a mixture of all isomers
and is used in the manufacturing of
Molecular formula: C6H4N2O4 dyes, explosives, and organic syntheses
Structural formula: [ACGIH 2001].
Synonyms:
O
O O-
N+
N+
O-
O N+ N+ O
O-
O- O- N+

m-DNB o-DNB N+ p-DNB

O O-
[CAS No. 99–65–0] [CAS No. 528–29–0] [CAS No. 100–25–4]

1.2 Purpose Intelligence Bulletin (CIB) 61: A Strategy

for Assigning New NIOSH Skin Nota-
This Skin Notation Profile presents (1) a tions [NIOSH 2009]. The summarized
brief summary of technical data associated information and health hazard assessment
with skin contact with DNB* and (2) the are limited to an evaluation of the poten-
rationale behind the hazard-specific skin tial health effects of dermal exposure to
notation (SK) assignment for DNB. The DNB. A literature search was conducted
SK assignment is based on the scientific through July 2010 to identify information
rationale and logic outlined in the Current on DNB, including but not limited to data
relating to its toxicokinetics, acute toxicity,
*The exposure guidelines and SK assignment stat- repeated-dose systemic toxicity, carcinoge-
ed in this document apply to all isomeric forms nicity, biological system/function–specific
of DNB, including m-, o-, and p-DNB. Unless effects (including reproductive and devel-
otherwise specified, the abbreviation DNB is
used to represent all three substances.
opmental effects and immunotoxicity),

Skin Notation Profiles | DNB 1

 DNB

Table 1. Summary of the SK assignments for DNB

Skin notation Critical effect Available data

SK: SYS Methemoglobinemia Limited human data

irritation, and sensitization. Information investigation of the onset of five cases of

was considered from studies of humans, methemoglobinemia in workers employed
animals, or appropriate modeling systems as steam-press operators in a rubber plant
that are relevant to assessing the effects of [NIOSH 1987]. The workers applied an
dermal exposure to DNB. adhesive to bond metal studs into rubber
bumper strips, without wearing gloves.
Bulk analysis revealed that the adhesive
1.3 Overview of SK Assignment was contaminated with p-DNB (1% w/w).
for DNB The report indicated that the main route
DNB is potentially capable of causing ad- of entry for p-DNB was skin absorption.
verse systemic effects following skin con- The workers experienced yellowing of the
tact. A critical review of available data has hands, cyanosis of the lips and nail beds,
resulted in the following SK assignment headache, dizziness, nausea, chest pain,
for DNB: SK: SYS. Table 1 provides an confusion, and difficulty in concentration
overview of the critical effects and data [NIOSH 1987].
used to develop the SK assignment for
The potential of DNB to pose a skin ab-
DNB.
sorption hazard was evaluated with use of
a predictive algorithm for estimating and
evaluating the health hazards of dermal
2 Systemic Toxicity from Skin exposure to chemical substances [NIOSH
Exposure (SK: SYS) 2009]. The evaluation method compares
an estimated chemical dose accumulated
No in vivo or in vitro toxicokinetic stud- in the body from skin absorption and an
ies that evaluated the potential of DNB estimated dose from respiratory absorp-
to be absorbed through human or animal tion associated with a reference occupa-
skin were identified. Ishihara et al. [1976] tional exposure limit. On the basis of this
reported a case of m-DNB intoxication algorithm, a ratio of the skin dose to the
involving a woman exposed to an aque- inhalation dose (SI ratio) of 0.12 was cal-
ous mixture containing 0.5% (weight by culated for DNB. An SI ratio of ≥0.1 indi-
weight; w/w) m-DNB while handling cates that a chemical is capable of produc-
parts immersed in the aqueous mixture. ing systemic toxicity from skin exposure
After ruling out the possibility of exposure [NIOSH 2009]. Additional information
via the inhalation of vaporized m-DNB, on the SI ratio and the variables used in its
Ishihara et al. [1976] concluded that the calculation are included in the appendix.
main route of exposure was dermal absorp-
tion, despite the use of personal protective No dermal lethal concentration (LDLo) for
equipment in the form of latex gloves. Ad- humans has been identified for DNB. In
ditional evidence of the ability of DNB to addition, no dermal LD50 value (the dose
be dermally absorbed was identified in an resulting in 50% mortality in the exposed

