United States
Environmental Protection
1=1 m m Agency
EPA/690/R-10/028F
Final
6-28-2010
Provisional Peer-Reviewed Toxicity Values for
1,2,3 -Trimethylbenzene
(CASRN 526-73-8)
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:
Jason Lambert, National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY:
Syracuse Research Corporation
7502 Round Pond Road
North Syracuse, NY 13212
INTERNAL REVIEW PANEL:
National Center for Environmental Assessment, Cincinnati, OH
Dan Petersen
Jay Zhao
Jon Reid
National Center for Environmental Assessment, Research Triangle Park, NC
Anu Mudipalli
Geniece Lehmann
Nicole Hagan
Paul Reinhart
National Center for Environmental Assessment, Washington, D.C.
Audrey Galizia
Martin Gehlhaus
Sanjivani Diwan
Susan Makris
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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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
IRIS
Integrated Risk Information System
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 (oral)
RfC
reference concentration (inhalation)
RfD
reference dose
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
1,2,3-TRIMETHYLBENZENE (CASRN 526-73-8)
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 new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a five-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 manuscripts 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 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
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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
No RfD, RfC, or carcinogenicity assessment for 1,2,3-trimethylbenzene (hemimellitene
or 1,2,3-TMB) is available on IRIS (U.S. EPA, 2008). The HEAST (U.S. EPA, 1997) states that
data were inadequate for quantitative risk assessment for trimethylbenzenes and are based on a
Health and Environmental Assessment (HEA) for Trimethylbenzenes (U.S. EPA, 1987). The
Drinking Water Standards and Health Advisories list (U.S. EPA, 2006) does not include
1,2,3-trimethylbenzene. The Chemical Assessments and Related Activities record (CARA;
U.S. EPA, 1991, 1994a) lists only the previously mentioned HEA (U.S. EPA, 1987). ATSDR
(2008) has not produced a Toxicological Profile for 1,2,3-trimethylbenzene, and no
Environmental Health Criteria Document is available from the World Health Organization
(WHO, 2008). The carcinogenicity of 1,2,3-TMB has not been assessed by the International
Agency for Research on Cancer (IARC, 2008) or the National Toxicology Program (NTP, 2005,
2008). The Occupational Safety and Health Administration (OSHA, 2008) has not established a
permissible exposure limit (PEL) for 1,2,3-TMB. The National Institute for Occupational Safety
and Health (NIOSH, 2008) has set a recommended exposure limit (REL) of 25 ppm (125 mg/m )
for 1,2,3-TMB based on central nervous system (CNS) effects, irritation, and anemia, and the
American Conference of Governmental Industrial Hygienists (ACGIH, 2001, 2007) recommends
a threshold limit value (TLV) of 25 ppm for mixed isomers of trimethylbenzene based on the
same endpoints. CalEPA (2002, 2005, 2008) has not derived a recommended exposure limit
(REL) or a cancer potency factor for 1,2,3-TMB.
Literature searches were conducted from the 1960s through December 2007 for studies
relevant to the derivation of provisional toxicity values for 1,2,3-TMB. Databases searched
include MEDLINE, TOXLINE (Special), BIOSIS, TSCATS 1/TSCATS 2, CCRIS,
DART/ETIC, GENETOX, HSDB, RTECS, and Current Contents. An updated literature search
was conducted from January, 2008, through September, 2009, in MEDLINE. Reviews by
Delic et al. (1992) and Henderson (2001) were also examined for studies that might inform
hazard identification and/or dose-response assessment for 1,2,3-TMB.
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REVIEW OF PERTINENT DATA
Human Studies
Oral Exposure
No information was located regarding the oral toxicity of 1,2,3-TMB in humans.
Inhalation Exposure
A single study was located regarding inhalation exposure of humans to 1,2,3-TMB.
Jarnberg et al. (1996) studied healthy human volunteers exposed to 1,2,3-TMB in an exposure
chamber. Caucasian males (n = 10; average age of 35 years, average weight of 76.5 kg, not
occupationally exposed to solvents) were exposed on four separate occasions for 2 hours to
1,2,3-TMB (90-95% purity) at an air concentration of 25 ppm (123 mg/m3) while pedaling an
ergometer bicycle at 50 watts (light physical work). There was an interval of at least 2 weeks
between successive exposures. Although the study was focused on the uptake and distribution of
1,2,3-TMB and other trimethylbenzene isomers, the study authors also evaluated irritation and
CNS-related symptoms using a questionnaire. The subjects rated symptoms before, during, and
after exposure using a 100-mm analog scale ranging from "not at all" to "almost unbearable."
No irritation of the eyes, nose, throat, or airways, no CNS-related symptoms (headache, fatigue,
nausea, dizziness, intoxication), and no difficulty in breathing were reported by the volunteers.
The toxicokinetic data indicated a respiratory uptake of-56%, moderately rapid elimination
(-0.63 L/hr-kg, total blood clearance), a large volume of distribution (-30 L/kg), and long
terminal half-life in blood (-78 hr); the study authors indicated that the large volume of
distribution and long terminal blood half-life implied a significant accumulation of 1,2,3-TMB in
adipose tissue (Jarnberg et al., 1996). Approximately 37% of the total clearance of 1,2,3-TMB
was through exhalation. Based on a lack of subjectively reported eye and respiratory tract
irritation, and of CNS-related symptoms, the NOAEL for this acute, intermittent-exposure study
"3
in humans is 123 mg/m . Because this was the only exposure level tested, a LOAEL cannot be
determined.
