United States
Environmental Protection
1=1 m m Agency
EPA/690/R-06/016F
Final
6-16-2006
Provisional Peer Reviewed Toxicity Values for
1,4-Dinitrobenzene (/?-Dinitrobenzene)
(CASRN 100-25-4)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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Acronyms and Abbreviations
bw	body weight
cc	cubic centimeters
CD	Caesarean Delivered
CERCLA	Comprehensive Environmental Response, Compensation and Liability Act
of 1980
CNS	central nervous system
cu.m	cubic meter
DWEL	Drinking Water Equivalent Level
FEL	frank-effect level
FIFRA	Federal Insecticide, Fungicide, and Rodenticide Act
g	grams
GI	gastrointestinal
HEC	human equivalent concentration
Hgb	hemoglobin
i.m.	intramuscular
i.p.	intraperitoneal
IRIS	Integrated Risk Information System
IUR	inhalation unit risk
i.v.	intravenous
kg	kilogram
L	liter
LEL	lowest-effect level
LOAEL	lowest-observed-adverse-effect level
LOAEL(ADJ)	LOAEL adjusted to continuous exposure duration
LOAEL(HEC)	LOAEL adjusted for dosimetric differences across species to a human
m	meter
MCL	maximum contaminant level
MCLG	maximum contaminant level goal
MF	modifying factor
mg	milligram
mg/kg	milligrams per kilogram
mg/L	milligrams per liter
MRL	minimal risk level
MTD	maximum tolerated dose
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MTL
median threshold limit
NAAQS
National Ambient Air Quality Standards
NOAEL
no-observed-adverse-effect level
NOAEL(ADJ)
NOAEL adjusted to continuous exposure duration
NOAEL(HEC)
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-observed-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
PBPK
physiologically based pharmacokinetic
PPb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor
Hg
microgram
|j,mol
micromoles
voc
volatile organic compound
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06-16-2006
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
1,4-DINITROBENZENE (p-DINITROBENZENE) (CASRN 100-25-4)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because science and available information evolve, PPRTVs are initially derived with a
three-year life-cycle. However, EPA Regions or the EPA Headquarters Superfund Program
sometimes request that a frequently used PPRTV be reassessed. Once an IRIS value for a
specific chemical becomes available for Agency review, the analogous PPRTV for that same
chemical is retired. It should also be noted that some PPRTV manuscripts conclude that a
PPRTV cannot be derived based on inadequate data.
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Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
This document has passed the STSC quality review and peer review evaluation indicating
that the quality is consistent with the SOPs and standards of the STSC and is suitable for use by
registered users of the PPRTV system.
INTRODUCTION
The HEAST (U.S. EPA, 1997) lists a subchronic RfD of 4E-3 mg/kg-day and a chronic
RfD of 4E-4 mg/kg-day for 1,4-dinitrobenzene derived by analogy to 1,3-dinitrobenzene. The
assessment for 1,3-dinitrobenzene (m-dinitrobenzene) was based on a subchronic NOAEL of 0.4
mg/kg-day and LOAEL of 1.1 mg/kg-day for increased splenic weight in rats, and included an
uncertainty factor (UF) of 100 (10 for extrapolation from animal data and 10 for sensitive
individuals) for the subchronic RfD, and 1000 (including an additional UF of 10 for the use of a
subchronic study) for the chronic RfD. The source document was a Health and Environmental
Effects Profile (HEEP) for dinitrobenzenes (U.S. EPA, 1985) that derived a chronic allowable
2

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daily intake (ADI) for 1,4-dinitrobenzene by analogy equal to the chronic ADI for 1,3-
dinitrobenzene. Because the HEAST derivations did not employ UFs for database deficiencies,
the RfDs for 1,4-dinitrobenzene in the HEAST are higher than the current RfD for 1,3-
dinitrobenzene on IRIS (1E-4 mg/kg-day), which added a database uncertainty factor of 3 (total
UF = 3000) to the previous assessment (U.S. EPA, 2006). The HEAST (U.S. EPA, 1997) does
not list an RfC or cancer assessment for 1,4-dinitrobenzene. However, a Health and
Environmental Effects Document (HEED) for dinitrobenzenes (U.S. EPA, 1991a) assigned 1,4-
dinitrobenzene to weight-of-evidence Group D, not classifiable as to human carcinogenicity,
because of a lack of human and animal data and negative results for genotoxicity in bacteria.
