.. . ._ FINAL DRAF J
United States fr.n riw rn,n
Environmental Protection CtrtU-tlH-liU4U
A8ency April, 1989
Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR DIBROMOCHLOROMETHANE
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
DRAFT: DO NOT CITE OR QUOTE HOPQUMHtlllUBHUf
ENVWOMft^ML PROTECTION
NOTICE w«HiNen*o.t20««
This document Is a preliminary draft. It has not been formally released
by the U.S. Environmental Protection Agency and should not at this stage be
construed to represent Agency policy. It Is being circulated for comments
on Its technical accuracy and policy Implications.
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DISCLAIMER
This document has been reviewed In accordance with the U.S. Environ-
mental 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
Health and Environmental Effects Documents (HEEOs) are prepared for the
Office of Solid Waste and Emergency Response (OSHER). This document series
Is Intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as well as to provide health-related limits and goals for emer-
gency and remedial actions under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA}. Both published literature and
Information obtained for Agency Program Office files are evaluated as they
pertain to potential human health, aquatic life and environmental effects of
hazardous waste constituents. The literature searched for 1n this document
and the dates searched are Included 1n "Appendix: Literature Searched."
Literature search material Is current up to 8 months previous to the final
draft date listed on the front cover. Final draft document dates (front
cover) reflect the date the document 1s sent to the Program Officer (OSWER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include Reference doses (RfOs)
for chronic and subchronlc exposures for both the Inhalation and oral
exposures. The subchronlc or partial lifetime RfO, 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. This type of
exposure estimate has not been extensively used, or rigorously defined as
previous risk assessment efforts have focused primarily on lifetime exposure
scenarios. Animal data used for subchronlc estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subchronlc RfDs 1s the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
In the case of suspected carcinogens, RfDs are not estimated. Instead,
a carcinogenic potency factor, or q-|* {U.S. EPA, 1980a), Is provided.
These potency estimates are derived for both oral and Inhalation exposures
where possible. In addition, unit risk estimates for air and drinking water
are presented based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxldty and carclno-
genldty are derived. The RQ Is used to determine the quantity of a hazard-
ous substance for which notification 1s required 1n the event of a release
as specified under the Comprehensive Environmental Response, Compensation
and Liability Act (CERCLA). These two RQs (chronic toxldty and cardnc-
genlcHy) represent two of six scores developed (the remaining four reflect
1gn1tab1l1ty, reactivity, aquatic toxldty, and acute mammalian toxlclty).
Chemical-specific RQs reflect the lowest of these six primary criteria. The
methodology for chronic toxldty and cancer based RQs are defined 1n U.S.
EPA, 1984 and 1986a, respectively.
Ill
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EXECUTIVE SUMMARY
Dlbromochloromethane Is a colorless liquid at ambient temperatures. It
is slightly soluble 1n water, but 1s easily soluble/mlsclble in a number of
common organic solvents (Weast, 1985). No data has been found to Indicate
that this compound Is currently produced In the United States on an
industrial scale (U.S. EPA, 1985). Dlbromochloromethane 1s used In the
manufacture of fire extinguishers, aerosol propellants, refrigerants and
pesticides; and 1n organic synthesis (Verschueren, 1983).
The sources of dibromochloromethane In the environment are both natural
and anthropogenic. Several raacroalgae available in seawater can release
this compound at a rate of ng-yg of the compound/day/g of dry algae
(Gschwend et al., 1985). One of the most Important anthropogenic sources of
this compound is Its inadvertent production during chlorlnatlon of drinking
water and wastewater under appropriate conditions (U.S. EPA, 1985). The
amount of trihalomethanes Including dibromochloromethane formed during
chlorlnatlon depends on a variety of parameters including water temperature,
pH, bromide ion concentration, the concentration of fulvlc and humlc
substances and the chlorlnatlon practices (U.S. EPA, 1985). The fate of
this compound in the atmosphere Is not well studied. Based on the reaction
rates of chemically similar compounds, the atmospheric half-life of
dibromochloromethane (which Is due to Its reaction with OH radicals),
probably its most Important abiotic reaction In the atmosphere, has been
estimated to be -80 days. The removal of vapor phase dibromochloromethane
by wet deposition may not be significant (Llgockl et al., 1985). Therefore,
this compound may be persistent in the atmosphere. From the available data,
It Is concluded that there Is no known abiotic process that may be
significant in the removal of this compound from water under aerobic
1v
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compound from water under aerobic conditions. Under anoxlc conditions,
significant removal of this compound was observed by unknown abiotic pro-
cesses (Bouwer and McCarty, 1983a). The removal of dlbromochloromethane
from water by aerobic blodegradatlon processes may not be significant (Tabak
et al., 1981; Bouwer et al., 1981), although the compound was shown to be
degraded by a few microorganisms under anaerobic conditions (Bouwer and
McCarty, 1983a,b; Bouwer and Wright, 1986; Souwer, 1985; Bouwer et al.,
1984}. Although the anaerobic blodegradatlon may occur under anoxlc condi-
tions, the half-life of dlbromochloromethane that 1s due to this reaction In
natural waters cannot be estimated. Perhaps the most Important process that
may account for the loss of this compound from water 1s volatilization. The
half-life of dlbromochloromethane that Is due to evaporation from water may
be <1 hour to 17 days, depending on the nature of water (Kaczmar et al.,
1984; Francois et al., 1979). Dlbromochloromethane should not bloaccumulate
significantly In aquatic organisms. Although anaerobic blodegradatlon may
occur In deeper layers of soil, the two Important transport processes that
may dominate the fate of this compound In soil are evaporation and leaching
(Wilson et al., 1981; Roberts et al.f 1982; Greenberg et al., 1982).
The measurement of atmospheric dlbromochloromethane concentrations In 89
locations In the United States during 1977-1980 showed an arithmetic average
concentration of 3.8 ppt (Brodzlnsky and Singh, 1982). On the basis of this
concentration and the assumption that an Individual Inhales 20 m3 of air
per day, the average dally Inhalation exposure would be 0.6 pg. Levels of
dlbromochloromethane detected In wastewaters, groundwaters and surface
waters are shown 1n Table 3-1. A maximum concentration of 55 ^q/i
dlbromochloromethane was reported 1n a groundwater sample from a disposal
site (Rao et al., 1985). In a National Organlcs Reconnaissance Survey of
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drinking waters from 80 locations across the United States, the concentra-
tion range of dlbromochloromethane was <0.4-100 yg/1, with a median
value of 1.2 ug/S. (Williams et al., 1980; Symons et al., 1975). On the
basis of this median concentration and the assumption that an adult consumes
2 8, of water/day, the average dally Ingestlon exposure to dlbromochloro-
methane from drinking water would be 2.4 yg. This compound has not been
reported to be present 1n any foods.
Reports of the toxlclty of dlbromochloromethane to aquatic organisms are
limited to a single static-renewal acute study with common carp, Cyprlnus.
carplo. embryos (Mattlce et al., 1981). Recently fertilized eggs (100-300
per treatment) were exposed to dlbromochloromethane In 300-ml glass dishes
at a temperature of 26°C until hatching was complete (within 3-5 days).
Test solutions were renewed 45 minutes after eggs were placed In test
solutions and every 8 hours thereafter. The LC5Q for eggs exposed to
dlbromochloromethane from the end of water hardening of the egg to hatching
was 52 mg/X which was not significantly different from that obtained when
eggs were exposed Immediately after fertilization to hatching (53 mg/i).
Mattlce et al. (1981) also calculated a weighted LC™ to take Into account
degradation of dlbromochloromethane between changes of toxicant solution.
The weighted LC5Q was calculated to be 34 mg/i with 95% confidence
limits ranging from 31-35 mg/l. The calculated half-life for dlbromo-
chloromethane under the conditions of the study was 5.6 hours. Dlbromo-
chloromethane was more toxic to common carp embryos than other trlhalo-
methanes tested (I.e., chloroform, bromodlchloromethane and bromoform)
(Mattlce et al.. 1981).
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Pertinent data regarding the effects of chronic exposure of aquatic
organisms to dlbromochloromethane or the effects of exposure of aquatic
plants to dlbromochloromethane were not located In the available literature
cited In Appendix A.
The available pharmacoklnetic data Indicate that dlbromochloromethane Is
absorbed readily by rats and mice following oral exposure. Eight hours
after an oral dose of [l4C]-d1bromochloromethane In corn oil, -66 and 84%
of the radioactivity was expired by male Sprague-Dawley rats and male B6C3F1
mice, respectively (M1nk et al., 1986). In mke, 71.56 and 12.31% of the
dose was expired as 14C02 and unmetabollzed compound, compared with 18.2
and 48.1% expired as 14C02 and unmetabollzed compound In rats. These
results Indicate that dlbromochloromethane 1s metabolized more readily In
mice than rats. Less than 2% of the dose In both mice and rats was excreted
In the urine as unidentified compounds, within 8 hours after dosing, with
1.4 and 5.02% remaining 1n the organs of rats and mice, respectively.
Anders et al. (1978) reported that carbon monoxide blood levels In rats
following an Intraperltoneal Injection of dlbromochloromethane were higher
than levels following an Injection of bromodlchloromethane, but much lower
than carbon monoxide blood levels following similar Injections of bromoform
or lodoform.
No Inhalation studies concerning the toxIcHy of dlbromochloromethane
were located. The most consistent effects noted 1n oral studies of dlbromo-
chloromethane In rats and mice were liver effects, which were dose-related
In Incidence or severity. The available studies, however, do not clearly
Identify a NOEL. Acute studies (NTP, 1985; Condle et al., 1983; Hunson et
al., 1982) have reported Increased liver weights, Increased SGOT or SGPT and
mottled livers at doses >125 mg/kg/day In rats and mice.
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Subchronlc studies (Chu et al., 19825; NTP, 1985; Dunnlck et al., 1985;
Borzelleca and Carchman, 1982) have reported liver effects In rats and mice
(fatty Infiltration of the hepatocytes and hyperplasla) at doses >19
mg/kg/day. In chronic studies, gross signs of liver toxlclty (yellow liver)
have been observed In rats at doses >10 mg/kg/day (Tobe et al., 1982), while
NTP (1985) reported dose-related Increases In the frequency of fatty liver
In rats treated by gavage with dlbromochloromethane at 28.6 and 57.1
mg/kg/day and In mice treated at 35.7 and 71.4 mg/kg/day.
Data concerning the carclnogenlclty of dlbromochloromethane 1n humans
are not adequate. Human epidemiology studies have shown a weak relationship
between rectal, colon and bladder cancer In humans and water chlorlnatlon
(Crump and Guess, 1982). The contribution of the Individual trlhalomethanes
(Including dlbromochloromethane) and nonvolatile organks to the association
between cancer and chlorlnatlon Is not yet known. The NTP (1985) cancer
bloassay In experimental animals found no evidence of the carclnogenlclty of
dlbromochloromethane In male or female rats treated by gavage with
dlbromochloromethane at 0, 40 or 80 mg/kg, 5 days/week for 104 weeks. From
hepatic tumor Incidences In mice, the NTP (1985) concluded that there was
equivocal evidence of carclnogenlclty In male mice and "some evidence of
carclnogenlclty" In female mice treated by gavage at 50 and TOO mg/kg, 5
days/week for 105 weeks. Interpretation of this study was complicated by a
dosing error that killed 35 male low-dose mice. In a Russian study (Voronln
et al., 1987), tumor Incidences were not Increased significantly In mice
treated with dlbromochloromethane In drinking water at doses of 0, 0.0076,
0.76 or 76 mg/kg/day for 104 weeks.
