TECHNICAL REPORT DATA
(Heat retd Inspections on the reverse be fort completing)
1. REPORT NO.
EPA/60Q/8-88/057
2.
3. RECIPIENT'S ACCESSION NO.
PB88-176367
4. TITLE AND SUBTITLE
Health Effects Assessment for 1,2,4-Trichlorobenzene
5. REPORT DATE
«. PERFORMING ORGANIZATION CODE
'. AUTHOR(S)
I. PERFORMING ORGANIZATION REPORT NO
«. PERFORMING ORGANIZATION NAME AND AOORE5S
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
13. TYPE Of REPORT AND PERIOD COVERED
14. SPONSORING AGENCY CODE
EPA/600/22
15. SUPPLEMENTARY NOTES
16. ABSTRACT
This report summarizes and evaluates information relevant to a preliminary interim
assessment of adverse health effects associated with specific chemicals or compounds.
The Office of Emergency and Remedial Response (Superfund) uses these documents in
preparing cost-benefit analyses.under Executive Order 32991 for decision-making under
CERCLA. All estimates of acceptable intakes and carcinogenic potency presented in
this document should be considered as preliminary and reflect limited resources
allocated to this project. The intent in these assessments is to suggest acceptable
exposure levels whenever sufficient data are available. The interim values presented
reflect the relative degree of hazard associated with exposure or risk to the
chemical(s) addressed. Whenever possible, two categories of values have been
estimated for systemic toxicants (toxicants for which cancer is not the endpoint of
concern). The first, RfD5 or subchronic reference dose, is an estimate of an exposure
level that would not be expected to cause adverse effects when exposure occurs during
a limited time interval. The RfD is an estimate of an exposure level that would not
be expected to cause adverse effects when exposure occurs for a significant portion
of the lifespan. For compounds for which there is sufficient evidence of
carcinogenicity, qj*s have been computed, if appropriate, based on oral and
inhalation data if available.
7.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.lDENTIFIERS/OPEN ENDED TERMS C. COSATI Field/Group
8. DISTRIBUTION STATEMENT
Public
19. SECURITY CLASS (ThuReportl
Unclassified
21. NO. OF PAGES
20. SECURITY CLASS (Thispagt)
Unclassified
22. PRICE
P«nn 2220-1 (R«». 4-77) PREVIOUS EDITION i* OBSOLETE
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EPA/600/8-88/057
June, 1987
HEALTH EFFECTS ASSESSMENT
FOR 1,2,4-TRICHLOROBENZENE
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
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DISCLAIMER
This document has been reviewed In accordance with the U.S.
Environmental Protection Agency's peer and administrative review policies
and approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with 1,2,4-trl-
chlorobenzene. All estimates of acceptable Intakes and carcinogenic potency
presented In this document should be considered as preliminary and reflect
limited resources allocated to this project. Pertinent toxlcologlc and
environmental data were located through on-line literature searches of the
TOXLINE, CANCERLINE and the CHEMFATE/OATALOG data bases. The basic litera-
ture searched supporting this document 1s current up to June, 1986. Secon-
dary sources of Information have also been relied upon 1n the preparation of
this report and represent large-scale health assessment efforts that entail
extensive peer and Agency review. The following Office of Health and
Environmental Assessment (OHEA) sources have been extensively utilized:
U.S. EPA. 1980a. Ambient Water Quality Criteria Document for
Chlorinated Benzenes. Prepared by the Office of Health and
Environmental Assessment, Environmental Criteria and Assessment
Office, Cincinnati, OH for the Office of Water Regulations and
Standards, Washington, DC. EPA 440/5-80-028. NTIS P881-117392.
U.S. EPA. 1980b. Hazard Profile for 1,2.4-Trlchlorobenzene.
Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Solid Waste, Washington, DC.
U.S. EPA. 1983a. Reportable Quantity Document for l,2,4-Tr1-
chlorobenzene. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office,, Cincin-
nati, OH for the Office of Emergency and Remedial Response, Wash-
ington, DC.
U.S. EPA. 1985a. Health Assessment Document for Chlorinated
Benzenes. Office of Health and Environmental Assessment, Environ-
mental Criteria and Assessment Office, Cincinnati, OH. EPA
600/8-84-015F. NTIS PB85-150332.
U.S. EPA. 1986. Integrated Risk Information System (IRIS).
Reference Dose (RfD) for Oral Exposure for 1,2,4-Tr1chlorobenzene.
Online (verification date 2/26/86). Office of Health and Environ-
mental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH.