2 Skin Notation Profiles | DNB

 DNB
population) for animals has been reported. associated with exposure to an industrial
No additional acute toxicity was identi- chemical. The authors concluded that the
fied for DNB. The lack of sufficient data absence of m-DNB in the ambient air and
precludes adequate evaluation of the po- the results of a simulation study conduct-
tential of DNB to elicit acute toxicity fol- ed as part of this investigation indicated
lowing dermal exposure. that the worker was dermally exposed to
m-DNB, potentially resulting in the onset
No epidemiological studies or occupational
of methemoglobinemia [Ishihara 1976].
case reports were identified in the litera-
ture search. In addition, no repeat-dose, Although no epidemiological, repeat-dose,
subchronic, or chronic toxicity studies in- or subchronic or chronic toxicity stud-
volving animals following dermal exposure ies have evaluated the potential of DNB
to DNB were identified. No reports were isomers to cause systemic effects in ani-
found on standard toxicity or specialty stud- mals following dermal exposure, NIOSH
ies evaluating biological system/function– [1987] investigated five cases of methemo-
specific effects (including reproductive and globinemia in workers employed at a rub-
developmental effects and immunotoxic- ber plant. The workers were identified as
ity) following dermal exposure to DNB. steam-press operators who presented with
The three isomeric forms of DNB and/ multiple symptoms, including cyanosis of
or their metabolites are considered potent the lips and nail beds, yellowing of the
cyanogenic agents in all routes of entry hands, dizziness, confusion, difficulty con-
[Linch 1974]. Evidence of a link between centrating, and chest pains following ex-
dermal exposures to DNB and the forma- posure to a solvent-based adhesive used to
tion of methemoglobin (metHb) and the bond metal studs to rubber bumper strips
onset of metHb-induced cyanosis (e.g., [NIOSH 1987]. One worker suffered a
methemoglobinemia) is limited. Ishihara seizure. The steam-press operators had
et al. [1976] described a case of m-DNB handled the adhesive without the use of
intoxication in a female worker exposed gloves prior to the onset of the described
to an aqueous solution containing 0.5 % symptoms. Medical screening of the af-
w/w m-DNB. The woman was employed fected workers revealed blood metHb lev-
as a production line worker within a fac- els ranging from 3.8% to 41.2% (normal
tory manufacturing electronic parts. As level, <1%) [NIOSH 1987]. Prior to the
part of her job duties, the worker handled NIOSH study, a plant supervisor oper-
parts immersed in the aqueous mixture ated the steam-press using the adhesive-
containing m-DNB, while wearing “pro- coated studs for about 2 hours, as part
tective” latex gloves. Within three days of of a simulation study conducted by the
the introduction of the aqueous mixture Ohio Industrial Commission. The plant
containing m-DNB to the production line, supervisor’s blood metHb level after the
the female worker presented with cya- simulation was 12.5%. The NIOSH in-
notic lips and finger nails, in addition to vestigation revealed that bulk samples of
pale skin [Ishihara et al. 1976]. The worker the adhesive were contaminated with p-
was hospitalized because of a relapse and DNB (1% w/w) [NIOSH 1987]. On the
reemergence of her symptoms follow- basis of the results of the investigation,
ing a one-day rest period at home. The the manufacturers immediately replaced
clinical diagnosis was hemolytic jaundice the p-DNB-contaminated adhesive. No

Skin Notation Profiles | DNB 3

 DNB

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

governmental and nongovernmental organizations

Organization Carcinogenic designation

NIOSH [2005] None
NTP [2009] None
USEPA [2009] Group D: Not classifiable as to human carcinogenicity
IARC [2009] None
EC [2010] None
ACGIH [2001] None
Abbreviation: ACGIH = American Conference of Governmental Industrial Hygienists; EC = European Commission, Joint Re-
search, Institute for Health and Consumer Protection; IARC = International Agency for Research on Cancer; NIOSH = Nation-
al Institute for Occupational Safety and Health; NTP = National Toxicology Program; USEPA = United States Environmental
Protection Agency.
*Note: The listed cancer designations were based on data from nondermal (such as oral or inhalation) exposure rather than dermal
exposure.