Dlbromochloromethane was positive for reverse mutation 1n S. typhlmurlum
strain TA100, only when tested 1n the vapor phase 1n a desiccator (Simmon et
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al.t 1977). Results were negative when plate Incorporation (Simmon et al.,
1977) or preincubation (NTP, 1985; Zelger et al., 1987} methods were used.
Dlbromochloromethane has also tested positive In a test for gene conversion
in S. cerevisiae strain D4 (Nestmann and Lee, 1985), and in tests for SCE In
human lymphocytes and in bone marrow cells of mice treated orally {Morlmoto
and Koizumi, 1983). Borzelleca and Carchman (1982) reported negative
results in a dominant lethal study using mice,
A teratogenicity rat study (Ruddick et al., 1983} and a multi-generation
study (Borzelleca and Carchman, 1982) using mice did not find significant
effects on the offspring at doses below those that caused maternal effects.
Based on the level of positive carcinogenic evidence found in B6C3F1
mice, dlbromochloromethane can be considered a Group C carcinogen. Using
the dose-response data for hepatocellular adenomas and carcinomas in female
mice from the NTP (1985) carcinogenlclty bloassay, a q,* of 8.4xlQ~2
(mg/kg/dayr1 was calculated for oral exposure to dlbromochloromethane.
A verified oral RfD for dlbromochloromethane Is available on IRIS (U.S.
EPA, 1987a), it was therefore considered appropriate to derive RfDs in the
HEED. Based on the NTP (1985) rat subchronic study, subchronlc and chronic
oral RfDs for dlbromochloromethane of 0.2 mg/kg/day and 0.02 mg/kg/day,
respectively, were derived. An RQ for systemic toxlcity of 100 was
calculated on the basis of reduced survival of rats in the NTP (1985)
subchronlc study. An RQ for carcinogenlclty of 100 was calculated from the
NTP (1985) female mouse liver tumor Incidence data.
1x
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TABLE OF CONTENTS
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 2
1.5. SUMMARY 2
2. ENVIRONMENTAL FATE AND TRANSPORT 3
2.1. AIR 3
2.2. WATER 4
2.3. SOIL 6
2.4. SUMMARY 8
3. EXPOSURE 10
3.1. AIR 10
3.2. WATER 11
3.3. FOOD 11
3.4. OTHER MEDIA 11
3.5. SUMMARY 17
4. AQUATIC TOXICITY 18
5. PHARMACOKINETCS 19
5.1. ABSORPTION 19
5.2. DISTRIBUTION 19
5.3. METABOLISM 19
5.4. EXCRETION 20
5.5. SUMMARY 20
6. EFFECTS 22
6.1. SYSTEMIC TOXICITY 22
6.1.1. Inhalation Exposure 22
6.1.2. Oral Exposure 22
6.1.3. Other Relevant Information 28
6.2. CARCINOGENICITY 30
6.2.1. Inhalation 30
6.2.2. Oral 30
6.2.3. Other Relevant Information 36
6.3. MUTAGENICITY 39
6.4. TERATOGENICITY 39
6.5. OTHER REPRODUCTIVE EFFECTS 41
6.6. SUMMARY 43
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TABLE OF CONTENTS (coot.)
Page
7. EXISTING GUIDELINES AND STANDARDS 45
7.1. HUMAN 45
7.2. AQUATIC 45
8. RISK ASSESSMENT 46
8.1. CARCINOGENICITY 46
8.1.1. Inhalation 46
8.1.2. Oral 46
8.1.3. Other Routes 47
8.1.4. Weight of Evidence 47
8.1.5. Quantitative Risk Estimates 47
8.2. SYSTEMIC TOXICITY 48
8.2.1. Inhalation Exposure 48
8.2.2. Oral Exposure 48
9. REPORTABLE QUANTITIES 57
9.1. BASED ON SYSTEMIC TOXICITY 57
9.2. BASED ON CARCINOGENICITY 60
10. REFERENCES 63
APPENDIX A: LITERATURE SEARCHED 82
APPENDIX B: SUMMARY TABLE FOR OIBROMOCHLOROMETHANE 85
x1
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No.
3-1
3-2
6-1
6-2
LIST OF TABLES
Title
Levels of Dlbromochloromethane 1n a Few Wastewater,
Surface Water and Groundwater Samples
Levels of Dlbromochloromethane In a Few Drinking Waters . .
Incidence of Liver Tumors In B6C3F1 Mice Treated by Gavage
with Dlbromochloromethane 5 Days/Week for 105 Weeks . . . .
Page
12
14
32
Total Tumor Incidences and Time to First Tumor in
C8AxC57Bl/6 Mice Treated with Dlbromochloromethane In
the Drinking Water for 104 Weeks 34
6-3
6-4
6-5
8-1
9-1
9-2
9-3
9-4
Incidences of Compound-Related Neoplastlc Lesions in Rats
and Mice Administered TMhalomethanes
Doses of Trlhalomethanes Administered to Rats and Mice In
NCI/NTP Carclnogenlclty Studies
Mutagenlcity Testing of Dlbromochloromethane
Cancer Data Sheet for Derivation of q-|* for Oral Exposure . .
Summary of the Oral Toxlclty of Dlbromochloromethane
Composite Scores for Oral Exposure to Dlbromochloromethane. .
Oibromochloromethane: Minimum Effective Dose (MED) and
Reportable Quantity (RQ)
Derivation of Potency Factor (F) for Dlbromochloromethane . .
37
38
40
49
58
59
61
62
xll
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LIST OF ABBREVIATIONS
BCF Bloconcentratlon factor
BUN Blood urea nitrogen
CAS Chemical Abstract Service
CS Composite score
GTP Guanoslne 5'-trlphosphate
Koc Soil sorptlon coefficient
Kow Octanol/water partition coefficient
Concentration lethal to 50% of recipients
{and all other subscripted dose levels)
D°se lethal to 50% of recipients
LOAEL Lowest-observed-adverse-effect level
MCL Maximum contaminant level
MED Minimum effective dose
NOEL No-observed-effect level
OCT Ornlthlne dtrulUne transferase
ppb Parts per billion
ppm Parts per million
ppt Parts per trillion
RfD Reference dose
RQ Reportable quantity
RV
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
Dlbromochloromethane 1s also known by the synonyms chlorodlbromomethane
and methane, dlbromochloro- (HSDB, 1988). The structure, molecular formula,
molecular weight and CAS Registry number For this chemical are as follows:
Br
I
Cl-C-Br
I
H
Molecular formula: CHBr.Cl
Molecular weight: 208.29
CAS Registry number: 124-48-1
1.2. PHYSICAL AND CHEMICAL PROPERTIES
Dlbromochloromethane U a colorless liquid at ambient temperatures. It
Is slightly soluble In water, but 1s easily soluble 1n ethanol, ethyl ether
and benzene (Weast, 1985). Since dlbromochloromethane Is an alkyl hallde,
1t Is likely to undergo nucleophlllc substitution reactions under certain
conditions (Gutsche and Pasto, 1975); however, under environmental condi-
tions, this compound 1s remarkably stable towards chemical reactions
(Section 2.1.}. Some of the relevant physical properties of dlbromochloro-
methane are given below:
Melting point: <-20°C Verschueren, 1983
Boiling point: 119-120°C at 748 mm Hg Weast, 1985
Density: 2.451 g/cm3 at 20°C Weast, 1985
Vapor pressure: 76 mm Hg at 20°C Mabey et al., 1981
Water solubility: 4400 mg/l at 22°C Mabey et al., 1981
1050 mg/l at 30°C U.S. EPA, 1985
0116d -1- 04/18/89
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Log Kow: 2.24 Mabey et al.t 1981
Conversion factor In air: 1 ppm = 8.659 mg/m3
at 20°C and 1 atm
1.3. PRODUCTION DATA
No Information regarding the method used for the manufacture of dlbromo-
chloromethane was found In the available literature; however, the vapor
phase bromlnatlon of chloroform yields a mixture of chlorobromomethanes
(DeShon, 1979) and Is likely to produce dlbromochloromethane as well.
According to the TSCA Inventory of Chemical Production Data In the United
States (U.S. EPA, 1977), <1000 pounds of this chemical was produced 1n the
United States In 1977. Data regarding U.S. manufacturers of dlbromochloro-
methane were not located In the available literature; therefore, 1t 1s
likely that dlbromochloromethane Is not manufactured on an Industrial scale
1n the United States.
1.4. USE DATA
Dlbromochloromethane has potential use as a fire extinguisher; 1n the
manufacture of aerosol propellants, refrigerants and pesticides; and 1n
organic synthesis (Verschueren, 1983).
1.5. SUMMARY
Dlbromochloromethane Is a colorless liquid at ambient temperatures. It
Is slightly soluble In water, but Is easily soluble/mlsclble In a number of
common organic solvents (Weast, 1985). This compound Is probably not
currently produced 1n the United States on an Industrial scale. It has
potential use as a fire extinguisher; In the manufacture of aerosol propel-
lents, refrigerants and pesticides; and In organic synthesis (Verschueren,
1983).
0116d -2- 06/06/88
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2. ENVIRONMENTAL FATE AND TRANSPORT
The sources of dlbromochloromethane In the environment are both natural
and anthropogenic. Several macroalgae available In seawater can release
this compound at a rate of yg to ng of compound/day/g of dry algae
(Gschwend et a>., 1985). Anthropogenlcally, this compound Is produced
Inadvertently during chlorlnatlon of water containing humlc and fulvlc
substances. The chlorlnatlon of water produces hypochlorous acid (HOC1) and
OC1~ Ions In water. Bromide Ion present In natural waters 1s oxidized to
hypobromous acid (HOBr) by the aqueous chlorlnatlon products. The HOC1 and
HOBr then react with the fulvlc and humlc substances present In the water to
form dlbromochloromethane and other trlhalomethanes. The amount of trlhalo-
methanes formed during chlorlnatlon depends upon a variety of parameters
Including water temperature, pH, bromide Ion concentration, the concentra-
tion of fulvlc and humlc substances and the chlorlnatlon treatment practices
(U.S. EPA, 1985).
2.1. AIR
Insufficient data were available In the literature to evaluate with
certainty the fate of this compound 1n the atmosphere. Photolysis of
dlbromochloromethane Is not expected to be an environmentally significant
process (Habey et al., 1981). No experimental data regarding the rate
constant for the most Important atmospheric reaction (I.e., reaction of this
compound with OH radicals In the atmosphere) were available. Based on the
rate constants for structurally similar compounds (e.g., CH.,Br, CHCU)
(Atkinson, 1985), the estimated rate constant for OH radical reaction with
dlbromochloromethane 1s ~1Q~13 cmVmolecule-sec. If the concentration
of OH radicals 1n the atmosphere Is assumed to be 10* radicals/cm3, the
01164
-3-
04/18/89
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atmospheric half-life of this compound that Is due to this reaction Is -80
days. If this half-life value 1s correct, no significant transfer of this
chemical will occur from the troposphere to the stratosphere.