The Intent 1n these assessments 1s to suggest acceptable exposure levels
for noncardnogens and risk cancer potency estimates for carcinogens
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited In
scope tending .to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard or risk associated with exposure to the chemlcal(s) addressed.
111
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Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer Is not the endpolnt of
concern). The first, RfD$ (formerly AIS) or subchronlc reference dose, 1s
an estimate of an exposure level that would not be expected to cause adverse
effects when exposure occurs during a limited time Interval (I.e., for an
Interval that does not constitute a significant portion of the Hfespan).
This type of exposure estimate has not been extensively used, or rigorously
defined, as previous risk assessment efforts have been primarily directed
towards exposures from toxicants In ambient air or water where lifetime
exposure Is assumed. Animal data used for RFD$ estimates generally
Include exposures with durations of 30-90 days. Subchronlc human data are
rarely available. Reported exposures are usually from chronic occupational
exposure situations or from reports of acute accidental exposure. These
values are developed for both Inhalation (RfOgi) and oral (RfO$o)
exposures.
The RfO (formerly AIC) 1s similar In concept and addresses chronic
exposure. It Is an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the Hfespan [see U.S. EPA (1980c) for a discussion of this concept]. The
RfO 1s route-specific and estimates acceptable exposure for either oral
(RfDrj) or Inhalation (RfDi) with the Implicit assumption that exposure
by other routes 1s Insignificant.
Composite scores (CSs) for noncarclnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development 1s explained In U.S.
EPA (1983b).
For compounds for which there Is sufficient evidence of cardnogenlclty
RfD$ and RfO values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980c). Since cancer Is a
process that Is not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-]*s have been computed, 1f appro-
priate, based on oral and Inhalation data If available.
1v
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ABSTRACT
In order to place the risk assessment evaluation In proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate
Interpretation and use of the quantitative estimates presented.
An RfD$g of 14 mg/day and an RfOg of 1.4 mg/day were calculated for
1,2,4-tMchlorobenzene based on a NOAEL of 20 mg/kg/day from a 90-day gavage
study 1n male rats (Carlson and Tardlff, 1976). Altered enzyme activities
were observed at all treatment levels but Increased relative Hver weight
was observed only at 40 mg/kg/day, the highest dose tested. The U.S. EPA
(1986) also derived an RfO of 1.4 mg/day on the same basis. A CS of 12.4
was calculated for oral exposure to 1,2,4-trlchlorobenzene (U.S. EPA, 1983a)
based on Increased adrenal weights 1n rats In a mult1generation reproduction
study (Robinson et a!., 1981).
An RfO$i of 1-75 mg/day and RfDj of 0.18 mg/day were calculated from
a NOAEL In rats exposed to 3 ppm (22 mg/m3) for 3 months (Watanabe et a"!.,
1978). Increased urinary uroporphyrln was noted at 10 ppm.
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Dr. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and John Helms (Office of
Toxic Substances) was the Project Officer. The final documents 1n this
series were prepared for the Office of Emergency and Remedial Response,
Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of Air Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by the following:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by the
following:
Bette Zwayer, Jacky Bohanon and K1m Davidson
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
6.
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1. ORAL
2.2. INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. . .
3.1.2. Inhalation
3.2. CHRONIC. . .
3.2.1. Oral.
3.2.2. Inhalation
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.3.1. Oral. .
3.3.2. Inhalation
3.4. TOXICANT INTERACTIONS
CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral
4.1.2. Inhalation „
4.2. BIOASSAYS
4.2.1. Oral.
4.2.2. Inhalation
4.3. OTHER RELEVANT DATA
4.4. WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfDs)
6.1.1. Oral (RfDso)
6.1.2. Inhalation (RfDcr)
Page
. . . 1
. . . 3
. . . 3
. . . 3
. . . 4
. . . 4
. . . 4
. . . 5
. . . 5
. . . 5
6
. . . 6
. . . 6
. . . 7
7
. . . 8
. , . 8
. . . 8
8
. . . 8
. . . 8
8
. . . 8
9
, , , 10
11
, , , 11
. . . 11
. . . 11
V11
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TABLE OF CONTENTS (cent.)