reoccurrence of methemoglobinemia was dermal exposure to DNB can be evalu-

observed at the rubber plant in a follow- ated. Available human data are associated
up survey. NIOSH concluded that dermal with m- and p-DNB. These chemicals are
exposures to p-DNB-contaminated adhe- readily absorbed through the skin and
sive resulted in the formation of metHb may substantially contribute to systemic
and the cyanotic symptoms in the affected toxicity through the formation of metHb
workers [NIOSH 1987]. [Ishihara 1976; NIOSH 1987†]. Math-
ematical evaluation of the potential of the
The literature search revealed no standard substance to pose a skin hazard (according
toxicity or specialty studies evaluating bi- to the NIOSH [2009] methodology based
ological system/function–specific effects on the m-isomer) indicated that DNB has
(including reproductive effects and im- the potential to be absorbed through the
munotoxicity) in humans following der- skin, be systemically available, and cause
mal exposure to DNB isomers. No studies methemoglobinemia. Therefore, on the ba-
have evaluated the carcinogenic potential sis of the data for this assessment, DNB is
of DNB following dermal exposure. Table assigned the SK: SYS notation.
2 provides a summary of carcinogenic des-
ignations from multiple governmental and
nongovernmental organizations for DNB. 3 Direct Effect(s) on the Skin
Despite the absence of data for o-DNB, (SK: DIR)
all isomers are assumed to have similar
No data on the skin corrosivity of DNB
toxic potency, on the basis of their similar
were identified from in vivo tests in hu-
physiochemical properties. For example,
mans or animals or from in vitro tests with
the log KOW for the m-, o-, and p-DNB are
human or animal skin models or cadaver
1.49, 1.69, and 1.46, respectively [HSDB
skin (for skin integrity). Additionally, no
2010]. There are few data from acute or
repeat-dose toxicity studies upon which †
References in bold text indicate studies that served
the potential for systemic effects following as the basis of the SK assignment.

4 Skin Notation Profiles | DNB

 DNB
studies evaluating the skin-irritating po- that DNB is readily absorbed through the
tential of the substance in humans or skin and may result in methemoglobin-
animals were identified. Exposure to a emia [Ishihara 1976; NIOSH 1987]. Ad-
p-DNB-contaminated adhesive was re- ditional evidence supporting the potential
ported to cause yellow discoloration of the for DNB to pose a skin-absorption hazard
hands of five workers employed at a rub- is provided by a mathematical evaluation
ber plant [NIOSH 1987]. No additional based on data for the m-isomer. No studies
information was provided. The structure- were identified that investigated the poten-
activity relationship model, Deductive Es- tial of the substance to cause skin irritation
timation of Risk from Existing Knowledge or to be corrosive to the skin of humans or
(DEREKTM) for Windows, predicted the animals. A structure-activity-relationship
substance to be negative for skin irritation. model predicted the substance to be nega-
The findings of this assessment show that tive for skin irritation and skin sensitiza-
the data are insufficient to assign the SK: tion. No studies were identified that evalu-
DIR notation to DNB. ated the skin-sensitization potential of the
substance. Therefore, on the basis of these
assessments, DNB is assigned a composite
4 Immune-mediated skin notation of SK: SYS.

Responses (SK: SEN) Table 3 summarizes the skin hazard des-

ignations for DNB previously issued by
No occupational exposure studies that in- NIOSH and other organizations. The
vestigated the skin-sensitization potential of equivalent dermal designation for DNB,
DNB were identified. No human patch tests according to the Globally Harmonized
or predictive tests (guinea pig maximiza- System (GHS) of Classification and La-
tion tests, Buehler tests, murine local lymph beling of Chemicals, is Acute Toxicity
node assays) or any other studies that evalu- Category 1 (Hazard statement: Fatal in
ated the potential of the substance to cause contact with the skin).
skin sensitization were identified. DNB is
predicted by DEREKTM to be negative for
sensitization. This assessment shows that References
the data are insufficient to assign the SK: Note: Asterisks (*) denote sources cited in
SEN notation to DNB. text; daggers (†) denote additional resources.
*ACGIH (American Conference of Governmental
5 Summary Industrial Hygienists) [2001]. Dinitrobenzene
(all isomers). In: Documentation of threshold
Limited data were identified for assess- limit values and biological exposure indices. 7th
Ed., Vol. 1. Cincinnati, OH: American Confer-
ing the potential of all isomers of DNB to
ence of Governmental Industrial Hygienists.
be absorbed through the skin or to cause *EC (European Commission) [2009]. Dinitroben-
systemic toxicity following dermal expo- zene. In: EINICS (European Inventory of Exist-
sure. On the basis of the similar physical ing Commercial Chemical Substances) [http://
and chemical properties of the isomeric ecb.jrc.ec.europa.eu/esis/]. Accessed 07–07–10.
*European Parliament, Council of the European
forms of DNB, it is assumed that all three Union [2008]. Regulation (EC) No 1272/2008
compounds exhibit similar toxic potency. of the European Parliament and of the Coun-
The limited available human data indicate cil of 16 December 2008 on classification,