The vapor pressure of dlbromochloromethane 1s such that It Is expected
to be present almost exclusively In the vapor phase and not In the partlcle-
sorbed state tn the atmosphere (Elsenrelch et al., 1981). The removal of
vapor phase dlbromochloromethane by wet deposition may not be significant;
L1gock1 et al. (1985) did not detect this compound during rain events 1n
Portland, OR, but did detect 1t In the atmospheric gas phase during the same
period.
2.2. WATER
The fate and transport of dlbromochloromethane In aquatic systems are
more well studied than In the atmosphere. The rate constant for the
hydrolysis of this compound at 25°C and at a pH of 7 Is S.OxKTWsec
(Mabey and Mill, 1978). This corresponds to a half-life of 274 years.
Therefore, hydrolysis Is not an Important process 1n most natural waters.
Although experimental data regarding the photolysis of dlbromochloromethane
In aqueous solutions were not found In the literature, Mabey et al. (1981)
predicted that such a reaction Is environmentally Insignificant. Similarly,
U has been suggested that dlbromochloromethane will not be easily oxidized
by oxldants present In most natural waters (Mabey et al., 1981; Callahan et
al., 1979a).
The blodegradablllty of dlbromochloromethane under both aerobic and
anaerobic conditions has been studied by a few Investigators. Using the
static-culture, flask-screening procedure with settled domestic wastewater
as mlcroblal Inoculum, dlbromochloromethane was not readily susceptible to
aerobic blodegradatlon; only 39% of the compound at an Initial concentration
of 5 mg/i was lost 1n 28 days (Tabak et al., 1981).
0116d -4- 06/06/88
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Bouwer et al. (1981) Investigated the blodegradablllty of dlbromochloro-
methane under aerobic and anaerobic conditions. With primary sewage
effluent as mixed bacterial Inoculum, no degradation of the compound was
observed under aerobic conditions. Anaerobic degradation studies, conducted
with mixed methanogenlc bacterial cultures, showed total degradation of the
compound within 2 weeks; however, substantial loss (as high as 80% In 6
weeks) of the compound was also observed In the sterile control that lead
the authors to conclude that a chemical mechanism may also be Involved with
the anaerobic procedure. The degradation of dlbromochloromethane under
methanogenlc conditions In batch bacterial cultures and 1n a continuous-flow
methanogenlc fixed-film laboratory-scale column showed that the degradation
of the compound was rapid with seeded cultures and slow with the controls
(Bouwer and HcCarty, 1983a). In a blodegradatlon study of the compound
under anoxlc conditions In the presence of denitrifying bacteria, >70X of
the compound was degraded 1n 8 weeks relative to the sterile control (Bouwer
and McCarty, 1983b). .Removal of >99X of dlbromochloromethane present at low
concentrations (25-34 \ig/i) by anaerobic bacteria attached as blofllms
to solid surfaces has been reported (Bouwer and Wright, 1986; Bouwer, 1985;
Bouwer and McCarty, 1984). Similar anaerobic blodegradatlon of the compound
present at low concentrations under Infiltration conditions as In artificial
recharge of groundwater by Infiltration of treated wastewater was also
observed (Bouwer et al., 1984).
Kaczmar et al. (1984) measured the gas transfer rate constants of oxygen
and dlbromochloromethane, and the ratio of these constants was found to
remain relatively constant over a wide range of temperature (4-25°C) and
turbulence conditions used In the laboratory. Based on the measured gas
transfer ratio and the published values of oxygen reaeratlon rate constants
0116d -5- 05/17/88
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In typical water bodies, the half-life of evaporation of dlbromochloro-
methane In different waters (ponds, rivers and lakes) was calculated to be
1n the range of 43 minutes to 16.6 days. Francois et al. (1979) measured
the evaporation rate of dlbromochloromethane from water at 25°C and found
that It followed first-order kinetics. Based on the measured rate constant,
the evaporation half-life was estimated to be 62 minutes. The volatility of
this compound from water can also be qualitatively predicted from Us
measured Henry's Law constant of l.lxlO'3 atm-mVmol {Nicholson et al.,
1984) and 0.8x10~3 atm-mVmol at 25°C (Shen, 1982). Based on the
volatility characteristics associated with various ranges of Henry's Law
constant (Lyman et al., 1982), It can be predicted that this compound will
volatilize significantly from water.
No measured steady-state 8CF value for dlbromochloromethane was found In
the literature. Based on the regression equation, log BCF = 0.76 log K
- 0.23 (Lyman et al., 1982) and a log KQW value of 2.24 (see Section
1.2.), a BCF value of 30 Is estimated for this compound. This value
suggests that dlbromochloromethane should not bloaccumulate significantly In
aquatic organisms.
2.3. SOIL
There Is a paucity of data regarding the fate of dlbromochloromethane In
soil. The blodegradatlon data presented 1n Section 2.2. Indicate that this
compound may undergo blodegradatlon under anoxlc soil conditions. The soil
Infiltration study of Roberts et al. (1982) found that when an aqueous
solution of dlbromochloromethane at a concentration of 5 yg/j. was
Injected Into an aquifer, the concentration of the compound decreased below
the detection limit (0.1 vg/l) within 150 days In the Infiltrated water.
0116d -6- 05/17/88
-------
From the concentration patterns in other trlhalomethanes, these authors
concluded that the decrease In concentration for dlbromochloromethane was
primarily due to blodegradatlon and not sorptlon. Data regarding the fate
of this chemical that 1s due to chemical hydrolysis and surface photolysis
In soil were not available, but drawing analogy from the discussion about
these processes In water, they may not be Important In soil.
The Teachability of the chemical from soil Is expected to depend on the
K standardized to Its organic carbon content. From the theoretical
regression equation, log K = -0.557 log S +• 4.277 (Lyman et al., 1982)
and a value of 2.1x10* ymol/1 for S (see Section 1.2.), the KQc value
Is calculated to be 74. This value of K Indicates that this compound
oc
should not sorb strongly to soil and 1s expected to be moderately to highly
mobile In soil. Field studies that estimated a soil retardation factor
(with respect to chloride Ion) of 6 {Roberts and Valocchl, 1981; Roberts et
al., 1982) tend to confirm that this compound may be leached from soil to
groundwater. The detection of dlbromochtoromethane In New Jersey ground-
water (Greenberg et al., 1982) and 1n dune-Infiltrated water In the Nether-
lands (Plet et al., 1981) confirms that this compound Is readily leachable,
particularly In soils with low organic carbon content. In a soil percola-
tion study with sandy soil, It was shown that ~50X of the applied bromodl-
chloromethane volatilized from the soil column (Wilson et al., 1981).
Therefore, In conformity with Us high volatility from water, dlbromochloro-
methane 1s also expected to volatilize significantly from dry soils. In
moist soils, the percent loss from volatilization will be less because It
will be In competition with significant leaching and an undetermined
blodegradatlon rate.
0116d
-7-
06/06/88
-------
2.4. SUMMARY
The sources of dlbromochloromethane In the environment are both natural
and anthropogenic. Several macroalgae available In seawater can release
this compound at a rate of ng-pg of the compound/day/g of dry algae
(Gschwend et al., 1985). One of the most Important anthropogenic sources of
this compound is Us Inadvertent production during chlorlnatlon of water
containing bromide and humlc and fulvlc substances (U.S. EPA, 1985). The
amount of tMhalomethanes Including dlbromochloromethane formed during
chlorlnatlon depends on a variety of parameters Including water temperature,
pH, bromide concentration, the concentration of fulvlc and humlc substances
and the chlorlnatlon practices (U.S. EPA, 1985). The fate of this compound
1n the atmosphere 1s not well studied. Based on the reaction rates of
chemically similar compounds, the atmospheric half-life of dlbromochloro-
methane (which Is due to Us reaction with OH radicals), probably Its most
Important abiotic reaction In the atmosphere, has been estimated to be -80
days. The removal of vapor phase dlbromochloromethane by wet deposition may
not be significant (Llgockl et al., 1985). Therefore, this compound may be
persistent In the atmosphere. From the available data, 1t 1s concluded that
there 1s no known abiotic process that may be significant In the removal of
this compound from water under aerobic conditions. Under anoxlc conditions,
significant removal of this compound was observed by unknown abiotic
processes (Bouwer and McCarty, 1983a). The removal of dlbromochloromethane
from water by aerobic blodegradatlon processes may not be significant (Tabak
et al., 1981; Bouwer et al., 1981), although the compound was shown to be
degraded by a few microorganisms under anaerobic conditions (Bouwer and
McCarty, 1983a,b; Bouwer and Wright, 1986; Bouwer, 1985; Bouwer et al.,
1984). Although the anaerobic blodegradatlon may occur under anoxlc condi-
tions, the half-life of dlbromochloromethane that Is due to this reaction In
0116d -8- 04/18/89
-------
natural waters cannot be estimated. Perhaps the most Important process that
may account for the loss of this compound from water Is volatilization. The
half-life of dlbromochloromethane from evaporation may be <1 hour to 17
days, depending on the nature of water (Kaczmar et al., 1984; Francois et
al., 1979). Dlbromochloromethane should not bloaccumulate significantly In
aquatic organisms. Although anaerobic blodegradatlon may occur 1n deeper
layers of soil, the two Important transport processes that may dominate the
fate of this compound 1n soil are evaporation and leaching (Wilson et al.,
1981; Roberts et al., 1982; Greenberg et al., 1982).
0116d -9- 06/06/88
-------
3. EXPOSURE
3.1. AIR
The atmospheric levels of dibromochloromethane In different parts of the
world have been measured by a few Investigators. Olbromochloromethane was
detected (detection 11mH 0.01 ppb) 1n only 17% of air samples collected
from four southern California locations during 1982-1983. The mean
concentration In all samples that contained dibromochloromethane at
concentrations higher than the detection HmH was only slightly above the
detection limit. The maximum concentration was detected in samples from Los
Angeles that had a composite atmospheric mean concentration of 0.05 ppb,
with a maximum reported value In any sample of 0.29 ppb (Shlklya et al.,
1984). The atmospheric concentration of this compound In Portland, OR,
during rain events in 1984 ranged from 0-1.3 ng/m3 (0-0.15 ppt) (Ugockl
et al., 1985). Dlbromochloromethane has been detected 1n air over the
Atlantic ocean and continental trophosphere over southern Germany at a
concentration ranging, from 0.06-10 ppt, and the source of the compound was
speculated to be the biosynthesis of marine macroalgae (Class et al.,
1986). The air samples from several urban and one rural area (Bayonne and
Elizabeth, NJ; Greensboro, NC; Devils Lake, NO; Los Angeles, CA; and Antloch
and Pittsburgh, CA} In the United States, and the breath samples from people
residing in these areas were monitored for dibromochloromethane (Wallace et
al., 1986). At a detection limit of ~1 pg/m3, this compound was not
detected In any of the samples wHh the exception of <1X of the samples from
New Jersey. The measurement of atmospheric dibromochloromethane concentra-
tions in 89 locations In the United States during 1977-1980 showed an
average concentration of 3.8 ppt (Brodzlnsky and Singh, 1982). On the basis
of this concentration and the assumption that an Individual Inhales 20 m3
of air per day, the dally Inhalation exposure would be -0.6 ug.