Page
6.2. REFERENCE DOSE (RfO) 11
6.2.1. Oral (RfD0) 11
6.2.2. Inhalation (RfDj) 14
6.3. CARCINOGENIC POTENCY (q-|*) 15
6.3.1. Oral 15
6.3.2. Inhalation 15
7. REFERENCES 16
APPENDIX: Summary Table for 1,2,4-TMchlorobenzene 22
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LIST OF ABBREVIATIONS
CS Composite score
EPN 0-ethyl 0-para-n1trophenyl phenylphosphorothloate
LOAEL Lowest-observed-adverse-effect level
MED Minimum effective dose
NOAEL No-observed-adverse-effect level
ppm Parts per million
RfO Reference dose
RfDj Inhalation reference dose
RfDrj Oral reference dose
RfOs Subchronlc reference dose
RfD$i Subchronlc Inhalation reference dose
RfD$g Subchronlc oral reference dose
RQ Reportable quantity
RVd Dose-rating value
RVe Effect-rating value
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Selected chemical and physical properties and environmental fate of
1,2,4-trlchlorobenzene are presented In Table 1-1.
In the atmosphere, 1,2,4-tMchlorobenzene 1s expected to exist primarily
In the vapor phase and would be subject to removal by reaction with photo-
chemlcally generated HO radical. Based on an observed reaction rate
constant of 0.532xlO~13 cm3/molecule-sec at 23°C (Atkinson, 1985) and an
ambient HO radical concentration of 8.0x10* molecule/sec. The hydroxyl
reaction half-life 1s -18.8 days.
In water, 1,2,4-trlchlorobenzene should adsorb to suspended solids and
sediments and may bloaccumulate 1n some aquatic organisms. Significant
volatilization from water Is expected, since a volatilization half-life of
11-22 days was determined during mesocosm experiments with aerated seawater
(Wakeham et al., 1983); a volatilization half-life of 6.9 hours was
estimated for a river 1 m deep flowing at 1 m/sec with a wlndspeed of 3
m/sec, based on the method of Lyman et al. (1982). The overall aquatic
half-lives for 1,2,4-trlchlorobenzene In rivers, lakes and groundwater were
estimated to be 0.3-3, 3-30 and 30-300 days, respectively (Zoeteman et al.,
1980).
In soil, 1,2,4-trlchlorobenzene Is expected to remain strongly sorbed
and therefore will not leach appreciably Into the groundwater; however,
1,2,4-trlchlorobenzene has been detected In some groundwater samples which
Indicates that H can be transported In soils under certain conditions. A
blodegradatlon study (Marlnucd and Bartha, 1979) suggests that this
compound may blodegrade slowly 1n aerobic soil, but 1t 1s not expected to
blodegrade In groundwater (Roberts et al., 1980).
0093h -1- 12/03/86
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TABLE 1-1
Selected Chemical and Physical Properties and Environmental Fate
of 1,2,4-Trlchlorobenzene
Property
Reference
CAS number:
Chemical class:
Molecular weight:
Vapor pressure:
Water solubility:
Log octanol/water
partition coefficient:
Bloconcentratlon factor:
Soil adsorption
coefficient:
Half-lives In
Air:
Surface Water:
Soil:
120-82-1
haloaromatlc compound
181.46
0.45 mm Hg at 25°C
25-35 mg/l at 25°C
4.12
1200-3200, rainbow trout
(Salmo qalrdnerl)
2800, fathead minnow
{Plmephales proroelas)
182-815, blueglll sunflsh
(Lepomls macrochlrus)
-1000-5000
-19 days (estimated)
0.3-30 days (estimated)
NA
Mackay and Shu1, 1981
Hackay and Shu1, 1981
Hansch and Leo, 1986
Oliver and N11m1, 1983
Ve1th et a!., 1979
Barrows et a!., 1980;
U.S. EPA, 1980a
Frlesel and Stelner,
1984; Chlou et al.,
1983; Wilson et al.,
1981; U.S. EPA, 1985a
Atkinson, 1985
Zoeteman et al., 1980
NA
NA = Not available
009 3 h
-2-
12/03/86
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2. ABSORPTION FACTORS IN HUMANS AND'EXPERIMENTAL ANIMALS
2.1. ORAL
Male Charles River rats and female rhesus monkeys excreted a mean of 84
and 40%, respectively, of the radioactivity associated with an oral dose of
10 mg l4C-l,2,4-tr1chlorobenzene/kg 1n the urine In 24 hours while fecal
elimination accounted for only 11 and 1%, respectively (L1ngg et al., 1982).
These results Indicate that this compound Is absorbed from the gastrointes-
tinal tract of these species to at least 89 and 99% of the dose In male rats
and female monkeys, respectively.
2.2. INHALATION
As Indicated by systemic effects observed 1n the Inhalation toxlclty
study performed by Koclba et al. (1981), 1,2,4-trlchlorobenzene Is absorbed
by the respiratory tract. This study was not designed to give Information
on absorption rates; therefore, no further quantitative data are available.