Skin Notation Profiles | DNB 5

 DNB

Table 3. Summary of the previously issued skin hazard designations for DNB

Organization Skin hazard designation

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

OSHA [2000] [skin]: Based on potential contribution to the overall exposure by the cutaneous
route, including the mucous membranes and the eyes, either by airborne par-
ticles or, more particularly, by direct contact with the substance
ACGIH [2001] [skin]: Based on data demonstrating toxicity following absorption through in-
tact skin of humans and animals
EC [EC 2010] R27: Very toxic in contact with skin

Abbreviations: ACGIH = American Conference of Governmental Industrial Hygienists; EC = European Commission, Joint Re-
search, Institute for Health and Consumer Protection; NIOSH = National Institute for Occupational Safety and Health; OSHA
= Occupational Safety and Health Administration.

labelling and packaging of substances and mix- Division of Standards Development and Tech-
tures, amending and repealing Directives 67/548/ nology Transfer, Publications Dissemination Sec-
EEC and 1999/45/EC, and amending Regu- tion, Centers for Disease Control and Prevention,
lation (EC) No 1907/2006. OJEU, Off J Eur National Institute for Occupational Safety and
Union L353:1–1355 [http://eur-lex.europa.eu/ Health. HETA Report No. 86-350-1815. [http://
LexUriServ/LexUriServ.do?uri=OJ:L:2008:3 www.cdc.gov/niosh/hhe/reports/pdfs/1986-
53:0001:1355:EN:PDF]. Accessed 07–07–10. 0350-1815.pdf ]. Accessed 07–07–10.
*HSDB (Hazardous Substance Data Bank) [2010]. *NIOSH [2006]. NIOSH pocket guide to chemi-
Dinitrobenzene. In: Toxnet [http://toxnet.nlm. cal hazards. Cincinnati, OH: U.S. Department
nih.gov/cgi-bin/sis/htmlgen?HSDB]. ��� Ac- of Health and Human Services, Centers for
cessed 07–07–10. Disease Control and Prevention, National In-
*IARC (International Agency for Research on stitute for Occupational Safety and Health,
Cancer) [2009]. Agents reviewed by the IARC DHHS (NIOSH) Publication No. 2005–149
monographs. In: IARC monographs on the eval- [http://www.cdc.gov/niosh/npg/]. Accessed
uation of carcinogenic risks to humans [http:// 07–07–10.
monographs.iarc.fr/ENG/Classification/Lista- *NIOSH [2009]. Current intelligence bulletin
gentsalphorder.pdf ]. Accessed 07–07–10. 61: a strategy for assigning new NIOSH skin
*Ishihara N, Kanaya A, Ikeda m [1976]. m-Dini- notations. Cincinnati, OH: U.S. Department
trobenzene intoxication due to skin absorption. of Health and Human Services, Centers for
Int Arch Occup Environ Health 36: 161-168. Disease Control and Prevention, National In-
†Ishihara N, Ikeda M [1979]. Effects of solvents stitute for Occupational Safety and Health,
and solutes on the percutaneous absorption of DHHS (NIOSH) Publication No. 2009–147
m-dinitrobenzene. Int Arch Occup Environ [http://www.cdc.gov/niosh/docs/2009-147/
Health 44(2):91–98. pdfs/2009-147.pdf ]. Accessed 07–07–10.
*Linch AL [1974]. Biological monitoring for in- *NTP (National Toxicology Program) [2009]. 11th
dustrial exposures to cyanogenic aromatic nitro Report on carcinogens [http://ntp.niehs.nih.gov/
and amino compounds. Am Ind Hyg Assoc J index.cfm?objectid=32BA9724-F1F6-975E-
35(7):426–432. 7FCE50709CB4C932]. Accessed 07–07–10.
*Linch AL, Wuertz RL, Charsha RC [1971]. *OSHA [2000]. Occupational health and safety
Chemical cyanosis and anemia control. In: guideline for dinitrobenzene (all isomers). In:
Steere NV (Ed.), Handbook of laboratory safe- Health guidelines [http://www.osha.gov/SLTC/
ty. 2nd Ed. Cleveland: The Chemical Rubber healthguidelines/dinitrobenzeneallisomers/
Co., 342–378. recognition.html]. Accessed 07–07–10.
*NIOSH (National Institute for Occupational *UNECE (United Nations Economic Commis-
Safety and Health) [1987]. Barr Rubber Cor- sion for Europe) [2007]. Part 3: health hazards.
poration, Sandusky, Ohio. Cincinnati, OH: In: Globally harmonized system of classification

