United States
kS^laMIjk Environmental Protection
^J^iniiil m11 Agency
EPA/690/R-15/003F
Final
9-14-2015
Provisional Peer-Reviewed Toxicity Values for
2-Chlorobenzoic Acid
(CASRN 118-91-2)
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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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Dan D. Petersen, PhD, DABT
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
National Center for Environmental Assessment, Cincinnati, OH
This document was externally peer reviewed under contract to
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the contents of this document may be directed to the U.S. EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center (513-569-7300).
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS	iv
BACKGROUND	1
DISCLAIMERS	1
QUESTIONS REGARDING PPRTVs	 1
INTRODUCTION	2
REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER)	4
DERIVATION 01 PROVISIONAL VALUES	4
DERIVATION 01 ORAL REFERENCE DOSES	4
Feasibility of Deriving Subchronic and Chronic Provisional Reference Doses (p-RfDs)	4
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS	4
Feasibility of Deriving Subchronic and Chronic Provisional Reference Concentrations
(p-RfCs)	4
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR	4
MODE-OF-ACTION (MOA) DISCI SSION	4
ALTERNATIVE METHODS	5
REFERENCES	6
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COMMONLY USED ABBREVIATIONS AND ACRONYMS
a2u-g
alpha 2u-globulin
MN
micronuclei
ACGIH
American Conference of Governmental
MNPCE
micronucleated polychromatic

Industrial Hygienists

erythrocyte
AIC
Akaike's information criterion
MOA
mode of action
ALD
approximate lethal dosage
MTD
maximum tolerated dose
ALT
alanine aminotransferase
NAG
N-acetyl-P-D-glucosaminidase
AST
aspartate aminotransferase
NCEA
National Center for Environmental
atm
atmosphere

Assessment
ATSDR
Agency for Toxic Substances and
NCI
National Cancer Institute

Disease Registry
NOAEL
no-observed-adverse-effect level
BMD
benchmark dose
NTP
National Toxicology Program
BMDL
benchmark dose lower confidence limit
NZW
New Zealand White (rabbit breed)
BMDS
Benchmark Dose Software
OCT
ornithine carbamoyl transferase
BMR
benchmark response
ORD
Office of Research and Development
BUN
blood urea nitrogen
PBPK
physiologically based pharmacokinetic
BW
body weight
PCNA
proliferating cell nuclear antigen
CA
chromosomal aberration
PND
postnatal day
CAS
Chemical Abstracts Service
POD
point of departure
CASRN
Chemical Abstracts Service Registry
PODadj
duration-adjusted POD

Number
QSAR
quantitative structure-activity
CBI
covalent binding index

relationship
CHO
Chinese hamster ovary (cell line cells)
RBC
red blood cell
CL
confidence limit
RDS
replicative DNA synthesis
CNS
central nervous system
RfC
inhalation reference concentration
CPN
chronic progressive nephropathy
RfD
oral reference dose
CYP450
cytochrome P450
RGDR
regional gas dose ratio
DAF
dosimetric adjustment factor
RNA
ribonucleic acid
DEN
diethylnitrosamine
SAR
structure activity relationship
DMSO
dimethylsulfoxide
SCE
sister chromatid exchange
DNA
deoxyribonucleic acid
SD
standard deviation
EPA
Environmental Protection Agency
SDH
sorbitol dehydrogenase
FDA
Food and Drug Administration
SE
standard error
FEVi
forced expiratory volume of 1 second
SGOT
glutamic oxaloacetic transaminase, also
GD
gestation day

known as AST
GDH
glutamate dehydrogenase
SGPT
glutamic pyruvic transaminase, also
GGT
y-glutamyl transferase

known as ALT
GSH
glutathione
SSD
systemic scleroderma
GST
glutathione-S-transferase
TCA
trichloroacetic acid
Hb/g-A
animal blood-gas partition coefficient
TCE
trichloroethylene
Hb/g-H
human blood-gas partition coefficient
TWA
time-weighted average
HEC
human equivalent concentration
UF
uncertainty factor
HED
human equivalent dose
UFa
interspecies uncertainty factor
i.p.
intraperitoneal
UFh
intraspecies uncertainty factor
IRIS
Integrated Risk Information System
UFS
subchronic-to-chronic uncertainty factor
IVF
in vitro fertilization
UFd
database uncertainty factor
LC50
median lethal concentration
U.S.
United States of America
LD50
median lethal dose
WBC
white blood cell
LOAEL
lowest-observed-adverse-effect level


