TECHNICAL REPORT DATA
(flttu rtfd Instructions on the reverse be fort completing)
1 REPORT NO.
EPA/600/8-88/028
3. RECIPIENTS ACCESSION NQ_
PB88-179387/AS
4. TITLE AND SUBTITLE
Health Effects Assessment for Dichlorobenzene
B. REPORT DATE
6. PERFORMING ORGANIZATION CODE
AUTHOR(S)
. PERFORMING ORGANIZATION REPORT NO
9. PERFORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO
12. SPONSORING AGENCY NAME AND ADDRESS
13. TYPE OF REPORT AND PERIOD COVERED
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
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 12991 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 aavcjrse effects when exposure occurs for a significant portion
of the lifespan. For compounds for which there is sufficient evidence of
carcino^enicity, qi*s have been computed, if appropriate, based on oral and
inhalation data if available.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.lDENTIFIERS/OPEN ENDED TERMS C. COSATI Field Group
8. DISTRIBUTION STATEMENT
Public
EPA P*rm 2220-1 (R.». 4-77)
19. SECURITY CLASS (This ReponI
JJ n rl as sJ
21. NO. OF PAGES
20. SECURITY CLASS (Thiipage)
Unclassified
PREVIOUS COITION is OMOLKTC
22. PRICE
T-
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EPA/600/8-88/028
July, 1987"
HEALTH EFFECTS ASSESSMENT
FOR DICHLOROBENZENES
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 dlchloro-
benzenes. 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
Chemical Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data bases.
The basic literature searched supporting this document Is current up to May,
1986. Secondary sources of Information have also been relied upon In 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
Dlchlorobenzenes. Prepared by the Office of Health and Environ-
mental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Hater Regulations and Standards,
Washington, DC. EPA 440/5-80-039. NTIS PB81-117509.
U.S. EPA. 1983a. Reportable Quantity Document for 1,2-01chloro-
benzene. 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,
Washington, DC.
U.S. EPA. 1983b. Reportable Quantity Document for 1,4-01chloro-
benzene. 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,
Washington, DC.
U.S. EPA. 1985. 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.
The Intent In 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 1n
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.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer Is not the endpolnt of
concern). The first, RfDs (formerly AIS) or subchronlc 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 (I.e., for an
Interval that does not constitute a significant portion of the llfespan).
111
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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 (RfD$i) and oral (RfOgg)
exposures.
The RfD (formerly AIC) Is similar In concept and addresses chronic
exposure. It Is an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the Hfespan [see U.S. EPA (1980b) for a discussion of this concept]. The
RfD is route-specific and estimates acceptable exposure for either oral
(RfDg) or Inhalation (RfOj) with the Implicit assumption that exposure
by other routes Is Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development 1s explained 1n U.S.
EPA (1984).
For compounds for which there 1s sufficient evidence of carclnogenlclty
RfD$ and RfD values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980b). Since cancer 1s a
process that Is not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-|*s have been computed, If appro-
priate, based on oral and Inhalation data If available.
1v
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ABSTRACT
In order to place the risk assessment evaluation 1n* 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 RfQsi of 31 mg/day and an RfOj of 3.1 mg/day were derived for
1,2-dlchlorobenzene based on a NOAEL In rats of 44.2 mg/kg/day associated
with 49 ppm (290 mg/ma) 7 hours/day, 5 days/week for 7 months
(HolUngsworth et al., 1958). Higher concentrations were associated with
decreased body weights. An RfD$Q of 63 mg/day was based on a NOAEL 1n
rats of 125 mg/kg, 5 days/week 1n a 13-week gavage study (NTP, 1985). An
Interim RfDg of 30 mg/day was based on a NOAEL of 60 mg/kg, 5 days/week 1n
a 103-week gavage study using rats (NTP, 1985). Higher doses were
associated with mild degenerative lesions 1n the liver. Hale mice treated
with 1,2-d1chlorobenzene developed mild kidney tubular degeneration followed
by regeneration (NTP, 1985). A CS of 9 was calculated for this effect 1n a
103-week gavage study (NTP, 1985).
Data were not sufficient to permit quantitative risk assessment for
l,3-d1chlorobenzene. Following the lead of U.S. EPA (1985b), risk assess-
ment was not performed for 1,3-d1chlorobenzene by analogy to the other
Isomers.
1,4-01chlorobenzene has been shown to be carcinogenic to rats and mice
when given chronically by gavage (NTP, 1986), but not when given chronically
by Inhalation (Loeser and Lltchfleld, 1983). In the gavage study, male and
female mice had an Increased Incidence of liver tumors and male rats had an
Increased Incidence of kidney tumors. A q-j* of 2.4xlO~2 mg/kg based on
the Incidence of liver tumors In male mice was chosen as an estimate of the
carcinogenic potential of 1,4-d1chlorobenzene to humans.
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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. Or. 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 Haste
Office of Toxic Substances
Office of Drinking Hater
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 OOSC (RfDs)
6.1.1. Oral (RfDso)
6.1.2. Inhalation (RfDci)
Paqe
1
4
. . 4
. . 4
. . 6
. . 6
. . 6
10
. . 10
. . 10
. . 12
. . 13
. . 13
. . 13
15
16
16
. . 16
16
16
. . 1ft
17
. . 20
21
23
25
25
. . 25
. . 26
V11
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TABLE OF CONTENTS (cont.)
.. Page
*
6.2. REFERENCE DOSE (RfO) 27
6.2.1. Oral (RfD0) 27
6.2.2. Inhalation (RfDj) 29
6.3. CARCINOGENIC POTENCY (q-j*) 30
6.3.1. Oral 30
6.3.2. Inhalation 31
7. REFERENCES 35
APPENDIX A: Summary Table for 1,2-D1chlorobenzene 44
APPENDIX B: Summary Table for 1,4-D1chlorobenzene 45
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LIST OF TABLES
No. TUIe Page
4
1-1 Select Chemical and Physical Properties and Environmental
Fate of the Dlchlorobenzenes 2
4-1 Incidence of Neoplastlc Lesions 1n Male Mice Treated by
Gavage with l,4-D1chlorobenzene 18
4-2 Incidence of Neoplastlc Lesions In Female Mice Treated by
Gavage with 1,4-D1chlorobenzene 19
6-1 Cancer Data Sheet for Derivation of q-j* 32
6-2 Cancer Data Sheet for Derivation of q-j* 33
6-3 Cancer Data Sheet for Derivation of q-j* 34
1x
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LIST OF ABBREVIATIONS
AAOI Adjusted acceptable dally Intake
ADI Acceptable dally Intake
BUN Blood urea nitrogen
CAS Chemical Abstract Service
CS Composite score
DCB Olchlorobenzene
GGTP Y-Glutamyl transpeptldase
1050 Dose lethal to 50% of recipients
LOAEL Lowest-observed-adverse-effect level
MED Minimum effective dose
NOAEL No-observed-adverse-effect level
NOEL No-observed-effect level
ppm Parts per million
RfD Reference dose
RfDj Inhalation reference dose
RfDg Oral reference dose
RfD$ Subchronlc reference dose
RfD$j Subchronlc Inhalation reference dose
RfDgQ Subchronlc oral reference dose
RMCL Recommended maximum contaminant level
RQ Reportable quantity
RV
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LIST OF ABBREVIATIONS (cont.)
SNARL Suggested no adverse response level
STEL Short-term exposed level
TLV Threshold limit value
TWA Time-weighted average
x1
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Selected chemical and physical properties and environmental fate of
1,2-d1chlorobenzene, 1,3-d1chlorobenzene and 1,4-d1chlorobenzene are listed
In Table 1-1.
In the atmosphere, the dlchlorobenzene Isomers should exist primarily 1n
the vapor phase and are expected to react with photochemlcally generated
hydroxyl radicals. The atmospheric half-lives listed In Table 1-1 were
calculated using observed rate constants of 0.42xlO~12, 0.72xlO~12 and
0.32xlO~12 cm3/molecule-sec at 22°C for 1,2-, 1,3- and 1,4-dlchloro-
benzene, respectively (Atkinson, 1985), and an ambient hydroxyl radical
concentration of 8.0x10* molecules/cm3. The detection of each of the
dlchlorobenzene Isomers In rainwater (Pankow et a!., 1984) suggests that
atmospheric removal through washout Is also possible.
In water, adsorption to sediments will be a major fate process based
upon extensive monitoring data In the Great Lakes area and K values
derived from these experimental data (Oliver and N1col, 1982; Oliver 1983;
Oliver and Charlton, 1984). Analysis of Lake Ontario sediment cores has
Indicated the presence and persistence of 1,2-, 1,3- and 1,4-d1chlorobenzene
(Oliver and Nlcol, 1982). The dlchlorobenzenes may volatilize from the
water column; the estimated half-life for volatilization from a river 1 m
deep flowing at a speed of 1 m/sec with a wind velocity of 3 m/sec 1s ~4
hours for each of the dlchlorobenzenes (Lyman et al., 1982). Adsorption to
sediments will greatly reduce volatilization.
