United States
kS^laMIjk Environmental Protection
^J^iniiil m11 Agency
EPA/690/R-10/004F
Final
9-30-2010
Provisional Peer-Reviewed Toxicity Values for
o-Chlorotoluene
(CASRN 95-49-8)
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
Nina Ching Y. Wang, Ph.D.
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
ICF International
9300 Lee Highway
Fairfax, VA 22031
PRIMARY INTERNAL REVIEWERS
Geniece M. Lehmann, Ph.D.
National Center for Environmental Assessment, Research Triangle Park, NC
Amanda S. Persad, Ph.D., DABT
National Center for Environmental Assessment, Research Triangle Park, NC
Audrey Galizia, Dr. PH.
National Center for Environmental Assessment, Washington, DC
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	iii
BACKGROUND	1
HISTORY	1
DISCLAIMERS	1
QUESTIONS REGARDING PPRTVS	2
INTRODUCTION	2
REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER)	4
HUMAN STUDIES	7
Oral and Inhalation Exposure	7
ANIMAL STUDIES	7
Oral Exposure	7
Subchronic Studies	7
Chronic Studies	8
Developmental and Reproduction Studies	8
Inhalation Exposure	8
Subchronic Studies	9
Chronic Studies	9
Developmental and Reproduction Studies	9
Other Data (Short-Term Tests, Other Examinations)	10
Acute Studies	10
Short-term Studies	10
Metabolism Studies	10
Genotoxicity Studies	11
DERIVATION 01 PROVISIONAL VALUES	 12
DERIVATION OF ORAL REFERENCE DOSES	12
Derivation of Subchronic p-RfD	12
Adjusted for Daily Exposure	16
Derivation of Chronic p-RfD	17
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS	17
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR	18
YlODIi-OI -ACTION DISCI SSION	 18
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES	18
Derivation of p-OSF	18
Derivation of p-IUR	18
APPENDIX A. PROVISIONAL SCREENING VALUES	19
DERIVATION OF SCREENING SUBCHRONIC INHALATION REFERENCE
CONCENTRATION	19
APPENDIX B. DATA TABLES	22
APPENDIX C. BMD MODELING OUTPUTS FOR o-CHLOROTOLUENE	23
APPENDIX D. REFERENCES	24
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COMMONLY USED ABBREVIATIONS
BMC
benchmark concentration
BMD
benchmark dose
BMCL
benchmark concentration lower bound 95% confidence interval
BMDL
benchmark dose lower bound 95% confidence interval
HEC
human equivalent concentration
HED
human equivalent dose
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELhec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional reference concentration (inhalation)
p-RfD
provisional reference dose (oral)
POD
point of departure
RfC
reference concentration (inhalation)
RfD
reference dose (oral)
UF
uncertainty factor
UFa
animal-to-human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete-to-complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL-to-NOAEL uncertainty factor
UFS
subchronic-to-chronic uncertainty factor
WOE
weight of evidence
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
0-CHLOROTOLUENE (CASRN 95-49-8)
BACKGROUND
HISTORY
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA) 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 (PPRTVs) 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 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 a
panel of six EPA scientists and external peer review by three independently selected scientific
experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the multiprogram
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 new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a 5-year basis and updated into the active database. 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 documents conclude that
a PPRTV cannot be derived based on inadequate data.
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 Resource Conservation and Recovery Act (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.
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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 document 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.
o-Chlorotoluene is used as a basic chemical for the production of intermediates in the
synthesis of other organic chemicals, dyes, pharmaceuticals, and synthetic rubber chemicals, and
as a solvent for chemical processing and for the formulation of agricultural pesticides. It is a
colorless liquid with an aromatic odor. o-Chlorotoluene is produced commercially by
chlorinating toluene at 50°C in the presence of ferric chloride; the chlorotoluene isomers are then
separated by fractional distillation (HSDB, 2005). The molecular formula for o-chlorotoluene is
C7H7CI (see Figure 1). A table of chemico-physical properties is provided below (see Table 1).
In this document, "statistically significant" denotes a/>value of <0.05.
INTRODUCTION
CH
3
CI
Figure 1. o-Chlorotoluene Structure
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Table 1. Physical Properties Table (o-Chlorotoluene)"
Property (unit)
Value
Boiling point (°C)
158.97
Melting point (°C)
-35.59
Density (g/cm3)
1.0826
Vapor pressure (at 25°C)
3.43 mmHg
pH (unitless)
Not available
Solubility in water (mg/L at 25°C)
374
Relative vapor density (air =1)
4.38
Molecular weight (g/mol)
126.6
Flash point (°C)
47
Octanol/water partition coefficient (unitless)
3.42 (Log Kow)
aValues fromHSDB (searched online 03/16/2010; last reviewed 09/19/1996; last revised
06/23/2005).
The EPA IRIS database (U.S. EPA, 1990) reports a noncancer chronic oral RfD for
o-chlorotoluene of 0.02 mg/kg-day based on decreased body-weight gains in a subchronic oral
toxicity study in rats (Gibson et al., 1974a) but does not report an RfC. The Drinking Water
Standards and Health Advisories List (U.S. EPA, 2006) reports an RfD of 0.02 mg/kg-day, a
Drinking Water Equivalent Levels (DWELs) of 0.7 mg/L, and a lifetime Health Advisory (HA)
of 0.1 mg/L for o-chlorotoluene. CalEPA (2009a,b) has not derived toxicity values for exposure
to o-chlorotoluene but lists a drinking water action level of 140 |ig/L. A subchronic oral RfD of
0.02 mg/kg-day was reported in the HEAST (U.S. EPA, 1997), derived from a 103-day oral
gavage study in rats with a LOAEL of 80 mg/kg-day (based on decreased body-weight gains)
and an uncertainty factor (UF) of 100 (same study used by IRIS). The most recent EPA
Regional Screening Level (RSL) Master Table for December 2009 continued to list this value as
the oral RfD based on IRIS. The American Conference of Governmental Industrial Hygienists
(ACGIH, 2001) reported a threshold limit value (TLV) of 50 ppm, 259-mg/m3 time-weighted
average (TWA), and the National Institute of Occupational Safety and Health (NIOSH, 2005) set
"3
a Recommended Exposure Limit (REL) at 50 ppm, 250 mg/m . The Occupational Safety and
Health Administration (OSHA, 2009) set a permissible exposure limit (PEL) of 50 ppm for
o-chlorotoluene. The toxicity of o-chlorotoluene has not been reviewed by the ATSDR (2009) to
determine oral or inhalation Minimal Risk Levels (MRLs). The World Health Organization
(WHO) did not include o-chlorotoluene in the WHO Chemical Safety - Activity Report (WHO,
2009).
The IRIS database (U.S. EPA, 1990) stated that o-chlorotoluene had not undergone a
complete evaluation and determination under the IRIS program for evidence of human
carcinogenic potential. The Drinking Water Standards and Health Advisories List (U.S. EPA,
2006) reported an EPA cancer weight-of-evidence (WOE) classification of Group D (Not
Classifiable as to Human Carcinogenicity) for o-chlorotoluene based on the lack of
carcinogenicity studies in humans or animals. o-Chlorotoluene has not been evaluated under the
2005 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005). The International Agency
for Research on Cancer (IARC, 2009) has not reviewed the carcinogenic potential of
o-chlorotoluene. o-Chlorotoluene is not included in the National Toxicology Program's
11th Report on Carcinogens (NTP, 2005). CalEPA (2009b) has not prepared a quantitative
estimate of carcinogenic potential for o-chlorotoluene.
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Literature searches were conducted from 1900 through August 2010 for studies relevant
to the derivation of provisional toxicity values for o-chlorotoluene, CAS No. 95-49-8. We used
the EPA Health and Environmental Research Online (HERO) evergreen database of scientific
literature that searches the following databases: AGRICOLA; American Chemical Society;
BioOne; Cochrane Library; DOE: Energy Information Administration; DOE: Information
Bridge; DOE: Energy Citations Database; EBSCO: Academic Search Complete; GeoRef
Preview; GPO: Government Printing Office; Informaworld; IngentaConnect; J-STAGE: Japan
Science & Technology; JSTOR: Mathematics & Statistics; JSTOR: Life Sciences;
NSCEP/NEPIS (EPA publications available through the National Service Center for
Environmental Publications [NSCEP] and National Environmental Publications Internet Site
[NEPIS] database); PubMed (MEDLINE and CANCERLIT databases); SAGE; Science Direct;
Scirus; Scitopia; SpringerLink; TOXNET (Toxicology Data Network: ANEUPL; CCRIS;
ChemlDplus; CIS; CRISP; DART; EMIC; EPIDEM; ETICBACK; FEDRIP; GENE-TOX;
HAPAB; HEEP; HMTC; HSDB; IRIS; ITER; LactMed; Multi-Database Search; NIOSH; NTIS;
PESTAB; PPBIB; RISKLINE; TRI; and TSCATS); Virtual Health Library; Web of Science
(searches Current Content database among others); World Health Organization; and Worldwide
Science. The following databases outside of HERO were searched for risk assessment values:
ACGM; AT SDR; CalEPA; EPA IRIS; EPA HEAST; EPA HEEP; EPA OW; EPA
TSCATS/TSCATS2; NIOSH; NTP; OSHA; and RTECS.
REVIEW OF POTENTIALLY RELEVANT DATA
(CANCER AND NONCANCER)
Table 2 provides information for all of the potentially relevant studies. Entries for the
principal study are in bold and labeled "PS."
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Table 2. Summary of Potentially Relevant Data for o-Chlorotoluene (CASRN 95-49-8)