Animal Studies
Oral Exposure
No information was located regarding the oral toxicity of repeated doses of 1,2,3-TMB in
animals. Tomas et al. (1999) evaluated locomotor activity in rats (10 males/group) exposed to
1,2,3-TMB (90-95%) pure in olive oil) via single gavage doses of 0.002-0.032 mol/kg body
weight (240-3850 mg/kg). Locomotor activity, assessed as the number of times the rats crossed
square borders in a cage marked with eight equally sized squares, was evaluated in 10-minute
intervals before and up to 70 minutes after exposure. Exposure to 1,2,3-TMB was associated
with a statistically significant (p < 0.05) increase in locomotor activity at the highest dose, which
was also a frank-effect level for mortality (4/10), and significant clinical signs (disturbed gait,
paresis of hind limbs, tachypnea, tremor, piloerection, and secretion of bloody discharge from
the respiratory tract) observed at this dose. The study authors did not indicate whether problems
with gavage administration contributed to the clinical signs or mortality. In a similar acute-
exposure study, Tomas et al. (2000) evaluated alterations in electrocortical arousal in WAG/Rij
rats (6 males/group) exposed to 1,2,3-TMB (90-95%> pure in olive oil) via single gavage doses of
0.002-0.032 mol/kg body weight (240-3850 mg/kg). Rats of each dose group were implanted
with electrodes bilaterally in the frontoparietal cortex. Electrocortical arousal, assessed as
changes in the high-voltage spindle (HVS) activity of the brain, was recorded 20 minutes before
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and 20, 40, and 60 minutes after exposure. Exposure to 1,2,3-TMB was associated with a
statistically significant (p < 0.001) inhibition of HVS activity (i.e., electrocortical function) at all
doses tested, with the most pronounced effect occurring in the mid-dose (0.008 mol/kg body
weight; 962 mg/kg) group. An acute LOAEL of 240 mg/kg is identified from this single
exposure study based upon decreased electrocortical activity in male WAG/Rij rats. An acute
NOAEL cannot be determined as the lowest oral dose tested produced a significant effect
compared to controls.
Inhalation Exposure
No chronic inhalation animal studies were located for 1,2,3-TMB.
Korsak et al. (2000) studied the effects of subchronic exposure to 1,2,3-TMB
(>97% purity) in male and female outbred Imp:WISTAR rats. Animals (10/sex/group; 20/sex in
high-dose group) were exposed in a dynamic inhalation chamber to nominal concentrations of
0 ppm (sham control), 25 ppm (123 mg/m3), 100 ppm (492 mg/m3), or 250 ppm (1230 mg/m3),
6 hours/day, 5 days/week for 3 months. Concentrations in the exposure chamber were measured
every 30 minutes using a gas chromatograph with a flame-ionization detector. Actual measured
concentrations in the treatment groups were 128 ± 10, 523 ± 38, or 1269 ±36 mg/m3. Male and
"3
female rats of the 1230-mg/m group were observed for 1 month after termination of exposure.
Animals were observed twice a day for overt signs of toxicity. Body weights were recorded
prior to the first inhalation exposure and weekly thereafter during the exposure period. Food
consumption was measured weekly. One week prior to study termination (and 2 weeks after the
"3
end of exposure in the 1230 mg/m recovery group), blood was collected from the tail and
analyzed for erythrocyte, leukocyte, and platelet counts, hemoglobin concentration, hematocrit,
and clotting time. Clinical laboratory studies were conducted 18 hours after termination of
exposure, when rats were exsanguinated and blood samples processed for comprehensive serum
chemistry determinations (aspartate aminotransferase, alanine aminotransferase, alkaline
phosphatase, sorbitol dehydrogenase, gamma glutamyltransferase, bilirubin, total cholesterol,
glucose, total protein, albumin, creatinine, urea, and electrolytes [calcium, phosphorous, sodium,
potassium, and chloride]). All rats were subjected to gross necropsy. Organ weights were
determined for the lungs, liver, spleen, kidneys, adrenals, heart, and gonads. The following
organs were examined for histopathology: brain, nose, larynx, trachea, thymus, lungs, heart,
liver, spleen, kidney, adrenals, thyroid gland, pancreas, gonads, urinary bladder, stomach,
duodenum, small and large intestines, and salivary glands. Changes in the lungs reflecting the
degree of proliferation of peribronchial lymphatic tissue, lymphoepithelium in bronchial mucosa,
interstitial lymphocytic infiltration, macrophage infiltration, and inflammatory processes were
graded using an arbitrary scale of 0-3 or 0-4 (0 = normal, 1 = minimal, 2 = mild, 3 = moderate,
and 4 = marked).
The study authors did not observe mortality during the course of the study (Korsak et al.,
2000). No clinical observations of toxicological relevance were observed. Compared with
controls, there were no significant differences in body-weight gain or in food consumption (data
not shown). Statistically significant changes in hematological parameters included an increase in
percent reticulocytes, decrease in percent segmented neutrophils, decrease in red blood cell
counts, and an increase in percent lymphocytes (trend analyses for all indicatedp < 0.05). A
statistically significant increase in percent reticulocytes was seen in females at study termination
at 123 mg/m3 (77%, p < 0.05) and 492 mg/m3 (100%, p < 0.01), and at 14 days postexposure at
"3
1230 mg/m (162%, p <0 .01), compared to controls. An increase was also observed at study
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"3
termination at 1230 mg/m , but the difference was not statistically significant and the response
was less than that seen at the lower treatment concentrations. A significant increase in percent
"3
reticulocytes was observed in males in the 1230 mg/m group at study termination (61%,
p < 0.05) and 14 days postexposure (146%, p < 0.01). A significant decrease in percent
"3
segmented neutrophils was observed in females at study termination at 492 mg/m (29%,
p < 0.05) and 1230 mg/m3 (48%,p< 0.01), and in males at study termination at 1230 mg/m3
"3
only (29%), p < 0.05). Other significant hematological changes, observed only at 1230 mg/m at
study termination, were a decreased red blood cell count in males (15 %,p< 0 .05) and an
increase in percent lymphocytes in both males (11 %,p< 0.01) and females (15%,p < 0.01).