0093h -3- 12/03/86
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Carlson and Tardlff (1976) observed no effects on weight
gain nor consistent alteration In hemoglobin content or packed cell volume
1n male CD rats (6 animals/group) given 0, 10, 20 or 40 mg/kg/day,
1,2,4-trkhlorobenzene by the oral route for 90 days. At 40 mg/kg/day,
statistically significant Increased (p<0.05) llver-to-body weight ratios
persisting throughout a 30-day recovery period were observed. Altered liver
enzyme activities were observed 1n all treated groups.
Groups of five female rats (strain not reported) received dally oral
doses of 0, 50, 100 or 200 mg 1,2,4-trlchlorobenzene/kg/day In corn oil by
gavage for 30, 60, 90 or 120 days (Carlson, 1977). After 30 days of
exposure, significant Increases 1n liver porphyrlns were observed at >100
mg/kg and 1n urinary porphyrlns at 200 mg/kg. Slight but significant
Increases were also observed In liver weights at 200 mg/kg. Only liver
weights were Increased when the compound was administered for 60 days.
After 90 days of exposure, slight but significant Increases In "liver weights
at >50 mg/kg, 1n liver porphyrlns at >100 mg/kg and 1n urine porphyrlns at
200 mg/kg were observed. A significant Increase In liver porphyrlns was
found after 120 days of exposure at levels >50 mg/kg. Increased urinary
excretion of
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3.1.2. Inhalation. Koclba et al. (1981) exposed 20 male Sprague-Oawley
rats, 4 male New Zealand rabbits and 2 male beagle dogs to concentrations of
0, 30 ppm (223 mg/m3) or 100 ppm (742 mg/m3) 1,2,4-tMchlorobenzene for
7 hours/day, 5 days/week for a total of 30 exposures In 44 days. No signif-
icant treatment-related effects In any of the species tested were observed
by gross and comprehensive hlstologlcal examination. At the 100 ppm level,
Increased liver weights were observed In dogs and rats. Additionally,
Increased kidney weights were observed In rats. Rats exposed to 1,2,4-trl-
chlorobenzene at 30 or 100 ppm exhibited Increased urinary excretion of
porphyrln, which was Interpreted as a compound-specific physiological effect
rather than a toxic effect. The authors proposed that the urinary porphyrln
excretion was the result of P-450 Induction rather than a result of altera-
tions In heme destruction or synthesis. This hypothesis was not specific-
ally tested. This Interpretation was supported by a follow-up study. The
same team of Investigators exposed Sprague-Oawley rats of both sexes to
1,2,4-trlchlorobenzene at 0, 3 or 10 ppm (0, 22 or 74 mg/m3), 6 hours/day,
5 days/week for 3 months. As reported In an abstract (Hatanabe et al.,
1978), urinary excretion of porphyrlns was slightly Increased at 74.2
mg/m3 but returned to control range 2-4 months postexposure. Thus,
porphyrln excretion appeared to be the most sensitive Indicator of exposure
In rats. Exposure to trlchlorobenzene at 22.3 mg/m3 did not cause
Increased porphyrln excretion; therefore, 22.3 mg/m3 was considered a NOEL
for rats.
3.2. CHRONIC
3.2.1. Oral. Pertinent data regarding chronic oral exposure to 1,2»
4-trlchlorobenzene could not be located 1n the available literature.
0093h -5- 12/29/86
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3.2.2. Inhalation. Pertinent chronic Inhalation toxldty data could not
be located 1n the available literature.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. KHchln and Ebron (1983) gave oral doses of 0, 36, 120, 360
and 1200 mg/kg/ 1,24-trlchlorobenzene dissolved In corn oil to pregnant
Sprague-Dawley (CD strain) rats (>6/group) on days 9-13 of gestation.
Mortality Increased to 100 and 22% In the 120 and 360 mg/kg/day groups,
respectively. Body weight gains were greatly reduced at 360 mg/kg/day.
Signs of maternal hepatotoxldty, reflected by a slight and moderate hepato-
cellular hypertrophy, were observed In 1/9 and 7/8 rats at 120 and 360
mg/kg/day, respectively, but not at 36 mg/kg/day. These hlstologlcal
lesions were not accompanied by changes In maternal I1ver-to-body weight
ratios or hepatic mlcrosomal protein content. 1,2,4-Trlchlorobenzene was a
strong Inducer of hepatic enzymes at 120 and 360 mg/kg/day. Only fetuses In
the 0 and 360 mg/kg/day groups were examined for 1,2,4-trlchlorobenzene-
Induced embryonic effects. No statistically significant differences In
resorptlons, embryolethaHty or abnormalities were reported; however, 3/12
treated litters exhibited embryolethalHy as compared with 0/12 1n the
control Utters. Several embryonic parameters were significantly decreased^
Including embryonic head length, crown-rump length, somite number and total
embryo protein content (reduced 23%).