Number of Male/Female








Species and Strain, Study



BMDL/

Reference
Notes3
Category
Type, and Duration
Dosimetry15
Critical Effects
NOAELb
BMCLb
LOAEL"
(Comments)
Human
1. Oral (mg/kg-day)b

Subchronic
None

Chronic
None

Developmental
None

Reproductive
None

Carcinogenic
None
2. Inhalation (mg/mV

Subchronic
None

Chronic
None

Developmental
None

Reproductive
None

Carcinogenic
None
Animal
1. Oral (mg/kg-day)b
PS
Subchronic
20/20 Harlan rat,
0, 20, 80, or 320
Decreased body-weight gains
20
NA
80
Gibson et al.
IRIS

subchronic toxicity, daily

and decrease in absolute body



(1974a)
(1990),

oral gavage for 103 (males)

weight in males




NPR

or 104 (females) days






IRIS
Subchronic
4/4 beagle dog, subchronic
0, 5, 20, or 80
None observed
80
NA
NA
Gibson et al.
(1990),

toxicity, daily capsule for





(1974b)
NPR

96 (females) or 97 (males)








days







Metabolism
5/5 Harlan rat, subchronic
0,20, 80, or 320 (rat)
Separate report of enzyme
320 (rat)
NA
NA
Hoffman and


toxicity, daily oral gavage

activity analysis from



Bernhard


for 14 days, or 103-104 days

Gibson et al. (1974a)



(1974)


4/4 beagle dog, subchronic
0, 5, 20, or 80 (dog)
No effects of treatment on
80 (dog)





toxicity, daily capsule for

O-demethylation of />-nitroanisole






96-97 days







Chronic
None

Developmental
None

Reproductive
None

Carcinogenic
None
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Table 2. Summary of Potentially Relevant Data for o-Chlorotoluene (CASRN 95-49-8)


Number of Male/Female








Species and Strain, Study



BMDL/

Reference
Notes3
Category
Type, and Duration
Dosimetry15
Critical Effects
NOAELb
BMCLb
LOAEL"
(Comments)
2. Inhalation (mg/m3)b

Subchronic
None

Chronic
None
IRIS
Developmental
25 female Sprague-Dawley
0,250, 750, or 2250
Dams: slight ataxia; decreased
250
NA
750
Edwards et al.,
(1990)

rat, 14 days (GDs 6-19)

body-weight gains and food



(1982)




consumption; increased water








consumption








Fetuses: decreased mean litter
750

2250





weight and mean fetal weight, and








increased incidence of








malformation (brachydactyly) at








2250 mg/m3




IRIS
Developmental
16 female New Zealand
0, 375, 1000, or 2500
Does: partial ptosis; rapid
375
NA
1000
Edwards et al.,
(1990)

White rabbit, 23 days

respiration; decreased body-



(1983)


(GDs 6-28)