Statistically significant changes in clinical chemistry included increased alkaline
phosphatase activity, increased sorbitol dehydrogenase activity, and decreased alanine
aminotransferase activity (Korsak et al., 2000); only sorbitol dehydrogenase activity exhibited a
significant trend with 1,2,3-TMB concentration (p < 0.05). A significant increase in alkaline
phosphatase activity was reported for females at study termination at 492 mg/m3 (46%,p < 0.05)
"3
and 1230 mg/m (42%,p < 0 .05). Females also showed a significant decrease in alanine
aminotransferase activity at study termination at 1230 mg/m (23 %,p< 0 .05) only. Males
showed a significant increase in sorbitol dehydrogenase activity at study termination at
1230 mg/m3 (69%, p < 0 .05) only. The study authors reported a significant increase in relative
"3
liver weight in males at study termination at 1230 mg/m (9. 3%,/> < 0 .05); absolute liver weight
was not significantly increased. A significant decrease in absolute spleen weight was observed
in females at study termination at 492 mg/m3 (9.5%,p< 0.05) and 1230 mg/m3 (11 %,p< 0.05),
but relative spleen weight was not affected at any exposure. Table 1 summarizes the effects of
inhaled 1,2,3-TMB on hematology, clinical chemistry, and organ weights (Korsak et al., 2000).
Concentration-related histopathological changes were observed in the lower respiratory
tract (Korsak et al., 2000). A significant increase in the number of goblet cells was noted in the
bronchi of female rats at 492 mg/m3 (p < 0.05) and 1230 mg/m3 (p < 0.01); a trend analysis
"3
indicated significance atp = 0.001. At 1230 mg/m , there was a significant increase in the
intensity of lung perivascular and interstitial infiltration in males (p < 0.01); trend analysis
significance at p = 0.006. Data were reported in terms of the mean severity scores; incidences of
the lesions were not reported. Table 2 summarizes the observed pulmonary lesions. No
histopathological findings were reported for any other organs or tissues examined.
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Table 1. Effects on Hematology, Clinical Chemistry, and Organ Weights in Rats Exposed to
1,2,3-Trimethylbenzene Through Inhalation for 3 Monthsa

Control
0 mg/m3
(n = 10)
123 mg/m3
(n = 10)
492 mg/m3
(n = 10)
1230 mg/m3
(n = 10)
1230 mg/m3
(14 Days
Postexposure)
(n = 10)
Trend
Analysis
Males (mean ± SD)
Hematology
Red blood cell count
(xl06/mm3)
9.49 ±2.03
10.25 ± 1.29
10.11 ± 1.27
8.05 ± 1.38b
8.6 ±1.5
p = 0.0011
Segmented neutrophil (%)
24.8 ±4.5
25.4 ±5.8
20.7 ±5.8
17.7 ± 8.3b
27.5 ± 9.2
p = 0.0032
Lymphocyte (%)
71.2 ±5.0
71.6 ±6.8
75.4 ±4.7
79.3 ± 78.0C
63.7 ±11.3
p = 0.0015
Reticulocyte (%)
2.8 ±1.3
2.1 ±1.7
3.8 ±2.1
4.5 ± 1.8b
6.9 ± 3.1°
p = 0.0017
Clinical Chemistry

Sorbitol dehydrogenase (U/dL)
1.6 ± 0.7
2.3 ±1.3
2.5 ±0.9
2.7 ± 0.7b
ND
p = 0.0083
Relative Organ Weight
Liver
2.208 ±0.163
2.271 ±0.129
2.287 ±0.115
2.414 ±0.214b
ND
p = 0.0117
Females (mean ± SD)
Hematology
Segmented neutrophil (%)
23.1 ±6.1
19.7 ±3.4
16.4 ±4.2b
11.9 ±7.1c
19.6 ±8.3
p = 0.0000
Lymphocyte (%)
73.2 ±7.9
77.5 ±4.9
80.4 ±5.1
84.0 ± 78.0C
75.7 ±9.9
p = 0.0003
Reticulocyte (%)
2.6 ±0.9
4.6 ±2.5b
5.2 ± 0.5C
4.4 ±3.0
6.8 ± 3.5C
p = 0.0459
Clinical Chemistry
Alanine aminotransferase
(U/dL)
39.7 ±3.5
39.5 ±6.4
36.2 ±3.3
30.5 ± 9.9b
ND
p = 0.1844
Alkaline phosphatase (U/dL)
21.5 ± 2.7
25.8 ±8.4
31.1 ±8.6b
30.5 ± 9.9C
ND
p = 0.1740
Absolute Organ Weight (g)
Spleen
0.63 ±0.05
0.61 ±0.10
0.57 ± 0.05b
0.56 ± 0.06b
ND
p = 0.0042
aKorsak et al., 2000; Tables 1, 2, and 3
bp < 0.05
cp < 0.01
ND = Not Determined
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Table 2. Pulmonary Lesions (Mean Severity Scores) in
Rats Exposed to
1,2,3-Trimethylbenzene Through Inhalation for 3 Monthsa


Control





0 mg/m3
123 mg/m3
492 mg/m3
1230 mg/m3
Trend
Change
(n = 10)
(n = 10)
(m = 10)
(n = 10)
Analysis
Males (mean of 0-3 grading system)
Interstitial lymphocytic infiltrations
0.4
0.1
0.4
1.5b'c
p = 0.006
Females (mean of 0-3 grading system)
Goblet cells
1.3
1.6
2.0b
2.4d
p = 0.001
aKorsak et al., 2000, Table 4
hp < 0.05
0 Although Table 4 indicatedp < 0.05, the text indicated p < 0,01
d/?<0.01
The study authors suggested that the signs of anemia (increased percent reticulocytes,
decreased red blood cell counts) and increased sorbitol dehydrogenase activity could be
associated with hepatotoxic effects (Korsak et al., 2000). Furthermore, a significant increase in
relative liver weight was observed in the livers of male rats at the high dose; however, the study
authors noted that histological examination of the liver tissue did not show any treatment-related
changes in either sex at any 1,2,3-TMB exposure concentration. The study authors, therefore,
postulated that the anemia, the increases in white blood cells, and the increase in alkaline
phosphatase activity were more likely the result of inflammation in the respiratory tract
(indicated by the pulmonary lesions). Although a statistically significant increase in percentage
of reticulocytes was seen at the lowest exposure level of 123 mg/m3, this change is not
considered biologically-significant in the absence of related organ/tissue effects at this
concentration. Therefore, based on pathological changes in the lower respiratory tract (i.e., an
"3
increased number of goblet cells in females), the LOAEL for this subchronic study is 492 mg/m ;
hematologic and clinical chemistry changes were also observed in females exposed to this
"3
concentration. TheNOAELis 123 mg/m .