0116d -10- 06/06/88
-------
3.2. WATER
Since Rook (1974) found that chloMnatlon of natural waters can produce
haloforms, Including dlbromochloromethane, there have been many studies
reporting the presence of these compounds In water. The levels of dlbromo-
chloromethane have been determined 1n several kinds of water samples,
Including landfill leachates, Industrial effluents, urban runoffs, surface
waters and groundwaters. Table 3-1 lists the concentration levels of this
compound In these waters as determined by various authors. A large number
of Investigators have reported the detection of dlbromochloromethane In
drinking waters. Table 3-2 shows data regarding a few drinking waters where
this compound has been detected. Cech et al. (1982) reported spatial
variations of dlbromochloromethane concentrations In the Houston, TX, area.
Seasonal variations \n concentration of this compound 1n drinking waters
have been observed, and the maximum concentration In this study, occurs
around March and the minimum concentration around September-October
(Veenstra and Schnoor, 1980). Given that the median concentration of
dlbromochloromethane \n U.S. drinking waters 1s 1.2 yg/a (Williams et
al., 1980) and that an adult consumes 2 j. of water/day, the median dally
Ingestlon of this compound from drinking water would be 2.4 pg.
3.3. FOOD
Pertinent data regarding exposure to dlbromochloromethane from Ingestlon
of foods were not located In the available literature cited 1n Appendix A.
3.4. OTHER MEDIA
Dlbromochloromethane was detected, but not quantified, In 1 of 8
mother's milk samples In the United States {Pelllzarl et al., 1982). In a
National Human Adipose Tissue Survey for fiscal year 1982, dlbromochloro-
methane was not found In 100 tissue samples analyzed for this compound at a
detection limit of 1 ng/g of wet tissue (Stanley, 1986).
0116d
-11-
05/17/88
-------
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3.5. SUMMARY
The measurement of atmospheric dlbromochloromethane concentrations In 89
locations In the United States during 1977-80 showed an arithmetic average
concentration of 3.8 ppt (Brodzlnsky and Singh, 1982). On the basis of this
concentration and the assumption that an Individual Inhales 20 m3 of air
per day, the average dally Inhalation exposure would be 0.6 pg. Levels of
dlbromochloromethane detected In wastewaters, groundwaters and surface
waters are shown In Table 3-1. A maximum concentration of 55 vg/a
dlbromochloromethane was reported In a groundwater sample from a disposal
site (Rao et al., 1985). In a National Organlcs Reconnaissance Survey of
drinking waters from 80 locations across the United States, the concentra-
tion range of dlbromochloromethane was <0.4-100 yg/l, with a median
value of 1.2 wg/8. (Williams et al., 1980; Symons et al., 1975). On the
basis of this median concentration and the assumption that an adult consumes
2 J. of water/day, the average dally Ingestlon exposure to dlbromochloro-
methane from drinking water would be 2.A yg. This compound has not been
reported to be present 1n any foods.
0116d -17- 05/17/88
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4. AQUATIC TOXICITY
Reports of the toxldty of dlbromochloromethane to aquatic organisms are
"limited to a single static-renewal acute study with common carp, Cyprlnus
carplo. embryos (Mattlce et a!., 1981). Recently fertilized eggs (100-300
per treatment) were exposed to dlbromochloromethane In 300-mfc glass dishes
at a temperature of 26°C until hatching was complete (within 3-5 days).
Test solutions were renewed 45 minutes after eggs were placed In test
solutions and every 8 hours thereafter. The LC^n for eggs exposed to
dlbromochloromethane from the end of water hardening of the egg to hatching
was 52 mg/l, which was not significantly different from that obtained when
eggs were exposed Immediately after fertilization to hatching (53 mg/4).
Mattlce et al. (1981) also calculated a weighted LC50 to take Into account
degradation of dlbromochloromethane between changes of toxicant solution.
The weighted LC,- was calculated to be 34 mg/l with 95% confidence
limits ranging from 31-35 mg/i. The calculated half-life for dlbromo-
chloromethane under the conditions of the study was 5.6 hours. Dlbromo-
chloromethane was more toxic to common carp embryos than other trlhalo-
methanes tested (I.e., chloroform, bromodlchloromethane and bromoform)
(Mattlce et al.. 1981).
Pertinent data regarding the effects of chronic exposure of aquatic
organisms to dlbromochloromethane or the effects of exposure of aquatic
plants to dlbromochloromethane were not located 1n the available literature
cited 1n Appendix A.
0116d -18- 05/17/88
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5. PHARMACOKINETICS
5.1. ABSORPTION
Eight hours after an oral dose of 100 mg/kg [14C]-d1bromoch1oromethane
1n corn oil, male Sprague-Dawley rats expired 66.3% of the radioactivity and
excreted 1.1% of the radioactivity 1n their urine (M1nk et a!., 1986). Male
B6C3F1 mice treated orally with [14C]-d1bromochloromethane at a dose of
150 mg/kg expired 83.89% of the dose and excreted 1.9% of the dose In the
urine within 8 hours after dosing. These results Indicate that dlbromo-
chloromethane Is readily absorbed following oral exposure.
5.2. DISTRIBUTION
Mink et al. (1986) reported that 8 hours following a single oral dose of
[i*Cj-dlbromochloromethane In corn oil, 1.4 and 5.02% of the dose were
recovered In the organs of male rats (100 mg/kg dose) and male mice (150
mg/kg dose), respectively. The bladder, brain, kidneys, liver, lungs,
pancreas, -1 g of skeletal muscle, the empty stomach and the thymus were
analyzed. Although radioactivity levels In Individual organs were not
reported, the Investigators stated that radioactivity levels were highest In
the stomach, liver and kidneys 1n both species.
5.3. METABOLISM
Eight hours after male rats were given a single oral dose of
[l4C]-d1bromochloromethane (100 mg/kg), 18.2% of the radioactivity was
expired as 14C02, and 48.1% of the radioactivity was expired as
unmetabollzed compound (Mink et al., 1986). In male mice given a single
dose of [14C]-d1bromochloromethane (150 mg/kg), 71.58 and 12.31% of the
radioactivity were expired as 14CO? and the unmetabollzed compound,
respectively. Radioactive compounds recovered In the urine of rats and mice
treated with [l4CJ-d1bromochloromethane were not Identified.
0116d -19- 05/17/88
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Anders et al. (1978) reported that blood carbon monoxide levels were
Increased after male Sprague-Dawley rats were given an IntraperHoneal
Injection of dlbromochloromethane (97% pure) 1n corn oil at a dose of 1
mmol/kg (208 mg/kg), Indicating that dlbromochloromethane was metabolized to
carbon monoxide. Blood carbon monoxide levels following an Injection of
dlbromochloromethane, which peaked at -400 nmol/ms. blood, were higher than
levels following a similar Injection of bromodlchloromethane, but much lower
than carbon monoxide levels following similar Injections of bromoform (-1300
nmol/ma blood) or lodoform (-1500 nmol/ma blood).
5.4. EXCRETION
Mink et al. (1986) found that 66.3 and 1.1% of the radioactivity from an
oral dose of [a*C]-d1bromochloromethane (100 rag/kg) In corn oil was
expired In the air and excreted In the urine of male rats 8 hours after
dosing. Male mice treated orally with [l4C]-d1bromochloromethane (150
mg/kg) In corn oil expired 83.89% of the dose and excreted 1.9% of the dose
In the urine within 8 hours after dosing. Total recovery of radioactivity
from expired air, urine and organs 8 hours after dosing was 70.3% 1n rats
and 91.63% In mice. The half-life of dlbromochloromethane was reported to
be 1.2 hours 1n rats and 2.5 hours In mice. The determination of half-lives
was not described.
5.5. SUMMARY
The available pharmacoklnetlc data Indicate that dlbromochloromethane Is
absorbed readily by rats and mice following oral exposure. Eight hours
after an oral dose of [l4C]-d1bromochloromethane 1n corn oil, -66 and 84%
of the radioactivity was expired by male Sprague-Dawley rats and male 86C3F1
mice, respectively (H1nk et al., 1986). In mice, 71.56 and 12.31% of the
dose was expired as 14CO? and unmetabollzed compound, compared with 18.2
0116d -20- 06/06/88
-------
and 48.1% expired as 1*CQ? and unmetabollzed compound in rats. These
results Indicate that dlbromochloromethane Is metabolized more readily 1n
mice than rats. Less than 2% of the dose In both mice and rats was excreted
In the urine as unidentified compounds, within 8 hours after dosing, with
1.4 and 5.02% remaining In the organs of rats and mice, respectively.
Anders et al. (1978) reported that carbon monoxide blood levels In rats
following an Intraperltoneal Injection of dlbromochloromethane were higher
then levels following an Injection of bromodlchloromethane, but much lower
than carbon monoxide blood levels following similar Injections of bromoform
or todoform.
0116d
-21-
05/17/88
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6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposure. Pertinent data regarding the toxIcHy of
dlbromochloromethane following subchronlc or chronic Inhalation exposure
were not located In the available literature cited 1n Appendix A.
6.1.2. Oral Exposure.
6.1.2.1. SUBCHRONIC — In abstracts, Schuller et al. (1978) and
Munson et al. (1978) reported studies In which unspecified numbers of male
and female ICR mice were treated by gavage with dlbromochloromethane at 12.5
or 125 mg/kg/day (vehicle unspecified), for 90 days beginning 7 days after
birth. In the Schuller et al. (1978) study, which also examined mice
treated for 90 days at doses of 0.2 mg/kg/day, delayed hypersensHlvHy
(izsj-labeled albumin extravasation Into the foot pad 18 hours after a
second challenge with SRBC) and humoral Immunity (antibody levels to SRBC}
were not affected. Munson et al. (1978) found that dlbromochloromethane
treatment resulted 1n no changes 1n phagocytlc Index; however, a dose-
dependent decrease In hepatic phagocytosis was observed In both sexes and
splenic phagocytosis was depressed by 27 and 40% In males at 12.5 and 125
mg/kg/day, respectively.
In a behavioral study, Balster and Borzelleca (1982) reported that
treatment of 12 male ICR mice by gavage with dlbromochloromethane [1n
emulphor (polyoxyethylated oil nonlonlc surfactant):water, 1:8] at 400
mg/kg/day for up to 60 days significantly altered operant training to press
a lever and receive dripper reward presentation of sweetened milk. The 400
mg/kg/day dose also resulted 1n an unspecified number of deaths. No effects
on operant behavior were noted 1n mice treated for 60 days at a dose of 100
mg/kg/day. In 14- and 90-day studies, no effects on screen test, cling
0116d -22- 06/06/88
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test, hole-board, swimming endurance or passive avoidance were observed In
male ICR mice (groups of 6-9) treated by gavage with dlbromochloromethane at
up to 10 mg/kg/day. The single dose oral ED5Q for the screen test was
reported to be 454 mg/kg in male ICR mice.