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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
2-CHLOROBENZOIC ACID (CASRN 118-91-2)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant
scientific literature using established Agency guidance on human health toxicity value
derivations. All PPRTV assessments receive internal review by a standing panel of National
Center for Environment Assessment (NCEA) scientists and an independent external peer review
by three scientific experts.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
The PPRTV review process provides needed toxicity values in a quick turnaround
timeframe while maintaining scientific quality. PPRTV assessments are updated approximately
on a 5-year cycle for new data or methodologies that might impact the toxicity values or
characterization of potential for adverse human health effects and are revised as appropriate. It is
important to utilize the PPRTV database flittp://hhpprtv.ornl.gov) to obtain the current
information available. When a final Integrated Risk Information System (IRIS) assessment is
made publicly available on the Internet (http://www.epa.eov/iris). the respective PPRTVs are
removed from the database.
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
limitations of the data. All users are advised to review the information provided in this
document to ensure that the PPRTV used is appropriate for the types of exposures and
circumstances at the site in question and the risk management decision that would be supported
by the risk assessment.
Other U.S. Environmental Protection Agency (EPA) programs or external parties who
may choose to use PPRTVs are advised that Superfund resources will not generally be used to
respond to challenges, if any, of PPRTVs used in a context outside of the Superfund program.
This document has been reviewed in accordance with U.S. EPA policy and approved for
publication. Mention of trade names or commercial products does not constitute endorsement or
recommendation for use.
QUESTIONS REGARDING PPRTVs
Questions regarding the contents and appropriate use of this PPRTV assessment should
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).
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INTRODUCTION
2-Chlorobenzoic acid (CASRN 118-91-2) is an industrial chemical used as a solvent and
an intermediate in the manufacture of surfactants, pharmaceuticals, and other organic
compounds. The molecular formula of 2-chlorobenzoic acid (also known as
ortho-chlorobenzoic acid) is C7H5CIO2 (see Figure 1). A list of physicochemical properties is
provided in Table 1.
°^0H
/N. XI
Figure 1. 2-Chlorobenzoic Acid Structure
Table 1. Physicochemical Properties of 2-Chlorobenzoic Acid (CASRN 118-91-2)3
Property (unit)
Value
Boiling point (°C)
287
Melting point (°C)
140.2
Density (g/cm3 at 20°C)
ND
Vapor pressure (lmnHg at 25°C)
0.0
pH (unitless)
ND
Solubility in water (mg/L at 25 °C)
2,090
Relative vapor density (air = 1)
ND
Molecular weight (g/mol)
156.5675
TliemTDnliis (2015V
ND = no data.
Table 2 provides a summary of available toxicity values for 2-chlorobenzoic acid from
U.S. EPA and other regulatory agencies or organizations.
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Table 2. Summary of Available Toxicity Values for
2-ChlorobenzoicAcid (CASRN 118-91-2)
Sou rce/Parameterab
Value (applicability)
Reference
Noncancer
ACGIH
NV
ACGIH (2015)
ATSDR
NV
ATSDR (2015)
Cal/EPA
NV
Cal/EPA (2014): Cal/EPA (2015a): Cal/EPA
(2015b)
NIOSH
NV
NIOSH (2015)
OSHA
NV
OSHA (2011). OSHA (2006)
IRIS
NV
U.S. EPA (2015)
DWSHA
NV
U.S. EPA (2012)
HEAST
NV
U.S. EPA (2011)
CARA HEEP
NV
U.S. EPA (1994)
WHO
NV
WHO (2015)
Cancer
IRIS
NV
U.S. EPA (2015)
HEAST/WOE
NV
U.S. EPA (2011)
IARC
NV
IARC (2015)
NTP
NV
NTP (2014)
Cal/EPA
NV
Cal/EPA (2015a): Cal/EPA (2015b):
Cal/EPA (2011)
"Sources: ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic
Substances and Disease Registry; Cal/EPA = California Environmental Protection Agency; CARA = Chemical
Assessments and Related Activities; DWSHA = Drinking Water Standards and Health Advisories;
HEAST = Health Effects Assessment Summary Tables; HEEP = Health and Environmental Effects Profile;
IARC = International Agency for Research on Cancer; IRIS = Integrated Risk Information System;
NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program;
OSHA = Occupational Safety and Health Administration; WHO = World Health Organization.
' Parameters: WOE = cancer weight of evidence (U.S. EPA. 20051.
NV = not available.
Literature searches were conducted on sources published from 1900 through March 2015
for studies relevant to the derivation of provisional toxicity values for 2-chlorobenzoic acid
(CASRN 118-91-2). The following databases were searched by chemical name, synonyms, or
CASRN: ACGIH, ANEUPL, ATSDR, BIOSIS, Cal/EPA, CCRIS, CDAT, ChemlDplus, CIS,
CRISP, DART, EMIC, EPIDEM, ETICBACK, FEDRIP, GENE-TOX, HAPAB, HERO, HMTC,
HSDB, IARC, INCHEM IPCS, IP A, ITER, IUCLID, LactMed, NIOSH, NTIS, NTP, OSHA,
OPP/RED, PESTAB, PPBIB, PPRTV, PubMed (toxicology subset), RISKLINE, RTECS,
TOXLINE, TRI, U.S. EPA IRIS, U.S. EPA HEAST, U.S. EPA HEEP, U.S. EPA OW, and
U.S. EPA TSCATS/TSCATS2. The following databases were searched for toxicity values or
exposure limits: ACGIH, ATSDR, Cal EPA, U.S. EPA IRIS, U.S. EPA HEAST, U.S. EPA
HEEP, U.S. EPA OW, U.S. EPA TSCATS/TSCATS2, NIOSH, NTP, OSHA, and RTECS.
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REVIEW OF POTENTIALLY RELEVANT DATA
(NONCANCER AND CANCER)
The available data on 2-chlorobenzoic acid primarily focuses on its biodegradation and
biotransformation by microorganisms and its synthesis and use in the development of analytical
methods. No information is available regarding repeated-dose oral or inhalation exposure of
humans or animals to 2-chlorobenzoic acid. A genetic toxicology study was conducted in
Salmonella (Zeiger et at.. 1992). which was negative. The chemical is being tested as part of
Tox 21 and is in the NTP 1408 compound library. However, these tests are mechanistic studies
and, do not provide endpoints that are currently usable for identifying a point of departure
(POD). PubChem lists 263 in vitro assays, in which the only positive result was for
antihemorrhagic activity in ddY mouse assessed as inhibition of Protobothrops flavoviridis
venom-induced hemorrhagic lesion formation. The only in vivo toxicological data available are
median lethal dose (LD50) values in rats of >500 mg/kg oral (NRC. 1953) (Verschueren. 1983).
although some references cite this value as being from rabbits, and 2,300 mg/kg intraperitoneally
in rabbits (Carminati et at.. 1973). There are also Draize test results in rabbits, where 20 mg was
scored moderate in the eye test and 500 mg was scored as mild in the skin test (ChemCas, 2015).
There is also some information about metabolism and excretion (Btacktedge et at.. 2000).
DERIVATION OF PROVISIONAL VALUES
DERIVATION OF ORAL REFERENCE DOSES
Feasibility of Deriving Subchronic and Chronic Provisional Reference Doses (p-RfDs)
No sub chronic-duration, chronic-duration, developmental toxicity, reproductive toxicity,
or carcinogenicity studies on 2-chlorobenzoic acid via the oral route have been identified. Thus,
no oral reference doses can be derived. However, as noted below, a computational toxicological
surrogate approach was attempted.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
Feasibility of Deriving Subchronic and Chronic Provisional Reference Concentrations
(p-RfCs)
No sub chronic-duration, chronic-duration, developmental toxicity, reproductive toxicity,
or carcinogenicity studies on 2-chlorobenzoic acid via the inhalation route have been identified.
Thus, no inhalation reference doses can be derived. However, as noted below, a computational
toxicological surrogate approach was attempted.