Korsak and Rydzynski (1996) examined the neurobehavioral effects of subchronic
exposure to 1,2,3-TMB (90-95% purity) in male Wistar rats of IMP:DAK outbred stock.
Animals were exposed at concentrations of 0 ppm (sham control), 25 ppm (123 mg/m3),
3	3
100 ppm (492 mg/m ), or 250 ppm (1230 mg/m ) in a dynamic inhalation chamber for
6 hours/day, 5 days/week, for 3 months. Animals in the 1230 mg/m3 group were observed and
tested for 2 weeks following exposure termination. Concentrations in the inhalation chamber
were measured every 30 minutes using a gas chromatograph with a flame-ionization detector.
Animals were observed for clinical signs during the course of the study. Body weights were
measured at the beginning and end of the study. Food and water consumption were not
measured. Rotarod performance was tested on each group (10/group) prior to the start of the
study, weekly during the experiment and 2 weeks following exposure termination (1230-mg/m3
group only). Rotarod performance, an index of neuromuscular function, tested the ability of the
rats to remain on a rotating rod for 2 minutes. Hot-plate behavior was tested in all groups
immediately following termination of exposure and 2 weeks after exposure (high-concentration
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group only). Hot-plate behavior, a measure of pain sensitivity (analgesia), recorded the latency
of the paw-lick response following the placement of the rat on a hot plate.
The study authors reported no mortalities during the study (Korsak and Rydzynski,
1996). No remarkable clinical signs or significant changes in final body weights were observed
in any group (data not shown). Exposure to 1,2,3-TMB was associated with time- and
dose-dependent decreases in both rotarod performance and pain sensitivity. The rotarod data
were reported graphically; only the results for the testing conducted at study initiation, 4 and
8 weeks following study initiation, exposure termination, and 2 weeks following exposure
termination were presented. Changes in rotarod performance (increased percent of failures
compared with the control) were reported to be statistically significant (p < 0.005) in the
3	3
492 mg/m group at study termination, and in the 1230 mg/m group at 4 and 8 weeks following
study initiation, at exposure termination, and 2 weeks following exposure termination. The study
"3
authors observed no statistically significant changes in rotarod performance in the 123 mg/m
group. The hot-plate behavior data were reported in tabular form. Changes in hot-plate behavior
(increased latency of the paw-lick response compared with the control) were reported to be
statistically significant (p < 0.05) at study termination in all treatment groups. The mean latency
of the paw-lick response, when compared with the control group, was increased by 22%, 68%,
and 78%) in the 123-, 492-, and 1230-mg/m3 groups, respectively. Partial recovery in behavior
(13%o increase in latency compared with the control) was observed 2 weeks after cessation of
exposure. Table 3 presents the data for the hot-plate behavior test. Based on an increased
"3
latency of the paw-lick response, the study identifies a subchronic LOAEL of 123 mg/m for
neurobehavioral impairment. Because the LOAEL was the lowest inhalation exposure
concentration tested, a NOAEL cannot be determined for the study.
Table 3. Effects of a 3-Month Inhalation Exposure to 1,2,3-Trimethylbenzene on the
Latency of the Paw-Lick Response (Hot-Plate Behavior) in Ratsa
Group
Number of Animals
(n)
Latency of the Paw-Lick Response
(seconds, mean ± SD)b
Control (0 mg/m3)
30
9.7 ±2.1
123 mg/m3
20
11.8 ± 3.8b
492 mg/m3
10
16.3 ± 6.3°
1230 mg/m3
10
17.3 ± 3.4d
1230 mg/m3
(2 weeks after exposure termination)
10
11.0 ±2.4
aKorsak and Rydzynski, 1996, Table 1
V < 0.05
0 Although the text of the original study reported that the results were statistically significant at all exposure
concentrations, Table 1 of the paper did not indicate significance at 492 mg/m3; this may have been a
typographical error. The results of an ad-hoc Kruskal-Wallis test performed for this review indicated p < 0,01,
d/?<0.01
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Neurobehavioral effects were studied in male Wistar rats exposed to 1,2,3-TMB (purity
not reported) in a dynamic inhalation chamber at concentrations of 0 ppm (sham control, n= 13),
25 ppm (123 mg/m3, n = 13), 100 ppm (492 mg/m3, n = 14), or 250 ppm (1230 mg/m3, n = 13)
6 hours/day, 5 days/week for 4 weeks (Wiaderna et al., 1998). Air samples from the inhalation
chambers were collected at 30-minute intervals and analyzed using a gas chromatograph with a
flame-ionization detector. Body weights were determined at the onset of exposure, weekly
during exposure, and every 2 weeks up to 60 days following the last exposure. The study
authors did not measure food and water consumption, but they did conduct the following
neurobehavioral battery of tests, primarily during the postexposure period: (1) radial maze (test
of spatial working memory, conducted 1 week preexposure and 14-18 days postexposure),
(2) open-field activity (test of spontaneous activity, conducted 25 days postexposure), (3) passive
avoidance (test of long-term memory, and learning ability, conducted 39-48 days postexposure),
(4)	hot-plate test (test of sensitivity to pain, conducted 50 and 51 days postexposure), and
(5)	conditioned active avoidance reaction (test of long-term memory and learning ability,
conducted 54 and 60 days postexposure).
No mortalities were noted by the study authors (Wiaderna et al., 1998). There were no
treatment-related effects on body weight at any test concentration (data not shown). Data for the
behavioral tests were shown graphically. Compared with the control group, significant effects of
1,2,3-TMB exposure were noted for the passive avoidance test (reduced ability to withhold a
locomotor response, i.e., stepping down) in the 123 mg/m3 group during Trial 4 (p < 0.05), Trial
5 (p < 0.05), and Trial 6 (p < 0.001) and in the 492 mg/m3 group during Trial 6 (p < 0.001).