The half-lives of the dlchlorobenzene Isomers 1n soil could not be
located In the available literature. The wide range 1n K values
Indicates that the dlchlorobenzenes can be moderately to tightly adsorbed to
0079h -1- 08/29/86
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soil (Swann et al., 1984). The detection of these compounds In groundwaters
Indicates that leaching can occur under certain conditions (Page, 1981;
Hutchlns et al., 1983). Based on the vapor pressure of the dlchloroben-
zenes, volatilization from soil surfaces may be an Important transport
mechanism, although Volatilization may be reduced by adsorption or leaching.
It Is possible that slow blodegradatlon In soil under aerobic condtlons will
occur (Haider et al., 1974).
0079h -3- 08/29/86
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
In reviews on chlorinated benzenes, Hare and West (1977) and U.S. EPA
(1985a) concluded that all three Isomers (1,2-, 1,3- and 1,4-d1chloroben-
zene) are absorbed through the gastrointestinal tracts of humans and experi-
mental animals.
Quantitative data on the absorption of 1,2- or 1,3-d1chlorobenzene after
oral exposure could not be located In the available literature.
Experimental excretion data Indicate that most of the orally adminis-
tered 1,4-d1chlorobenzene Is absorbed from the gastrointestinal tract
(Hawkins et a!., 1980). Two female CFY (Sprague-Dawley derived) adult rats
weighing -200 g were treated by gavage with 250 mg/kg/day of radioactive
14C-1,4-d1chlorobenzene 1n sunflower oil for 10 days (Hawkins et al.,
1980). Recovery of radioactivity equivalent to 1.6 mg of 1,4-d1chloroben-
zene from the feces 5 days after termination of the treatment Indicated that
1,4-d1chlorobenzene was almost completely absorbed from the gastrointestinal
tract. In bile duct cannulated rats, the recovery of 9% of the administered
radioactivity from the feces within 24 hours of treatment. Is further
evidence that gastrointestinal absorption Is >90%. Peak levels of radio-
activity In plasma at 2-4 hours following the last of 10 dally gavage doses
Indicate the rapidity of gastrointestinal absorption.
2.2. INHALATION
In reviews of chlorinated benzenes, Hare and West (1977) and U.S. EPA
(1985a) concluded that all three Isomers (1,2-, 1,3- and 1,4-dlchloroben-
zene) of dlchlorobenzene are absorbed by the lungs of humans and experi-
mental animals.
0079h -4- 11/12/86
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Quantitative data on the absorption of 1,2- or 1,3-d1chlorobenzene after
Inhalation exposure could not be located In the available literature.
Experimental data Indicate, however, that a substantial amount of the admin-
istered 1,4-d1chlorobenzene Is absorbed In rats after Inhalation (Hawkins et
al., 1980). Two female CFY (Sprague-Oawley derived) rats were exposed to
1000 ppm of radioactive 14C-1,4-d1chlorobenzene for 3 hours/day for up to
10 days. Recovery of radioactivity equivalent to 53.5 mg of 1,4-dlchloro-
benzene from the urine and feces, collectively, within 5 days after termina-
tion of the treatment, Indicated that substantial 1,4-d1chlorobenzene had
been absorbed by the lungs, although a more quantitative estimate cannot be
made from these data.
-5- 08/29/86
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Groups of 10 male and 10 female B6C3F1 mice and 10 male and
10 female F344/N rats were treated by gavage with 0, 30, 60, 125, 250 or 500
mg/kg/day of 1,2-d1chlorobenzene 1n corn oil 5 days/week for 13 weeks (NTP,
1985). Parameters evaluated Included mortality, body and organ weights,
clinical chemistry (1n rats only), hematology and histology. Decreased
spleen-to-body weight ratios unaccompanied by hlstologlcal changes were
observed 1n female mice at all dose levels tested. Liver necrosis was
observed In the male mice but not the females treated with 250 mg/kg/day.
Increased mortality, decreased body weight, Increased liver weight accom-
panied by hepatocellular degeneration and necrosis, lymphold depletion In
the spleen and thymus and an Increased Incidence of heart and skeletal
muscle lesions were observed 1n male and female mice treated with 500
mg/kg/day.
Dose-related Increases In liver weight accompanied by hepatocellular
necrosis were observed 1n rats treated with 2bO or 500 mg/kg/day of
1,2-d1chlorobenzene. Although relative Hver weight was significantly
Increased In male and female rats treated with 125 mg/kg/day, the
hlstologlcal changes observed at 125 mg/kg/day were less pronounced than
those at higher dose levels and occurred In 1 of 10 male rats and 2 or 3 of
10 female rats. The male rat with focal hepatic necrosis died early because
of a gavage error. Although no effects on serum levels of SGPT, GGTP or
alkaline phosphatase were observed, "slight" dose-related Increases In the
serum levels of cholesterol (30 and >125 mg/kg/day 1n males; >125 mg/kg/day
In females), trlglycerldes (500 mg/kg/day In males; 250 mg/kg/day In
females) and total protein (>250 mg/kg/day In males; >30 mg/kg/day 1n
0079h -6- 07/28/87
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females) were reported. In rats treated with 500 mg/kg/day of- 1,2-
dlchlorobenzene, slightly decreased hemoglobin and hematpcrlt level's and
thymlc and splenic lymphold depletion occurred 1n both sexes, Increased
kidney weight accompanied by renal tubular degeneration occurred In males
and decreased survival occurred In females.
The results of the NCI bloassay (NTP, 1985) support the earlier study of
HolUngsworth et al. (1958) In which groups of 10 white female rats were
treated by gavage with 0, 18.8, 188 or 376 mg/kg/day of 1,2-dlchlorobenzene
(>99% purity) In olive oil 5 days/week for a total of 138 treatments 1n 192
days. Increased liver and kidney weights were observed 1n rats treated with
188 or 376 mg/kg/day of 1,2-d1chlorobenzene. The Increased liver weight was
accompanied by cloudy swelling 1n rats treated with 376 mg/kg/day of
1,2-dlchlorobenzene. No adverse effects were observed In the rats treated
with 18.8 mg/kg/day of 1,2-dlchlorobenzene.
Pertinent data regarding the systemic toxlclty of 1,3-d1chlorobenzene
after subchronlc oral exposure could not be located In the available
literature.
The NTP (1986) performed two subchronlc oral studies with 1,4-d1chloro-
benzene In B6C3F1 mice. In the first 13-week study, groups of 10 male and
10 female B6C3F1 mice were treated by gavage with 0, 600, 900, 1000, 1500 or
1800 mg/kg/day of 1,4-dlchlorobenzene In corn oil 5 days/week. Endpolnts
evaluated Included mortality, body and organ weight, hematology clinical
chemistry urlnalysls and histology of the major organs-. Body weight was
significantly depressed and the Incidence of hepatocellular degeneration
significantly Increased In male and female mice at all dose levels tested.
In addition, there was a significant decrease 1n the number of white blood
cells In male mice at all dose levels tested and In female mice only at 1000
0079h -7- 07/28/87
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and 1500 mg/kg/day. Mortality was significantly Increased 1n male mice
treated with 1000 mg/kg/day of 1,4-dlchlorobenzene and 1n- male and female
mice treated with >1500 mg/kg/day. No effect was observed on hematocrlt or
SGPT levels. In the second 13-week study, groups of 10 male and 10 female
B6C3F1 mice were treated by gavage with 0, 84.4, 168.8, 337.15, 675 or 900
mg/kg/day of 1,4-d1chlorobenzene 1n corn oil 5 days/week. Endpolnts
evaluated Included mortality rate, body weight and histology; no effects
were reported on mortality or body weight. The Incidence of centrllobular
hepatocytomegaly was significantly Increased 1n both male and female mice
treated with 675 or 900 mg/kg/day of 1,4-dlchlorobenzene. No adverse
hepatic effects were observed In mice of either sex treated with <337.5
mg/kg/day of 1,4-dlchlorobenzene.
The NTP (1986) also performed two subchronlc oral studies with 1,4-dl-
chlorobenzene In F344 rats. In the first 13-week study, groups of 10 male
and 10 female F344 rats were treated by gavage with 0, 300, 600, 900, 1200
or 1500 mg/kg/day of 1,4-dlchlorobenzene In corn oil 5 days/week. Endpolnts
evaluated Include mortality, body and organ weight, hematology, clinical
chemistry, urlnalysls and histology of the major organs. Decreased survival
occurred In males receiving 1200 or 1500 mg/kg/day and In females receiving
1500 mg/kg/day. Decreased weight gain was observed 1n the male rats at all
dose levels tested but In the female rats only at UOO and 1500 mg/kg/day.
L1ver-to-bra1n weight ratios were Increased In both male and female rats
treated with >900 mg/kg/day of 1,4-dlchloroberizene; k1dney-to-bra1n weight
ratios were Increased only In male rats treated with >600 mg/kg/day.
Hematologlcal changes {decreased hematocrlt, red blood cell count and
hemoglobin levels and Increased number of retlculocytes) occurred 1n male
rats at all dose levels tested, but not females. No changes In SGPT levels
0079h -8- 11/12/86
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were reported, but BUN levels were significantly Increased 1n male rats
treated with >900 mg/kg/day. Renal tubular degeneration was observed at all
dose levels tested 1n male rats but not In female rats. Hepatocellular
degeneration, bone marrow hypoplasla and lymphold depletion 1n the spleen
and thymus were observed 1n male and female rats treated with 1200 or 1500
mg/kg/day.