1,4-Dinitrobenzene is not included on IRIS (U.S. EPA, 2006) or the Drinking Water Standards
and Health Advisories list (U.S. EPA, 2000). Aside from the HEEP, no additional relevant
documents are included in the CARA list (U.S. EPA, 1991b, 1994).
ACGIH (2001a,b) established a TLV-TWA of 0.15 ppm (1 mg/m3) for all three isomers
(1,2-, 1,3- and 1,4- isomers) of dinitrobenzene, with a skin notation, to protect against anoxia
resulting from methemoglobin formation. This value was based on the TLV-TWA of 2 ppm (7.6
mg/m3) for aniline (ACGIH, 2001c) and the relatively higher methemoglobin-producing capacity
of dinitrobenzenes compared to aniline. The NIOSH (2001) REL-TWA for 1,4-dinitrobenzene is
also 1 mg/m3 with a skin notation to protect against methemoglobinemia and effects on the liver,
cardiovascular system, eyes, skin, and central nervous system. OSHA (2002a,b) established a
PEL-TWA of 1 mg/m3 with a skin notation for all dinitrobenzenes to protect against the same
effects and, in addition, kidney damage.
ATSDR (2002) and the WHO (2002) have not published toxicological reviews on 1,4-
dinitrobenzene; ATSDR (1995) published a toxicological profile on 1,3-dinitrobenzene, but this
document has no information about 1,4-dinitrobenzene. IARC (2002) and the NTP (2002) have
not evaluated the carcinogenicity of 1,4-dinitrobenzene. Toxicity reviews on aromatic nitro
compounds (Benya and Cornish, 1994; Weisburger and Hudson, 2001) were consulted for
relevant information. Literature searches were conducted for the period from 1984 to December
2001 to identify data relevant for the derivation of a provisional RfD, RfC and cancer assessment
for 1,4-dinitrobenzene. The following databases were searched: TOXLINE, MEDLINE,
CANCERLIT, TOXLIT/BIOSIS, RTECS, HSDB, GENETOX, CCRIS, TSCATS,
EMIC/EMICBACK and DART/ETICBACK.
REVIEW OF PERTINENT DATA
Human Studies
No data were located regarding oral exposure of humans to 1,4-dinitrobenzene or
subchronic or chronic inhalation exposure of humans to 1,4-dinitrobenzene at known levels. In
general, occupational incidents involved combined inhalation and dermal exposure and exposure
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06-16-2006
levels were not reported (ACGIH, 2001b). Cyanosis and methemoglobinemia were the major
health effects. Following chronic exposures to dinitrobenzenes, anemia and sometimes hepatic
injury, impaired vision, and yellow discoloration of the conjunctiva and sclera of the eye were
observed.
Animal Studies
No data were located on the toxicity of 1,4-dinitrobenzene in animals following chronic
or subchronic oral or inhalation exposure.
Analogy to 1,3-Dinitrobenzene
Data on physical properties, pharmacokinetics and acute effects suggest that toxicity from
chronic oral exposure to 1,4-dinitrobenzene will be similar to that of 1,3-dinitrobenzene. The
physical properties of the two isomers are generally similar, except that the 1,4-isomer is
considerably less soluble in water and has a higher melting point (Table 1).
Table 1. Selected Properties of Dinitrobenzenes (U.S. EPA, 1985,1991a; O'Neil et al., 2001)
Physical and Chemical Property
1,4-Dinitrobenzene
1,3-Dinitrobenzene
Physical state
white crystalline solid
yellow crystalline solid
Melting point °C
172-173
89.9
Boiling point °C
299 (at 777 mm Hg)
291 (at 756 mm Hg)
Specific gravity
1.6
1.546
Vapor pressure (mm Hg)
2.11 x 10"4
2.23 x 10"4
Water solubility (mg/L)
80 at 20°C
370 at 20°C
Log octanol/water partition
coefficient
1.46
1.49
Pharmacokinetic data suggest a similar fate for all three dinitrobenzenes in mammalian
systems (U.S. EPA, 1991a). Gavage studies in rats and rabbits showed a high degree of
absorption by the gastrointestinal tract and urinary excretion as the major route of elimination;
significant biliary excretion was reported. In rabbits gavaged with single doses of 50-100 mg/kg
of l,3-dinitro-[14C]-benzene, absorption of was >95% of the dose. Recovery of radioactivity
over 48 hours accounted for 65-93% of the dose in urine and <5% in feces. In rats given single
doses of 25.2 mg/kg of radiolabeled isomer, absorption was at least 91.3% for 1,4-
dinitrobenzene, 82.6% for 1,3-dinitrobenzene and 92.4% for 1,2-dinitrobenzene. Radioactivity
4

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in urine accounted for 75.1, 63.2 and 81.3% of the dose, and in feces, 8.7, 17.4 and 7.6% of the
dose for 1,4-, 1,3- and 1,2-dinitrobenzene, respectively.
