United States
Environmental Protection
1=1 m m Agency
EPA/690/R-05/024F
Final
9-22-2005
Provisional Peer Reviewed Toxicity Values for
2,3,6-Trichlorotoluene
(CASRN 2077-46-5)
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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PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
2,3,6-TRICHLOROTOLUENE (CASRN 2077-46-5)
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 HQ Superfund Program) sometimes
request that a frequently used PPRTV be reassessed. Once an IRIS value for a specific chemical
becomes available for Agency review, the analogous PPRTV for that same chemical is retired. It
should also be noted that some PPRTV manuscripts conclude that a PPRTV cannot be derived
based on inadequate data.
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Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
The HE AST (U.S. EPA, 1997) lists a subchronic oral RfD of 5E-5 mg/kg-day for
2,3,6-trichlorotoluene based on a LOAEL of 0.5 ppm (0.05 mg/kg-day) for mild lesions of the
liver, kidney, and thyroid in a 28-day dietary study in Sprague-Dawley rats (Chu et al., 1984).
The source document for this assessment was a HEED for Selected Chlorinated Toluenes (U.S.
EPA, 1987). IRIS (U.S. EPA, 2005a) does not report an RfD, RfC, or cancer assessment for
2,3,6-trichlorotoluene, and this chemical is not included in the Drinking Water Standards and
Health Advisories List (U.S. EPA, 2002). The CARA list (U.S. EPA, 1991, 1994) includes no
relevant documents other than the HEED. ATSDR (2003) has not published a Toxicological
Profile that includes 2,3,6-trichlorotoluene, and no Environmental Health Criteria Document is
available for this chemical (WHO, 2003). ACGIH (2003), NIOSH (2003), and OSHA (2003)
have not developed occupational exposure limits for 2,3,6-trichlorotoluene. Neither IARC
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9-22-2005
(2003) nor NTP (2003) have evaluated the carcinogenicity of 2,3,6-trichlorotoluene. Literature
searches were conducted from 1987 through August, 2003 for studies relevant to the derivation
of provisional toxicity values for 2,3,6-trichlorotoluene. Databases searched included:
TOXLINE (supplemented with BIOSIS andNTIS updates), MEDLINE, CANCERLIT,
TSCATS, RTECS, CCRIS, DART/ETICBACK, EMIC/EMICBACK, HSDB, and GENETOX.
Additional literature searches from August 2003 through September 2004 were conducted by
NCEA-Cincinnati using MEDLINE, TOXLINE, Chemical and Biological Abstracts databases.
REVIEW OF PERTINENT DATA
Human Studies
Studies examining the toxicity or carcinogenicity of 2,3,6-trichlorotoluene in humans
were not located.
Animal Studies
Chu et al. (1984) fed several trichlorotoluene isomers, including 2,3,6-trichlorotoluene, to
Sprague-Dawley rats (10/sex/dose) at dietary concentrations of 0, 0.5, 5, 50, or 500 ppm for 28
days (the trichlorotoluene isomers were dissolved in corn oil and then mixed with food to
achieve appropriate concentration). Doses were estimated by the researchers to be 0.048 - 46
mg/kg-day in males and 0.053 - 53 mg/kg-day in females. The study evaluated the toxicity of
these chemicals based on general appearance, weekly body weight and food consumption,
hematology and serum chemistry, liver enzyme activity, gross tissue pathology, organ weights,
and histopathology. No clinical signs of toxicity were observed and all animals survived to the
end of exposure. Body weight and food consumption were unaffected. Hematology and clinical
chemistry investigations were unremarkable, except for a slight increase in serum SDH (sorbitol
dehydrogenase) in males at 5 ppm (35 ±125 mlU/mL vs. 19 ±4.8 mlU/mL for control). SDH was
apparently not increased in the 50 or 500 ppm males (data not included in study report).
Significant increases in absolute liver weight were observed in males fed 5 or 500 ppm as
compared to control (13.8 ±1.4 g and 14.1 ±1.6 g vs. 11.8 ±2.4 g, respectively), but apparently
not males fed 50 ppm (data not included in study report). Relative weights were not reported.
Weights of other major organs were not affected.
