United States
kS^laMIjk Environmental Protection
^J^iniiil m11 Agency
EPA/690/R-07/005F
Final
6-19-2007
Provisional Peer Reviewed Toxicity Values for
p-Chlorobenzoic acid
(CASRN 74-11-3)
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
i.v.	intravenous
IRIS	Integrated Risk Information System
IUR	inhalation unit risk
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
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MTD
maximum tolerated dose
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
(.imol
micromoles
voc
volatile organic compound
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6-19-2007
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
p-CHLOROBENZOIC ACID (CASRN 74-11-3)
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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6-19-2007
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.
INTRODUCTION
The HE AST (U.S. EPA, 1997) lists subchronic and chronic RfD values for
p-chlorobenzoic acid of 2E-0 and 2E-1 mg/kg-day, respectively. The source document for this
assessment was a Health and Environmental Effects Document (HEED) (U.S. EPA, 1987). Both
RfD values were based on a free-standing NOAEL of 26 mg/day (173 mg/kg-day) in a 5-month
study in rats (Kieckebusch et al., 1960); uncertainty factors of 100 and 1000 were used to derive
the subchronic and chronic RfD, respectively. No RfD assessment for p-chlorobenzoic acid is
available on IRIS (U.S. EPA, 2005a) or in the Drinking Water Standards and Health Advisories
list (U.S. EPA, 2002). Other than the HEED discussed above, the CARA list (U.S. EPA, 1991,
1994) does not include any relevant documents. The toxicity of p-chlorobenzoic acid has not
been evaluated by ATSDR (2003) or WHO (2003).
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An RfC for p-chlorobenzoic acid is not available on IRIS (U.S. EPA, 2005a) or in the
HEAST (U.S. EPA, 1997). The HEED reports that there were no available inhalation toxicity
data in humans or animals when the document was prepared. Occupational exposure limits for
p-chlorobenzoic acid have not been derived by ACGIH (2003), NIOSH (2003), or OSHA (2003).
The HEED (U.S. EPA, 1987) assigned p-chlorobenzoic acid to cancer weight of evidence
Group D (not classifiable as to human carcinogenicity) based on lack of data via any exposure
route. A cancer assessment for p-chlorobenzoic acid is not available on IRIS (U.S. EPA, 2005a)
or in the Drinking Water Standards and Health Advisories list (U.S. EPA, 2002). The
carcinogenicity of p-chlorobenzoic acid has not been assessed by NTP (2003) or IARC (2003).
Literature searches were conducted from 1986 through September, 2003 for studies
relevant to the derivation of provisional toxicity values for p-chlorobenzoic acid. Databases
searched included: TOXLINE (supplemented with BIOSIS and NTIS updates), MEDLINE,
CANCERLIT, TSCATS, RTECS, CCRIS, DART, EMIC/ EMICBACK, HSDB, and
GENETOX.
REVIEW OF PERTINENT DATA
Human Studies
No data regarding the toxicity of p-chlorobenzoic acid in humans were located.
Animal Studies
Several studies of limited value for toxicity evaluation of p-chlorobenzoic acid have been
conducted in laboratory animals (Kieckebusch et al., 1960; Wuehrer, 1931; D'eng et al., 1983).
Kieckebusch et al. (1960) maintained young (unspecified age) Elberfeld rats (20 per sex and
dose) on commercial feed supplemented with p-chlorobenzoic acid (unspecified purity) at 0%,
0.1%, or 0.2% (w/w) for 5 months (0, 13, or 26 mg/day of p-chlorobenzoic acid, as calculated by
the researchers). Dividing by the estimated rat mean body weight of 0.15 kg (based on rat body
weights at the start and end of the study) yields average estimated doses of 0, 87, or 173 mg/kg-
day. Body weight, food consumption, and protein efficiency (weight gain per gram of food
consumed) were reported for two-week intervals for the first 8 weeks of treatment; values for
these parameters were not reported at time intervals after week 8. Mortality and clinical signs of
toxicity appeared to be evaluated; however, specifics regarding scheduled clinical observations
were not included in the study report. Animals were mated after the first 8 weeks of treatment
and again 2 months later to evaluate the effects of treatment on reproductive ability. The
following reproductive parameters were evaluated: percentage of sterile females, percentage of
females with delayed sexual maturity, number of littered pups per female, survival of pups to 21
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6-19-2007
days of age, and pup weight at 21 days of age. Urine was collected from all treated and control
animals "towards the end" of the 5-month exposure period and examined for protein and sugar
content. Urine sediment was also microscopically examined. All animals were then sacrificed;
the liver, kidneys, heart, spleen, and testes were weighed, and the liver and kidneys were
microscopically examined. The authors reported that no treatment-related effects were observed
on any of the endpoints evaluated. Although they indicated an increase in the percentage of
treated females with delayed sexual maturity in the treated groups (5%, 40%, and 40% in the
control, low-, and high-dose groups, respectively), the study authors concluded that the number
of treated animals was not sufficient to evaluate whether this was a treatment-related effect.