Analysis of urinary metabolites in rats gavaged with dinitrobenzenes revealed some
differences in metabolic pathways (U.S. EPA, 1991a; Benya and Cornish, 1994). The major
urinary metabolites of 1,3-dinitrobenzene were 3-aminoacetanilide (22%), 4-acetamidophenyl
sulfate (6%), 1,3-diacetamidobenzene (7%) and 3-nitroanilinc-A''-glucuronidc. The major urinary
metabolites of 1,2-dinitrobenzene were 5*-(2-nitrophenyl)-A^-acetylcysteine (42%), 2-nitroaniline-
/Y-glucuronide (4%), 2-amino-3-nitrophenyl sulfate (1.5%) and 2-(A,'-hydroxylaminc)-
nitrobenzene (1-2%). The major urinary metabolites of 1,4-dinitrobenzene were 2-amino-5-
nitrophenyl sulfate (35%), 5*-(4-nitrophenyl)-A^-acetylcysteine (13%) and 1,4-
diacetamidobenzene (7%). These results indicate that 1,3-dinitrobenzene was metabolized
exclusively by reduction of the nitro groups to amines, which were subsequently acetylated. No
direct conjugation to glutathione was detected for 1,3-dinitrobenzene, whereas that process was
the major metabolic pathway for 1,2-dinitrobenzene. 1,4-Dinitrobenzene was metabolized by
both of these pathways, but its major pathway involved reduction of a nitro group followed by
hydroxylation of the phenyl ring and sulfate conjugation of the phenol.
Comparative in vitro analysis of the metabolites in rat erythrocytes or hepatocytes
exposed for 30 minutes also demonstrated differences and similarities among the isomers (U.S.
EPA, 1991a; Rickert, 1987). In erythrocytes, 6% of added 1,4-dinitrobenzene was conjugated to
glutathione, 10% was reduced to 4-nitrophenylhydroxylamine and 40% was covalently bound to
erythrocyte macromolecules. In erythrocytes treated with 1,3-dinitrobenzene, no metabolites
were detected, but 2% was covalently bound to macromolecules. In erythrocytes treated with
1,2-dinitrobenzene, 37% was conjugated to glutathione and 24% was conjugated to
macromolecules. In hepatocytes, a significant proportion of all three isomers was converted to
the related nitroaniline (30% 2-nitroaniline, 74% 3-nitroaniline and 81% 4-nitroaniline) and no
covalent binding of any isomer was detected. Glutathione conjugation represented 48% of the
1,2-dinitrobenzene added to hepatocytes. These experiments indicate that all dinitrobenzene
isomers, to some degree, covalently bind to macromolecules in erythrocytes and are metabolized
to another methemoglobin-producing compound (nitroaniline) in the liver (see below).
Acute oral exposure to dinitrobenzenes causes methemoglobin formation in humans and
animals (U.S. EPA, 1985, 1991a). In an acute occupational incident, five steampress operators
exposed to an adhesive containing 1% 1,4-dinitrotoluene as a contaminant developed blood
methemoglobin levels as high as 41.2% and symptoms including cyanosis, headache, nausea,
chest pain, dizziness and confusion (U.S. EPA, 1991a; Benya and Cornish, 1994). One worker
had a seizure. In a simulation later conducted by OSHA, the blood methemoglobin level of the
steampress operator rose to 12.5% after 2 hours. The incident involved combined inhalation and
dermal exposure. An acute oral LD0 of 28 mg/kg has been reported for 1,3-dinitrobenzene in
humans (U.S. EPA, 1991a). The acute oral LD0 in rats was 29 mg/kg for 1,4-dinitrobenzene and
27 mg/kg for 1,3-dinitrobenzene (U.S. EPA, 1991a). The acute oral LD0s in rats were 250, 27
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and 29 mg/kg for 1,2-, 1,3- and 1,4-dinitrobenzene, respectively (Watanabe et al, 1976; U.S.