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
Limitations in the available data preclude development of a weight-of-evidence (WOE)
descriptor.
MODE-OF-ACTION (MOA) DISCUSSION
Limitations in the available data preclude determination of a mode of action (MOA)
discussion.
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ALTERNATIVE METHODS
The surrogate approach allows for the use of data from related compounds to calculate
screening values when data for the compound of interest are limited or unavailable. Details
regarding searches and methods for surrogate analysis are presented in Wane et al. (2012).
Three types of potential surrogates (structural, metabolic, and toxicity) are identified to facilitate
the final surrogate chemical selection. The surrogate approach may or may not be route-specific
or applicable to multiple routes of exposure. All information has been considered together as
part of the final WOE approach to select the most suitable surrogate, both toxicologically and
chemically.
An initial surrogate search focused on identifying structurally similar chemicals with
toxicity values from the Integrated Risk Information System (IRIS), PPRTV, and Health Effects
Assessment Summary Tables (HEAST) databases to take advantage of the well-characterized
chemical-class information. This task was accomplished by searching the U.S. EPA's DSSTox
database (DSSTox, 2012) at similarity levels >60% and the National Library of Medicine's
ChemlDplus database (ChemlDplus. 2015) at similarity levels >80%. The search revealed
several structurally related chemicals could serve as potential surrogates for 2-chlorobenzoic
acid. DSS-Tox identified several related chemicals: (1) four dichlorobenzoic acid isomers (2,3-;
2,4-; 2,5-; and 2,6-); (2) two monochlorobenzoic acid isomers (3- and 4-);
(3) 2,3,6-trichlorobenzoic acid; and (4) chlorobenzaldehyde. These eight unique compounds had
similarity scores over 70%. ChemlDplus identified three others, including 2-iodobenzoic acid,
2-fluorobenzoic acid, and 2-bromobenzoic acid. However, there is no in vivo repeated-dose
information on any of these closely related compounds to compare with 2-chlorobenzoic acid for
matching health effects. Because 2-chlorobenzoic acid is primarily excreted in the urine as the
glycine conjugate (Blackledae et al.. 2000). no other metabolic surrogates are available. The
only data available are LD50 values. Due to a lack of repeated-dose toxicity information for any
of the potential structural surrogates, derivation of risk values (e.g., oral reference dose [RfD],
inhalation reference concentration [RfC], and oral cancer slope factor [OSF]) based on the
computational toxicological surrogate approach (Wane et al.. 2012) is not feasible for
2-chlorobenzoic acid.
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REFERENCES
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AT SDR (Agency for Toxic Substances and Disease Registry). (2015). Minimal risk levels
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to cause cancer or reproductive toxicity August 25, 2015. (Proposition 65 list).
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Cal/EPA (California Environmental Protection Agency). (2015b). OEHHA toxicity criteria
database [Database], Sacramento, CA: Office of Environmental Health Hazard
Assessment. Retrieved from http://www.oehha.ca.gov/tcdb/index.asp
Carminati- GM; Chiabotto. L; Duzzi. L. (1973). [Inhibition of the appearance of gastric ulcers in
rats, using benzoic acid derrivatives]. Boll Chim Farm 112: 53-63.
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evaluation of carcinogenic risk to humans. Geneva, Switzerland: International Agency for
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NTP (National Toxicology Program). (2014). Report on carcinogens. Thirteenth edition.
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