There were no significant differences noted for the high-dose (1230 mg/m3) group. In the active
avoidance test (impaired acquisition of avoiding an unconditioned stimulus, i.e., footshocks, after
the presentation of a conditioned stimulus, i.e., pulsing tone), when compared with the control
"3
group, a significant difference was noted during training in the 492 mg/m group (p < 0.05)—but
not in the 123 mg/m3 or 1230 mg/m3 groups. The study authors observed no significant
differences from control in any treatment group during retraining or retention testing. Significant
differences between the treatment and control groups were not reported for the hot-plate test. No
significant differences between the treatment and control groups for the radial maze performance
and open-field activity tests were noted by the study authors. Based on impairment of the
"3
passive avoidance response, the study identifies a subchronic LOAEL of 123 mg/m for
neurobehavioral impairment. Because the LOAEL was the lowest exposure concentration tested,
a NOAEL cannot be determined.
Neurobehavioral effects were studied in male Wistar rats (10-11/treatment group) that
"3
were exposed to 0 or 100 ppm (492 mg/m ) of 1,2,3-TMB (purity not reported) 6 hours/day,
5 days/week for 4 weeks in whole-body dynamic inhalation chambers (Gralewicz and Wiaderna,
2001). Air samples from the inhalation chambers were collected for analysis 20 minutes after
exposure onset and at 30-minute intervals thereafter, and analyzed using a gas chromatograph
with a flame-ionization detector. The purpose of the study was to compare the effects of
w-xylene to the effects of each of the trimethylbenzene isomers (1,2,3-, 1,2,4-, and 1,3,5-). The
tests conducted were the same as those used in a previous study using 1,2,3-TMB
(Wiaderna et al., 1998) and were performed on the same schedule. No mortalities were reported.
Body-weight gain was not affected by exposure to 1,2,3-TMB (data not shown). The data for the
behavioral tests are shown graphically. In the active avoidance test, 1,2,3-TMB caused a
statistically significant (p < 0.05) impairment of acquisition—but not retention—of the two-way
active avoidance response (i.e., increase in number of trials to the avoidance criterion). The
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mean number of trials to criterion during training was significantly higher than the control in all
solvent-exposed groups—but was lowest in the 1,2,3-TMB group; the differences between
solvent-exposed groups were not statistically significant. There were no statistically significant
differences between groups during retraining (data not shown). No statistically significant
differences between the 1,2,3-TMB and control groups were found for any of the other
behavioral tests; some differences were noted between the 1,2,3-TMB group and the other
isomer groups. These results were inconsistent with those of Wiaderna et al. (1998), which
indicated significant differences in both the active and passive avoidance tests at the 492 mg/m3
exposure level. Gralewicz and Wiaderna (2001) suggested that the discrepancies between the
results for the two studies may have been due to different sensitivities in the rat population or to
"undetected differences in other experimental variables." Based on the impairment of
acquisition in the active avoidance response test, the study identified a subchronic LOAEL of
"3
492 mg/m for neurobehavioral impairment. Because this was the only exposure concentration
tested, a subchronic NOAEL could not be determined.
Other Studies
Acute Studies
Korsak and Rydzynski (1996) examined the neurobehavioral effects of acute-exposure to
1,2,3-TMB (90-95% purity) in male Wistar rats of IMP:DAK outbred stock. Animals were
exposed in a dynamic inhalation chamber at concentrations of 0 ppm (sham control) or
250-2000 ppm (1230-9840 mg/m3) for 4 hours (10/dose group). Rotarod performance and
hot-plate behavior were tested on each group as described above for the subchronic study
conducted by Korsak and Rydzynski (1996). No mortalities were noted by the study authors.
Acute-exposure caused concentration-related decreases in rotarod performance and pain
sensitivity. The acute EC50 (median effective concentration) for impaired rotarod performance
"3
was calculated to be 768 ppm (3779 mg/m ), with 95% confidence intervals of 578-942 ppm
(2832-4615 mg/m3). The acute EC50 for the hot-plate test (concentration that increased the
latency of the paw-lick response to 50% over control) was calculated to be 848 ppm
(4155 mg/m3), with 95% confidence intervals of 694-982 ppm (3400-4811 mg/m3).
Respiratory irritation resulting from acute-exposure to 1,2,3-TMB (90-95% purity) was
investigated in male Balb/c mice (Korsak et al., 1997). Animals (8-10/group) were exposed in
3	3
dynamic inhalation chambers at 266 ppm (1309 mg/m ), 511 ppm (2514 mg/m ), 842 ppm
(4143 mg /m3), or 1591 ppm (7828 mg/m3) for 6 minutes. The respiratory rate, measured by the
whole-body plethysmographic method, was recorded continuously 10 minutes before the
exposure, during 6 minutes of exposure, and 6 minutes after termination of exposure. No
mortalities were reported. The maximum decrease in respiratory rate at each exposure
concentration, observed in the second minute of exposure, was used for the calculation of an
RD50 (concentration depressing the respiratory rate to 50% of control). The RD50 was calculated
to be 2662 mg/m3 (95% confidence intervals of 1343-4074 mg/m3). During the 6-minute period
"3
following termination of exposure, the respiratory rate for the 1309 and 2514 mg/m exposure
groups recovered to approximately 80% of the control; the respiratory rate for the 4143-mg/m3
"3
and 7828-mg/m exposure groups recovered to close to 100% of the control.
Genotoxicity
Genotoxicity of 1,2,3-TMB was evaluated in vitro and in vivo by
Janik-Spiechowicz et al. (1998). Mutagenicity was tested in a standard Ames assay using the
S. typhimurium strains TA97a, TA98, TA100, and TA102 in the presence or absence of rat
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S9 cytosolic protein fraction. 1,2,3-TMB exhibited characteristics of a direct-acting mutagen as
the mutation frequency was significantly elevated in at least one or more exposure groups for
each tester strain in the absence of metabolic activation. 1,2,3-TMB was also evaluated in a
micronucleus assay and sister chromatid exchange (SCE) assay in bone marrow cells from male
and female Imp:Balb/c mice exposed by intraperitoneal injection. 1,2,3-TMB was negative for a
micronucleus response in polychromatic erythrocytes of the bone marrow of male mice exposed
to doses of 1468 or 2936 or mg/kg, or female mice exposed to 2160 mg/kg. 1,2,3-TMB did,
however, exhibit clastogenic potential, as a statistically significant dose-dependent increase in
SCE frequency was observed at all doses tested (730, 1470, and 2200 mg/kg).
FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL RfD VALUES FOR 1,2,3-TRIMETHYLBENZENE
There were no oral studies on which to base the derivation of oral p-RfDs for 1,2,3-TMB.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR 1,2,3-TRIMETHYLBENZENE
A review of the existing literature failed to identify any chronic duration human or animal
studies evaluating inhalation exposure to 1,2,3-TMB. Dose-response data addressing the
toxicological effects of inhalation exposure to 1,2,3-TMB include the results of one
intermittent-exposure study in humans (Jarnberg et al., 1996), two acute-exposure studies in
animals (Korsak and Rydzynski, 1996; Korsak et al., 1997), and four subchronic duration animal
studies (Korsak et al., 2000; Korsak and Rydzynski, 1996; Wiaderna et al., 1998; Gralewicz and
Wiaderna, 2001). Of the available studies, only the data from the four subchronic animal studies
are relevant to the derivation of p-RfC values for 1,2,3-TMB. The durations of exposure in the
human study (four 2-hour exposures at a minimum of 2-week intervals) and acute animal studies
(single exposures of 4 hours or 6 minutes) do not inform the derivation of either subchronic or
chronic p-RfC values.
Subchronic p-RfC
Of the subchronic studies, all conducted in rats, one (Korsak et al., 2000) was a
comprehensive systemic study that evaluated body weight, hematological parameters, clinical
chemistry, organ weights, gross necropsy, and histopathology. The other three studies assessed
neurobehavioral effects using performance testing (Korsak and Rydzynski, 1996;
Wiarderna et al., 1998; Gralewicz and Wiaderna, 2001).
In the comprehensive subchronic toxicity study (Korsak et al., 2000), a LOAEL of
"3
492 mg/m is identified based on an increase in goblet cells in the bronchi of female rats; the
NOAEL is identified to be 123 mg/m3. No formal assessment of neurobehavioral function was
included in the Korsak et al. (2000) study. Conversely, no other available repeated exposure
inhalation studies of 1,2,3-TMB evaluated endpoints beyond neurological function. In one of the
neurobehavioral studies, Korsak and Rydzynski (1996) exposed rats to 0, 123, 492, or
1230 mg/m3 1,2,3-TMB for 6 hours/day, 5 days/week, for 3 months. Wiaderna et al. (1998)
exposed rats to the same inhalation concentrations on the same exposure schedule for 4 weeks.
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"3
A LOAEL of 123 mg/m is identified for each of these studies based on neurobehavioral
impairment; NOAELs could not be determined. Korsak and Rydzynski (1996) reported a
statistically significant decrease in pain sensitivity, manifested as an increased latency in
paw-lick response in the hot-plate test, at all treatment concentrations, and disturbances in
"3
rotarod performance at 492 and 1230 mg/m . Wiaderna et al. (1998) also performed a hot-plate
test, however, in contrast to the results for the Korsak and Rydzynski (1996) study, there were no
statistically significant differences between the treatment and control groups. In addition, data
for the hot-plate test in the Korsak and Rydzynski (1996) study were linear, whereas
neurobehavioral changes observed in the Wiaderna et al. (1998) study exhibited a nonlinear
(inverted U-shaped) relationship to exposure. The differences in results for the two hot-plate
tests in these studies may be due, at least in part, to the differences in duration of exposure,
3 months vs. 4 weeks, and the time of testing, immediately following exposure vs. 50-51 days
postexposure, for the Korsak and Rydzynski (1996) and Wiaderna et al. (1998) studies,
respectively. In the Wiarderna et al. (1998) study, statistically significant impairments in
"3
performance were also observed in the passive avoidance test at 123 and 492 mg/m —but not at
1230 mg/m3—and in the active avoidance test at 492 mg/m3—but not at 123 or 1230 mg/m3.
Due to the uncertain dose-response characteristics of the neurobehavorial effects observed in rats
of the Wiaderna et al. (1998) study, this study was not further considered in the derivation of a
p-RfC.
Decreased pain sensitivity in rats, as reported in the Korsak and Rydzynski (1996) study,
"3
was chosen as the critical effect as it provided the lowest effect level (LOAEL =123 mg/m )
from a positively correlated concentration-response for inhaled 1,2,3-TMB. The results of the
hot-plate test, which were presented quantitatively in tabular form, showed a concentration-
dependent and statistically-significant effect on neurobehavioral performance at exposure
"3
concentrations of 123, 492, and 1230 mg/m . Table 3 summarizes these data. The pain
sensitivity data (i.e., latency in paw-lick response) for rats from the Korsak and Rydzynski
(1996) study was evaluated to determine suitability for benchmark dose (BMD) modeling.
Appendix A provides details of the BMD modeling and results. The recommended Benchmark
Response (BMR) of 1 standard deviation (SD) from the control mean (U.S. EPA, 2000) was used
in the absence of a biologically based benchmark response level for this neurobehavioral
endpoint. No model fit was achieved with all of the exposure groups. However, adequate fit
was achieved when the highest-exposure group was dropped from the analysis. For the reduced
data set, the nonhomogenous variance model in the software provided adequate fit to the
variance data, and the linear model provided adequate fit to the means. The benchmark
concentration (BMCisd) and the 95% lower confidence limit (BMCLisd) resulting from this
model were 152 and 97 mg/m3 (unadjusted concentrations), respectively.