EPA, 1991a). In rats injected i.p. with 100 |iM dinitrobenzene isomer, methemoglobin levels
five hours after injection were 13.1, 25.5 and 29.5% for 1,2-, 1,3- and 1,4-dinitrobenzene,
respectively (Watanabe et al., 1976). In single-dose studies in rats, treatment with >16 mg/kg of
1,3-dinitrobenzene caused testicular lesions that were not caused by the other dinitrobenzenes
(U.S. EPA, 1991a).
In vitro studies demonstrated that 1,4-dinitrobenzene was about ten times more potent
than 1,2-dinitrobenzene in inducing methemoglobin formation in freshly-drawn sheep
erythrocytes, and neither compound required metabolic activation for its effect (French et al.,
1995); 1,3-dinitrobenzene was not effective on sheep erythrocytes. Methemoglobin levels about
four times higher than control were produced by treatment with 0.005 mM 1,4-dinitrobenzene or
0.05 mM 1,2-dinitrobenzene. The related nitroanilines were also significant inducers of
methemoglobin formation, but their effect required the presence of an NADP bioactivation
system. 4-Nitroaniline was more potent than 2- or 3-nitroaniline; approximately four-fold
increases in methemoglobin were induced by 0.005 mM 4-nitroaniline, 0.25 mM 3-nitroaniline
or 0.05 mM 2-nitroaniline.
There is some in vitro evidence for genotoxicity of 1,4- and 1,3-dinitrobenzene (U.S.
EPA, 1985, 1991a). With or without metabolic activation, 1,4- and 1,3-dinitrobenzene did not
induce reverse mutations in Salmonella typhimurium strains TA100NR (nitroreductase-deficient)
or TA1537. 1,3-Dinitrobenzene yielded positive results in strains TA98 and TA1538, and
conflicting, but usually positive, results in TA100 and TA1535, whereas 1,4-dinitrobenzene
gave conflicting results in all of these strains and only tested positively at higher concentrations
(U.S. EPA, 1985, 1991a). Neither 1,4- nor 1,3-dinitrobenzene induced unscheduled DNA
synthesis in cultured rat hepatocytes (U.S. EPA, 1991a). 1,4-Dinitrobenzene, as well as the 1,2-
and 1,3- isomers, induced chromosomal aberrations in peripheral lymphocytes obtained from a
human male donor (Huang et al., 1996); in this study, all three isomers tested positive at
concentrations of > 1 mmol/1.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL RfD VALUES FOR 1,4-DINITROBENZENE
BY ANALOGY TO 1,3-DINITROBENZENE
No data are available for the chronic or subchronic oral toxicity of 1,4-dinitrobenzene in
humans or animals. However, a chronic RfD of 1E-4 mg/kg-day is available for 1,3-
dinitrobenzene on IRIS (U.S. EPA, 2006) and a related subchronic RfD1 of 1E-3 is available for
'The HEAST (1997) misstates the uncertainty factor for the subchronic RfD for 1,3-dinitrobenzene; it was
300 and not 100.
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1.3-dinitrobenzene	in the HEAST (U.S. EPA, 1997). The chronic RfD was based on increased
splenic weight (apparently secondary to erythrocyte effects) in rats treated with 8 ppm of 1,3-
dinitrobenzene in drinking water for 16 weeks (Cody et al., 1981). The chronic RfD for 1,3-
dinitrobenzene was calculated by applying an uncertainty factor of 3000 (10 for extrapolation
from rats to humans, 10 to protect sensitive individuals, 10 for the use of a subchronic study, and
3 for database deficiencies) to the NOAEL of 0.4 mg/kg-day (3 ppm).