Robinson et al. (1981) gave male and female Charles River rats (each
treatment group contained 17-23 Utters) 0, 25, 100 or 400 ppm In drinking
water 1n a 3-generatlon reproductlve-teratogenlc effect study. The authors
estimated that at 83 days of age the FQ rats had received approximately
the following doses: males 2.5, 8.9 and 33 mg/kg/day for the 25, 100 and
400 ppm groups, respectively, and females 3.7, 14.8 and 53.6 mg/kg/day for
0093h -6- 12/29/86
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the same respective nominal exposure concentrations. At 400 ppm, signifi-
cantly enlarged adrenals were observed at 95 days of age (p<0.006) In both
sexes of the FQ and F, generations. There were no effects on fertility,
survival, growth, locomotor activity or blood chemistries.
3.3.2. Inhalation. Inhalation data concerning the teratogenlclty of
1,2,4-trlchlorobenzene were not available.
3.4. TOXICANT INTERACTIONS
Townsend and Carlson (1981) demonstrated that a dose of 181.5 mg/kg (1
mmol/kg) of 1,2,4-trlchlorobenzene given to Swiss mice for 7 days protected
them from the toxic effects of malathlon, malaoxon, parathlon and paraoxon.
0093H -7- 12/03/86
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4. CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral. Human oral carc1nogen1dty data could not be located In the
available literature.
4.1.2. Inhalation. Human Inhalation cardnogenlcUy data could not be
located 1n the available literature.
4.2. BIOASSAYS
4.2.1. Oral. Oral bloassays could not be located In the available
literature.
4.2.2. Inhalation. Inhalation bloassays could not be located In the
available literature. The NTP (1986) has not scheduled 1,2,,4-tMchloro-
benzene for carclnogenlclty testing.
4.3. OTHER RELEVANT DATA
Yamamoto et al. (1957) applied 0.03 ml/application of a 30 and 60%
solution of 1,2,4-tr1chlorobenzene 1n acetone to the skin of male and female
mice twice weekly for 2 years. Mean survival days were significantly
reduced In treated mice of both sexes at 60% and In females at 30%. Nine
different tumors were found In the high-dose males as compared with three
and eight tumors found 1n the low-dose and control groups, respectively.
The English translation of this Japanese study did not provide sufficient
detail of expressed Incidence data as the number of animals with tumors/
animals examined.
Negative results were obtained 1n the Salmonella typhlmurlum reverse
mutation assay 1n strains TA98, TA100, TA1535, TA1537 and TA1538 with or
without rat liver S-9 metabolic activation (Schoeny et al., 1979; Lawlor et
al., 1979). In general, this test system 1s Insensitive to chlorinated
compounds (Rlnkus and Legator, 1980).
0093h -8- 09/20/86
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4.4. HEIGHT OF EVIDENCE
Only qualitative evidence concerning the possible carcinogenic effect of
1,2,4-trlchlorobenzene was available. Yamamoto et al. (1957) observed a
tumorlgenlc effect of 1,2,4-trlchlorobenzene In a skin-painting test 1n
mice. These data are Inadequate for determining carcinogenic risk 1n humans
(U.S. EPA, 1985a). According to the guidelines proposed by EPA for evalua-
tion of carcinogenic potential to humans (U.S. EPA, 1986a), 1,2,4-trlchloro-
benzene Is an EPA Group D - Not Classified and IARC Group 3 chemical,
meaning that available data are Inadequate for assessment.
0093h -9- 12/03/86
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5. REGULATORY STANDARDS AND CRITERIA
An ambient water quality criteria for the trlchlorobenzenes was not
derived by the U.S. EPA (1980a). ACGIH (1986) adopted a celling limit of 5
ppm (-40 mg/m3) for 1,2,4-tr1chlorobenzene. An RfO of 1.4 mg/day for a 70
kg man (0.02 mg/kg/day) has been verified (U.S. EPA, 1986b). This value was
obtained by applying an uncertainty factor of 1000 to the NOAEL of 20
mg/kg/day 1n the Carlson and Tardlff (1976) 90-day study In male CD rats.