In the second 13-week study, groups of 10 male and 10 female F344 rats
were treated by gavage with 0, 37.5, 75, 150, 300 or 600 mg/kg/day of
1,4-d1chlorobenzene 1n corn oil 5 days/week. Endpolnts evaluated Included
mortality rate, body weight and histology. No compound-related deaths
occurred and there was no effect on the body weight gain of rats of either
sex treated with 1,4-d1chlorobenzene. Dose-related Increases 1n the
Intensity of renal tubular degeneration occurred In male rats treated with
>150 mg/kg/day. M1ld renal tubular degeneration was reported In 7/10
vehicle control male rats; mild to moderate renal tubular degeneration 1n
5/10 male rats treated with 150 mg/kg/day; moderate renal tubular degenera-
tion 1n 3/10 male rats treated with 300 mg/kg/day; and moderate renal
tubular degeneration In 9/10 male rats treated with 600 mg/kg/day of
1,4-dlchlorobenzene.
Groups of 10 white female rats were treated by gavage with 0, 18.8, 188
or 376 mg/kg/day of 1,4-d1chlorobenzene In olive oil 5 days/week for a total
of 138 treatments 1n 192 days {HolUngsworth et al., 1956). Increased
kidney and liver weights were observed 1n rats treated with 188 mg/kg/day.
The Increased liver weight was accompanied by cirrhosis and focal necrosis
In rats treated with 376 mg/kg/day. Mo adverse effects were observed 1n the
rats treated with 18.8 mg/kg/day.
0079h -9- 08/29/86
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3.1.2. Inhalation. Groups of 7-8 male and 7-8 female guinea pigs and
16-20 male and 17-20 female rats were exposed to 0, 49 ppm (290 mg/m3) or
93 ppm (560 mg/m3) of 1,2-dlchlorobenzene, 7 hours/day, 5 days/week for up
to 7 months (Holllngsworth et al.t 1958). The only effect reported In
guinea pigs was decreased spleen weight unaccompanied by any hlstologlcal
alteration 1n the males exposed to 560 mg/m3. In rats, the only effect
reported was significantly depressed body weight In the males exposed to 560
mg/ma. No effects were reported 1n rats or guinea pigs exposed to 290
mg/ma of 1,2-dlchlorobenzene. In addition, no adverse effects were
observed In two male and two female rabbits and two female monkeys exposed
to 560 mg/m3 by the same protocol.
Pertinent data regarding the systemic toxlclty of subchronlc Inhalation
of 1,3-dlchlorobenzene could not be located In the available literature.
Groups of 10-20 male and 10-20 female rats and 8-10 male and 8-10 female
guinea pigs were exposed 'to 0, 96 ppm (580 mg/m3), 158 ppm (950 mg/m3)
or 341 ppm (2050 mg/m3) of 1,4-dlchlorobenzene, 7 hours/day, 5 days/ week
for up to 7 months (Holllngsworth et al., 1956). At >950 mg/m3, adverse
effects were observed In the livers of rats and decreased growth was
observed In the guinea pigs. No adverse effects were observed In rats or
guinea pigs exposed to 580 mg/m3. In addition, 10 female mice, 1 female
monkey and 1 rabbit of each sex that were exposed to 580 mg/m3 of 1,4-dl-
chlorobenzene for 7 hours/day, 5 days/week for 6-7 months had no adverse
effects associated with 1,4-dlchlorobenzene exposure.
3.2. CHRONIC
3.2.1. Oral. In groups of 50 male and 50 female 86C3F1 mice treated by
gavage with 0, 60 or 120 mg/kg/day of 1,2-dlchlorobenzene In corn oil, 5
days/week for 103 weeks and killed 2 weeks later, there was a dose related
0079h -10- 07/28/87
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Increase 1n the Incidence of renal tubular regeneration 1n males (NTP,
1985). Renal tubular regeneration occurred 1n 8/48 mice 1n the control
group, 12/50 In the low-dose group and 17/49 In the high-dose group
(p=0.035, Fisher Exact Test). No other adverse effects were reported.
Treatment by gavage of groups of 50 male and 50 female F344 rats with 0,
60 or 120 mg/kg/day of 1,2-d1chlorobenzene In corn oil 5 days/week for 103
weeks resulted In no observed adverse effects on survival, body weight or
the histology of any organ Including the liver, kidney, bone marrow and
spleen (NTP, 1985). Gavage errors appear to be responsible for decreased
survival observed 1n the high-dose male rats.
Pertinent data regarding the toxldty of chronic oral exposure to
1,3-d1chlorobenzene could not be located 1n the available literature.
Groups of 50 male and 50 female B6C3F1 mice were treated by gavage with
0, 300 or 600 mg/kg/day of 1,4-d1chlorobenzene In corn oil 5 days/week for
103 weeks and killed -2 weeks after the last treatment (NTP, 1986).
Endpolnts evaluated Included mortality rate, body weight and histology of
major organs. No effects were observed on the mortality rate or body weight
of either sex. Nonneoplastlc lesions occurred 1n the livers and kidneys of
both male and female mice. Although more prevalent In the male mice,
hepatocellular degeneration, cell size alteration and focal necrosis were
significantly Increased In both males and females at both dose levels
evaluated. Degeneration of the renal tubular epithelium occurred in both
male and female mice at both dose levels evaluated. The Incidence, however,
was higher In the male mice. Renal tubular regeneration was also observed
In the female mice but not 1n the male mice. Adrenal medullary and capsular
hyperplasla and thyroid folllcular cell hyperplasla occurred In a dose-
related manner 1n male mice but not females.
0079h -11- 07/28/87
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Groups of 50 male F344 rats were treated by gavage with 0, 150 or 300
rag/kg/day of 1,4-dlchlorobenzene and groups of 50 female F344 rats were
treated by gavage with 0, 300 or 600 mg/kg/day of 1,4-d1chloirobenzene, 1n
corn oil, 5 days/week for 103 weeks and killed ~1 week after the last treat-
ment (NTP. 1986). Endpolnts evaluated Included mortality rate, body weight
and histology of major organs. The mortality rate was significantly
Increased In the high-dose males. Mean body weight of the high-dose female
rats was 5-7% lower than the control value. 1,4-01chlorobenzene Increased
the Incidence of nonneoplastlc nephropathy, characterized by renal tubular
atrophy, degeneration and regeneration, tubular dilation, thickening of the
basement membrane, minimal accumulation of Interstitial collagen and the
presence of granular casts 1n dosed female rats (control 21/49; low 32/50;
high 41/49), but not In male rats where the Incidence of nephropathy was
equally high In all three groups (control 42/50; low 42/50; high 46/50).
Renal pelvic epithelial cell and tubular cell hyperplasla, as well as
parathyroid hyperplasla, occurred 1n a dose-related manner In male rats but
not females.
3.2.2. Inhalation. Pertinent data regarding the toxlclty of chronic
Inhalation of 1,2- or 1,3-d1chlorobenzene could not be located 1n the
available literature.
No adverse effects on body weight, food and water consumption, mortality
rate or the histology of the major organs that was due to exposure to
1,4-d1chlorobenzene were observed 1n groups of 75 male and 75 female SPF
Alderly Park Swiss strain mice exposed to 0, 75 or 500 ppm (0, 450 or 3000
mg/ma) of 1,4-d1chlorobenzene, 5 hours/day, 5 days/week for 57 weeks
(Loeser and Lltchfleld, 1983). The females were observed for an additional
0079h -12- 11/12/86
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19 weeks after the end of treatment, but the males were killed at the end of
the treatment period because of the large number of males' (80%) that died
from fighting and respiratory Infections.
No treatment-related effects on body weight, food or water consumption,
mortality rate, blood biochemistry hematology or the histology of the major
organs were observed In groups of 76-79 male and 76-79 female Alderly Park
W1star-der1ved rats exposed to 0, 75 or 500 ppm (0, 450 or 3000 mg/ma) of
1,4-d1chlorobenzene, 5 hours/day, 5 days/week for 76 weeks (Loeser and
Utchfleld, 1983). The rats of both sexes were observed for an additional
36 weeks after the last exposure. The endpolnts evaluated Included body and
organ weights, clinical chemistry, hematology, urlnalysls and histology of
the major organs. At the 500 ppm exposure level. Increased liver and kidney
weights accompanied by "slightly" elevated urinary coproporphyrln levels
were reported. Hlstopathologlcal lesions were not observed 1n the liver or
kidney at either dose tested. "Small* Increases 1n the heart and lung
weight unaccompanied by any hlstologlcal alteration were reported 1n the
rats exposed to 500 ppm of 1,4-d1chlorobenzene. "Some suggestions of
Increased liver weights" were reported 1n the rats exposed to 75 ppm, but
the authors concluded that no adverse effects were observed 1n the rats
exposed to 75 ppm.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Pertinent data regarding the teratogenlc or reproductive
effects of oral exposure to 1,2-d1chlorobenzene, 1,3-d1chlorobenzene or
1,4-d1chlorobenzene could not be located In the available literature.