"3
The rat BMCLisd of 97 mg/m was converted to a human equivalent concentration
(HEC) (BMCL[hec]) in accordance with U.S. EPA guidance (U.S. EPA, 1994b). The BMCLisd
was first converted to an equivalent continuous exposure concentration (BMCL[adj]) by
adjusting for the exposure frequency and duration of the study (i.e., number of hours/day and
days/week). The BMCLhec was then calculated from the duration-adjusted effect level
(BMCLadj) by multiplying by the appropriate dosimetric adjustment (rat-to-human blood:air
partition coefficient ratio). For the Korsak and Rydzynski (1996) study data, the BMCL was
based on an extrarespiratory effect, thus, as a Category 3 gas, the ratio of blood:air partition
coefficients was used in the dosimetric adjustment (EPA, 1994b). Blood:air partition
coefficients for several volatile organic compounds, including 1,2,3-TMB, have been reported
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for human and rat in Meulenberg and Vijverberg (2000). The reported partition coefficients of
66.5 (human) and 62.6 (rat) for 1,2,3-TMB are used in the calculation of a BMCLhec shown
below:
BMCLadj	= 97 mg/m3 x 6 hours ^ 24 hours x 5 days ^ 7 days
= 17 mg/m3
BMCLhec =	BMCLadj x (Hb/g)A ^ (Hb/g)H
=	17 mg/m3 x 0.94
=	16 mg/m3
where,
(Hb/g)A (Hb/g)H =	rat-to-human blood:air partition coefficient ratio
and,
(Hb/g)A = 62.6; (Hb/g)H = 66.5 (Meulenberg and Vijverberg, 2000)
This BMCLhec value is used as the point of departure for both the subchronic and
chronic p-RfCs for 1,2,3-TMB. The BMCLhec of 16 mg/m3 is divided by a composite UF of
300 to derive a subchronic p-RfC as follows:
Subchronic p-RfC = BMCLhec UF
= 16 mg/m3 -^300
= 5 x 10"2 mg/m3
The composite UF of 300 includes component factors of 3 for extrapolation from rats to
humans, 10 for human variability, and 10 for database insufficiencies, as explained below.
•	An UF of 1 for extrapolation from a LOAEL to NOAEL (UFl) is applied because the
current approach is to address this extrapolation as one of the considerations in selecting
a BMR for BMD modeling. In this case, a BMR of 1 standard deviation increase over
the control mean for latency in paw-lick response was selected under an assumption that
it represents a minimal biologically significant change.
•	A 3-fold UF is applied for interspecies extrapolation (UFa). This factor comprises two
areas of uncertainty: pharmacokinetics and pharmacodynamics. In this assessment, the
pharmacokinetic component is addressed by the dosimetric adjustment—i.e., calculation
of the HEC according to the procedures in the RfC methodology (U.S. EPA, 1994b).
Consequently, only the pharmacodynamic area of uncertainty remains as a partial factor
of 3 for interspecies extrapolation.
•	A 10-fold UF for intraspecies differences is applied to account for potentially susceptible
human subpopulations (UFH). In the absence of information on the variability in
response of humans to 1,2,3-TMB, the full factor of 10 is applied.

A 10-fold UF is applied to account for deficiencies in the available 1,2,3-TMB database
(UFd). No subchronic human studies are available. The relevant inhalation database
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includes one 3-month comprehensive systemic toxicity study and one 3-month and two
4-week neurobehavioral studies, all in rats. Developmental and reproductive toxicity
studies are lacking for both the inhalation and oral routes, as are subchronic studies in a
second species, therefore a full factor of 10 is applied.
Confidence in the principal study (Korsak and Rydzynski, 1996) is low-to-medium.
Although several exposure levels are used, aNOAEL is not identified, and only one species and
sex was tested. Confidence in the database is low; supporting neurobehavioral studies and a
comprehensive 3-month study are available, but a second species has not been tested and no tests
of reproductive or developmental effects have been located. Low confidence in the subchronic
p-RfC follows.
Chronic p-RfC
No chronic inhalation toxicity study of 1,2,3-trimethybenzene was located. However, the
study on which the subchronic p-RfC is based is of sufficient duration (3 months) to support the
derivation of a chronic p-RfC. The same uncertainty factors (UFs) described in the derivation of
a subchronic p-RfC are applied here, with an additional UF of 10 applied to extrapolate from a
subchronic to chronic exposure duration. Application of the composite UF of 3000 to the
"3
BMCLhec of 16 mg/m results in a chronic p-RfC as follows:
Chronic p-RfC = BMCLhec-UF
= 16 mg/m3 3000
= 5 x 10 3 mg/m3
The composite UF of 3000 includes component factors of 3 for extrapolation from rats to
humans, 10 for human variability, 10 for database insufficiencies, and a factor of 10 for
extrapolation from sub chronic-to-chronic exposure duration.
Confidence in the subchronic toxicity study used to derive the chronic p-RfC is
low-to-medium, and confidence in the database is low, as discussed in the subchronic p-RfC
derivation. Confidence in the database is further reduced by the lack of chronic toxicity data.
Low confidence in the chronic p-RfC follows.
PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR 1,2,3-TRIMETHYLBENZENE
Weight-of-Evidence Descriptor
Studies evaluating the carcinogenic potential of oral or inhalation exposure to 1,2,3-TMB
in humans or animals were not identified in the available literature. A limited number of
genotoxicity studies exist for 1,2,3-TMB. Under the Guidelines for Carcinogen Risk Assessment
(U.S. EPA, 2005), there is "Inadequate Information to Assess [the] Carcinogenic Potential' of
1,2,3-TMB.
Quantitative Estimates of Carcinogenic Risk
Derivation of quantitative estimates of cancer risk for 1,2,3-TMB is precluded by the lack
of carcinogenicity data.
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values for chemical substances and physical agents and biological exposure indices. Cincinnati,
OH.
ATSDR (Agency for Toxic Substances and Disease Registry). 2008. Toxicological Profile
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Potency Values. Online, http://www.oehha.ca.gov/air/hot spots/pdf/TSDlookup2002.pdf.
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CalEPA (California Environmental Protection Agency). 2008. OEHHA/ARB Approved
Chronic Reference Exposure Levels and Target Organs. Online, http://www.arb.ca.gov/toxics/
healthy at/chroni c. pdf.
Delic, J., R. Gardner, J. Cocker et al. 1992. Trimethylbenzenes: Criteria document for an
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Gralewicz, S. and D. Wiaderna. 2001. Behavioral effects following subacute inhalation
exposure to m-xylene or trimethylbenzene in the rat: A comparative study. Neurotoxicology.
22(l):79-89.
Henderson, R.F. 2001. Aromatic Hydrocarbons - Benzene and Other Alkylbenzenes. In:
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Janik-Spiechowicz, E., K. Wyszynska and E. Dziubaltowska. 1998. Genotoxicity evaluation of
trimethylbenzenes. Mutation Research 412:299-305.
