United States
Environmental Protection
1=1 m m Agency
EPA/690/R-05/025F
Final
9-23-2005
Provisional Peer Reviewed Toxicity Values for
a-2,6-Trichlorotoluene
(CASRN 2014-83-7)
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
|j,mol
micromoles
voc
volatile organic compound
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PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
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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 HEAST (U.S. EPA, 1997) lists a subchronic oral RfD of 5E-5 mg/kg-day for
a,2,6-trichlorotoluene based on a LOAEL of 0.5 ppm (0.05 mg/kg-day) for mild lesions of the
liver, kidney, and thyroid from 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
a,2,6-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 for a,2,6-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 a,2,6-trichlorotoluene. Neither IARC (2003) nor
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NTP (2003) have evaluated the carcinogenicity of a,2,6-trichlorotoluene. Literature searches
were conducted from 1987 through August, 2003 for studies relevant to the derivation of
provisional toxicity values for cc,2,6-trichlorotoluene. Databases searched included: TOXLINE
(supplemented with BIOSIS and NTIS 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 a,2,6-trichlorotoluene in humans
were not located.
Animal Studies
Chu et al. (1984) fed several isomers of trichlorotoluene, including a,2,6-trichlorotoluene,
to Sprague-Dawley rats (10/sex/dose) at dietary concentrations of 0, 0.5, 5, 50, or 500 ppm for 28
days (the chemicals were dissolved in corn oil and then mixed with food). 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. Male rats fed
500 ppm of a,2,6-trichlorotoluene exhibited increased activities of hepatic microsomal amino-
pyridine-N-demethylase as compared to control (62 ±9.2 vs. 47 ±7.2 nmole HCHO/hr-mg
protein, respectively). There was no effect on weight of the liver or other major organs.
The researchers observed mild histopathological lesions in the liver, kidney, and thyroid
of rats exposed to a,2,6-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 a,2,6-trichlorotoluene. The renal
changes included accumulation of eosinophilic intracytoplasmic inclusions in the epithelium of
proximal tubules associated with focal glomerular adhesions and interstitial scarring due to
aging. The hepatic and renal effects resulting from exposure to a,2,6-trichlorotoluene were more
pronounced than those seen with the other trichlorotoluene isomers tested. Histological
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alterations in the thyroid resulting from exposure to cc,2,6-trichlorotoluene were mild and
consisted of 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 cc,2,6-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. Treatment with a,2,6-trichlorotoluene resulted in statistically
significant reductions in maternal weight gain at 200 and 400 mg/kg-day. Histopathologic
lesions in the thyroid, bone marrow, kidney, and liver were observed in exposed dams (doses not
specified). 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 mutagenicity of a,2,6-trichlorotoluene were not located.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL RfD VALUES FOR
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DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR
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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, 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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