3.3.2. Inhalation. Groups of -30 pregnant F344 rats and -30 pregnant New
Zealand white rabbits were exposed to 0, 100, 200 or 400 ppm (0, 600, 1200
or 2400 mg/m3} of 1,2-d1chlorobenzene, 6 hours/day on days 6-15 (rats) or
0079h -13- 11/12/86
-------
days 6-18 (rabbits) of gestation (Hayes et al., 1985). Endpo'lnts evaluated
Included maternal and fetal body weights, maternal organ weights, number of
Utters/groups, number of fetuses/Utter, number of resorptlons/lHter,
number of Utters with resorptlons, and the Incidence of visceral and
skeletal malformations. Maternal body weight gain was significantly
depressed 1n all groups of rats exposed to 1,2-dlchlorobenzene. Relative
and absolute liver weight was significantly Increased \n the dams exposed to
400 ppm; only relative liver weight was significantly Increased In the dams
exposed to 100 ppm. No adverse effects were observed In the rabbit dams,
and no teratogenlc or adverse developmental effects were observed In either
the rats or the rabbits.
Pertinent data regarding the teratogenlc or other reproductive effects
of Inhaled 1,3-dlchlorobenzene could not be located In the available
literature.
Loeser and LHchfield (1983) summarized a report by Hodge et al. (1977)
In which groups of 20 pregnant SPF rats were exposed to 0, 75, 200 or 500
ppm (0, 450, 1200 or 3000 mg/m3) of 1,4-d1chlorobenzene for 6 hours/day on
days 6-15 of gestation. Endpolnts evaluated Included maternal organ
weights, maternal and fetal body weight, number of viable fetuses, number of
resorptlons and the Incidence of visceral and skeletal malformations. There
was no evidence of maternal toxldty. One fetus In each group was reported
to have a malformation. No significant teratogenlc, embryo or fetotoxlc
effects were associated with Inhalation exposure to 1,4-d1chlorobenzene 1n
rats.
Groups of 29 or 30 pregnant New Zealand rabbits were exposed to 0, 100,
300 or 800 ppm (0, 600, 1800 or 4800 mg/m3) of 1,4-d1chlorobenzene for 6
hours/day on days 6-18 of gestation (Hayes et al., 1985). Endpolnts
0079h -14- 11/12/86
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evaluated Included maternal organ weights, maternal and fetal body weights,
number of Implantation sites, resorptlons and viable fetuses and the Inci-
dence of visceral and skeletal malformations. No significant teratogenlc,
embryo or fetotoxlc effects were associated with Inhalation exposure to
1,4-d1chlorobenzene 1n rabbits.
The U.S. EPA (1983c) has decided to require no further teratogenlcHy
testing of the dlchlorobenzenes.
3.4. TOXICANT INTERACTIONS
As reviewed by U.S. EPA (1980a, 1985a), the dlchlorobenzenes as a class
have been reported to Induce hepatic xenoblotlc metabolizing enzymes. For
example, oral administration of 1 mmol/kg of 1,4-d1chlorobenzene In corn oil
to male mice for 7 days decreased the toxldty of orally administered
malathlon, as Indicated by an Increased LD5Q (Townsend and Carlson, 1981).
1,4-01chlorobenzene, however, was not as potent as the trlchlorlnated
benzenes In reducing the toxldty of some organophosphates (Townsend and
Carlson, 1981). 1,3-D1chlorobenzene Induced the hepatic enzyme, <$-ALA
synthetase, 1n female rats treated by gavage for up to 5 days (Poland et
a!., 1971); however, ALA synthetase activity as well as serum levels of
1,3-d1chlorobenzene decreased with Increased duration of 1,3-d1ch1orobenzene
treatment, Indicating that 1,3-dlchlorobenzene may stimulate Us own metabo-
lism (Poland et al., 1971). On the other hand, Reid et al. (1973) and Reid
and Krishna (1973) reported that pretreatment of rats with phenobarbUal
Increased the metabolism of subsequently administered 1,2-, 1,3- and 1,4-dl-
chlorobenzene, whereas SKF525-A or plperonyl butoxlde, mlcrosomal enzyme
Inhibitors, decreased the metabolism of subsequently administered 1,2-,
1,3- and 1,4-dlchlorobenzenes. All drugs were administered IntrapeMto-
neally In both studies (Reid et al., 1973; Reid and Krishna, 1973).
0079h -15- 07/28/87
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4. CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral. Pertinent data regarding the carclnogenlclty of Ingested
1,2-, 1,3- or 1,4-d1chlorobenzene In humans could not be located 1n the
available literature.
4.1.2. Inhalation. Pertinent quantitative data regarding the carclno-
genlclty of Inhaled 1,2-, 1,3- or 1,4-d1chlorobenzene In humans could not be
located In the available literature. IARC (1982a) reported that five case
histories described by Glrard et al. (1969) suggest a possible association
between leukemia and Inhalation, and perhaps percutaneous, exposure to the
dlchlorobenzene Isomers.
4.2. BIOASSAYS
4.2.1. Oral. Increased Incidences of tumors were not observed In groups
of 50 male and 50 female B6C3F1 mice or 1n groups of 50 male and 50 female
F344/N rats treated by gavage with 0, 60 or 120 mg/kg/day of 1,2-dlchloro-
benzene 1n corn oil, 5 days/week for 103 weeks (NTP, 1985) (see Section
3.2.1.).
Pertinent data regarding the carclnogenlclty of orally administered
1,3-d1chlorobenzene could not be located 1n the available literature.
In the NTP (1986) bloassay described 1n Section 3.2.1., groups of 50
male and 50 female 86C3F1 mice and 50 female F344/N rats were treated by
gavage with 0, 300 or 600 mg/kg/day of 1,4-d1chlorobenzene In corn oil, 5
days/week for 103 weeks. Groups of 50 male F344/N rats were treated by
gavage with 0, 150 or 300 mg/kg/day of 1,4-d1chlorobenzene In corn oil, 5
days/week for 103 weeks (NTP, 1986). All rats anc1 mice were killed ~1 week
after the last treatment. Oral exposure to 1,4-d1chlorobenzene signifi-
cantly Increased the Incidence of hepatocellular adenomas and/or carcinomas
In male and high dose female mice (Tables 4-1 and 4-2). The NTP (1986)
0079h -16- 07/28/87
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Indicated that although the statistical significance of the Increased
Incidence of thyroid folHcular cell adenoma In males and adrenal
pheochromocytomas In females was only marginally statistically significant,
biological significance may be Implied because of the Increased Incidence of
hyperplasla observed 1n these organs and because thyroid tumors have been
reported In male hamsters treated with a related compound hexachlorobenzene
(Cabral et al., 1977).
In rats, oral exposure to 1,4-dlchlorobenzene significantly Increased
the Incidence of renal tubular cell adenocarclnoma (control, 1/50; low,
3/50; high, 7/50) and renal tubular cell adenoma or adenocarclnoma (control
1/50; low, 3/50; high, 8/50) 1n high dose males but not females. Although
the Incidence of mononuclear cell leukemia was significantly Increased In
the high-dose male rats but not females (control, 5/50, low, 7/50, high,
11/50 1n water), the NTP (1986) concluded that the Increase may not have
been treatment-related because the Incidence of mononuclear cell leukemia Is
variable and low In concurrent controls (10%) when compared with Us
Incidence 1n historical'vehicle (corn oil) controls (17%).
4.2.2. Inhalation. Pertinent data regarding the carclnogenlclty of
Inhaled 1,2- or 1,3-d1chlorobenzene could not be located 1n the available
literature.
No treatment-related effect on the Incidence of tumors was observed In
groups of 75 female SPF, Alderly Park Swiss mice exposed to 0, 75 or 500 ppm
(0, 450 or 3000 mg/m3) of 1,4-dlchlorobenzene, 5 hours/day, 5 days/week
for 57 weeks and subsequently observed for an additional 19 weeks after the
last treatment (loeser and LHchfleld, 1983) (see Section 3.2.2.). The male
mice exposed to 0, 75 or 500 ppm of 1,4-d1chlorobenzene 5 hours/day, 5
days/week were killed after 57 weeks because most (-80%) died during the
treatment period from fighting or respiratory Infections.
0079h -17- 07/28/87
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TABLE 4-1
Incidence of Neoplastlc Lesions 1n Male Mice Treated by
Gavage with 1,4-D1chlorobenzenea
Tumor Type
Hepatocellular adenoma
Hepatocellular carcinoma
Hepatocellular adenoma or
carcinoma'3
Hepatoblastoma
FolUcular cell adenoma
(thyroid)
Pheochromocyfomas (benign
or malignant, combined)
0
14/50
5/50
17/50
0/50
NS
0/47
Incidence (mq/kq/day)
300
11/49
12/49
22/49
0/50
NS
2/48
600
32/50
16/50
40/50
4/50c
NS
4/49
aSource: NTP, 1986
e that had both hepatocellular adenoma and hepatocellular carcinoma
were counted only once.
CA11 hepatoblastomas occurred In mice that also had hepatocellular
carcinomas.
NS = Not statistically significant
0079h
-18-
08/29/86
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TABLE 4-2
Incidence of Neoplastlc Lesions 1n Female Mice Treated by
Gavage with 1,4-D1ch1orobenzenea
Tumor Type
Hepatocellular adenoma
Hepatocellular carcinoma
Hepatocellular adenoma or
carcinoma'5
Hepatoblastoma
0
5/50
10/50
15/50
0/50
Incidence (mq/kg/day)
300
5/48
6/48
10/48
0/48
600
19/50
21/50
23/50
0/50
FolUcular cell adenoma
(thyroid) 0/48 0/45 3/46
Pheochromocytomas (benign
or malignant, combined) NS NS NS
aSource: NTP, 1986
e that had both hepatocellular adenoma and hepatocellular carcinoma
were counted only once.