Jarnberg, J., G. Johanson and A. Lof. 1996. Toxicokinetics of inhaled trimethylbenzenes in
man. Toxicol. Appl. Pharmacol. 140:281-288.
Korsak, Z. and K. Rydzynski. 1996. Neurotoxic effects of acute and subchronic inhalation
exposure to trimethylbenzene isomers (pseudocumene, mesitylene, hemimellitene) in rats. Int. J.
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Korsak, Z., K. Rydzynski and J. Jajte. 1997. Respiratory irritative effects of trimethylbenzenes:
an experimental animal study. Int. J. Occup. Med. Environ. Health. 10:303-311.
Korsak, Z., J. Stetkiewicz, W. Majcherek, I. Stetkiewicz, J. Jajte and K. Rydzynski. 2000.
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Meulenberg C.J.W. and H.P.M. Vijverberg. 2000. Empirical relations predicting human and rat
tissue:air partition coefficients of volatile organic compounds. Toxicol. Appl. Pharmacol.
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OSHA (Occupational Safety and Health Administration). 2008. OSHA Standard 1910.1000
Table Z-l. Part Z, Toxic and Hazardous Substances. Online, http://www.osha.gov/pls/oshaweb/
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Tomas, T., P. Lutz, and D. Wiaderna. 2000. Changes in electrocortical arousal following acute
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Tomas, T., R. Swiercz, D. Wiaderna et al. 1999. Effects of acute-exposure to aromatic
hydrocarbons C9 on locomotor activity in rats. Trimethylbenzene isomers. Int. J. Occup. Med.
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U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by
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EPA/540/R-97/036. NTIS PB97-921199.
U.S. EPA. 2000. Benchmark Dose Technical Guidance Document [external review draft],
EPA/630/R-00/001. Online, http://www.epa.gov/iris/backer-d.htm.
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Wiaderna, D., S. Gralewicz and T. Tomas. 1998. Behavioural changes following a four-week
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APPENDIX A. DETAILS OF BENCHMARK DOSE MODELING
FOR SUBCHRONIC AND CHRONIC INHALATION p-RfCs
Model Fitting Procedure for Continuous Data:
The model fitting procedure for continuous data is as follows. The simplest model
(linear) in the EPA BMDS (version 1.4.1c) is first applied to the data while assuming constant
variance. If the data are consistent with the assumption of constant variance (p> 0.1), then, all
of the available models are fit to the data while assuming constant variance. Among the models
providing adequate fit to the means (p> 0.1), the one with the lowest AIC for the fitted model is
selected for BMD derivation. If the test for constant variance is negative, the linear model is run
again while applying the power model integrated into the BMDS to account for nonhomogenous
variance. If the nonhomogenous variance model provides an adequate fit (p> 0.1) to the
variance data, then all of the available models are fit to the data and evaluated while the variance
model is applied. Among those providing adequate fit to the means (p> 0.1), the one with the
lowest AIC for the fitted model is selected for BMD derivation. If the test for constant variance
is negative and the nonhomogenous variance model does not provide an adequate fit to the
variance data, then the data set is considered unsuitable for modeling.
Model Fitting Results for Latency of Paw-Lick Response in Rats (Korsak and Rydzynski,
1996)
The data on latency of paw-lick response were modeled according to the procedure
outlined above using BMDS version 1.4.1 with default parameter restrictions. Table A-l shows
the data modeled.
In the absence of a biologically relevant response level, the BMR was chosen to be
1 standard deviation from the control mean, as recommended by U.S. EPA (2000). Neither the
constant nor modeled variance models in the software provided adequate fit to the variance data
for the full data set, indicating that the full data set is not suitable for BMD. The high-dose
group was dropped from the model in an effort to achieve model fit. Using the reduced data set,
the test for homogenous variance was negative, but the variance model in the software provided
adequate fit to the variance information, and the linear model provided adequate fit to the means
(see Table A-2). With only three dose groups (including controls) available for modeling, other
model forms requiring more parameters either reverted to linear or left insufficient degrees of
freedom to test model fit. A BMCisd and BMCLisd of 152.07 and 97.19 mg/m3, respectively,
were predicted using these data. Figure A-l shows the fit of the linear model (nonconstant
variance) to these data.
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Table A-l. Latency of Paw-Lick Response in Rats Exposed to
1,2,3-Trimethylbenzene for 90 Daysa
Effect
Exposure Concentration (mg/m3)
0
123
492
1230
Latency of paw-lick
(sec, mean ± SD)
9.7 ±2.1
(n = 30)
11.8 ± 3.8
(n = 20)
16.3 ±6.3
{n =10)
17.3 ±3.4
(n = 10)
aKorsak and Rydzynski, 1996
Table A-2. Model Predictions for Latency (sec) of Paw-Lick in Rats Exposed to
1,2,3-Trimethylbenzene for 90 Daysa
Model
Variance
p-\alueb
Means
p-V alueb
AIC
bmc1sd
(mg/m3)
bmcl1sd
(mg/m3)
All exposure concentrations
Linear (constant variance)0
0.0001146
0.01728
259.99
577.56
442.59
Linear (modeled variance)0
0.07076
0.00032
254.41
319.65
195.99
High-exposure group dropped
Linear (constant variance)0
<0.0001
0.6445
218.51
265.69
195.64
Linear (Modeled Variance)0
0.5008
0.2016
201.71
152.07
97.19
2-Degree polynomial (modeled variance)0
0.5008
0.2016
201.71
152.07
97.19
Power (modeled variance)d
0.5008
0.2016
201.71
152.07
97.19
Hill (modeled variance/
NA
NA
NA
NA
NA
aKorsak and Rydzynski, 1996
bValues <0.10 fail to meet conventional goodness-of-fit criteria
Coefficients restricted to be positive
dPower restricted to >1
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~rear Model with 0.95 Corfidsrce Le^/el
Dose
21:31 09^172008
Figure A-l. Fit of Linear Model (Nonconstant Variance) to Data on Latency of Paw-Lick
Response (Korsak and Rydzynski, 1996)
BMCs and BMCLs indicated are associated with a change of 1 SD from the control and are in units of mg/m3.
20
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