weight gains and food








consumption








Fetuses: slightly but not
1000

2500





statistically significantly








decreased mean fetal weight





Reproductive
None

Carcinogenic
None
aNotes: a: IRIS = Utilized by IRIS, date of last update; PS = Principal study, b: NPR = Not peer reviewed.
bDosimetry, NOAEL, BMDL/BMCL, and LOAEL values are converted to Human Equivalent Dose (HED in mg/kg-day) or Human Equivalent Concentration (HEC
in mg/m3) units. Noncancer oral data are only adjusted for continuous exposure.
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HUMAN STUDIES
Oral and Inhalation Exposure
No studies investigating the effects of subchronic or chronic oral exposure to
o-chlorotoluene in humans have been identified. No quantitative data were located regarding the
toxicity of o-chlorotoluene to humans following chronic or subchronic inhalation exposure. The
ACGIH reported a TLV of 50 ppm (259 mg/m3 TWA) and stated that this value was
recommended based on good occupational hygiene practice, rather than on supporting data.
Further, unpublished communications regarding worker experience from exposure to
o-chlorotoluene indicated a lack of irritant or pulmonary effects and recommended an exposure
value (maximum allowable concentration) of 75 to 200 ppm, which is equivalent to 390 to
1040 mg/m3 (ACGIH, 2001). An online search of Haz-map (2010) reported that o-chlorotoluene
is a respiratory irritant and that exposure to high concentrations may produce "systemic toxic
effects." Additionally, o-chlorotoluene may cause skin irritation.
ANIMAL STUDIES
Oral Exposure
The effects of oral exposure of animals to o-chlorotoluene have been evaluated in
unpublished subchronic (Gibson et al., 1974a,b) toxicity studies that were used as principal
studies by the IRIS Summary for o-Chlorotoluene (U.S. EPA, 1990). No chronic oral toxicity
studies or oral developmental or reproductive toxicity studies were located. A report
summarizing the acute oral toxicity of o-chlorotoluene (Kodak, 1994) is presented in Other Data
below.
Subchronic Studies—The study by Gibson et al. (1974a) is selected as the principal
study for deriving the subchronic p-RfD. Male and female (20/sex/dose) weanling Harlan rats
were administered o-chlorotoluene (purity not provided) in 5% aqueous acacia at doses of 0, 20,
80, or 320 mg/kg-day (dose volume 2 mL/kg) by daily oral gavage for 103 (males) or
104 (females) days. Dosing emulsions were prepared daily. The rats were observed for signs of
toxicity daily; body weights and food consumption were recorded weekly. On Day 14,
five rats/sex/dose were killed by carbon dioxide asphyxiation, and portions of the livers were
processed for determination of microsomal enzyme activities. At termination, the livers of an
additional five rats/sex/dose were processed for similar determinations. The results of the
enzyme activity determinations were presented in a separate report (Hoffman and Bernhard,
1974). This report indicated there were no treatment-related effects by o-chlorotoluene on
hepatic (9-demethylation activity. Hematology parameters (hematocrit, hemoglobin, erythrocyte
count, leukocyte count) were measured on all rats; prothrombin time was determined for half of
the animals; and clinical chemistry parameters (blood urea nitrogen [BUN], glutamic pyruvic
transaminase, and glucose) were measured on the remaining half of the rats. At termination, the
rats were necropsied, organ weights (liver, kidney, heart, spleen, thyroid, adrenal, prostate,
testes, and/or uterus and ovaries) were recorded, and histopathological examinations (weighed
organs, colon, duodenum, ileum, jejunum, lungs, lymph nodes, mammary gland, pancreas,
parathyroid, salivary gland, skin, stomach, skeletal muscle, thymus, and urinary bladder) were
performed. In the males, body-weight gains were statistically significantly decreased by 15 and
22%, absolute body weight was decreased by 11 and 16% (see Appendix B, Table B.l), and feed
efficiency was decreased by 9 and 16% at 80 and 320 mg/kg-day, respectively. In addition, a
statistically significant increase in adrenal glands, heart and testes weights, and white blood cell
count, and a decrease in prothrombin time were observed in males in the 320-mg/kg-day dose
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group. At the 80-mg/kg-day dose level, BUN was statistically significantly increased in males.
No other changes were observed in histopathological examinations or hematological parameters.
A NOAEL of 20 mg/kg-day is identified, and the LOAEL is 80 mg/kg-day.
In a companion study by Gibson et al. (1974b), male and female (four/sex/dose) beagle
dogs (age not provided) were administered o-chlorotoluene (purity not provided) in 5% aqueous
acacia at doses of 0, 5, 20, or 80 mg/kg-day (dose volume 0.5 mL/kg) daily by capsule for
97 (males) or 96 (females) days. Dosing emulsions were prepared daily. The dogs were
observed for signs of toxicity daily; body weights were recorded weekly. Physical and
ophthalmological examinations, and hematology (leukocyte counts, erythrocyte counts,
hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean
corpuscular hemoglobin concentration, prothrombin time, sedimentation rate, blood clotting
time, platelet count, leukocyte differential count, nucleated erythrocytes, and erythrocyte
morphology), clinical chemistry (calcium, inorganic phosphorus, glucose, BUN, uric acid,
cholesterol, total protein, albumin, total bilirubin, alkaline phosphatase, lactic acid
dehydrogenase, and serum glutamic oxaloacetic transaminase), and urinalysis (specific gravity,
sugar, pH, protein occult blood, and abnormal color and appearance) parameters were measured
on all dogs prior to the initiation of treatment, and at 1, 2, and 4 weeks, and monthly thereafter.
At termination, the dogs were necropsied, organ weights (liver, kidney, heart, spleen, thyroid,
adrenal, testes, and/or ovaries) were recorded, and histopathological examinations (weighed
organs, colon, duodenum, ileum, jejunum, lungs, lymph nodes, mammary gland, pancreas,
parathyroid, prostate, salivary gland, skin, stomach, skeletal muscle, thymus, urinary bladder,
and uterus) were performed. A liver sample from each dog was used to determine microsomal
enzyme activities; the results of these determinations were presented in a separate report. No
treatment-related effects by o-chlorotoluene on hepatic O-demethylation activity in dogs treated
for 96-97 days were observed (Hoffman and Bernhard, 1974). Overall, no treatment-related
findings were reported at any dose level (see Appendix B, Table B.2.). The NOAEL was
80 mg/kg-day at the highest dose tested; no LOAEL was identified.
The results of a metabolism study by Hoffman and Bernhard (1974) concerning the effect
of o-chlorotoluene on hepatic O-demethylation of />nitroanisole were cited in both of the
subchronic studies above. This additional study indicated there were no treatment-related effects
by o-chlorotoluene on hepatic O-demethylation activity in rats treated for 14 days or
103-104 days, or in dogs treated for 96-97 days.
Chronic Studies—No studies could be located regarding the effects of chronic oral
exposure of animals to o-chlorotoluene.
Developmental and Reproduction Studies—No studies could be located regarding the
effects of oral exposure of animals to o-chlorotoluene on fetal development or reproduction.
Inhalation Exposure
The effects of inhalation exposure of animals to o-chlorotoluene have been evaluated in
two developmental toxicity studies (Edwards et al., 1982; 1983). Furthermore, a short-term
inhalation study (Arthur and Owen, 1974) and a report summarizing acute dermal, ocular, and
inhalation toxicity (Kodak, 1994) were located and are presented in Other Data below.
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Subchronic Studies—No studies could be located regarding the effects of subchronic
inhalation exposure of animals to o-chlorotoluene.
Chronic Studies—No studies could be located regarding the effects of chronic inhalation
exposure of animals to o-chlorotoluene.
Developmental and Reproduction Studies—No studies could be located regarding the
effects of inhalation exposure of o-chlorotoluene on reproductive toxicity.
Edwards et al. (1982) exposed groups of 25 time-mated Sprague-Dawley female rats
(body weights 166-208 g) via whole-body inhalation exposure to o-chlorotoluene
(purity 96.5% w/v) at nominal concentrations of 0, 1, 3, or 9 mg/L (equivalent to 0, 250, 750, or
"3