NS = Not statistically significant
0079h -19- 08/29/86
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No treatment-related effect on the Incidence of tumors was observed 1n
groups of 76-79 male and 76-79 female Alderly Park H1s-tar-derived rats
exposed to 0, 75 or 500 ppm (0, 450 or 3000 mg/m3) of 1,4-d1chlorobenzene,
5 hours/day, 5 days/week for 76 weeks and subsequently observed for an
additional 36 weeks after the last treatment (Loeser and LHchfleld, 1983)
(see Section 3.2.2.).
4.3. OTHER RELEVANT DATA
l,2-D1chlorobenzene was not mutagenlc to Salmonella typhlmurlum strains
TA98, TA100, TA1535 and TA1537 with or without metabolic activation (NTP,
1985). As summarized 1n U.S. EPA (1985a), other studies (Anderson et al.,
1972; Lawlor et al., 1979) have reported that 1,2-dlchlorobenzene Is not
mutagenlc In S_. typhlmurlum. An Increased Incidence of chromosomal aberra-
tions. Including single and double chromosome breaks, was reported In 8 male
and 18 female humans accidentally exposed to vapors of 1,2-d1chlorobenzene
for four 8-hour workdays (Zapata-Gayon et al.,t 1982).
All three Isomers of dlchlorobenzene Increased the frequency of back
mutations 1n an auxotrophlc strain of Asperglllus nldulans (U.S. EPA, 1985a).
1,4-01chlorobenzene was not mutagenlc to S. typhlmurlum strains TA98,
TA100, TA1535, TA1537 and TA1538 with or without rat liver mlcrosomal acti-
vation (Lawlor et al., 1979; NTP, 1986). In a review, Loeser and LHchfleld
(1983) reported that an unpublished study by Anderson (1976) also concluded
that 1,4-dlchlorobenzene was not mutagenlc to S. typhlmurlum strains TA98,
TA100, TA1535 and TA1538 with or without metabolic activation. 1,4-01-
chlorobenzene did not Increase the mutation frequency In cultivated
L5178Y/TK mouse lymphoma cells with or without metabolic activation,
nor did It Increase the frequency of sister-chromatld exchange or chromo-
somal aberrations 1n Chinese hamster ovary j_n vitro (NTP, 1986).
0079h -20- 11/12/86
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A dominant lethal study (Anderson and Hodge, 1976) reviewed by L-oeser
and LUchfleld (1983) Indicated that l,4-d1chlorobenzene was not mut'agenlc
to the sperm cells of mice exposed to 75, 225 or 450 ppm of 1,4-d1chloro-
benzene for 6 hours/day for 5 days.
4.4. WEIGHT OF EVIDENCE
1,2-D1chlorobenzene has been classified as an IARC Group 3 and EPA
Group 0 chemical based on Inadequate evidence for carclnogenlcHy 1n humans,
animals and short-term tests (U.S. EPA, 1985b). In the NTP (1985) study
using 1,2-d1chlorobenzene, survival rates were comparable for all groups
except high-dose males: 19/50 vs. 42/50 1n controls. Seventeen of the
high-dose males were acddently killed by gavage procedures. Thus, we
cannot conclude that survival was lower In any group of rats or mice. Body
weights were not significantly affected In either species and treatment-
related lesions were not detected. On this basis 1t would appear that the
maximum tolerated dose was not reached and this study Is therefore
Inadequate to fully assess carclnogenlclty of 1,2-dlchlorobenzene.
Mutagenesls studies were limited and results In most but not all cases were
negative. Therefore, based on the above evidence, 1,2-d1chlorobenzene would
be classified as a Group D chemical (U.S. EPA, 1986).
1,3-01chlorobenzene has not been classified by IARC but belongs In IARC
Group 3 (IARC, 1982b). 1,3-D1chlorobenzene Is most appropriately placed In
EPA Group D because Its carclnogenlclty In animals and humans has not been
evaluated and therefore cannot be classified as to Us carcinogenic
potential (U.S. EPA, 1985b).
Based on the results of the NTP (1986) bloassay In which a significantly
Increased Incidence In hepatocellular carcinoma or adenoma was observed In
male and female B6C3F1 mice treated by gavage with 1,4-d1chlorobenzene 5
0079h -21- 07/28/87
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days/week for 103 weeks and a significantly Increased Incidence 1n renal
tubular cell carcinoma or adenoma was observed In male F344/N rats treated
by gavage 5 days/week for 103 weeks, this chemical belongs In EPA Group B2
(U.S. EPA, 1986) and IARC Group 28. EPA Group 82 chemicals are probable
human carcinogens and Include chemicals for which the evidence for cardno-
genldty Is adequate 1n animals but Inadequate 1n humans. IARC Group 28
Includes chemicals for which there Is sufficient evidence of cardnogenlcHy
In animals but Inadequate cardnogenlcHy data for humans.
0079h -22- 01/28/87
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5. REGULATORY STANDARDS AND CRITERIA
The ACGIH (1985. 1986) and OSHA (1985) has recommended a celling limit
of 50 ppm (-300 mg/m3) for 1,2-d1chlorobenzene to prevent serious eye and
nasal Irritation as well as headache, nausea and throat Irritation. Absorp-
tion through the skin may contribute substantially to the body burden of an
Individual exposed to 1,2-d1chlorobenzene (ACGIH, 1986). An ambient water
quality criterion of 400 yg/8, was calculated for 1,2-d1chlorobenzene
based on an RfO of 0.94 mg/day derived from the NOEL of 18.8 mg/kg/day, 5
days/week In the 192-day gavage study by Holllngsworth et al. (1958). This
criterion assumes the consumption of 2 l of water and 6.5 g of fish/day.
A proposed drinking water guideline of 0.3 yg/l was reported for
1,2-d1chlorobenzene based on organoleptlc considerations only (U.S. EPA,
1985b). A RMCL of 0.62 mg/l was derived from an AAOI of 0.09 mg/kg/day
(3.12 mg/l) for 1,2-dlchlorobenzene, assuming consumption of 21 of
•
water/day and a 20% contribution to total exposure from drinking water (U.S.
EPA, 1985b). This determination was based on the NOAEL of 125 mg/kg, 5
days/week In the 13-week gavage study using rats and mice by NTP (1985).
The ACGIH (1985, 1986) has recommended a 7LV-THA of 75 ppm (-450
mg/m3), with a STEL of 110 ppm (-665 mg/m3), for 1,4-d1chlorobenzene to
protect against acute and chronic poisoning. OSHA (1985) reported an
occupational standard of 75 ppm (-450 mg/m3) for 1,4-dlchlorobenzene. An
RfD of 0.013 mg/kg/day of 1,2-d1chlorobenzene was derived by multiplying the
NOAEL of 18.8 mg/kg/day from the Holllngsworth et al. (1956) study by 5/7
days and dividing by an uncertainty factor of 1000 (U.S. EPA, 1980a).
0079h -23- 07/28/87
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The U.S. EPA (1980a) derived an ambient water quality criterion of 400
vg/l based on an RfO of 0.94 mg/day (0.013 mg/kg/day) derived from the
NOEL of 18.8 mg/kg In the 192-day study using rats by Holllngsworth et al.
(1956).
The U.S. EPA (1980a) adopted the ambient water quality criterion of 400
jig/I derived for 1,2- and 1,4-d1chlorobenzene as the criterion for
1,3-d1chlorobenzene on the basis of "the similarity of tox1c1t1es among the
DCS Isomers."
The U.S. EPA (1985b) Is considering the appropriateness of deriving
drinking water regulatory criteria for 1,3-d1chlorobenzene based on the
toxldty data available for 1,2-dlchlorobenzene.
0079h -24- 11/12/86
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfD$)
6.1.1. Oral (RfD.g). Two subchronlc oral studies (HolUngsworth et
al.t 1958; NTP, 1985) were available from which to derive an RfD-g for
l,2-d1chlorobenzene. The U.S. EPA (1980a) derived an RfD of 0.94 mg/day,
equivalent to 0.013 mg/kg/day, from the NOEL of 18.8 mg/kg/day In the
192-day rat gavage study by HolUngsworth et al. (1958). Because the rats
were treated for 5 days/week, the dose of 18.8 mg/kg/day was converted to
13.4 mg/kg/day and multiplied by 5/7 days to correct for continuous
exposure. The corresponding RfD™ of 0.13 mg/kg/day (9.4 mg/day) can be
derived from this dosage by application of an uncertainty factor of 100. In
this experiment, only elevated liver and kidney weights, without evidence of
hlstopathologlcal lesions, were observed at 188 mg/kg the next highest dose
tested.
More recent data suggest that an RfOSQ based on the NOEL of 18.8 mg/kg
may be unnecessarily conservative. In the 13-week gavage study using rats
and mice (NTP, 1985), the dose of 125 mg/kg 1,2-dlchlorobenzene appeared to
be a NOAEL In both species. Decreased relative spleen weight In female
mice, the only effect In mice at this dose, occurred In all treated groups.