0093h -10- 12/03/86
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfD$)
6.1.1. Oral (RfDSQ). U.S. EPA (1986b) derived an RfO of 1.4 mg/day for
a 70 kg man based on an oral subchronlc NOAEL of 20 mg/kg/day (Carlson and
Tardlff, 1976) (Section 6.2.1.). An uncertainty factor of 1000 (10 for
Interspecles extrapolation, 10 for Intraspedes variation and 10 for the use
of subchronlc data) was used. An RfD~0 of 0.2 mg/kg/day or 14 mg/day 1s
calculated based on the same NOAEL but omitting the factor of 10 for a
subchronlc study.
6.1.2. Inhalation (RfD$I). In the study by Watanabe et al. (1978),
rats were exposed to 0, 3 or 10 ppm (0, 22.3 or 74.2 mg/m3) 1,2,4-trl-
chlorobenzene for 6 hours/day, 5 days/week for 3 months. Increased urinary
porphyrln excretion was observed at 74.2 mg/m3 but not at 22.3 mg/m3.
Thus, a NOEL of 2.5 mg/kg/day [transformed dose was calculated using
exposure data provided by the authors and by assuming an Inhalation rate of
0.223 mVday (U.S. EPA, 1980b) and a body weight of 0.35 kg (U.S. EPA,
1985b) for the rat] was defined (U.S. EPA, 1985a). Koclba et al. (1981)
provided further support for this estimate by reporting a rat Inhalation
LOAEL of 30 ppm (223 mg/m3), 5 days/week for -6 weeks, based on the same
endpolnt. An RfD$I 1s calculated by dividing the NOAEL of 2.5 mg/kg/day
by an uncertainty factor of 100 (10 for Interspecles extrapolation and 10
for Intraspedes variation) to yield 0.025 mg/kg/day or an RfDST of 1.8
mg/day for a 70 kg man.
6.2. REFERENCE DOSE (RfD)
6.2.1. Oral (RfDQ). U.S. EPA (1986b) based the RfD for 1,2,4-trl-
chlorobenzene of 1.4 mg/day on a 90-day study by Carlson and Tardlff (1976)
In which male CO rats were given oral doses of 0, 10, 20 and 40 mg/kg/day.
0093h -11- 06/17/87
-------
Induction of the enzymes of xenoblotlc metabolism and Increased Hver-
to-body weight ratio, which persisted for 30 days, was observed at 40
mg/kg/day. Enzyme Induction, but not altered llver-to-body weight ratio,
was observed at 20 mg/kg/day. Although enzyme Induction was a sensitive
endpolnt, 1t was not necessarily an adverse effect; therefore, 20 mg/kg/day
was considered a NOAEL. This NOAEL was divided by an uncertainty factor of
1000 (10 for Interspedes extrapolation, 10 for Intraspecles variation and
10 for a subchronlc study) to yield an RfO of 0.02 mg/kg/day or 1.4 mg/day
for a 70 kg man. The NOAEL defined 1n the Carlson and Tardlff (1976) study
was supported by a range of values defined 1n other subchronlc studies.
NOAELs of 14.8 and 8.9 mg/kg/day for female and male rats, respectively,
were reported 1n the multlgeneratlon reproduction study by Robinson et al.
(1981), and a 120-day LOAEL of 50 mg/kg/day based on the endpolnt of
Increased liver porphyMn In rats was observed as well (Carlson, 1977).
An oral CS of 12.4 (Table 6-1) based on a LOAEL defined by a multi-
generation reproduction study (Robinson et al., 1981) In which rats exposed
to 400 ppm of 1,2,4-trlchlorobenzene 1n drinking water exhibited Increased
adrenal weight In the first two generations, but not the third, was derived
by U.S. EPA (1983a). No effect on adrenal weight was observed at 100 ppm.
Doses expressed as mg/kg/day based on water consumption data were provided
by the Investigators; however, these were not used by U.S. HPA (1983a) to
calculate the MED. The preferred approach 1s to use the experimentally
determined values rather than reference values; however, the difference
between the resulting MED values 1s trivial (33.5 and 37.2 mg/day, respec-
tively). The CS of 12.4 calculated by U.S. EPA (1983a) 1s adopted as the CS
for oral exposure to 1,2,4-trlchlorobenzene for the purposes of this
document.
0093h -12- 06/17/87
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-------
6.2.2. Inhalation (RfDj). No Information concerning the chronic
Inhalation toxldty of 1,2,4-tMchlorobenzene was available; however, the
RfOSI of 0.025 mg/kg/day (see Section 6.1.2.) based on a subchronlc NOAEL
of urinary porphyrln excretion (Watanabe et al., 1978) may be divided by an
additional factor of 10 to approximate chronic exposure. This yields an
RfOj of 2.5xlO~3 mg/kg/day or 0.18 mg/day for a 70 kg man.