6 Skin Notation Profiles | DNB

 DNB
and labeling of chemicals (GHS). 2nd rev. ed. *USEPA [2009]. Integrated risk information sys-
[http://www.unece.org/trans/danger/publi/ghs/ tem (IRIS) [http://www.epa.gov/ncea/iris/]. Ac-
ghs_rev02/02files_e.html]. Accessed 07–07–10. cessed 07–07–10.

Skin Notation Profiles | DNB 7

 DNB

Appendix: Calculation of the SI Ratio for DNB

This appendix presents an overview of the The algorithm is flexible in the data re-
SI ratio and a summary of the calculation of quirement and can operate entirely on the
the SI ratio for the dinitrobenzene isomers. basis of the physicochemical properties
Although the SI ratio is considered in the of a substance and the relevant exposure
determination of a substance’s hazard po- parameters. Thus, the algorithm is inde-
tential following skin contact, it is intended pendent of the need for biologic data. Al-
only to serve as supportive data during the ternatively, it can function with both the
assignment of the NIOSH SK. An in-depth physicochemical properties and the ex-
discussion on the rationale and calculation perimentally determined permeation co-
of the SI ratio can be found in Appendix B efficient when such data are available and
of the Current Intelligence Bulletin (CIB) 61: appropriate for use.
A Strategy for Assigning New NIOSH Skin
Notations [NIOSH 2009]. The first step in the evaluation is to deter-
mine the Kp for the substance to describe
the transdermal penetration rate of the
Overview substance [NIOSH 2009]. The Kp, which
The SI ratio is a predictive algorithm for represents the overall diffusion of the sub-
estimating and evaluating the health haz- stance through the stratum corneum and
ards of skin exposure to substances. The al- into the blood capillaries of the dermis, is
gorithm is designed to evaluate the poten- estimated from the compound’s molecular
tial for a substance to penetrate the skin weight (MW) and base-10 logarithm of
and induce systemic toxicity [NIOSH its octanol–water partition coefficient (log
2009]. The goals for incorporating this KOW ). In this example, Kp is determined for
algorithm into the proposed strategy for a substance with use of Equation 1. A self-
assigning the SYS notation are as follows: consistent set of units must be used, such
as centimeters per hour (cm/hr), outlined
1. Provide an alternative method to eval- in Table A1. Other model-based estimates
uate substances for which no clinical of Kp may also be used [NIOSH 2009].
reports or animal toxicity studies exist
or for which empirical data are insuf- Equation 1: Calculation of Skin Permeation
ficient to determine systemic effects.
Coefficient (Kp)
2. Use the algorithm evaluation results to
determine whether a substance poses a
skin absorption hazard and should be
labeled with the SYS notation.
3. The algorithm evaluation includes three
steps: (1) determining a skin perme-
ation coefficient (Kp) for the substance
of interest, (2) estimating substance
uptake by the skin and respiratory where Kpsc is the permeation coefficient
absorption routes, and (3) evaluating in the lipid fraction of the stratum cor-
whether the substance poses a skin ex- neum, Kpol is the coefficient in the protein
posure hazard. fraction of the stratum corneum, and Kaq