No evidence of hlstopathologlcal lesions were associated with this effect
below 500 mg/kg. In rats, elevated liver weight was noted, accompanied by
mild hlstopathologlcal lesions of degeneration at 125 mg/kg; similar lesions
were not observed at 188 mg/kg In the earlier Holllngsworth et al. (1958)
study or at 120 mg/kg 1n the chronic NTP (1985) study using rats. The 125
mg/kg dose In the subchronlc rat study (NTP, 1985) was selected by the U.S.
EPA (1985b) as the basis for the RMCL for 1,2-d1chlorobenzene and Is
regarded as the appropriate basis for the RfDso- Multiplication by 5/7
0079h -25- 07/28/87
-------
days to reflect treatment 5 days/week and application of an uncertainty
factor of 100 results In an RfDSQ for l,2-d1chlorobenzene of 0.9 mg/Jcg/day
or 63 ing/day for a 70 kg human.
Pertinent data regarding the subchronlc oral toxldty of 1 ,3-d1chloro-
benzene could not be located 1n the available literature. The U.S. EPA
(1980a) derived a water quality criterion for 1 ,3-d1chlorobenzene by analogy
to 1,2- and 1 ,4-dlchlorobenzene. Since this derivation, the 1,4-lsomer has
been shown to be a carcinogen 1n both rats and mice (NTP, 1986). In a more
recent analysis, the U.S. EPA (1985b) declined to promulgate drinking water
regulations for the 1,3-lsomer and questioned the appropriateness of
deriving a criterion by analogy to the other Isomers. No RfDrn for
1 ,3-d1chlorobenzene will be derived, pending a more adequate data base.
The results of the NTP (1986) bloassay In which 1,4-dlchlorobenzene was
associated with significantly Increased liver tumors In male and female mice
and significantly Increased renal tumors In male rats (see Section 6.3.)
preclude the derivation of an RfDSQ for 1 ,4-d1chlorobenzene.
6.1.2. Inhalation (RfD.,). Based on the study by Holllngjworth et al.
(1958) In which groups of 7-8 male and 7-8 female guinea pigs and 16-20 male
and 17-20 female rats were exposed to 0, 49 ppm (290 mg/m3) or 93 ppm (560
mg/m3) of 1 ,2-d1chlorobenzene for 7 hours/day, 5 days/week for up to 7
months, the highest NOEL below which no effects were reported occurred In
the rats exposed to 290 mg/ma. The higher dose caused significantly
decreased body weight In the male rats and significantly decreased spleen
weight unaccompanied by hlstologlcal alteration In the male guinea pigs. A
NOAEL of 44.2 mg/kg/day Is estimated by multiplying the exposure dose (290
mg/ma) by 7/24 hours and 5/7 days and the dally reference Inhalation
volume of a rat of 0.223 mVday (U.S. EPA, 1980b) and by dividing by the
0079h -26- 07/28/87
-------
experimentally reported final average rat body weight of 0.305 kg (290 * 5/7
x 7/24 x 0.223 x 1/0.305). The RfD of 31 mg/day (0.44 mg/kg/day) Is
Ol
obtained by multiplying the NOEL of 44.2 mg/kg/day by the reference human
body weight of 70 kg (U.S. EPA, 1980b) and by dividing by an uncertainty
factor of 100 to account for Interspecles extrapolation and the range of
sensitivity within the human population to xenoblotlcs.
Pertinent data regarding the toxldty of 1,3-d1chlorobenzene after
subchronlc Inhalation could not be located In the available literature. For
the reasons discussed 1n Section 6.1.1., an RfDCT for the 1,3-lsomer shall
O 1
not be derived by analogy to the other dlchlorobenzene Isomers.
The results of the NTP (1986) bloassay 1n which 1,4-d1chlorobenzene was
associated with significantly Increased liver tumors In male and female mice
and significantly Increased renal tumors In rats precludes the derivation of
an RfDSI for 1,4-dlchlorobenzene.
6.2. REFERENCE DOSE (RfO)
6.2.1. Oral (RfOQ). Two subchronlc experiments, the HolUngsworth et
al. (1958) study and the NTP (1985) study have been used to derive chronic
oral RfDs for 1,2-d1chlorobenzene. Based on the Holllngsworth et al. (1958)
study, a NOEL of 18.8 mg/kg/day was Identified. An RfD of 0.94 mg/kg for
l,2-d1chlorobenzene was derived from this NOEL by the U.S. EPA (1980a).
From the NTP (1985) experiment, the U.S. EPA (1985b) Identified a NOAEL of
125 mg/kg and derived a provisional AAOI of 3.12 mg/J., equivalent to 6.24
mg/day or 0.09 mg/kg/day.
Subsequent to these evaluations, the NTP (1985) conducted a 103-week
gavage study using rats and mice In which there was a dose-related Increased
Incidence of renal tubular regeneration 1n male B6C3F1 mice at 2 weeks
0079h -27- 07/28/87
-------
following gavage treatment with 60 or 120 mg/kg/day of 1,2-dlchlorobenzene 5
days/week for 103 weeks. A NOAEL of 60 mg/kg/day was Identified. A more
appropriate RfOQ can be derived from the chronic studies than from the
subchronlc studies, because the uncertainty associated with extrapolation
from subchronlc to chronic exposure Is removed. An Interim RfDn of 30
mg/day (0.43 mg/kg/day) 1s derived by multiplying the NOAEL of 60 mg/kg/day
by 5/7 days and the reference human body weight of 70 kg (U.S. EPA, 1980b)
and dividing by an uncertainty factor of 100 to account for Interspecles
extrapolation and the range of sensitivity to xenoblotlcs within the human
population. This chemical 1s currently undergoing review by the RfD
committee; therefore, this RfD 1s being recommended as an Interim RfDQ
pending final verification.
The U.S. EPA (1983a) derived an RQ of 1000 for 1,2-d1chlorobenzene (CS,
8.8; RVg, 4; RVd, 2.2) based on a LOAEL of 188 mg/kg/day associated with
Increased liver and kidney weights 1n female rats from the subchronlc
Holllngsworth et al. (1958) study.
Since the U.S. EPA (1983a) analysis, chronic data have become available
that are a more appropriate basis for a CS based on chronic toxlclty. A CS
of 9 can be obtained from the LOAEL of 120 mg/kg/day from the NTP (1985)
chronic study In which a significant Increase In the Incidence of renal
tubular regeneration occurred 1n male mice treated by gavage with 120
mg/kg/day of 1,2-dlchlorobenzene, 5 days/week for 103 weeks and k111ed_2
weeks after the last treatment. A human MED of 498 mg/day can be derived by
multiplying the LOAEL of 120 mg/kg/day by 5/7 days, by the cube root of the
ratio of the body weight of male mice (estimated at 0.04 kg from data
provided by Investigators) to that of reference man (70 kg) and by 70 kg to
express the result 1n terms of mg/day for a 70 kg human. The MED of 498
0079h -28- 09/22/87
-------
rag/day Is equivalent to an RV. of 1.5. The effects 1n the kidney ra-te an
RVe of 6. The CS of 9 based on the chronic NTP (1985J study Is" more
appropriate than the RQ based on the subchronlc HolUngsworth et al. (1958)
study.
Pertinent data regarding the toxlclty of 1,3-d1chlorobenzene after
chronic oral exposure could not be located In the available literature and
no RfDQ 1s calculated for this Isomer.
The results from the NTP (1986) bloassay In which groups of 50 male and
50 female B6C3F1 mice and F344/N rats were treated by gavage with
1,4-d1chlorobenzene Indicate that a significant Increase 1n the Incidence of
hepatocellular carcinomas or adenomas In male and female mice and of renal
tubular cell adenoma or adenocarclnoma In male rats Is associated with the
Ingestlon of 1,4-dlchlorobenzene. Therefore, It Is not appropriate to
derive an RfO or a chronic toxldty CS based on systemic toxldty of
1,4-dlchlorobenzene. Although the U.S. EPA (1983b) reported an RQ of 1000
(CS, 9.0; RV , 5; RV , 1.8) for 1,4-dlchlorobenzene based on the adverse
liver effects observed after Inhalation of 1,4-dlchlorobenzene by rats,
rabbits and guinea pigs (HolUngsworth et al., 1956), the RQ was derived
before the completion of the NTP (1986) bloassay with 1,4-dlchlorobenzene.
6.2.2. Inhalation (RfO.). Pertinent data regarding the toxldty of
1,2-d1chlorobenzene and 1,3-d1chlorobenzene after chronic Inhalation could
not be located 1n the available literature. Lacking chronic data for
1,2-dlchlorobenzene, a provisional RfO. of 3.1 mg/day can be estimated by
applying an additional uncertainty factor of 10 to the RfDSI of 31 mg/day
calculated from the subchronlc study by HolUngsworth et al. (1958).
0079h -29- 07/28/87
-------
A CS of 10 can be calculated for Inhalation exposure to 1,2-dlch-loro-
benzene based on the depressed spleen weights In guinea pig; observed In the
subchronlc study by Holllngsworth et al. (1958); however, because of the
uncertainties associated with subchronlc to chronic extrapolation, this has
not been done and the CS of 9 associated with renal tubular necrosis and
regeneration In a chronic oral rat study Is chosen to represent the toxldty
associated with 1,2-dlchlorobenzene.