Chu et al. (1982a) treated groups of 10 male Sprague-Dawley rats with
dlbromochloromethane (>98% pure) In drinking water at 0, 5, 50 or 500 ppm
(0.13, 1.5 or 12 mg/rat/day, reported by Investigators) for 28 days.
Emulphor was used at a level of 0.25% to help dissolve the dlbromochloro-
methane 1n water. Treatment with dlbromochloromethane had no effect on
growth rate, food Intake, hematologlc and biochemical parameters, and
histology.
In a 90-day study, groups of 20 male and 20 female weanling Sprague-
Dawley rats were treated with 0, 5, 50, 500 or 2500 ppm dlbromochloromethane
dissolved In drinking water (1% emulphor 1n tap water) (Chu et al., 1982b).
Groups of control rats were provided with tap water or a 1% emulphor
solution. Doses calculated by the Investigators were 0.14, 1.5, 12 or 55
mg/rat/day for males and 0.11, 1.2, 9.5 or 38 mg/rat/day for females. U.S.
EPA (1982a) cited a personal communication (Chu, 1982) that provided body
weights so that doses of 0.442, 4.93, 39.5 and 202 mg/kg/day for males, and
0.585, 6.42, 49.5 and 211 mg/kg/day for female rats were calculated. At the
end of the 90-day treatment period, 10 rats/sex/group were sacrificed; the
remaining rats were maintained without treatment for an additional 90 days.
In addition to body weight, and food and water Intake, serum biochemical
profiles (sodium, calcium, potassium, Inorganic phosphorus, total bH1rub1n
and protein, cholesterol, glucose, uric add, alkaline phosphatase, lactate
dehydrogenase, sorbHol dehydrogenase), hematological parameters and hepatic
mlcrosomal enzyme activities were determined and gross and hlstologlcal
examinations were performed.
0116d -23- 05/17/88
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During the 90-day treatment period, food Intake and body weight gain
were significantly (p<0.05) decreased In male and female rats treated at
2500 ppm. During the recovery period, body weight gains were similar to
controls, although food Intake was still reduced. No significant dose-
related effects on biochemical or hematologlcal parameters were noted.
Hlstologlcal examinations at the end of the 90-day treatment period revealed
liver and thyroid alterations 1n all dlbromochloromethane dose groups and
the emulphor controls. The liver lesions were described as fatty Infiltra-
tion of hepatocytes and hyperplasla of the biliary epithelium. The
Incidence of liver lesions was not dose-related; similar numbers of rats
were affected In the emulphor control group and the dlbromochloromethane
treatment groups. The severity of liver lesions did seem to Increase with
Increasing concentration. When liver lesions were graded for severity on a
scale of 1-10, the mean severity differed significantly from controls
(p<0.05) at 2500 ppm In males and at 50 and 2500 ppm 1n females. Severity
of liver lesions In female rats at 500 ppm was similar to controls. Hlsto-
loglcal changes 1n the thyroid were described as a reduction In folUcular
size and colloid density, and an Increase 1n epithelial height. The
Incidence of thyroid lesions was not dose-related, although more severe
changes were observed with Increased frequency 1n the higher dose groups.
Following the 90-day recovery period, both liver and thyroid changes became
very mild and were similar to controls.
In a 13-week study (NTP, 1985; Dunnlck et al., 1985), groups of 10
F344/N rats/sex and 10 B6C3F1 mice/sex were treated by gavage with dlbromo-
chloromethane (>9854 pure) In corn oil at doses of 0, 15, 30, 60, 125 or 250
mg/kg, 5 days/week. All male rats and 9/10 female rats treated at 250 mg/kg
died. Mean body weights were reduced by 25 and 47% 1n male and female rats
0116d
-24-
05/17/88
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at 250 mg/kg, and by 7% 1n males at 125 mg/kg. Body weights of other dose
groups were not significantly affected. Fatty metamorphosis of the liver
was observed 1n all rats treated at 250 mg/kg and 1n 10/10, 10/10, 8/10,
7/10 and 4/10 male rats treated at 125, 60, 30, 15 and 0 mg/kg, respec-
tively. According to U.S. EPA (1987a), the Incidence of fatty metamorphosis
In male rats was not significant (Fisher exact test) compared with controls
at doses <30 mg/kg. Fatty metamorphosis was observed In 1/10 female control
rats and 0/10 females at 125 mg/kg. The livers of female rats at lower
doses were not examined. Toxic nephropathy, as well as Inflammation and
squamous metaplasia of the salivary gland, were observed 1n male and female
rats at 250 mg/kg, but not at 125 mg/kg or 1n controls; other treatment
groups were not examined.
Treatment-related deaths did not occur In mice. Final mean body weights
were depressed by 5.4 and 6.3% 1n male mice, and by 2.6 and 5.954 1n female
mice treated at 125 and 250 mg/kg, respectively. Fatty metamorphosis of the
liver was observed In 5/10 male mice treated at 250 mg/kg, but not In
females at 250 mg/kg, controls or male mice treated at 125 mg/kg (other dose
groups were not examined). Toxic nephropathy was observed 1n 5/10 male mice
at 250 mg/kg. This effect was not observed 1n females at 250 mg/kg male
mice at 125 mg/kg or 1n controls.
6.1.2.2. CHRONIC — NTP (1985) and DunnUk et al. (1985) reported an
oral chronic tox1c1ty/carc1nogen1c1ty study of dlbromochloromethane In
F344/N rats and B6C3F1 mice. In this study, groups of 50 rats/sex were
treated by gavage with dlbromochloromethane (>98X pure) In corn oil at doses
of 0, 40 or 80 mg/kg, 5 days/week for 104 weeks. Similar groups of mice
were treated at doses of 0, 50 or 100 mg/kg, 5 days/week for 105 weeks. The
survival of rats was not affected by dlbromochloromethane treatment. Mean
0116d
-25-
06/06/88
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body weights of high-dose male rats were lower than controls beginning at
week 20. Histologlc examinations revealed a dose-related Increase In the
frequency of fatty changes 1n the livers of both sexes (27/50, control;
47/50, low-dose; 49/50, high-dose males; 12/50, control; 23/50, low-dose;
50/50 high-dose females) and "ground glass" cytoplasmlc changes 1n the
hepatocytes of male rats. A dose-related Increase In nephrosls was also
observed In female (7/50, control; 11/50, low-dose; 14/50 high-dose) but not
male rats.
In mice, an accidental overdose (not described further) at week 58
reduced survival of low-dose male, but not female mice. Survival of
high-dose male mice was significantly reduced compared with controls. Mean
body weights of both sexes of high-dose mice were lower than controls. The
Incidence of fatty metamorphosis 1n the liver was Increased 1n mice of both
sexes at both dose levels. Liver necrosis and kidney nephrosls were also
observed 1n treated male mice, while an Increased Incidence of calcification
of the liver was observed In high-dose female mice. Results of this study
pertaining to possible cardnogenlclty of dlbromochloromethane are presented
1n Section 6.2.2.
Tobe et al. (1982) conducted a 2-year dietary study of dlbromochloro-
methane In Wlstar SPF rats. Groups of 40 rats/sex were treated with micro-
encapsulated dlbromochloromethane (containing 2-5% ethanol as a stabilizer)
In the diet at concentrations of 0.022, 0.088 or 0.35% (220, 880 or 3500
mg/kg diet). Groups of 70 male and 70 female rats fed diets with empty
mlcrocapsules at a similar level as the high-dose rats served as controls.
Based on body weight and food consumption data, the 0.022, 0.088 and 0.35%
concentrations correspond to doses of ~10, 39 or 210 mg/kg/day for males,
and 17, 66 or 350 mg/kg/day for females. Body weight and food consumption
0116d
-26-
06/06/88
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were determined weekly for the first 6 months, biweekly from 6-12 months and
every 4 weeks during the remainder of the study. At 18 months, 9 male and 9
female control rats and 5 male and 5 female rats from each treatment group
were sacrificed; at 24 months, 12 control rats/sex and 7 rats/sex/treatment
group were sacrificed. Gross necropsies and hematologlcal and serum
biochemical studies were completed on these rats. The surviving rats were
also sacrificed and necropsled at 24 months and tissues were prepared for
hlstologlcal examination. The results of the necropsies of rats used for
hlstologlcal examination were not presented In this preliminary study;
hlstologlcal examinations were reported to be In progress,
H1ld plloerectlon and emaciation were observed In high-dose male and
female rats. Mortality of rats was not treatment-related. A marked
suppression of body weight gain was observed In high-dose male and female
rats, and a mild decrease In body weight gain was observed In middle-dose
male and female rats. Dlbromochloromethane treatment had no effect on food
Intake or hematologlcal parameters. The only consistent dose-related
changes 1n serum biochemical parameters In male and female rats at 18 and 24
months were decreases In T-GLY (this term was not further specified by the
Investigators, but probably refers to total glyclne, which may Indicate
altered I1p1d metabolism) and Increases In y-GTP. Other serum biochemical
parameters were significantly different from controls but the changes were
not dose-related, nor were the changes consistent at 18 and 24 months. No
consistent dose-related organ weight changes were observed. Necropsies
completed at 18 and 24 months revealed liver effects, described as con-
cavities and convexities of the surface of the liver, yellowing of the liver
and transparent lobules. Liver hypertrophy was also reported. No similar
liver effects were observed In control rats. The Incidence and severity
OH&d
-27-
06/06/88
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of liver effects, which were reported only qualitatively, appeared to be
dose-related. In general, liver effects were more severe In male than In
female rats. At 18 months, "almost all" low-dose male rats had yellow
livers and "some" had transparent lobules and at 24 months, "some" had liver
effects (yellowing and transparent lobules); at 18 months, one low-dose
female rat had mild liver hypertrophy; and at 24 months, two female rats had
yellow spots 1n the liver and one had hypertrophy and transparent lobules.
6.1.3. Other Relevant Information. The oral LD5(s for dlbromochloro-
methane (dissolved 1n emulphor:alcohol:sa!1ne, 1:1:8) In ICR Swiss mice were
800 mg/kg (667-960) In males and 1200 mg/kg (945-1524) In females (Bowman et
al., 1978). The mice were observed for 14 days. Sedation and anesthesia
were noted In mice treated at doses >500 mg/kg. Necropsies of mice that
died revealed fatty Infiltration of the livers, pale kidneys and hemorrhag-
Ing In the adrenals, lungs and brain.
Chu et al. (1980,1982a) reported oral LD5Qs for dlbromochloromethane
(dissolved 1n corn oil) 1n Sprague-Dawley rats of 1186 mg/kg (997-1421) In
males and 848 mg/kg (576-1090) 1n females. Hlstologlcal examinations
revealed mild to moderate morphological changes In the liver (variations 1n
the size of hepatocytes, veslculatlon of biliary epithelial nuclei) and
kidney (bilateral focal Interstitial nephritis and Mbrosls).