In order to derive an oral p-RfD for 1,4-dinitrobenzene by analogy to 1,3-dinitrobenzene,
the two isomers must be sufficiently similar in physical properties, fate in the body and nature of
their toxic effects to justify the extrapolation. This is largely a matter of judgement. As noted
above, the physical properties of 1,4- and 1,3-dinitrobenzene are similar and both isomers have
the ability to convert hemoglobin to methemoglobin. Although there are differences in
pharmacokinetic pathways, the major hepatic metabolites (nitroanilines) of both compounds are
also methemoglobin-producing. The similar acute toxicity of 1,4- and 1,3-dinitrobenzene
suggests that p-RfDs based on 1,3-dinitrobenzene will be sufficiently protective for exposures to
1.4-dinitrobenzene.	Therefore, the chronic RfD of 1E-4 mg/kg-day for 1,3-dinitrobenzene on
IRIS (U.S. EPA, 2006) is adopted as the chronic p-RfD for 1,4-dinitrobenzene. The subchronic
RfD for 1,4-dinitrobenzene is derived by eliminating the uncertainty factor of 10 for use of the
subchronic study, resulting in a subchronic p-RfD of 1E-3 mg/kg-day for 1,4-dinitrobenzene.
These RfD values are lower than those in the HEAST (U.S. EPA, 1997) because the new
derivations include uncertainty factors for data base deficiencies.
Confidence in the p-RfDs for 1,4-dinitrobenzene is low, as no relevant studies were
located and the RfDs were derived by analogy to the 1,3-dinitrobenzene isomer.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR 1,4-DINITROBENZENE
No data are available for the chronic or subchronic inhalation toxicity of 1,4-
dinitrobenzene in humans or animals. In addition, no information is available for the other
isomers of dinitrobenzene. In the absence of compound-specific data or data on close analogs, it
is not feasible to derive subchronic or chronic p-RfCs for 1,4-dinitrobenzene.
DERIVATION OF A PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR 1,4-DINITROBENZENE
No human or animal carcinogenicity data were located for 1,4-dinitrobenzene. In vitro
genotoxicity data indicate that the compound is sometimes mutagenic in bacteria and that it may
induce chromosomal aberration in human lymphocytes. Under the U.S. EPA (2005) cancer
guidelines, the available data are inadequate for an assessment of human carcinogenic potential.
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06-16-2006
Derivation of quantitative estimates of cancer risk for 1,4-dinitrobenzene is precluded by
the absence of carcinogenicity data.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2001a. Threshold limit
values (TLV) for chemical substances and physical agents and biological exposure indices.
ACGIH, Cincinnati, OH. p. 29.
ACGIH (American Conference of Governmental Industrial Hygienists). 2001b. Dinitrobenzene
(All Isomers). Documentation of the Threshold Limit Values and Biological Exposure Indices,
7th Ed. ACGIH, Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hygienists). 2001c. Aniline.
Documentation of the Threshold Limit Values and Biological Exposure Indices, 7th ed. ACGIH,
Cincinnati, OH.
ATSDR (Agency for Toxic Substances and Disease Registry). 1995. Toxicological Profile for
1,3-Dinitrobenzene and 1,3,5-Trinitrobenzene. PB/95/264289/AS.
ATSDR (Agency for Toxic Substances and Disease Registry). 2002. Internet HazDat-
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Benya, T.J. and H.H. Cornish. 1994. Aromatic nitro and amino compounds. In: Patty's
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Cody, T.E., S. Witherup, L. Hastings et al. 1981. 1,3-Dinitrobenzene: Toxic effect in vivo and
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French, C.L., S.-S. Yaun, L.A. Baldwin et al. 1995. Potency ranking of methemoglobin-forming
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Huang, Q.-G., L.-R. Kong, Y.-B. Liu and L.-S. Wang. 1996. Relationships between molecular
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IARC (International Agency for Research on Cancer). 2002. Search IARC agents and summary
evaluations. Online, http://monographs.iarc.fr/
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NIOSH (National Institute for Occupational Safety and Health). 2001. p-Dinitrobenzene.
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http://www.cdc.gov/niosh/npg/npgd0233.html
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OSHA (Occupational Safety and Health Administration). 2002b. Occupational safety and health
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U.S. EPA. 2000. Drinking Water Standards and Health Advisories. Office of Water,
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