8 Skin Notation Profiles | DNB

 DNB
is the coefficient in the watery epidermal Equation 3: Determination of Inhalation Dose
layer. These components are individually Inhalation dose = OEL × Inhalation
estimated by volume × RF
log Kpsc = −1.326 + 0.6097 × log KOW − = OEL (mg/m3) × 10 m3
0.1786 × MW 0.5 × 0.75
Kpol = 0.0001519 × MW −0.5 The final step is to compare the calculated
skin and inhalation doses and to present
Kaq = 2.5 × MW −0.5 the result as a ratio of skin dose to inhala-
The second step is to calculate the bio- tion dose (the SI ratio). This ratio quan-
titatively indicates (1) the significance of
logic mass uptake of the substance from
dermal absorption as a route of occupa-
skin absorption (skin dose) and inhalation
tional exposure to the substance and (2)
(inhalation dose) during the same period the contribution of dermal uptake to sys-
of exposure. The skin dose is calculated temic toxicity. If a substance has an SI ra-
as a mathematical product of the Kp, the tio greater than or equal to 0.1, it is con-
water solubility (SW) of the substance, the sidered a skin absorption hazard.
exposed skin surface area, and the dura-
tion of exposure. Its units are milligrams
Calculation
(mg). Assume that the skin exposure con-
tinues for 8 hours to unprotected skin on Table A1 summarizes the data applied
in the previously described equations to
the palms of both hands (a surface area of
determine the SI ratio for DNB. The cal-
360 cm2).
culated SI ratio was 0.12. On the basis of
these results, DNB is predicted to repre-
Equation 2: Determination of Skin Dose sent a skin absorption hazard.
Skin dose = Kp × SW × Exposed skin surface
area × Exposure time Appendix References
NIOSH [2005]. NIOSH pocket guide to chemical
= Kp(cm/hr) × SW (mg/cm3) ×
hazards. Cincinnati, OH: U.S. Department of
360 cm2 × 8 hr Health and Human Services, Centers for Dis-
ease Control and Prevention, National Institute
The inhalation dose (in mg) is derived for Occupational Safety and Health, DHHS
on the basis of the occupational expo- (NIOSH) Publication No. 2005–149 [http://
sure limit (OEL) of the substance—if the www.cdc.gov/niosh/npg/]. Accessed 07–07–10.
NIOSH [2009]. Current intelligence bulletin: a
OEL is developed to prevent the occur- strategy for assigning new NIOSH skin nota-
rence of systemic effects rather than sen- tions. Cincinnati, OH: Department of Health
sory/irritant effects or direct effects on the and Human Services, Centers for Disease Con-
trol and Prevention, National Institute for Occu-
respiratory tract. Assume a continuous pational Safety and Health, DHHS (NIOSH)
exposure of 8 hours, an inhalation volume Publication No. 2009–147 [http://www.cdc.gov/
of 10 cubic meters (m3) inhaled air in 8 niosh/docs/2009-147/pdfs/2009-147.pdf ]. Ac-
hours, and a factor of 75% for retention of cessed 07–07–10.
SRC [2009]. Interactive PhysProp database demo
the airborne substance in the lungs during [http://www.srcinc.com/what-we-do/databas-
respiration (retention factor, or RF). eforms.aspx?id=386]. Accessed 12–02–09.

Skin Notation Profiles | DNB 9

 DNB

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

Variables used in calculation Units Value

Skin permeation coefficient
Permeation coefficient of stratum corneum lipid
path(Kpsc) cm/hr 0.00245
Permeation coefficient of the protein fraction of the
stratum corneum (Kpol) cm/hr 1.17155 × 10-5
Permeation coefficient of the watery epidermal layer
(Kaq) cm/hr 0.19282
Molecular weight (MW) *
amu 168.11
Base-10 logarithm of its octanol–water partition co-
efficient (Log KOW )* None 1.69
Calculated skin permeation coefficient (Kp) cm/hr 0.00243
Skin dose
Water solubility (Sw)* mg/cm3 0.13
Calculated skin permeation coefficient (Kp) cm/hr 0.00243
Estimated skin surface area (palms of hand) cm 2
360
Exposure time hr 8
Calculated skin dose mg 0.93
Inhalation dose
Occupational exposure limit (OEL)† mg/m3 1
Inhalation volume m 3
10
Retention factor (RF) None 0.75
Inhalation dose mg 7.5
Skin dose–to–inhalation dose (SI) ratio None 0.12

Variables identified from SRC [2009].

*

The OEL used in calculation of the SI ratio was the NIOSH-recommended exposure limit (REL)
†

[NIOSH 2005].

10 Skin Notation Profiles | DNB

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