Munson et al. (1982) conducted a 14-day study In which groups of 7-12
CD-I mice/sex were treated by gavage with dlbromochloromethane In a 10%
emulphor:water solution at doses of 50, 125 or 250 mg/kg/day. High-dose
mice experienced decreased body weight gain, Increased liver weights,
decreased spleen weights, decreased flbrlnogen concentrations, decreased
serum glucose levels, Increased SGOT and SGPT, and effects on both humoral-
and cell-mediated Immunity. Increased relative liver weights and Immune
0116d
-28-
06/06/88
-------
system effects were also observed 1n mice at 125 mg/kg/day. There were no
differences between low-dose mice and controls In any of the parameters
measured. Hlstologlcal examinations of major organs were not performed.
Condle et al. (1983) treated groups of 10 male CD-I mice by gavage with
dlbromochloromethane (technical grade) 1n corn oil at doses of 37, 74 or 147
mg/kg/day for 14 days. Sixteen mice treated with corn oil served as
controls. No effects on body weight or serum BUN or creatlnlne were noted.
A significant (p<0.05) Increase In serum SGPT was observed In mice treated
at 147 mg/kg/day. Determination of p-am1noh1ppurate uptake by renal
cortical slices (Indicator of the function of the renal proximal tubules)
Indicated a significant (p<0.05) Inhibition only at the high dose. Hlsto-
pathologlc examinations revealed an Increase 1n the Incidence of epithelial
hyperplasla In the kidney of high-dose mice, and a treatment-related
Increase In the Incidence and severity of mesanglal hypertrophy 1n the
kidney. In the liver, a treatment-related Increase of mltotlc figures and
cytoplasmlc vacuollzatlon were observed. The changes In both the kidney and
the liver were considered to be mild to slight 1n severity.
NTP (1985) conducted a 14-day study In which groups of five F344/N
rats/sex and five B6C3F1 mice/sex were treated by gavage with dlbromochloro-
methane {>98% pure) 1n corn oil. Rats were treated at doses of 0, 60, 125,
250, 500 or 1000 mg/kg/day and mice were treated at 0, 30, 60, 125, 250 or
500 mg/kg/day. All rats treated at 1000 mg/kg/day, and 5/5 female and 3/5
male rats treated at 500 mg/kg/day died. Effects observed at 500 and 1000
mg/kg/day Included lethargy, ataxla, labored breathing, mottled livers and
darkened renal medullae. Significant treatment-related effects were not
observed 1n rats at lower doses. In mice, 4/5 males and 3/5 females treated
at 500 mg/kg/day died. The effects described for rats were also observed 1n
Ollbd
-29-
05/17/88
-------
mice treated at 500 mg/kg/day. In addition, white paplllomatous nodules In
the stomach were observed 1n 1/5 male mice at doses >125 mg/kg/day, and 1n
1/5 and 2/5 female mice at 125 and 500 mg/kg/day.
Hewitt et al. (1983) found that oral pretreatment of male Sprague-Dawley
rats with acetone (15 mmol/kg) 18 hours before a single oral dose of
dlbromochloromethane (0.25-1.0 ma/kg) 1n corn oil greatly enhanced acute
hepatotoxldty, which was assayed by monitoring plasma GTP and OCT levels 24
hours following dlbromochloromethane administration. The Investigators
stated that under the conditions of this study, acetone converted dlbromo-
chloromethane from a weak hepatotoxln to a strong hepatotoxln. Pretreatment
of rats with acetone and dlbromochloromethane resulted 1n a degree of liver
Injury that was equal or greater than liver toxldty In rats following
treatment with acetone and an equlmolar dose of chloroform, which Is a more
potent hepatotoxln than dlbromochloromethane when the compounds are given
without acetone pretreatment. The mechanisms resulting In the enhanced
hepatotoxldty of halogenated hydrocarbons (Including dlbromochloromethane)
by acetone are not known (Plaa, 1980).
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the cardnogenlcHy of
dlbromochloromethane following Inhalation exposure were not located 1n the
available literature cited 1n Appendix A.
6.2.2. Oral. U.S. EPA (1987b) reviewed studies (Cantor et al., 1978;
Isacson et al., 1983) that reported an association between trlhalomethane
levels 1n drinking water and cancer rates. Crump and Guess (1982) reviewed
a number of epidemiology studies that examine the relationship of cancer In
humans to drinking water quality. They concluded that the studies provide
weak evidence for an association between water chlorlnatlon and rectal,
0116d
-30-
06/06/88
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colon and bladder cancer. The contribution of the Individual trlhalo-
methanes (Including dlbromochloromethane) and nonvolatile organlcs to the
association between cancer and drinking water quality Is not known.
In a 2-year carclnogenldty bloassay (see Section 6.1.2.2.) (NTP, 1985),
no significant Increase 1n tumor Incidence was observed In F344/N rats
treated by gavage with dlbromochloromethane at 0, 40 or 80 mg/kg, 5 days/
week. Liver tumor Incidence data for B6C3F1 mice treated with dlbromo-
chloromethane at 0, 50 or 100 mg/kg, 5 days/week (0, 35.7 or 71.4 mg/kg/day)
for 105 weeks are presented In Table 6-1. During week 58 of the study,
low-dose mice were given an overdose that did not affect females but killed
35 males, making the size of the low-dose male group Inadequate for analysis
of neoplasms. The Incidence of hepatocellular carcinomas was significantly
Increased 1n high-dose male mice, while the combined Incidence of adenomas
or carcinomas was only marginally Increased. As presented 1n Table 6-1, the
Incidence of adenomas, and the combined Incidences of adenomas and
carcinomas were significantly (p<0.05) Increased In female mice. The NTP
(1985) concluded that under the conditions of these studies, there was no
evidence of the carclnogenldty of dlbromochloromethane In male or female
F344/N rats, equivocal evidence In male mice and "some evidence of cardno-
genlclty" 1n female mice.
In a Russian study (Voronln et al., 1987), the carclnogenldty of
dlbromochloromethane was examined In CBAxC57Bl/6 mice treated In the
drinking water. In this study, groups of 50-55 mice/sex were treated with
dlbromochloromethane 1n the drinking water at 0.04, 4.0 or 400 mg/s, for
104 weeks. An untreated control group consisting of 75 male and 50 female
mice was also maintained. Multiplying the exposure concentrations by 0.0057
8,/day drinking water consumption and dividing by 0.03 kg mouse body weight
0116d
-31-
03/24/89
-------
TABLE 6-1
Incidence of Liver Tumors 1r> B6C3F1 Mice Treated by Gavage
with Dlbromochloromethane 5 Days/Week for 105 Weeks3
Sex Dose
{mg/kg)
F 0
50
100
0
50
100
0
50
100
Md 0
100
0
100
0
100
Tumor Type
adenoma
carcinoma
combined adenoma
or carcinoma
adenoma
carcinoma
combined adenoma
or carcinoma
Tumor Incidence
(p value)
2/50 (0.004)b
4/49 (0.329)c
11/50 (0.007)C
4/45 (0.141}b
6/49 (0.357}c
8/50 (0.178)c
6/50 (0.002)b
10/49 (0.194)c
19/50 (0.002}c
14/50 (0.188
negative trend)b
10/50 (0.241
negative trend)c
10/50 (0.025)b
19/50 (0.038)c
23/50 (0.240}b
27/50 (0.274)c
QUALITY OF EVIDENCE
Strength of Study: The compound (>98% pure) was administered to both sexes.
The study used adequate numbers of animals and an
adequate duration of exposure.
Weakness of Study: Low-dose mice were overdosed at week 58, killing 35 males
so that the number of males In the low-dose group was
Inadequate for analysis of neoplasms. Compound was given
by gavage rather than 1n the feed or drinking water.
Overall Adequacy: Females * Adequate; Males - Inadequate
Source: NTP, 1985
'cochran-Armltage Test
"Fisher exact test
Number of low-dose males was Inadequate for analysis of neoplasms.
0116d
-32-
06/06/88
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(U.S. EPA, 1986c), the 0, 0.04, 4.0 and 400 mg/l drinking water concentra-
tions correspond to dlbromochloromethane doses of 0, 0.0076, 0.76 and 76
mg/kg/day. Organs and tissues (lungs, esophagus, stomach, liver, kidneys,
spleen and suspected tumors) of mice dying during the study and those killed
after 104 weeks were stained with hematoxylln-eoslne and examined micro-
scopically. The results, which were analyzed using the \3 test, did not
reveal statistically significant Increased tumor Incidences In either male
or female mice. Total tumor Incidences based on the number of mice surviv-
ing until the detection of the first tumor are presented In Table 6-2. As
Indicated In Table 6-2, no relationship between dlbromochloromethane dose
and time to first tumor was observed. No other parameters were examined In
this study.
In the Tobe et al. (1982) study (see Section 6.1.2.2.), Wlstar SPF rats
(40 rats/sex/dose group) were fed mlcroencapsulated dlbromochloromethane 1n
the diet at concentrations that provided the males with doses of 0, 10, 39
or 210 mg/kg/day and the females with doses of 17, 66 or 350 mg/kg/day.
Necropsies of five rats/sex/treatment group at 18 months Identified a
subcutaneous abdominal "phymata" in one female middle-dose rat. Results of
necropsies of seven rats/sex/treatment group at 24 months revealed one
phymata of the pituitary 1n low-dose males and a single case of phymata of
the glandular stomach 1n middle-dose females. H1stolog1cal examinations
were not completed but were reported to be In progress for rats surviving to
24 months. The investigators stated that because of the low frequency of
phymata at necropsy it was unlikely that dlbromochloromethane was carcino-
genic in rats, but they reserved further discussion until hlstologlcal
examinations are completed.
0116d
-33-
04/18/89
-------
TABLE 6-2
Total Tumor Incidences and Time to First Tumor In CBAxC57Bl/6 Mice
Treated with Dlbromochloromethane In the Drinking Water for 104 Weeks3
Sex
Dose
(mg/i)
Tumor Locations
and Types
Tumor
Incidence^
Time to
First Tumor
(days)
0.04
4.0
400
2 lung
1 other
(lympholeukosls)
1 other
(solid cancer of
mammary gland)
1 other
(unspecified)
1 liver
(hemangloma)
2 skin
(planocellular
cancer)
2 lung
1 other
(adenoma of the
sebaceous glands)
3/34
2/27
538
581
3/40
446
3/32
644
0 1 liver (hepato-
cellular carcinoma)
2 lung
1 other
(lympholeukosls)
0.04 1 skin
(planocellular
cancer)
0.04 1 spleen
(hemanglosarcoma)
4/63
470
1/13
1/33
699
596
0116d
-34-
05/17/88
-------
TABLE 6-2 (cont.)
Sex
Dose
(mg/i)
Tumor Locations
and Types
Tumor
Inddenceb
Time to
First Tumor
(days)
400
1 liver
(hepatocellular
carcinoma)
2 lungs
1 kidney
1 skin
(planocellular
cancer)
5/39
480
Strength of Study:
Weakness of Study;
QUALITY OF EVIDENCE
The compound was administered In drinking water to both
sexes at three dose levels. The high-dose level was
similar to that used 1n the NTP {1985} study. The study
used adequate numbers of mice per group and the period
of exposure was adequate.
Additional toxldty data, Including survival Information
were not provided. Although the highest concentration
used did not exceed the solubility limits of
dlbromochloromethane In water, other Investigators using
drinking water exposure have used the surfactant,
emulphor, to help dissolve the compound. The study does
not Indicate 1f the reported concentrations were
confirmed with analytical methods.