The results of the NTP (1986) bloassay In which oral exposure to
1,4-dlchlorobenzene was associated with significantly Increased Incidences
of tumors In mice and rats preclude derivation of an RfO, for
1,4-dlchlorobenzene. Although no Increase 1n the Incidence of tumors was
observed 1n the Loeser and Lltchfleld (1983) study In which groups of 76-79
male and 76-79 female Aderly Park Mister-derived rats exposed to l,4-d1-
chlorobenzene by Inhalation, the demonstration of Increased tumor Incidences
In mice and rats orally exposed to 1,4-dlchlorobenzene requires that no
RfO, be derived unless the carclnogenldty of 1,4-dlchlorobenzene can be
demonstrated to be route specific. Currently, Insufficient data are
available to determine the effects of route of exposure on the carclno-
genldty of 1,4-dlchlorobenzene. Therefore, no RfD, or chronic toxlclty
CS for 1,4-dlchlorobenzene has been derived.
6.3. CARCINOGENIC POfCNCY (q.,*)
6.3.1. Oral. No evidence of carclnogenldty was observed In male or
female B6C3F1 mice or F344 rats treated with 60 or 120 mgAg/day of
l,2-d1chlorobenzene for 2 years (NTP, 1985).
Data regarding the carclnogenlclty of 1,3-d1chlorobenzene could not be
located In the available literature.
0079h -30- 07/28/87
-------
1,4-D1chlorobenzene was associated with a significantly Increased
Incidence of hepatocellular carcinoma or adenoma In male afid female B6C3F1
mice and renal tubular cell adenoma or adenocarclnoma In male F344/N rats
(NTP, 1986). Data used to calculate the q * values are summarized In
Tables 6-1, 6-2 and 6-3. The animal q * was calculated using the
Incidence of animals surviving to the time of first tumor 1n the multistage
model adapted by the U.S. EPA and updated by Howe and Crump (1982). The
human q * was derived by multiplying the animal q * by the cube root of
the ratio of the human to animal body weights and the ratio of the length of
the experiment to the Hfespan of the animal which, In this case. Is 1 for
both mice and rats. The q * 2.4xlO~a (mg/kg/day)"1, 1s derived from
the hepatocellular carcinoma or adenoma Incidence data 1n the male mice and
1s selected as most stringently representing the oral carcinogenic potency
of 1,4-dlchlorobenzene to humans.
6.3.2. Inhalation. Pertinent data regarding the cardnogenlclty of
1,2- and 1,3-dlchlorobenzene after Inhalation exposure could not be located
1n the available literature.
No Increased Incidence of tumors was observed In mice or rats exposed to
1,4-d1chlorobenzene by Inhalation for 57 or 76 weeks, respectively (Loeser
and LHchfleld, 1983). Data are not available from which to derive an
Inhalation q * for 1,4-d1chlorobenzene.
0079h -31- 09/22/87
-------
TABLE 6-1
Cancer Data Sheet for Derivation of q-|*
Compound: 1,4-d1chlorobenzene
Reference: NTP, 1986
Spec1es/strain/sex: m1ce/B6C3Fl/male
Route/vehicle: oral (gavage)/corn oil
Length of exposure (le) = 103 weeks
Length of experiment {Le) = 104 weeks
Llfespan of animal (L) = 104 weeks
Body weight = 0.042 kg (estimated from graphs)
Tumor site and type: hepatocellular carcinoma or adenoma
Exposure
(mg/kg/day)
0
300
600
Transformed Doset
(mg/kg/day)
0
212.2
424.5
Incidence
No. Responding/No.
17/44
22/40
40/42
Tested
Unadjusted q-]* = 2.042xlO~- (mg/kg/day)'1
Human q-!* = 2.4xlO~2 {mg/kg/day p1
^Transformed dose obtained by multiplying exposure dose by 5/7 days and
103/104 weeks.
0079H -32- 09/22/87
-------
TABLE 6-2
Cancer Data Sheet for Derivation of q-|*
Compound: 1,4-D1chlorobenzene
Reference: NTP, 1986
Specles/straln/sex: mice/ B6C3Fl/female
Route/vehicle: oral (gavage)/corn oil
Length of exposure (le) = 103 weeks
Length of experiment (Le) = 104 weeks
Llfespan of animal (L) = 104 weeks
Body weight = 0.033 kg (estimated from graphs)
Tumor site and type: hepatocellular carcinoma or adenoma
Exposure
(mg/kg/day)
0
600
Transformed Dosea
(mg/kg/day)
0
424.5
Incidence
No. Responding/No.
15/44b
36/44
Tested
Unadjusted q-|* = 4.434xlO~3 (mg/kg/day)'1
Human q-|* = 5.697xlO~2 (mg/kg/day)"1
transformed dose obtained by multiplying the exposure dose by 5/7 days
and 103/104 weeks.
^Number of animals surviving to week of first tumor
0079h -33- 01/28/87
-------
TABLE 6-3
Cancer Data Sheet for Derivation of a q-\* .
Compound: l,4-d1chlorobenzene
Reference: NTP, 1986
Spec1es/strain/sex: rats/F344/male
Route/vehicle: oral (gavage)/corn oil
Length of exposure (le) = 103 weeks
Length of experiment (Le) = 104 weeks
Llfespan of animal (L) = 104 weeks
Body weight = 0.475 kg (estimated from graphs)
Tumor site and type: renal tubular cell adenocardnoma or adenoma
Exposure
(mg/kg/day)
0
150
300
Transformed Doset
(mg/kg/day)
0
106.1
212.2
Incidence
No. Responding/No. Tested
1/50
3/50
8/50
Unadjusted q-j* = 1.037xl9"3 (mg/kg/day)'1
Human q-|* = 5.47xlO~3 (mg/kg/day)'1
^Transformed dose obtained by multiplying exposure dose by 5/7 days and
103/104 weeks.
0079h -34- 11/12/86
-------
7. REFERENCES
•4
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1985.
TLVs: Threshold limit values for chemical substances and physical agents 1n
the workroom environment with Intended changes for 1985-1986. Cincinnati,
OH. p. 15.
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986.
Documentation of the Threshold Limit Values, 5th ed. Cincinnati, OH.
p. 178-179.
Anderson, D. 1976. Paradlchlorobenzene: Estimation of Us Mutagenlc Poten-
tial In the Salmonella typhlmurlum Plate Incorporation Mutagenlclty Assay.
Unpublished report: Imperial Chemical Industries Ltd., Central Toxicology
Laboratory, Alderly Park, Maccles field, Cheshire UK. (Cited 1n Loeser and
Lltchfleld, 1983)
Anderson, D. and M.C.E. Hodge. 1976. Paradlchlorobenzene: Dominant Lethal
Study 1n the Mouse. Unpublished report: Imperial Chemical Industries Ltd.,
Central Toxicology Laboratory, Alderly Park, Macclesf1eld, Cheshire, UK.
(Cited In Loeser and Lltchfleld, 1983)
Anderson, K.J., E.G. Lelghty and M.T. Takahaskl. 1972. Evaluation of
herbicides for possible mutagenlc properties. J. Agrlc. Food Chem. 20(3):
649-656. (Cited 1n U.S. EPA, 1985a)
0079h -35- 08/29/86
-------
Atkinson, R. 1985. Kinetics and mechanisms of the gas phase reactions of
the hydroxyl radical with organic compounds under atmospheric conditions.
Chem. Rev. 85: 170.
Barrows, M.E., S.R. Petrocelll, K.J. Macek and J. Carroll. 1978. Blocon-
centratlon and elimination of selected water pollutants by blueglll sunflsh.
Am. Chem. Soc. Dlv. Environ. Chem. 18: 345-346.
Cabral, J., P. Shublk, T. Mollner and F. Raltano. 1977. Carcinogenic
activity of hexachlorobenzene 1n hamsters. Nature (London). 269: 510-511.
Chlou, C.T., L.J. Peters and V.H. Freed. 1979. A physical concept of soil-
water equilibria for nonlonlc organic compounds. Science. 206: 831-832.
Chlou, C.T., P.E. Porter and D.H. Schmeddlng. 1983. Partition equilibria
of nonlonlc organic compounds between soil organic matter and water.
Environ. Sc1. Technol. 17: 227-231.
Glrard, R., F. Tolot, P. Martin and J. Bourret. 1969. Severe hemopathles
and exposure to chlorinated derivation of benzene (1n relation to 7 cases).
J. Med Lyon. 50: 771-773. (Cited In IARC 1982a) .
Haider, K., G. Jagnow, R. Kohnen and S.U. Llm. 1974. Degradation of
chlorinated benzenes, phenols and cyclohexane derivatives by benzene and
phenol utilizing soil bacteria under aerobic conditions. Arch. M1crob1ol.
96: 183-200.
0079h -36- 07/28/87
-------
Hansch, C. and A.J. Leo. 1985. Medchem Project. Issue No. 26. Pomona
College, Claremont, CA.
Hawkins, O.R., L.F. Chasseaud, R.N. Woodhouse and D.G. Cresswell. 1980.
The distribution excretion and blotransformatlon of p-d1chloro-(l4C)ben-
zene In rats after repeated Inhalation, oral and subcutaneous doses.
Xenob1ot1ca. 10(2): 81-95.
Hayes, W.C., T.R. Hanley, T.S. Gushow, K.A. Johnson and J.A. John. 1985.