Kieckebusch et al. (1960) reproductive effects study, although limited in several aspects,
was strong in several respects. The number of animals was sufficient (20 rats per group). There
were 3 dose levels including the control (0, 0.1 % = 87 mg/kd-day, and 0.2% =173 mg/kg-day).
The duration of exposure was adequate (5 months). Endpoints included in the study were weight
gain, feed utilization, general health, number of litter young, histological examination of the liver
and kidneys, and organ weight.
Kieckebusch et al. (1960) described a study (Wuehrer, 1931) that evaluated the toxicity of
p-chlorobenzoic acid in dogs. Wuehrer (1931) maintained one dog (unspecified breed) on a diet
supplemented with 3 g per day of p-chlorobenzoic acid for just over a year (-13 months) and
maintained two dogs on a diet supplemented with 1.5 g per day of the substance for almost two
years (20.5 months). Histological examinations were conducted at the end of the exposures
(gastric and intestinal mucosa, unspecified organs). No effects were observed in any of the
treated dogs.
D'eng et al. (1983) reported decreased protein synthesis in the liver and increased levels
of urokaninase (urocanate hydratase) and histidase (markers for liver damage) in the serum of
animals (unspecified species) treated with unspecified oral doses of p-chlorobenzoic acid
(equivalent to 1/10 of the LD50 or 1/50 of the LD50) for up to 2 months. No further details were
available in the English abstract of this study from the Russian literature.
Other Studies
p-Chlorobenzoic acid was negative in Salmonella typhimurium strains TA1535, TA1537,
TA97, TA98, TA100, and TA104 and E. coli WP2UvrA with or without addition of exogenous
metabolic activation (S9) (Zeiger et al., 1992; Ohkubo et al., 1996). Genotoxicity studies using
other test systems were not located.
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DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL RfD VALUES FOR p-CHLOROBENZOIC ACID
No relevant data were located regarding the human toxicity of p-chlorobenzoic acid
following oral exposure. Wuehrer (1931) found no effects in one dog treated with 3 g per day of
p-chlorobenzoic acid for just over a year (-13 months) and two dogs treated with 1.5 g per day of
the substance for almost two years (20.5 months). D'eng (1983) identified the liver as a target
for p-chlorobenzoic acid, but experimental details were not available. The oral toxicity studies of
p-chlorobenzoic acid in animals are of limited utility for risk assessment. Kieckebusch et al.
(1960) found no effects in rats treated with p-chlorobenzoic acid in the diet for 5 months at doses
up to approximately 159 mg/kg-day, but only a limited array of endpoints were assessed. The
primary limitations of this study were the lack of detail on general methods and the apparent
delayed sexual maturity, lack of histology on organs other than liver and kidney, and lack of
methods for calculating exposure. No differences were found in terms of growth, feed utilization
and state of health of the dams. The histological examination of the liver and kidneys did not
reveal any adverse effects. No histological study was done on the reproductive organs and no
endocrine study was done. No differences were found in the number of littered young and their
rearing compared to the controls. The authors noted delayed sexual maturity in 40% of the dams
for both test groups, as compared with the 5% in the controls. The authors concluded that this
effect was not significant because of small sample size but did not report a statistical test.