U.S. EPA (1983a) derived an Inhalation CS (see Table 6-1) for 1,2,4-tM-
chlorobenzene based on an Inhalation LOAEL defined by Watanabe et al.
(1978). In that study, rats exposed to 10 ppm (74 mg/ma) of l,2,4-tr1-
chlorobenzene, 6 hours/day, 5 days/week for 3 months exhibited a reversible
Increase 1n uroporphyrln. No effect on uroporphyrln levels was observed at
22.3 mg/m3 with the same exposure schedule. A few discrepancies between
current and previous methodology for deriving a CS were noted. U.S. EPA
(1983a) calculated a transformed dose assuming continuous exposure, a human
Inhalation rate of 20 mVday and an absorption coefficient of 0.5; the
transformed dose was divided by a factor of 10 to expand from subchronlc to
chronic exposure. Using current methodology, a transformed dose 1s calcu-
lated by assuming continuous exposure, an Inhalation rate of 0.223 mVday
for the rat (U.S. EPA, 1980b) and a body weight of 35 kg (U.S. EPA, 1985b).
When the transformed dose was divided by 10 for a subchronlc study, multi-
plied by the cubed root of the animal body weight to human body weight ratio
and multiplied by 70 kg, a human MED of 10.15 mg/day was obtained, which was
substantially similar to the MED of 13.2 mg/day reported 1n U.S. EPA
(1983a). The Impact of this discrepancy on the RV. was minimal, yielding
4.0 by current methodology and 3.8 by previous methodology. U.S. EPA
(1983a) assigned an effect ranking of 1 to Increased uroporphyrln. The CSs
calculated by previous and current methodologies would be 3.8 and 4.1,
0093h ; -14- 06/17/87
-------
respectively. Since this CS Is lower than that based on oral exposure, the
oral CS of 12.4 1s chosen to represent the chronic toxlclty of 1,2,4-tM-
chlorobenzene.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. The lack of data regarding the cardnogenlclty of Ingested
1,2,4-trlchlorobenzene precluded assessment of carcinogenic risk.
6.3.2. Inhalation. The lack of data regarding the cardnogenlclty of
1,2,4-trlchlorobenzene by Inhalation precluded assessment of carcinogenic
risk.
0093h -15- 12/03/86
-------
7. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986.
Documentation of the Threshold Limit Values, 5th ed. Cincinnati, OH.
p. 593.
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the hydroxyl radical with organic compounds under atmospheric conditions.
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Barrows, M.E., S.R. PetrocelH, K.J. Hacek and J.J. Carroll. 1980. Blocon-
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Carlson, G.P. 1977. Chlorinated benzene Induction of hepatic porphyrla.
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Chlou, C.T., P.E. Porter and D.W. Schmeddlng. 1983. Partition equilibria
of nonlonlc organic compounds between soil organic matter and water.
Environ. Sc1. Techno!. 17: 227-231.
0093h -16- 12/03/86
-------
Frlesel, P.M. and B. Stelner. 1984. Interactions of halogenated hydro-
carbons with soils. Fresenlus Z. Anal. Chem. 319: 160-164.
Goto, M., M. Hattorl, T. Mlyagawa and M. Enomoto. 1972. Be1tra"ge zur
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HCH-1someren 1n hohen dosen. Chemosphere. 6: 279-282. (Ger.) (CHed In
U.S. EPA, 1985a)
Hansch, C. and A.J. Leo. 1986. MedChem Project. Issue No. 26. Pomona
College, Claremont, CA.
Kltchln, K.T. and M.T. Ebron. 1983. Maternal hepatic and embryonic effects
of 1,2,4-trlchlorobenzene 1n the rat. Environ. Res. 31: 362-373.
Kodba, R.J., B.K. Leong and R.E. Hefner, Or. 1981. Subchronlc toxlclty
study of 1,2,4-trlchlorobenzene 1n the rat, rabbit and beagle dog. Drug
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Lawlor, T., S.R. Haworth and P. Voytek. 1979. Evaluation of the genetic
activity of nine chlorinated phenols, seven chlorinated benzenes, and three
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L1ngg, R.D., W.H. Kaylor, S.M. Pyle, et al. 1982. Comparative metabolism
of 1,2,4-trlchlorobenzene 1n the rat and rhesus monkey. Drug Metabol.