2250 mg/m after duration and concentration adjustments; see Appendix A, Table A.l) for
6 hours per day during Gestation Days (GDs) 6-19. Vapor generation was achieved by
atomizing o-chlorotoluene, heating the atomized liquid to approximately 100°C, and delivering
the vapor to the exposure chamber by dilution with heated air. The desired exposure
"3
concentrations were maintained in 1-m stainless steel, glass-fronted chambers using a target
total airflow of 250 L/min, yielding a calculated 95% equilibration time of 12 minutes.
o-Chlorotoluene concentrations were measured at 30-minute intervals using a portable infrared
gas analyzer. The variation of chamber concentrations during exposures was small and within
acceptable limits. In the dams, clinical signs observed included slight ataxia at 3 mg/L
(750 mg/m3), and slight-to-moderate ataxia and occasional lacrimation and/or salivation at
"3
9 mg/L (2250 mg/m ). Food consumption was decreased during treatment (GDs 6-19) at 3 and
9 mg/L (p < 0.001 at 9 mg/L). Cumulative body-weight gains (relative to GD 6) were decreased
during treatment at 3 and 9 mg/L. There was an increase in water consumption at 3 and 9 mg/L.
In the fetuses, mean litter weight and mean fetal weight were both decreased (p < 0.01) at
9 mg/L. Additionally, at this dose, an increased incidence of brachydactyly, a malformation, was
observed (6 fetuses; 4 litters). A NOAEL of 1 mg/L (250 mg/m3) for maternal toxicity is
identified for this report, and the LOAEL is 3 mg/L (750 mg/m3). A NOAEL of 3 mg/L
(750 mg/m3) for developmental toxicity is identified, and the LOAEL is 9 mg/L (2250 mg/m3).
Edwards et al. (1983) exposed groups of 16 mated New Zealand White rabbits (group
mean body weights 3240-3290 g) via whole-body inhalation exposure to o-chlorotoluene
(purity 96.5%) w/v) at nominal concentrations of 0, 1.5, 4, or 10 mg/L (equivalent to 0, 375,
"3
1000, or 2500 mg/m after duration and concentration adjustment; see Appendix A, Table A.2)
for 6 hours per day during GDs 6-28. Vapor generation and exposure parameters were the same
as described above. In the does, clinical signs observed included partial ptosis and rapid
respiration at 4 mg/L (1000 mg/m3), and lacrimation and salivation, partial or complete ptosis,
"3
and rapid respiration following exposure at 10 mg/L (2500 mg/m ). There was a dose-related
decrease in mean food consumption at 4 and 10 mg/L during GDs 6-13. Cumulative
body-weight gains (relative to GD 6) were decreased during GDs 6-14 at 4 mg/L and during
GDs 6-19 at 10 mg/L. In the fetuses, mean fetal weight was slightly but not statistically
"3
significantly (p > 0.05) decreased at 10 mg/L. A NOAEL of 1.5 mg/L (375 mg/m ) for maternal
toxicity is identified for this report, and the LOAEL is 4 mg/L (1000 mg/m3). A NOAEL of
"3
4 mg/L (1000 mg/m ) for developmental toxicity is identified, and the LOAEL is 10 mg/L
(2500 mg/m3). Both developmental studies (Edwards et al., 1982; 1983) are not published and
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have not been peer-reviewed but were mentioned in the IRIS Summary for o-Chlorotoluene as
additional studies (U.S. EPA, 1990).
Other Data (Short-Term Tests, Other Examinations)
Acute Studies—Kodak (1994) performed an abbreviated acute toxicity test on three rats
(strain not provided) and concluded that the oral LD50 was >1600 mg/kg. When undiluted
o-chlorotoluene (purity not provided) was held in occluded contact with the skin of guinea pigs
for 24 hours, it was moderately irritating. There was some evidence of systemic toxicity due to
dermal absorption, but the LD50 was >10 cc/kg (1100 mg/kg). One drop of undiluted
o-chlorotoluene in the eye of a rabbit produced moderate irritation; however, the eye recovered
and was normal after 14 days. Rats exposed by inhalation to a calculated concentration of
14,000 ppm (72,000 mg/m ) for 6 hours showed respiratory tract irritation and sympathetic nerve
"3
stimulation. When the calculated concentration was increased to 175,000 ppm (906,000 mg/m ),
one of the three rats died. The surviving two rats displayed prostration.
Short-term Studies—In a short-term inhalation study by Arthur and Owen (1974),
groups of 10 Harlan rats/sex/dose group were exposed to aerosolized o-chlorotoluene (purity not
provided) by head-only inhalation exposure at concentrations of either 33,000 or 62,000 mg/m3
for 1 hour per day, 5 days a week, for 3 weeks (15 exposures). A control group was similarly
exposed to an aerosol of tap water. The test material was sprayed from a nebulizer into a 61-L
exposure chamber. The nebulizer was designed to produce aerosol particles from 3-10 microns
in diameter at a controlled air flow of 388 L/hour. The volume of aerosolized solvent was
recorded daily to facilitate the calculation of mean chamber concentrations. Several of the
33,000-mg/m3 rats displayed slight ataxia immediately following each exposure. One female in
this group became emaciated and died on Day 5; this death was attributed to acute necrotizing
pneumonia in lungs. At 62,000 mg/m3, animals developed severe ataxia following each
exposure, and approximately half of the animals became prostrate for 15-30 minutes.
One female in this group lost 50 g of body weight during the last nine exposures. Additionally at
this dose, two males died on Day 12, and two females died on Day 10; these deaths were
attributed to "respiratory embarrassment." The experimental design was modified by decreasing
"3
the exposure time of the 62,000-mg/m group to 30 minutes for the last three exposures. Another
62,000-mg/m3 female suffocated in the holding chamber on Day 1. None of the deaths at either
dose were attributed to treatment with o-chlorotoluene. All other findings were considered
incidental to treatment by the study authors.
Metabolism Studies—In a metabolism study by Wold (1974), 14C-o-chlorotoluene
(position of radiolabel not specified) in 1% aqueous Span 80/Tween 80 (1:1) was administered
by oral gavage to three male Harlan rats at a dose level of 320 mg/kg (1.25 |iCi/kg) in a dose
volume of 0.5 mL/100 g body weight. The rats were housed individually in glass metabolism
cages for the first 24 hours after dosing; they were then transferred to stainless steel metabolism
cages for the remainder of the study. Air was drawn through the glass metabolism cages and into
two traps; the traps consisted of two, 500-mL gas washing bottles, each filled with methanol at
room temperature. The efficiency of the trap system was confirmed by introducing a known
quantity of 14C-o-chlorotoluene in ethanol into a cage and drawing air through the cage and traps
for 3-hour periods. The recovery of 14C-o-chlorotoluene was 98.2%. At 24 and 48 hours
postdosing, urine and feces were collected, and the cages were rinsed with distilled water.
Radioactivity in aliquots of urine and cage wash was quantitated by liquid scintillation counting;
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feces were air-dried for 48 hours, weighed, powdered, and aliquots were combusted. Urine
samples were acidified to pH 1, vortexed with ethyl acetate, and centrifuged. The aqueous layer
was reextracted with ethyl acetate; the organic extracts were combined and evaporated to
dryness. The residue was resuspended in methanol, derivatized with diazomethane, and
analyzed by gas chromatography (GC) or GC/mass spectrometry (MS) for metabolite
identification. Urine samples were also subjected to enzyme hydrolysis; conjugates were
identified by thin-layer chromatography (TLC). Urinary metabolites were quantified by TLC.
Total recovery of radioactivity was 94.3-97.9% of the administered dose (AD). Unmetabolized
o-chlorotoluene was present in the expired air and accounted for 11.3% AD. The majority of
radioactivity was found in the urine (81.7% AD) with a minor amount in the feces (3.5% AD).
o-Chlorotoluene was rapidly and extensively metabolized and excreted by the rat.
Unmetabolized o-chlorotoluene was not found in the urine. The major urinary metabolite was
o-chlorobenzyl alcohol glucuronide (37.5-45.8% AD), followed by chloro-methyl-
phenylmercapturic acid (21-22%) AD) and o-chlorohippuric acid (17-20%) AD). The following
urinary metabolites were also identified but were present at <2.4% AD: o-chlorobenzyl alcohol;
o-chlorobenzoic acid; o-chlorobenzoic acid glucuronide; and unidentified polar metabolites.
In a study by Quistad et al. (1983), [U-ring-14C]-o-chlorotoluene (2-chloro[U-ring-
14C]toluene) in corn oil was administered by oral gavage to four Sprague-Dawley rats/sex at a