Overall Adequacy: Limited
aSource: Voronln et al., 1987
bNumber of mice with tumors surviving until detection of first tumor.
0116d
-35-
06/06/88
-------
6.2.3. Other Relevant Information. The results of the carclnogenlcity
studies of five different halomethanes and the doses used In those studies
are tabulated in Table 6-3. Table 6-4 expresses the dose as mllllmoles per
kilogram body weight to facilitate the comparison between related compounds
with different molecular weights. Trlbromomethane produced a weaker
response than bromodlchloromethane for large Intestine cancer 1n male rats.
At nearly equivalent dally doses (0.8 mmol/kg for trlbromomethane and 0.6
mmol/kg for bromodlchloromethane), the Incidence of large Intestine cancer
was 15 times greater for bromodlchloromethane. This difference, however,
may be due in part to the reduced survival of the high-dose male rats given
trlbromomethane. Bromodlchloromethane also produced a 26% incidence of
large Intestine cancer at the lower dose (0.3 mmol/kg), whereas no large
Intestine cancer was observed in male rats administered 0.4 mmol/kg
tribromomethane. In female rats, these two trihalomethanes were similar in
potency for induction of large intestine cancer. The lack of large
Intestine tumors In rats treated with chlorodlbromomethane may be due to the
lower dally doses used In that study.
The metabolism of trihalomethanes Involves the formation of highly
reactive Intermediate (not Identified) dihalocarbonyls. The reactivity of
dlhalocarbonyls with cellular nucleophlles should follow this order:
dllodocarbonyl > dlbromocarbonyl > bromochlorocarbonyl > dlchlorocarbonyl.
Consistent with this suggestion 1s the observation that the rate of
metabolism of trihalomethanes to carbon monoxide ^ vivo by rat liver
mlcrosomal fractions followed this order: trHodomethane > trlbromomethane
chlorodlbromomethane > bromodlchloromethane > chloroform. The carcinogenic
potential of these compounds for liver or kidney, however, Is the reverse of
this order (see Table 6-3). The one possible explanation for this
0116d -36- 03/24/89
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observation Is that the cellular lifetime of Intermediates such as
bromochlorocarbonyl are extremely short because of their rapid reactivity
with cellular nucleophlle (I.e., glutathlone). Consequently, macromolecular
binding to cellular constituents that might lead to cancer Induction Is
reduced. The less reactive dlhalocarbonyl, such as dlchlorocarbonyl, may be
sufficiently stable to Induce a carcinogenic process. The structure-
actlvHy relationships among the trlhalomethanes do not provide a support to
Incorporate into the weight of evidence characterization. More research Is
required to explain the observed discrepancies. Therefore, only existing
cancer bioassay data has been utilized In consideration of the weight of
evidence classification.
6.3. MUTAGENICITY
Mutagenicity data for dlbromochloromethane are presented in Table 6-5.
Dibromochloromethane tested positive in S. typhlmurium strain TA100 In a
vapor phase test performed 1n a desiccator (Simmon et al., 1977). Results
were negative when plate incorporation (Simmon et al., 1977) or prelncuba-
tion (NTP, 1985; Zeiger et al., 1987) methods were used. Nestmann and Lee
(1985) reported positive results for gene conversion in S. cerevislae strain
D4 without but not with S-9, and negative results for mutation 1n strain
XV185-14C both with and without metabolic activation. Dlbromochloromethane
has tested positive for sister chromatld exchange in human lymphocytes and
in bone marrow cells of mice treated orally (MoMmoto and Koizumi, 1983).
Borzelleca and Carchman (1982) reported negative results in a dominant
lethal mutation study In mice.
6.4. TERATOGENICITY
Ruddlck et al. (1983) treated groups of 10 pregnant Sprague-Dawley rats
with dlbromochloromethane (98% pure) In corn oil at 50, 100 or 200 mg/kg/day
on gestation days 6-15. A group of 12 pregnant rats treated with corn oil
0116d
-39-
03/24/89
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served as controls. The fetuses were collected on gestation day 22; 2
fetuses/litter were examined hlstologlcally, 2/3 of the fetuses from each
Utter were examined for skeletal anomalies and the remaining fetuses were
examined for visceral changes. At 200 mg/kg, maternal weight gain was
reduced by 25%. Oibromochloromethane treatment had no effect on maternal
organ weights, histology, hematology or fetal parameters (resorptlon sites,
number of fetuses, fetal weight). Examination of fetuses revealed no
treatment-related hlstologlcal, skeletal or visceral changes.
As part of a multlgeneratlon study (Section 6.5.), Borzelleca and
Carchman (1982) observed no Increased Incidences of terata In ICR mice from
dams treated wHh dlbromochloromethane In their drinking water (1% emulphor
solution) at 0.1, 1.0 or 4 mg/ml.
6.5. OTHER REPRODUCTIVE EFFECTS
Borzelleca and Carchman (1982) conducted a multlgeneratlon study In
which groups of 10 male and 30 female ICR mice were provided with drinking
water containing dlbromochloromethane In emulphor (1:1000, emulphor:delon-
1zed distilled water) at 0, 0.1, 1.0 or 4.0 mg/mH. (0, 100, 1000 or 4000
mg/a). Multiplying the exposure concentrations by 0.0057 I/day mouse
drinking water consumption and dividing by 0.03 kg mouse body weight (U.S.
EPA, 1986c), the 0.1, 1.0 and 4.0 mg/a drinking water concentrations
correspond to dlbromochloromethane doses of 19, 190 and 760 mg/kg/day. The
mice were treated 35 days before mating and through the births of F, ,
F, and F, Utters (a total of -27 weeks). The F,. offspring were
treated after weaning for 11 weeks at the same dlbromochloromethane concen-
tration as their parents and mated to produce F« and F_, litters.
Dominant lethal (treated males mated to control females) and teratology
studies (treated females mated to control males) were completed at the last
mating of the Ffl and F,. generations (see Sections 6.3. and 6.4.).
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Except for the F^b generation, Utters were sacrificed on postlmplantatlon
day 21, with necropsies completed on one male and one female mouse from each
Utter.
Average terminal body weights of both male and female F_ mice were
reduced significantly at 4 mg/ma dlbromochloroethane. Terminal body
weights of female mice treated at 1 mg/ma were also significantly reduced.
Survival of Fn mice was not affected; 0/6 male and 15/30 female F.. mice
w Ib
treated at 4 mg/ma survived. Times of death were not provided. Survival
of the untreated control group and emulphor F, control group was 13/19
and 5/10 for males and 50/60 and 27/30 for females, respectively. At
necropsy, a majority of mice treated with dlbromochloromethane had enlarged
livers with "morphology characteristic of hepatotoxIcHy." The severity of
liver lesions, which was dose-related, ranged from slight yellow-gray color,
presumably from fat accumulation, to gray and black discoloration with large
nodules. The Incidences of liver lesions 1n F male and female mice were
0/15, 5/20, 16/20 and 22/22 among vehicle controls, 0.1, 1.0 and 4.0 mg/ma
groups, respectively. A similar response (0/36, vehicle controls; 7/39, 0.1
mg/ma; 24/38, 1.0 mg/ma; 20/20, 4.0 mg/ma) was observed among F,
mice. Results of the Fisher Exact test completed at Syracuse Research Corp.
(SRC) showed that the Increased Incidence of liver lesions at the low dose
was statistically significant compared wHh controls In the F generation
(p=0.048) and In the Flfa generation (p=0.008). Hlstologlc examinations
were not performed. In mice treated at 4 mg/ma, inter size, gestation
Index and the percentage of live born pups surviving to 4 days of age were
significantly reduced. Treatment at 1.0 mg/ma resulted In sporadic
changes In reproductive parameters; litter size was significantly reduced
only In the F, generation, postnatal body weight was significantly
reduced In the F-. generation, and survival to day 4 was significantly
0116d
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reduced in the F^b generation. Survival from day 4 to day 21 was reduced
sporadically with a significant reduction 1n the F_ generation at 4.0
mg/ma, and significant reductions In the Flfa and F.. generations at
1.0 mg/mi. Postnatal body weight was significantly reduced at all doses
only In the f^ generation. No effects were noted In mice necropsled at
21 days of age.
6.6. SUMMARY
No Inhalation studies concerning the toxlclty of dlbromochloromethane
were located. The most consistent effects noted In oral studies of dlbromo-
chloromethane 1n rats and mice were liver effects, which were dose-related
In Incidence or severity. The available studies, however, do not clearly
Identify a NOEL. Acute studies (NTP, 1985; Condie et al., 1983; Munson et
al., 1982) have reported Increased liver weights, Increased SGOT or SGPT,
and mottled livers at doses >125 mg/kg/day In rats and mice. Subchronlc
studies (Chu et al., 1982b; NTP, 1985; Ounnick et al., 1985; Borzelleca and
Carchman, 1982) have reported liver effects In rats and mice (fatty Infil-
tration of the hepatocytes and hyperplasla) at doses >19 mg/kg/day. In
chronic studies, gross signs of liver toxlclty (yellow liver) have been
observed In rats at doses >10 mg/kg/day (Tobe et al., 1982), while NTP
(1985) reported dose-related Increases In the frequency of fatty liver In
rats treated by gavage with dlbromochloromethane at 28.6 and 57.1 mg/kg/day
and In mice treated at 35.7 and 71.4 mg/kg/day.
Data concerning the carcinogenlclty of dlbromochloromethane 1n humans
are not conclusive. Epidemiology studies have shown a weak relationship
between rectal, colon and bladder cancer 1n humans and water chlorination In
water heavily contaminated with organics (Crump and Guess, 1982). The
contribution of the Individual trihalomethanes (Including dlbromochloro-
methane) and nonvolatile organics to the association between cancer and
0116d -43- 03/24/89
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chlor'ination is not known. The NTP (1985) bloassay found no evidence of the
care Inogenlc Hy of dlbromochloromethane In male or female rats treated by
gavage with dlbromochloromethane at 0, 40 or 80 mg/kg, 5 days/week for 104
weeks. From hepatic tumor Incidences 1n mice, the NTP (1985) concluded that
there was equivocal evidence of cardnogenlclty In male mice and "some
evidence of carclnogenldty" in female mice treated by gavage at 50 and TOO
mg/kg, 5 days/week for 105 weeks. Interpretation of this study was
complicated by a dosing error that killed 35 male low-dose mice. In a
Russian study (Voronln et a!., 1987), tumor Incidences were not Increased
significantly In mice treated with dlbromochloromethane In drinking water at
doses of 0, 0.0076, 0.76 or 76 mg/kg/day for 104 weeks.
Dlbromochloromethane was positive for reverse mutation in S. typhlmuMum
strain TA100, only when tested 1n the vapor phase 1n a desiccator (Simmon et
a!., 1977). Results were negative when plate incorporation (Simmon et al.,
1977) or prelncubatlon (NTP, 1985; Zelger et al., 1987) methods were used.