However, subsequent statistical analysis by the U.S. EPA showed statistical significance at the
low dose group by a t-test (p<0.01) and a statistically-significant trend across all dose groups
(Cochran-Armitage trend test; p<0.01). Kieckebusch et al. (1960) provided no indication of the
severity, duration of the delay of the sexual maturity or how it was observed. The adversity of
the reported effect is uncertain given that there were no other reproductive effects that might
have resulted from the delay. The RfDs in the HEED (U.S. EPA, 1987) and HEAST (U.S. EPA,
1997) were derived from the freestanding NOAEL in the Kieckebusch et al. (1960) study. The
Kieckebusch et al. study, although not sufficiently rigorous for development of PPRTV values,
does provide potentially useful information in this regard. However, the Appendix of this
document contains a Screening Value that may be useful in certain instances. Please see the
attached Appendix for details.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR p-CHLOROBENZOIC ACID
In the absence of subchronic or chronic data on the inhalation toxicity of p-chlorobenzoic
acid in humans or animals, derivation of provisional subchronic or chronic RfC values is
precluded.
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DERIVATION OF A PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR p-CHLOROBENZOIC ACID
There are no human or animal carcinogenicity data for p-chlorobenzoic acid by any
exposure route. The substance is not mutagenic in the Ames test (Zeiger et al., 1992; Ohkubo et
al., 1996), and has not been tested for genotoxicity in other systems. Therefore, under the cancer
guidelines (2005b) the data provide inadequate information to assess carcinogenic potential for
p-chlorobenzoic acid.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2003. 2003 Threshold
Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices.
Cincinnati, OH.
ATSDR (Agency for Toxic Substances and Disease Registry). 2003. Internet HazDat-
Toxicological Profile Query. Online, http://www.atsdr.cdc.gov/toxpro2.html
D'eng, B., A.I. Nikolaev, P.Z. Khasigov et al. 1983. [Evaluation of the hepatotoxic activity of
several chlor-nitro derivatives of benzoic acid.] Vopr. Med. Khim. 29(6): 113-117. (Rus.; Eng.
abstract)
IARC (International Agency for Research on Cancer). 2003. Search of IARC Monographs.
Online. http://193.51.164.il/cgi/iHound/Chem/iH Chem Frames.html
Kieckebusch W., W. Griem and K. Lang. 1960. [The tolerability of p-chlorobenzoic acids.]
Arzneimi Hel-Forsch. 10:999-1001. (Ger.; Eng. trans.)
NIOSH (National Institute for Occupational Safety and Health). 2003. NIOSH Pocket Guide to
Chemical Hazards. Online. http://www.cdc.gOv/niosh/npg/npgd0000.html#F
NTP (National Toxicology Program). 2003. Management Status Report. Online.
http://ntp-server.niehs.nih.gov/cgi/iH Indexes/ALL SRCH/iH ALL SRCH Frames.html
Ohkubo T., S. Goto, O. Endo et al. 1996. Mutagenicity of chlorinated aromatic hydrocarbons
containing oxygen. Kankyo Kagaku. 6(4): 533-540. (Cited in CCRIS database)
OSHA (Occupational Safety and Health Administration). 2003. OSHA Standard 1910.1000
Table Z-l. Part Z, Toxic and Hazardous Substances. Online.
http://www.osha-slc.gov/OshStd data/1910 1000 TABLE Z-l.html
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U.S. EPA. 1987. Health and Environmental Effects Document for p-Chlorobenzoic acid.
Prepared by the Environmental Criteria and Assessment Office, Office of Health and
Environmental Assessment, Cincinnati, OH for the Office of Solid Waste and Emergency
Response, Washington, DC.
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by
the Office of Research and Development, National Center for Environmental Assessment,
Cincinnati OH for the Office of Emergency and Remedial Response, Washington, DC. July.
EPA/540/R-97/036. NTIS PB97-921199.
U.S. EPA. 2002. 2002 Edition of the Drinking Water Standards and Health Advisories. Office
of Water, Washington, DC. EPA 822-R-02-038.
http://www.epa. gov/waterscience/drinking/standards/dwstandards .pdf
U.S. EPA. 2005a. Integrated Risk Information System (IRIS). Office of Research and
Development, National Center for Environmental Assessment, Washington, DC. Online.
http://www.epa. gov/ iris/
U.S. EPA. 2005b. Guidelines for Carcinogen Risk Assessment. Office of Research and
Development, National Center for Environmental Assessment, Washington, DC.