dose level of 1 mg/kg. One additional female was treated at 91 mg/kg; another female was
treated at 102 mg/kg. All animals were fasted 16 hours prior to dosing. Animals were housed in
all-glass metabolism chambers; expired air was trapped in 5% KOH (for CO2) and Amberlite
XAD-2 resin (volatile organics). An additional three male rats were dosed with 1 mg/kg as
above, and blood samples were obtained from the orbital sinus at regular intervals for
determination of pharmacokinetics. The general method for analysis of urinary metabolites
involved mild acidification followed by liquid chromatography (LC). The identities of
individual metabolites were confirmed by MS. Total recovery ranged from 97.8-103%) AD,
with the majority of radioactivity found in the urine (85-92%) AD), feces (5—8%), and expired
air (l-4%>). At least 84% of the volatile 14C was identified as unmetabolized o-chlorotoluene.
The major metabolites found in both urine and feces were o-chlorohippurate, o-chlorobenzyl
alcohol glucuronide, and o-chlorobenzyl alcohol mercapturic acid. Additionally, a small amount
of unmetabolized o-chlorotoluene was found in the feces (<2% AD). o-Chlorotoluene was
quickly absorbed, with a peak concentration in plasma observed at approximately 2 hours
postdosing. Virtually all of the administered dose was eliminated within 4 days, with <1% AD
remaining in the carcass. No significant sex-related metabolic differences were detected.
Genotoxicity Studies—In an Ames Salmonella mutagenicity test (Hooker Chem. and
Plastics Corp., 1982), the mutagenic activity of o-chlorotoluene (96.6%) o-chlorotoluene,
3.4% />chlorotoluene, 0.1% toluene) was tested in the presence and absence of liver microsomal
enzyme preparations (S9 homogenate) on S. typhimurium indicator organisms. The strains used
were TA1535, TA1537, TA1538, TA98, and TA100. A preliminary cytotoxicity test using the
TA100 strain was performed, followed by the mutagenicity assays. Positive and negative
controls were included. It was concluded that o-chlorotoluene was not considered mutagenic
under these test conditions.
In a mouse lymphoma forward mutation assay (Occidental Chemical Corp., 1985), the
mutagenic activity of o-chlorotoluene was tested in the presence and absence of liver microsomal
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enzyme preparations (S9 homogenate) on L5178Y TK +/- mouse lymphoma cells. A
preliminary cytotoxicity test was performed, followed by the mutagenicity assays. Positive and
negative controls were included. It was concluded that o-chlorotoluene was not considered
mutagenic under these test conditions.
Table 3 summarizes studies on acute toxicity, short-term inhalation, metabolism, and
genotoxicity of o-chlorotoluene.
DERIVATION OF PROVISIONAL VALUES
Table 4 below presents a summary of noncancer reference values. No cancer values
could be derived (see Table 5). For the oral noncancer studies by gavage, the only conversion
was to provide an average daily dose.
DERIVATION OF ORAL REFERENCE DOSES
Derivation of Subchronic p-RfD
The study by Gibson et al. (1974a) is selected as the principal study for derivation of the
subchronic p-RfD because it presents data to support the critical effects of decreased
body-weight gain (statistically significant) and decrease in absolute body weight (biologically
significant) in male rats as the most sensitive effect observed in response to subchronic oral
exposure to o-chlorotoluene (see Appendix B, Table B.l). This study is a nonpeer-reviewed,
unpublished report, but otherwise meets the standards of study design and performance with
numbers of animals. This study was conducted prior to implementation of GLP (Good
Laboratory Practice) standards. However, the study was used by IRIS for deriving a chronic
RfD for o-chlorotoluene (U.S. EPA, 1990). The test compound was administered as an emulsion
by oral gavage to avoid loss due to volatility (purity not provided). Not all toxicological
endpoints (e.g., neurological evaluations, urinalysis) were examined, but most endpoints were
evaluated. Details of study design are provided in the Review of Potentially Relevant Data
section. BMD modeling analysis is not possible with these data because standard deviations
were not provided, and individual data were not available for calculations. The POD derived
from this study is the NOAEL of 20 mg/kg-day based on decreased body-weight gain and
absolute body weight in male rats (Gibson et al., 1974a).
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Table 3. Other Studies
Tests
Materials and Methods
Results
Conclusions
References
Acute Toxicity
Administered orally to three rats at up to
1600 mg/kg; applied undiluted to the skin of
guinea pigs at up to 10 cc/kg; placed
undiluted in the eye of rabbit; exposed rats
to concentrations of 14,000 ppm for 6 hours
by inhalation, then increased concentration
to 175,000 ppm
All rats survived oral exposure;
moderately irritating to skin of guinea
pigs with some systemic toxicity;
moderately irritating to eye in rabbit;
inhalation at 14,000 ppm
(72,000 mg/m3) caused respiratory tract
irritation and sympathetic nerve
stimulation, inhalation of 175,000 ppm
(906,000 mg/m3) was fatal to one rat,
prostration in the surviving two rats
Oral LD50 >1600 mg/kg
Dermal LD50 >10 cc/kg
(1100 mg/kg)
Moderately irritating to skin
and eye
Exposure to high vapor
concentration may cause
respiratory irritation
Kodak (1994)
Short-term
Inhalation
Rat
10 Harlan rats/sex exposed to 0, 33,000, or
62,000 mg/m3 aerosol 1 hour per day,
5 days per week, for 3 weeks
Slight ataxia at 33,000 mg/m3, with
one death; severe ataxia at
62,000 mg/m3 with five deaths
Death at 33,000 mg/m3
attributed to acute necrotizing
pneumonia; deaths at
62,000 mg/m3 attributed to
suffocation in holding
chamber or "respiratory
embarrassment"
Arthur and Owen
(1974)
Metabolism Rat
Administered to three male Harlan rats at a
dose level of 320 mg/kg in aqueous
Span 80/Tween 80 by oral gavage.
Recovery determined in expired air, urine,
and feces. Identified urinary metabolites.
Unmetabolized compound detected in
expired air. Major urinary metabolites
were o-chlorobenzyl alcohol
glucuronide, o-chlorohippuric acid, and
chloro -methyl-phenylmercapturic acid
Compound is rapidly and
extensively metabolized and
excreted.
Wold (1974)
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Table 3. Other Studies
Tests
Materials and Methods
Results
Conclusions
References
Metabolism Rat
Administered to four Sprague-Dawley
rats/sex at 1 mg/kg in corn oil by oral
gavage; also to 3 males at 1 mg/kg for
pharmacokinetics, 1 female at 97 mg/kg and
1 female at 102 mg/kg
Unmetabolized compound detected in
expired air. Major urinary and fecal
metabolites were o-chlorohippurate,
o-chlorobenzyl alcohol glucuronide,
and o-chlorobenzyl alcohol mercapturic
acid. Unmetabolized o-chlorotoluene
was found in the feces. Compound was
quickly absorbed, with a peak
concentration in plasma observed at
approximately 2 hours postdosing.
Virtually all of the administered dose
was eliminated within 4 days. No
significant sex-related metabolic
differences were detected.
Compound is rapidly and
extensively metabolized and
excreted.
Quistad et al.
(1983)
Genotoxicity
Tested for reverse mutation in Salmonella
typhimurium (Ames assay) with and without
metabolic activation.
Negative in strains TA1535, TA1537,
TA1538, TA98, and TA100 with or
without S9 activation.
Compound is not mutagenic
under the conditions of this
assay
Hooker Chem.
and Plastics Corp.
(1982)
Genotoxicity
Tested for reverse mutation in L5178Y TK
+/- cells (mouse lymphoma forward
mutation) with and without metabolic
activation.
Negative with or without S9 activation.
Compound is not mutagenic
under the conditions of this
assay
Occidental
Chemical Corp.
(1985)
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Table 4. Summary of Noncancer Reference Values for o-Chlorotoluene (CASRN 95-49-8)
Toxicity Type (Units)
Species/
Sex
Critical Effect
Reference
Value
POD
Method
POD
UFc
Principal Study
Subchronic p-RfD
(mg/kg-day)
Rat/M
Decreased body-
weight gains and
decrease in absolute
body weight
2 x 10~2
NOAEL
20
1000
Gibson et al. (1974a)
Chronic p-RfD (IRIS)
(mg/kg-day)
Rat/M
Decreased body-
weight gains
2 x 10~2
NOAEL
20
1000
Gibson et al. (1974a)
Screening Subchronic
p-RfC (mg/m3)
Rat/F
Slight ataxia,
decreased body-
weight gains and
food consumption,
and increased water
consumption
8 x 10_1
NOAEL
250
300
Edwards et al. (1982)
Chronic p-RfC
None
None
None
None
None
None
None