The researchers observed mild histopathological lesions in the liver, kidney, and thyroid
of rats exposed to 2,3,6-trichlorotoluene (Chu et al., 1984). Histopathological changes in the
liver consisted of mild regular and irregular lobular patterns. Hepatocytes had mild anisokaryosis
associated with pyknosis, and occasionally necrotic hepatocytes. Cytoplasmic vacuolization and
increased eosinophilia were seen in portal areas of the hepatic lobule. In the kidney, the authors
report mild, but significant changes associated with exposure to 2,3,6-trichlorotoluene. The renal
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changes included accumulation of eosinophilic intracytoplasmic inclusions in the epithelium of
proximal tubules associated with focal glomerular adhesions and interstitial scarring due to
aging. Histological alterations in the thyroid resulting from exposure to 2,3,6-trichlorotoluene
included mild reductions in follicular size and colloid density. The epithelial cells were
columnar and thickened, with focal and multifocal angular collapse of follicles. In addition,
focal and multifocal papillary proliferations and focal vacuolizations were observed. Although
the incidence and severity of lesions was reported to increase with increasing dose, the authors
did not specify the incidence of lesions in any tissue by dose. Because the specific doses at
which lesions were produced were not identified, NOAEL and LOAEL values could not be
identified.
The same group of researchers conducted a developmental toxicity study that was
reported only as an abstract (Ruddick et al., 1982). Gravid rats were given 0, 100, 200, or 400
mg/kg-day of 2,3,6-trichlorotoluene by gavage on gestation days 6-15. Maternal toxicity was
assessed by weight gain, organ weight, hematology, serum chemistry, and histopathology. Litter
size, fetal weight, skeletal and visceral examination, and microscopic examinations were used to
evaluate developmental toxicity. Histopathologic lesions in the thyroid, bone marrow, kidney,
and liver were observed in exposed dams (doses not specified). Fetal weight was reduced in the
400 mg/kg-day pups. Liver lesions were observed in pups (doses not specified), with the most
severe effects in the 400 mg/kg-day group. The available abstract provides insufficient
information to evaluate the study.
Other Studies
Pertinent data concerning the genotoxicity of 2,3,6-trichlorotoluene were not located.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL RfD VALUES FOR 2,3,6-TRICHLOROTOLUENE
No relevant data were located regarding the toxicity of 2,3,6-trichlorotoluene to humans
following oral exposure. Animal toxicity studies of 2,3,6-trichlorotoluene were limited to a 28-
day feeding study (Chu et al., 1984) and a developmental toxicity study (Ruddick et al., 1982),
neither of which was presented in sufficient detail to identify critical effect levels or permit
independent evaluation. Derivation of subchronic or chronic oral RfD values for 2,3,6-
trichlorotoluene is, therefore, precluded. The subchronic RfD in the HEED (U.S. EPA, 1987)
and HEAST (U.S. EPA, 1997) was derived by assuming, without any supporting information,
that lesions were found at all dose levels in the Chu et al. (1984) study.
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DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR 2,3,6-TRICHLOROTOLUENE
In the absence of subchronic or chronic data on the inhalation toxicity of
2,3,6-trichlorotoluene in humans or animals, derivation of provisional subchronic or chronic RfC
values is precluded.
DERIVATION OF A PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR 2,3,6-TRICHLOROTOLUENE
Data on the carcinogenicity of 2,3,6-trichlorotoluene in humans or animals are not
available. No genotoxicity testing results were located. Under the cancer guidelines (U.S. EPA,
2005b), the data provide inadequate information to assess the carcinogenic potential of
2,3,6-trichlorotoluene.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2003. Threshold Limit
Values for Chemical Substances and Physical Agents and Biological Exposure Indices. ACGIH,
Cincinnati, OH.
ATSDR (Agency for Toxic Substances and Disease Registry). 2003. Internet HazDat-
Toxicological Profile Query. Online, http://www.alsdr.cdc.gov/toxpro2.html
Chu, I., S.Y. Shen, D.C. Villeneuve et al. 1984. Toxicity of trichlorotoluene isomers: a 28-day
feeding study in the rat. J. Environ. Sci. Health. B19(2): 183-191.
IARC (International Agency for Research on Cancer). 2003. Search IARC Monographs.
Online. http://l 93.51.164.11/cgi/iHound/Chem/iH Chem Frames.html
NIOSH (National Institute for Occupational Safety and Health). 2003. Online NIOSH Pocket
Guide to Chemical Hazards. Index by CASRN. Online.
http://www.cdc.gov/niosh/npg/npgdcas.html
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
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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/OsliStd data/1910 1000 TABLE Z-l.html
Ruddick, J.A., D.C. Villeneuve, V.E. Secours and V.E. Valli. 1982. A transplacental and
teratological evaluation of three trichlorotoluene congeners in the rat. Teratology. 25(2):
72A-73A. (Cited in U.S. EPA, 1987)
U.S. EPA. 1987. Health and Environmental Effects Document for Selected Chlorinated
Toluenes. Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria Assessment Office, 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. Summer 2002. EPA 822-R-02-038. Online.
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
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