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0093h -17- 09/20/86
-------
Lyroan, J.W., W.F. Reehl and O.H. Rosenblatt. 1982. Handbook of Chemical
Property Estimation Methods. McGraw-Hill Book Co., New York. p. 15-13,
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Mackay, D. and W.Y. Sh1u. 1981. A critical review of Henry's Law constants
for chemicals of environmental Interest. J. Phys. Chem. Ref. Data. 19:
1175-1199.
Harlnucd, A.C. and R. Bartha. 1979. Blodegradatlon of 1,2.3- and
1,2,4-trlchlorobenzene In soil and liquid enrichment culture. Appl.
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NTP {National Toxicology Program). 1986. Management Status Report.
6/10/86. NTP, RTP, NC.
Oliver, B.G. and A.J. N11m1. 1983. Bloconcentratlon of chlorobenzenes from
water by rainbow trout: Correlations with partition coefficients and
environmental residues. Environ. Sc1. Technol. 17: 287-291.
Rlnkus, S.J. and M.S. Legator. 1980. The need for both In vitro and U^
vivo systems In mutagenlclty screening. In: Chemical Mutagens, Vol. 6, A.
Hollander, Ed. Plenum Press, New York. p. 365-473. (Cited 'in U.S. EPA,
1985a)
Roberts, P.V., P.L. McCarty, M. Relnhard and J. Schrelner. 1980. Organic
contaminant behavior during groundwater recharge. J. Hater Pollut. Control
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0093h -18- 09/20/86
-------
Robinson, K.S., R.J. Kavlock, N. Chernoff and I.E. Gray. 1981. Multi-
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Schoeny, R.S., C.C. Smith and J.C. Loper. 1979. Non-mutagen1c1ty for
Salmonella of the chlorinated hydrocarbons Arochlor 1254, 1,2,4-tMchloro-
benzene, mlrex and kepone. Mutat. Res. 68(2): 125-132.
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the toxldty and metabolism of malathlon, malaoxon, parathlon and paraoxon
1n mice. Toxlcol. Appl. Pharmacol. 60(1): 52-61.
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Benzenes. Prepared by the Office of Health and Environmental Assessment,
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PB81-117392.
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the Office of Health and Environmental Assessment, Environmental Criteria
and Assessment Office, Cincinnati, OH for the Office of Solid Waste,
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0093h -19- 06/17/87
-------
U.S. EPA. 1983a. Reportable Quantity Document for 1,2,4-Tr1chlorobenzene.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency
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U.S. EPA. 1983b. Methodology and Guidelines for Reportable Quantity Deter-
minations Based on Chronic Toxldty Data. Prepared by the Office of Health
and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC.
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Office of Health and Environmental Assessment, Environmental Criteria and
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DC.
U.S. EPA. 1986a. Guidelines for Carcinogen Risk Assessment. Federal
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U.S. EPA. 1986b. Integrated Risk Information System (IRIS). Reference
Dose (RfD) for Oral Exposure for 1,2,4-Trlchlorobenzene. Online (verifica-
tion date 2/26/86;. Office of Health and Environmental Assessment, Environ-
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0093h -20- 02/09/87
-------
Velth, G.D., D.L. Oelore and 8.V. Bergstedt. 1979. Measuring and estimat-
ing the bloconcentratlon factor of chemicals In fish. J. Fish Res. Board
Can. 36: 1040-1048.
Wakeham, S.G., A.C. Davis and J.L. Karas. 1983. Hesocosm experiments to
determine the fate and persistence of volatile organic compounds In coastal
seawater. Environ. Sc1. Techno!. 17: 611-617.
Watanabe, P.G., R.J. Kodba, R.E. Hefner, Jr., H.O. Yakel and B.K.J. Leong.
1978. Subchronlc toxldty studies of 1,2,4-tr1chlorobenzene 1n experimental
animals. Toxlcol. Appl. Pharmacol. 45(1): 322-333.
Wilson, J.T., C.G. Enfleld, W.J. Ounlap, R.L. Cosby, O.A. Foster and L.B.
Baskln. 1981. Transport and fate of selected organic pollutants 1n a sandy
soil. J. Environ. Qual. 10: 501-506.
Yamamoto, H., Y. Ohno, K. Nakamorl, T. Okuyama, S. Imal and Y. Tsubura.
1957. Chronic toxldty and carclnogenlclty test of 1,2,4-tr1chlorobenzene
on mice by dermal painting. J. Nara. Med. Assoc. 33: 132-145. (Jap.)
Zoeteman, B.C.J., K. Harmsen, J.B.H.J. Llnders, C.F.H. Morra and H. Slooff.
1980. Persistent organic pollutants In river water and ground water of the
Netherlands. Chemosphere. 9: 231-249.
0093h -21- 02/09/87
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