Table 5. Summary of Cancer Values for o-Chlorotoluene (CASRN 95-49-8)
Toxicity Type
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF
None
None
None
None
p-IUR
None
None
None
None
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Adjusted for Daily Exposure
The following dosimetric adjustments were made for each dose in the principal study for
dietary treatment.
NOAELadj = NOAEL x [conversion to daily dose]
= 20 mg/kg-day x (days of week dosed ^ 7)
= 20 x (7 4- 7)
= 20 mg/kg-day
The subchronic p-RfD for o-chlorotoluene, based on the NOAEL of 20 mg/kg-day (POD) in
male Harlan rats (Gibson et al., 1974a), is derived as follows:
Subchronic p-RfD = NOAELadj ^ UF
= 20 mg/kg-day ^ 1000
= 0.02 mg/kg-day or 2 x 10~2 mg/kg-day
Tables 6 and 7, respectively, summarize the UFs and the confidence descriptor for the
subchronic p-RfD for o-chlorotoluene.
Table 6. Uncertainty Factors for Subchronic p-RfD for o-Chlorotoluenea
UF
Value
Justification
UFa
10
A UFa of 10 is applied for interspecies extrapolation to account for potential
toxicokinetic and toxicodynamic differences between rats and humans.
There are no data to determine whether humans are more or less sensitive
than rats to general toxicity of o-chlorotoluene.
UFd
10
A UFd of 10 is applied because there are no available developmental and
reproductive studies via oral exposure.
UFh
10
A UFh of 10 is applied for intraspecies differences to account for potentially
susceptible individuals in the absence of information on the variability of
response in humans.
UFl
1
A UFl of 1 is applied because the POD was developed using a NOAEL.
UFs
1
A UFS of 1 is applied because a subchronic study (Gibson et al., 1974a) was
utilized as the principal study.
UFC <3000
1000