EPA/63 0/P-03/001F.
WHO (World Health Organization). 2003. Online catalogs for the Environmental Health
Criteria Series. Online, http://www.who.int/dsa/cat97/zehcl.htm
Wuehrer, J. 1931. [Title not specified]. Arch. Exp. Pathol. Pharmakol. 161:719. (Cited in
Kieckebusch et al., 1960)
Zeiger E., B. Anderson, S. Haworth et al. 1992. Salmonella Mutagenicity Tests: V. Results
from the Testing of 311 Chemicals. Environ. Mol. Mutagen. 19(Supplement 21): 2-141.
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APPENDIX
DERIVATION OF A SCREENING VALUE FOR
P-CHLOROBENZOIC ACID
For reasons noted in the main PPRTV document, it is inappropriate to derive provisional
toxicity values for p-chlorobenzoic acid, subchronic RfD. However, information is available for
this chemical which, although insufficient to support derivation of a provisional toxicity value,
under current guidelines, may be of limited use to risk assessors. In such cases, the Superfund
Health Risk Technical Support Center summarizes available information in an Appendix and
develops a "Screening Value." Appendices receive the same level of internal and external
scientific peer review as the PPRTV documents to ensure their appropriateness within the
limitations detailed in the document. In the OSRTI hierarchy, Screening Values are considered
to be below Tier 3, "Other (Peer-Reviewed) Toxicity Values."
Screening Values are intended for use in limited circumstances when no Tier 1, 2, or 3
values are available. Screening Values may be used, for example, to rank relative risks of
individual chemicals present at a site to determine if the risk developed from the associated
exposure at the specific site is likely to be a significant concern in the overall cleanup decision.
Screening Values are not defensible as the primary drivers in making cleanup decisions because
they are based on limited information. Questions or concerns about the appropriate use of
Screening Values should be directed to the Superfund Health Risk Technical Support Center.
The Kieckebusch et al. study, although not sufficiently rigorous for development of
PPRTV values, does provide potentially useful information in this regard. Thus, this appendix is
provided with screening values that could be useful for screening or other limited purposes
pursuant to consultation with the Superfund Technical Support Center. Delayed sexual maturity
observed in Kieckebusch et al. (1960) rat reproductive effects study would ordinarily be
considered adverse, and considering the high incidence in both treatment groups, a LOAEL of 80
mg/kg-day could be established based on food consumption of 13 mg/day and mean body weight
of 165 g. The mean body weight value was determined based on integration of the provided
body weight data and an assumption of linearity for the 8-20 week period. A screening
subchronic reference dose of 0.08 mg/kg-day could be derived from the LOAEL of 80 mg/kg-
day by applying an uncertainty factor (UF) of 1000. The UF of 1000 includes 3 (10°5) for
minimal LOAEL (UFL), 3 (10°5) for lack of additional reproductive and developmental toxicity
data (UFd), 10 for interspecies extrapolation (UFA) and 10 for sensitive humans (UFH).
Subchronic screening reference dose = LOAEL UF
= 80 mg/kg-day ^ 1000
= 0.08 (8E-2) mg/kg-day
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Confidence for the study is low because of the lack of detail on the critical effect and other
deficiencies noted in this document. Given the lack of additional studies, confidence in the
database is also low. Thus, confidence in the toxicity value is low.
If subsequent information becomes available indicating that the reported delayed sexual
maturity was not biologically significant, an alternative screening subchronic reference dose
based on a NOAEL at the highest dose could be derived. In this case, a screening subchronic
reference dose of 0.5 mg/kg-day can be calculated for a NOAEL of 160 mg/kg-day using a total
UF of 300 (UFa =10, UFh =10, UFD = 3). Confidence in the study and database would remain
low, yielding low confidence in the value. Given current information, however, the preferred
approach is the one based on the LOAEL for delayed sexual maturity at the low dose, which is
health protective. The quantitative impact of the LOAEL-based approach versus the less-
conservative NOAEL-based one is less an order of magnitude.
Regarding the chronic screening reference dose, applying an additional uncertainty factor
of 3 to the subchronic values gives chronic screening values of 0.03 and 0.2 mg/kg-day
respectively, relative to the two subchronic values discussed previously.
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