Teratogenlc potential of Inhaled dlchlorobenzenes 1n rats and rabbits.
Fund. Appl. Toxlcol. 5(1): 190-202.
Hodge, M.C.E., S. Palmer, J. Wilson and I.P. Bennett. 1977. Para-dlchloro-
benzene: Teratogen1c1ty Study In Rats. Unpublished Report: Imperial Chemi-
cal Industries Ltd., Central Toxicology Laboratory, Alderly Park, Maccles
Field, Cheshire, U.K. (CHed In Loeser and LHchfleld, 1983)
HolUngsworth, R.L., V.K. Rowe, F. Oyen, H.R. Hoyle and H.C. Spencer. 1956.
Toxldty of parachlorobenzene. Am. Med. Assoc. Arch. Ind. Health. (H):
138-143.
HolUngsworth, R.L., V.K. Rowe, F. Oyen, T.R. Torkelson and E.M. Adams.
1958. Toxldty of o-d1chlorobenzenes. Am. Med. Assoc. Arch. Ind. Health.
17(1): 180-187.
0079h -37- 07/28/87
-------
Howe, R.B. and K.S. Crump. 1982. GLOBAL 82. A Computer program to
extrapolate quanta! animal toxldty data to low doses. Prepared for -Office
of Carcinogen Standards OSHA. U.S. Dept. of Labor under Contract No. 41USC
252C3.
Hutchlns, S.R., M.B. Tomson and C.H. Hard. 1983. Trace organic contamina-
tion of ground water from a rapid Infiltration site: A laboratory-field
coordinated study. Environ. Toxlcol. Chem. 2: 195-216.
IARC (International Agency for Research on Cancer). 1982a. Ortho and para-
Dlchlorobenzenes. In: IARC Monographs on the Evaluation of the Carcinogenic
Risk of Chemicals to Humans. WHO, IARC, Lyon, France. Vol. 29,, p. 213-238.
IARC (International Agency for Research on Cancer). 1982b. Chemicals,
Industrial Process and Industries Associated with Cancer 1n Humans. In_:
IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to
Humans. WHO, IARC, Lyon, France. Vol. suppl. 4, p. 13-20.
Lawlor, T., S.R. Haworth and P. Voytek. 1979. Evaluation of the genetic
activity of nine chlorinated phenols, seven chlorinated benzenes and three
chlorinated hexanes. Environ. Mutagen. 1: 143. (CHed In U.S. EPA, 1985a)
Lewis, T.E., T. Sternback and C. Urchin. 1985. A comparison of sorptlon
charcaterlstlcs of o-, m- and p-dlchlorobenzene to Cohansey Aquifer (NJ)
soil. Ln: New Perspect. Environ. Toxlcol. Chem. Soc. Environ. Toxlcol.
Chem. 6th Meet. p. 7.
0079h -38- 07/28/87
-------
Loeser, E. and M.H. LHchfleld. 1983. Review of recent toxicology studies
on p-d1chlorobenzene. Food Chem. Toxlcol. 21(6): 825-832.
Lyman, W.J.. W.F. Reehl and D.H. Rosenblatt. 1982. Handbook of Chemical
Property Estimation Method. McGraw H111 Book Co., New York. p. 15-13,
15-21.
NTP (National Toxicology Program). 1985. Toxicology and Cardnogenesls
Studies of l,2-d1chlorobenzene In F344/N Rats and B6C3F1 mice. U.S. DHHS,
NIH Tech. Rep. Ser. No. 255. (Also publ. as NIH Publ. No. 86-2511 and
PB86-14488-8)
NTP (National Toxicology Program). 1986. Toxicology and Cardnogenesls
Studies of l,4-D1chlorobenzene In F344/N Rats and B6C3F1. Mice -- Galley
Draft. U.S. DHHS, PHS. NIH Tech. Rep. Ser. No. 319.
Oliver, B.G. 1983. Chlorinated contaminants In the Niagara River and
Adjacent Lake Ontario. In.: Symp. Am. Chem. Soc., D1v. Environ. Chem. 186th
Natl. Mtg. 23: 421-422.
Oliver, B.G. and M.N., Charlton. 1984. Chlorinated organic contaminants on
settling participates In the Niagara River vicinity of Lake Ontario.
Environ. Scl. Techno!. 18: 903-908.
Oliver, B.G. and K.D. Nlcol. 1982. Chlorobenzenes In sediments, water and
selected fish from Lakes Superior, Huron, Erie and Ontario. Environ. Sc1.
Technol. 16: 532-536.
0079h -39- 07/28/87
-------
Oliver, B.G. and A.J. N11m1. 1983. B1oconcentrat1on of chlorobenzenes from
water by rainbow trout: Correlations with partition coefficient and environ-
mental residues. Environ. Sc1. Technol. 17: 287-291.
OSHA (Occupational Safety and Health Administration). 1985. Occupation
Standards Permissible Exposure Limits. Code of Federal Regulations. 29 CFR
1910.1000.
Page, G.H. 1981. Comparison of groundwater and surface water for patterns
and levels of contamination by toxic substances. Environ. Sc1. Technol.
15: 1475-1481.
Pankow, J.F., L.H. Isabelle and W.E. Asher. 1984. Trace organic compounds
In rain. I. Sampler design and analysis by absorption/thermal desorptlon
(ATD). Environ. Scl. Technol. 18: 310-318.
Poland, A., J. Goldstein, P. Hlckman and V.W. Burse. 1971. Reciprocal
relation between the Induction of delta-amlnolevullnlc acid synthetase and
drug metabolism produced by m-d1chlorobenzene. Blochem. Pharmacol. 20(6):
1281-1290.
Reid, W.D. and G. Krishna. 1973. Centrolobular hepatic necrosis related to
covalent binding of metabolites fof halogenated aromatic hydrocarbons. Exp.
Hoi. Pathol. 18(10: 80-99.
Reid, W.O., G. Krishna, J.R. Glllete and B.B. Brodle. 1973. Biochemical
mechanism of hepatic necrosis Induced by aromatic hydrocarbons. Pharmacol-
ogy. 19(4): 193-214.
0079h -40- 07/28/87
-------
Swann, R.L., D.A. Laskowskl, P.J. McCall, K. Vander Kuy and H.J. Dlshburger.
1984. A rapid method for the estimation of the environmental parameters
octanol water partition coefficient son sorptlon constant water to air
ratio and water solubility. Res. Rev. 85: 17-28.
Townsend, 8.A. and G.P. Carlson. 1981. Effect of halogenated benzenes on
the toxldty and metabolism of malathlon, malaoxon, parathlon and paraoxon
1n mice. Toxlcol. Appl. Pharmacol. 60(1): 52-61.
U.S. EPA. 1980a. Ambient Water Quality Criteria Document for Dlchloro-
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 440/5-80-039. NTIS
PB81-117509.
U.S. EPA. 1980b. Guidelines and Methodology Used 1n the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 49347-49357.
U.S. EPA. 1983a. Reportable Quantity Document for 1,2-D1chlorobenzene.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency
and Remedial Response, Washington, DC.
U.S. EPA. 1983b. Reportable Quantity Document for 1,4-D1chlorobenzene.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency
and Remedial Response, Washington, DC.
0079h -41- 07/28/87
-------
U.S. EPA. 1983c. Chlorinated Benzenes. Federal Register. 48: 54836-54844.
*
U.S. EPA. 1984. Methodology and Guidelines for Reportable Quantity Deter-
minations Based on Chronic Tox1c1ty Data. Prepared by the Office of Health
and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Solid Haste and Emergency Response,
Washington, DC.
U.S. EPA. 1985a. Health Assessment Document for Chlorinated Benzenes.
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH. EPA 600/8-84-015F. NTIS PB85-150332.
U.S. EPA. 1985b. National Primary Drinking Hater Regulations; Synthetic
Organic Chemicals, Inorganic Chemicals and M1croorgan1ms; Proposed Rules.
Federal Register. 50(219): 46936-47022.
U.S. EPA. 1986. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
Ware, S.A. and H.L. West. 1977. Investigation of Selected Potential Envi-
ronments"1 Contaminants: Halogenated Benzenes. U.S. EPA, OTS, Washington, DC
20460. Final Report. EPA 560/2-77-004.
Weber, R.C., P.A. Parker and M. Bowseer. 1981. Vapor Pressure Distribution
of Selected Organic Chemicals. EPA-600/2-81-021. 39 p.
0079h -42- 07/28/87
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Zapata-Gayon, C., N. Zapata-Gayon and A. Gonzalez-Angulo. 1982. Clasto-
genlc chromosomal aberrations In 26 Individuals accidentally exposed to
ortho dlchlorobenzene vapors In the National Medical Center In Mexico CHy.
Arch. Environ. Health. 37: 231-235.
0079h -43- 07/28/87
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APPENDIX B
Summary Table for 1,4-D1ch1orobenzene*
Route Species
Oral mouse/
female
Experimental
Exposure/Dose
{mg/kg/day)
0, 300, 600
mg/kg/day,
5 days/week
for 103 weeks
(gavage)
Effect
Increased
Incidence of
hepatocellular
carcinoma or
adenoma
q-l* or
Unit Risk
2.4xlO~2
(mg/kg/day)'1
*Source: NTP. 1986
0079h
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09/22/87
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