aGibsonetal. (1974a).
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Table 7. Confidence Descriptor for Subchronic p-RfD for o-Chlorotoluene
Confidence
Categories
Designation"
Discussion
Confidence in Study
M
The study was given medium confidence because of the
number of animals and doses used, and because several
parameters were examined.
Confidence in
Database
L
The database was given a low confidence because there
is only one additional unpublished subchronic study
available, and no developmental or reproductive studies
are available.
Confidence in
Subchronic p-RfDb
L
The overall confidence in the subchronic p-RfD is low
because there are no chronic or pertinent oral
reproductive or developmental studies available.
aL = Low, M = Medium, H = High.
bThe overall confidence cannot be greater than the lowest entry in table.
DERIVATION OF CHRONIC p-RfD
A chronic RfD of 0.02 mg/kg-day is available on the IRIS database (U.S. EPA, 1990),
based on decreased body-weight gains in male Harlan rats exposed to 0, 20, 80, or
320 mg/kg-day o-chlorotoluene in 5% aqueous acacia by oral gavage for 103-104 days
(Gibson et al., 1974a). The POD was based on the NOAEL of 20 mg/kg-day in male rats. It was
stated that a screening-level literature review conducted in August 2003 did not identify any
significant new studies.
According to EPA (1990), "An uncertainty factor of 1000 was used: 10 to account for
interspecies extrapolation, 10 for differences in individual human sensitivity, and 10 for use of a
subchronic study." Notably, IRIS, at that time, did not apply a UF for database (UFD). The
confidence statement in the IRIS Summary for o-Chlorotoluene (U.S. EPA, 1990) is as follows:
The confidence in the study is medium because of the number of animals and doses used
and because several parameters were studied. The confidence in the database is low
since no specific pattern of toxicity was observed at the higher doses. Considering no
chronic or pertinent oral reproductive or developmental data are available, the overall
confidence in the RfD is rated low.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
The available data are not sufficient for derivation of a subchronic or chronic p-RfC for
o-chlorotoluene. However, a screening subchronic p-RfC can be derived based on a
developmental study and is provided in Appendix A.
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CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR
Table 8 identifies the cancer WOE descriptor for o-chlorotoluene.
Table 8. Cancer WOE Descriptor for o-Chlorotoluene
Possible WOE Descriptor
Designation
Route of Entry
(Oral, Inhalation, or
Both)
Comments
"Carcinogenic to Humans "
N/A
N/A
No human cancer studies are available.
"Likely to Be Carcinogenic to
Humans "
N/A
N/A
No animal cancer data are available.
"Suggestive Evidence of
Carcinogenic Potential"
N/A
N/A
There are no data available to suggest
that there is a carcinogenic potential.
"Inadequate Information to
Assess Carcinogenic Potential"
X
Both
There is not adequate information
available to assess carcinogenic
potential.
"Not Likely to Be Carcinogenic
to Humans "
N/A
N/A
No strong evidence of
noncarcinogenicity in humans is
available.
MODE-OF-ACTION DISCUSSION
The Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005) define mode-of-action
as "a sequence of key events and processes starting with the interaction of an agent with a cell,
proceeding through operational and anatomical changes, and resulting in cancer formation."
Examples of possible modes of carcinogenic action include mutagenic, mitogenic, antiapoptotic
(inhibition of programmed cell death), cytotoxic with reparative cell proliferation, and immune
suppression.
No chronic toxicity or carcinogenicity data are available on o-chlorotoluene.
o-Chlorotoluene tested negative in both a Ames Salmonella mutagenicity test (Hooker Chem.
and Plastics Corp, 1982) and a mouse lymphoma forward mutation assay (Occidental Chemical
Corp, 1985). It was not considered mutagenic in these tests.
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
Derivation of p-OSF
No human or animal studies examining the carcinogenicity of o-chlorotoluene following
oral exposure have been located. Therefore, derivation of a p-OSF is precluded.
Derivation of p-IUR
No human or animal studies examining the carcinogenicity of o-chlorotoluene following
inhalation exposure have been located. Therefore, derivation of a p-IUR is precluded.
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APPENDIX A. PROVISIONAL SCREENING VALUES
For the reasons noted in the main document, it is inappropriate to derive a subchronic
p-RfC for o-chlorotoluene. However, information is available 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 a supplemental appendix and develops a "screening value."
Appendices receive the same level of internal and external scientific peer review as the main
document to ensure their appropriateness within the limitations detailed in the document. Users
of screening toxicity values in a supplement to a PPRTV assessment should understand that there
is considerably more uncertainty associated with the derivation of a supplement screening
toxicity value than for a value presented in the body of the assessment. Questions or concerns
about the appropriate use of screening values should be directed to the Superfund Heath Risk
Technical Support Center.
DERIVATION OF SCREENING SUBCHRONIC INHALATION REFERENCE
CONCENTRATION
Subchronic toxicity studies for inhalation o-chlorotoluene exposures are not available.
However, there are two developmental studies (Edwards et al., 1982; 1983) that can be
considered for deriving a screening subchronic p-RfC. Between the two developmental studies
in rats and rabbits, respectively, the maternal effects observed in the rat study (Edwards et al.,
1982) were the most sensitive effects in response to o-chlorotoluene via inhalation. Therefore,
the rat study by Edwards et al. (1982) is chosen as the principal study. The critical effects were
slight ataxia (dose-dependent effect), decreased body-weight gains and food comsumption, and
increased water consumption at the LOAEL of 750 mg/m . The NOAEL was 250 mg/m3.
"3
The screening subchronic p-RfC is based on the NOAEL of 250 mg/m (adjusted for
HEC) in female dams exposed to o-chlorotoluene for 14 days in a rat developmental study
(Edwards et al., 1982). Because o-chlorotoluene is fairly insoluble (slightly soluble in water),
may be rapidly reversibly reactive in the surface-liquid/tissue of the respiratory tract, and can
cause both respiratory and systemic toxicity, it is considered to be a Category 2 gas.
Furthermore, exposure to o-chlorotoluene via inhalation caused extrarespiratory effects
(e.g., ataxia, etc.); therefore, HECs were calculated using the Category 3 equation (the
Category 3 equation is used for Category 2 gases causing extrarespiratory effects; U.S. EPA,
1994). The concentration adjustment data for the maternal effects in the Edwards et al. (1982)
study based on the critical effects of ataxia, decreased body-weight gain and food consumption,
and increased water consumption are presented in Table A. 1. Similarly, the concentration
adjustment data for the maternal effects in the Edwards et al. (1983) study are presented in Table
A.2.
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Table A.l. Concentration-Adjustment Data for o-Chlorotoluene (With
Concentrations Expressed in Terms of HEC for Systemic Effects) in Female
Rats Exposed by Inhalation for 14 Days"
Cone (mg/L)
Conc^ (mg/m3)b
Concise (mg/m3)c
0
0
0
1
250
250
3
750
750
9
2250
2250
aEdwards et al. (1982)
bConc[ADJ] = Cone x6-^24hx7-^7d
°ConC[HEci = Conc|A[,j x Cat. 3 Regional Gas Deposition Ratio (RGDR)
1)	Exposure concentration adjustment for continuous exposure
Coiicadj =	Cone x (hours exposed + 24 hours) x (days exposed + 7 days)
=	1 mg/L x (6 hours + 24 hours) x (7 days + 7 days)
=	0.25 mg/L
=	0.25 mg/dm3 x 1000 dm3/m3
=	250 m«/m3
2)	HEC conversion
ConcHEC = ConcADJ x Category 3 RGDR1
= ConcADJ x (H b/g)A (Hb/g)H
= 250 x 1
= 250 in«/m3
Table A.2. Concentration-Adjustment Data for o-Chlorotoluene (With
Concentrations Expressed in Terms of HEC for Systemic Effects) in Female
Rabbits Exposed by Inhalation for 23 Days"
Conc (mg/L)
ConcADJ (mg/m3)b
ConcnEc (mg/m3)c
0
0
0
1.5
375
375
4
1000
1000
10
2500
2500
aEdwards et al. (1983)
bConC[ADi] = Cone x6-^24hx7-^7d
cConC[HEci = CoiiC[adji x Cat. 3 RGDR
1 RGDR for Category 3 gas of 1.0 is used for the ratio of (H b/g)A/(Hb/g)H if (H b/g)A > (Hb/g)H or if these partition
coefficient values are unknown.
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The screening subchronic p-RfC for o-chlorotoluene based on the rat NOAELhec , is derived as
follows:
Screening Subchronic p-RfC = NOAELhec ^ UF
= 250 mg/m3 - 300
= 0.8 mg/m3 or 8 x 10_1 mg/m3
Table A.3 summarizes the UFs for the screening subchronic p-RfC for o-chlorotoluene.
Due to the short duration of developmental studies (14-23 days) and lack of longer-term studies
to detect more sensitive respiratory or systemic effects, no screening chronic p-RfC is derived.
Table A.3. Uncertainty Factors for Screening Subchronic p-RfC for o-Chlorotoluene
UF
Value
Justification
UFa
3
A UFa of 3 is applied for animal to human extrapolation to account for the
toxicodynamic portion of a UFAbecause the toxicokinetic portion (10°5) has
been addressed in dosimetric conversions.
UFh
10
A UFh of 10 is applied for intraspecies differences to account for potentially
susceptible individuals in the absence of information on the variability of
response to humans.
UFd
10
A UFd of 10 is selected because there are no two-generation reproduction
studies and neurotoxicity studies, as there are indications of potential
neurotoxicity (e.g., ataxia) that may be relevant for the database uncertainty
factor.
UFl
1
A UFl of 1 is applied because the POD was developed using a NOAEL.
UFs
1
A UFs of 1 is applied because a short-term study was used as the principal
study.
UFC
300

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APPENDIX B. DATA TABLES
Table B.l. Body-weight Gains and Feed Efficiency in Harlan Rats Exposed to
o-Chlorotoluene via Oral Gavage for 103-104 Daysa'b
Parameter
Exposure Group (mg/kg-day)
0
20
80
320
Males (103 days)
Body-weight Gains (g)
356.5
346.9
301.3° (J. 15)
276.7° (J.22)
Feed Efficiency (%)
13.64
13.36
12.44
11.48
Average Absolute Body Weight
(g)d
486.5
476.9
431.3 (|11)
406.7 (416)
Females (104 days)
Body-weight Gains (g)
172.9
181.1
174.9
151.1
Feed Efficiency (%)
7.90
8.39
8.66
7.57
aGibson et al. (1974a). Data were obtained from Table 1 on page 11 of the study report.
'Means only, () = percent change compared to control.
cSignificantly different from control, Dunnett's test.
dOriginal body weight for male rats was read off directly from Figure 1 on page 10 of the study report as 130 g (Week 0). The
absolute weight was calculated by adding the body-weight gain to the original body weight at Week 0, e.g., 130 + 356.5 =
486.5 g.
Table B.2. Body-weight Gains in Dogs Exposed to o-Chlorotoluene
via Capsule for 96-97 Daysa'b
Body-weight Gains (g)
Exposure Group (mg/kg-day)
0
5
20
80
Males (97 days)
-175 ± 854
425 ±888
400 ± 294
375 ±171
Females (96 days)
500 ± 752
175 ±655
725 ± 330
550 ±645
aGibson et al. (1974b). Data were obtained from Table 1 on page 11 of the study report.
•Means ± SD.
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APPENDIX C. BMD MODELING OUTPUTS FOR o-CHLOROTOLUENE
There are no BMD modeling outputs for o-chlorotoluene.
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APPENDIX D. REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). (2001)
o-Chlorotoluene: documentation of the threshold limit values and biological exposure indices.
Vol: 7th Ed. (ACGIH, 2001, 202164)
Arthur, B.H., and Owen, N.V. (1974) Subacute inhalational toxicity of o-chlorotoluene to rats.
Toxicology Division, Lilly Research Laboratories, June, 1974. Unpublished (Arthur and Owen,
1974, 202638")
ATSDR (Agency for Toxic Substances and Disease Registry). (2009) Toxicological profile
information sheet. U.S. Department of Health and Human Services, Public Health Service.
Available online at http://www.atsdr.cdc.gov/toxpro2.html
CalEPA (California Environmental Protection Agency). (2009a) Office of Environmental
Health Hazard Assessment. Search Chronic RELs. Available online at
http ://www. arb. ca.gov/toxics/healthval/chronic.pdf
http://www.oehha.ca.gov/air/chronic_rels/AllChrels.html
CalEPA (California Environmental Protection Agency). (2009b) Office of Environmental
Health Hazard Assessment. Search Toxicity Criteria Database. Available online at
http://www.oehha.ca.gov/air/hot_spots/pdf/TSDlookup2002.pdf
http://www.oehha.ca.gov/air/hot_spots/pdf/Appendix%20I2002.pdf
Edwards, J. A. et al. (1982) Effect of 2-chlorotoluene vapour on pregnancy of the rat.
Department of Inhalation Toxicology, Huntingdon Research Center, December 31, 1982.
OTS0507455 Unpublished (Occidental, 1983, 594423)
Edwards, J. A. et al. (1983) Effect of 2-chlorotoluene vapour on pregnancy of the New Zealand
White rabbit. Department of Inhalation Toxicology, Huntingdon Research Center, February 28,
1983. OTS0507455 Unpublished (Occidental, 1983. 594423)
Gibson, W.R. et al. (1974a) The toxicity of daily oral doses of o-chlorotoluene in the rat.
Toxicology Division, Lilly Research Laboratories, June, 1974. Unpublished (Gibson et al.,
1974, 202636)
Gibson, W.R. et al. (1974b) The toxicity of daily oral doses of o-chlorotoluene in the dog.
Toxicology Division, Lilly Research Laboratories, June, 1974. Unpublished (Gibson et al.,
1974, 202637)
Haz-map: (2010). o-Chlorotoluene Occupational Exposure to Hazardous Substances.
Available online at http://hazmap.nlm.nih.gov/cgi-bin/hazmap_generic?tbl=TblAgents&id=364
Accessed on 3/25/2010.
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Hoffman, D.G. and Bernhard, N.R. (1974) The effect of o-chlorotoluene (Compound 22679) on
hepatic/>nitroanisole O-demethylation in rats and dogs. Toxicology Division, Lilly Research
Laboratories, June, 1974. Unpublished (Hoffman and Bernhard, 1974, 202640)
Hooker Chemical and Plastics Corp. (1982) Mutagenicity evaluation of orthochlorotoluene in
the Ames Salmonella/microsome plate test. Litton Bionetics, Inc., March, 1982. Unpublished
(Litton, 1982, 202235)
HSDB (Hazardous Substances Data Bank). (2005) HSDB: 2-Chlorotoluene, CASRN: 95-49-8.
National Library of Medicine, National Toxicology Program, Bethesda, MD. Available online at
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IARC (International Agency for Research on Cancer). (2009) IARC Monographs on the
evaluation of carcinogenic risks to humans. Available online at
http://monographs.iarc.fr/ENG/Monographs/PDFs/index.php
Kodak. (1994) Toxicity and health hazard summary of o-chlorotoluene with cover letter dated
April 5, 1994. OTS0572387 Unpublished (Eastman Kodak, 1994. 202623)
NIOSH (National Institute for Occupational Safety and Health). (2005) NIOSH Pocket Guide
to Chemical Hazards. Index by CASRN. September 2005. Available online at
http://www.cdc.gov/niosh/npg/npgdcas.html
NTP (National Toxicology Program). (2005) 11th Report on Carcinogens. U.S. Department of
Health and Human Services, Public Health Service, National Institutes of Health, Research
Triangle Park, NC. Available online at http://ntp-server.niehs.nih.gov/
Occidental Chemical Corp. (1985) Mutagenicity of orthochlorotoluene (OCT) in a mouse
lymphoma mutation assay. Litton Bionetics, Inc., November, 1985 Unpublished
(Litton Bionetics Inc, 1985, 202628)
OSHA (Occupational Safety and Health Administration). (2009) o-Chlorotoluene: Chemical
Sampling Information. Last revision dated November 23, 1998 Available online at
http://www.osha.gov/dts/chemicalsampling/data/CH_228300.html
Quistad, G.B., Mulholland, K.M., and Jamieson, G.C. (1983) 2-Chlorotoluene metabolism by
rats. JAgric Food Chem 3 1: 1 158-1 162. (Quistad et al., 1983, 202129)
U.S. EPA. (U.S. Environmental Protection Agency). (1990) o-Chlorotoluene CASRN: 95-49-8
Integrated Risk Information System (IRIS). Office of Research and Development, National
Center for Environmental Assessment, Washington, DC. Available online at Last accessed on
December, 2009. http://www.epa.gov/ncea/iris/subst/0412.htm
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U.S. EPA. (U.S. Environmental Protection Agency). (1994) Methods for derivation of
inhalation reference concentrations and application of inhalation dosimetry. Environmental
Criteria and Assessment Office (ECAO), Research Triangle Park, NC, October. EPA/600/8-
90/066F. Available online at http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=71993
U.S. EPA. (U.S. Environmental Protection Agency). (1997) Health effects assessment
summary tables (HEAST). 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. (U.S. Environmental Protection Agency). (2005) Guidelines for carcinogen risk
assessment. Risk Assessment Forum, Washington, DC; EPA/630/P-03/001F. Federal Register
70(66): 17765-17817.
U.S. EPA. (U.S. Environmental Protection Agency). (2006) 2006 Edition of the Drinking
Water Standards and Health Advisories. Office of Water, Washington, DC. EPA 822-R-06-013.
Washington, DC. Available online at
http://www.epa.gov/waterscience/drinking/standards/dwstandards.pdf
Wold, J.S. (1974) The metabolism of o-chlorotoluene-14C in the rat Toxicology Division, Lilly
Research Laboratories, June, 1974 Unpublished (Wold, 1974. 202641)
WHO (World Health Organization). (2009) Chemical Safety - Activity Report. Online.
http://www.who.int/ipcs/about_ipcs/activity_report_2009.pdf
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