Dlbromochloromethane has also tested positive in a test for gene conversion
In S. cerevlslae strain D4 (Nestmann and Lee, 1985), and In tests for SCE In
human lymphocytes and In bone marrow cells of mice treated orally (Morlmoto
and Koizumi, 1983). Borzelleca and Carchman (1982) reported negative
results In a dominant lethal study 1n mice.
In a teratogenk study by RuddUk et al. (1983), no reproductive or
teratogenlc effects were reported 1n animals exposed to <200 mg/kg/day. In
a mult 1 generation study, Borzelleca and Carchman (1982) reported reduced
body weights, liver lesions and Increased mortality 1n offspring; however,
these effects were seen at doses 1n which there was also maternal toxUHy.
Sporadic reproductive effects (reduced "IHter size and numbers of live
pups/litter) were reported In both the F, and F_ generations; however,
these effects were not dose-responsive.
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
The Interim MCL for total tMhalomethanes (the sum of the concentrations
of bromodlchloromethane, dlbromochloromethane, bromoform and chloroform) Is
0.1 mg/i (U.S. EPA, 1982b). This HCL, promulgated 1n 1979, applies only
to water systems that add an oxldant to the water during the treatment
process and serve a population >10,000 people. The MCL 1s based on chronic
toxiclty data for chloroform and existing technology and treatment methods
(U.S. EPA, 1987a).
U.S. EPA (1980b) derived an ambient water quality criterion for total
halomethanes of 1.9 jjg/8, based on the carclnogenlclty of chloroform. In
the errata to the Ambient Water Criteria Document (U.S. EPA, 1982a), an RfO
of 0.0006 mg/kg/day for dlbromochloromethane based on the subchronlc study
by Chu et al. (1982a) was presented. Based on this RfO, a dally consumption
of 2 i of water and 6.5 g of fish and shellfish, an ambient water quality
criterion of 18 pg/l was recommended for dlbromochloromethane.
An RfD of 0.02 mg/kg/day, based on the NTP (1985) subchronlc study In
rats was verified recently and Is available on IRIS (U.S. EPA, 1987a).
7.2. AQUATIC
Guidelines and standards for the protection of aquatic life from expo-
sure to dlbromochloromethane were not located In the available literature
cited 1n Appendix A.
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8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the carclnogenlclty of
dlbromochloromethane following Inhalation exposure were not located 1n the
available literature cited In Appendix A.
8.1.2. Oral. A number of epidemiology studies reviewed by Crump and
Guess (1982) provided limited evidence for an association between water
chlorInation and rectal, colon and bladder cancer. The contribution of the
Individual trlhalomethanes (Including dlbromochloromethane) and nonvolatile
organlcs to the association between cancer and drinking water quality 1s not
known.
NTP (1985) found no evidence for the carclnogenlcHy of dlbromochloro-
methane (In corn oil) In F344/N rats treated by gavage at doses of 0, 40 or
80 mg/kg, 5 days/week for 104 weeks. In B6C3F1 mice treated by gavage with
dlbromochloromethane In corn oil at doses of 0, 50 or 100 mg/kg, 5 days/week
for 105 weeks (NTP, 1985), the combined Incidence of hepatocellular adenomas
and carcinomas was significantly Increased In female mice (see Table 6-1 for
tumor Incidences In mice). Because of a dosing error that killed 35
low-dose male mice, there was an Insufficient number available for analysis
of neoplasms. In high-dose male mice, the Incidence of hepatocellular
carcinomas was Increased significantly, but the combined Incidence of
adenomas or carcinomas was only marginally Increased.
Voronln et al. (1987) observed no significant tumor Increases In
CBAxC57Bl/6 mice treated with dlbromochloromethane 1n the drinking water at
concentrations of 0, 0.04, 4.0 or 400 mg/i (0, 0.008, 0.76 or 76
mg/kg/day) for 104 weeks (see Table 6-2).
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Preliminary results of an unpublished 2-year dietary study {Tobe et a].,
1982) reported no increase in gross tumors in male rats treated with
dlbromochloromethane at doses of 10, 39 or 210 mg/kg/day, or in female rats
treated at doses of 17, 66 or 350 mg/kg/day. Only five and seven rats/sex/
dose group were examined following 18 and 24 months of exposure.
8.1.3. Other Routes. Pertinent data regarding the carcinogenicity of
dlbromochloromethane following other routes of exposure were not located in
the available literature cited in Appendix A.
8.1.4. Weight of Evidence. According to U.S. EPA (1986b), dlbromochloro-
methane can be classified as a group C carcinogen, possible human carcino-
gen. The human data that showed an association between trlhalomethanes 1n
drinking water and cancer were considered Inadequate for dlbromochloro-
methane alone, although the evidence for chlorinated drinking water with
trthalomethane constituents Is considered. The animal data, positive
carcinogenic evidence In B6C3F1 mice (males and females), were considered
limited. Auxiliary evidence such as rautagenldty and structural similarity
to known carcinogens is equivocal. According to the U.S. EPA (1986)
carcinogen assessment guidelines, compounds with Inadequate human data and
limited animal data can be placed In EPA Group C.
8.1.5. Quantitative Risk Estimates.
8.1.5.1. INHALATION — The lack of data concerning the carcinogenic-
ity of dlbromochloromethane following inhalation exposure precludes the
derivation of a quantitative risk estimate.
8.1.5.2. ORAL — U.S. EPA (1987b) derived a quantitative risk
estimate for the carcinogenicity of dtbromochloromethane following oral
exposure from the positive results of the NTP (1985) bloassay in female
B6C3F1 mice.
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The data used to calculate the q * using the GLOBAL 82 multistage
model (Howe and Crump, 1982), are presented In Table 8-1. The human q *
of 8.4xlO~2 (mg/kg/day}'1 was calculated from the available animal data
by multiplying the unadjusted q^ of 6.7xlO~3 {mg/kg/day)~l by the
cube root of the ratio of the human body weight (70 kg} to the animal body
weight. Assuming a 70 kg human drinks 2 I of water/day, 1Q~5, 10"6
and 10~7 risk levels are associated wHh drinking water concentrations of
4x!Q~3, 4xlO~4 and 4xlO~5 mg/t. These water concentrations corre-
spond to doses of IxlO"4, lxlO~5 and IxlO'6 mg/kg/day for the 10'5,
10"6 and 10~7 risk levels, respectively.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure. Pertinent data regarding the toxldty of
dlbromochloromethane following Inhalation exposure were not located,
precluding the derivation of subchronlc and chronic Inhalation RfOs.
8.2.2. Oral Exposure. Animal data (NTP, 1985) Indicate that dlbromo-
chloromethane may be a carcinogen following oral exposure. Therefore, the
evaluation of noncarclnogenlc endpolnts of toxldty for the derivation of
subchronlc and chronic RfDs may not be necessary for the purposes of this
document. Because a verified oral RfD (U.S. EPA, 1987a) 1s available, the
derivation of subchronlc and chronic oral RfDs will be presented.
8.2.2.1. LESS THAN LIFETIME EXPOSURES — Abstracts of 90-day studies
reported no effect on delayed hypersens1t1v1ty or humoral Immunity (Schuller
et al., 1978), although a dose-dependent decrease In hepatic and splenic
phagocytosis (Munson et al., 1978) was observed 1n mice treated by gavage
with dlbromochloromethane at 12.5 and 125 mg/kg. Balster and Borzelleca
(1982) reported effects on operant behavior and deaths In mice treated by
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TABLE 8-1
Cancer Data Sheet for Derivation of q-|* for Oral Exposure
Compound: dlbromochloromethane
Reference: NTP, 1985
Species, strain, sex: mouse, 86C3F1, female
Body weight: 0.035 kg (estimated from growth curves)
Length of exposure (le) = 105 weeks
Length of experiment (Le) = 105 weeks
Llfespan of animal (L) = 105 weeks
Tumor site and type: hepatocellular adenomas or carcinomas
Route/vehicle: gavage, corn oil
Experimental Doses
or Exposures
0 mg/kg, 5 days/week
50 mg/kg, 5 days/week
100 mg/kg, 5 days/week
Transformed Dose
(mg/kg/day)
0
35.71
71.43
Incidence
No. Responding/No.
6/50
10/49
19/50
Examined
Unadjusted q-j* from study = 6.7xlO"3 (mg/kg/day) 1
Human q^ = 8.4xlO~2 (mg/kg/day)'1
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gavage with dibromochloromethane at doses of 400 mg/kg/day for up to 60
days. No effects on behavior were observed at doses <100 mg/kg/day for as
long as 90 days.
In a ?8-day study (Chu et al., 1982a), no effects were noted in rats
treated with dibromochloromethane in the drinking water (containing 0.25%
emulphor) at concentrations <500 ppm. In a 90-day study (Chu et al.,
1982b), liver effects (fatty infiltration of hepatocytes, hyperplasia of the
biliary epithelia) were observed in rats treated with dlbromochloromethane
in the drinking water (1% emulphor) at 5, 50, 500 or 2500 ppm. Although the
severity of liver effects seemed to be dose-related, since the number of
rats affected in the vehicle control group was similar to the number
affected In the treatment groups, the interpretation of this study is
difficult. Body weights were reduced significantly 1n both sexes treated at
2500 ppm (202 mg/kg/day, males; 211 mg/kg/day, females).
Dlbromochloromethane was not teratogenU In rats at doses <200 mg/kg/day
(Ruddlck et al., 1983), or 1n mice treated with dlbromochloromethane 1n the
drinking water at 4.0 mg/ms. [760 mg/kg/day, assuming a mouse drinks 0.0057
I/day and weighs 0.03 kg (U.S. EPA, 1986c)] (Borzelleca and Carchman,
1982).
In the NTP (1985) subchronlc study, rats and mice (10/sex/group) were
treated by gavage with dlbromochloromethane in corn oil at doses of 0, 15,
30, 60, 125 or 250 mg/kg, 5 days/week for 13 weeks. All but one rat
(female) treated at 250 mg/kg died. Fatty metamorphosis of the liver was
observed in 10/10, 10/10, 8/10, 7/10 and 4/10 male rats treated at 125, 60,
30, 15 and 0 mg/kg, respectively. Fatty metamorphosis was found In 1/10
female control rats and 0/10 females at 125 mg/kg; the livers of female rats
at lower doses were not examined. Treatment-related deaths did not occur In
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mice. Fatty metamorphosis of the liver was observed In male and female mice
treated at 250 mg/kg, but not In controls or mice treated at 125 mg/kg.
Toxic nephropathy was also observed In male but not female mice treated at
250 mg/kg.
U.S. EPA (1987a) derived a chronic RfO based on the NTP (1985) sub-
chronic study in rats (see Section 8.2.2.2.). A Fisher Exact test Indicated
that the incidence of liver changes 1n male rats was significant at doses
>60 mg/kg (10/10 at 60 mg/kg; 8/10 at 30 mg/kg); therefore, the 60 mg/kg
dose was presented as a LOAEL and the 30 mg/kg dose was presented as a NOEL.
Based on the 30 mg/kg NOEL; a subchronlc RfD of 0.2 mg/kg/day or 20 mg/day
for a 70 kg human can be derived by multiplying the 30 mg/kg NOEL by 5/7
days and dividing by an uncertainty factor of 100 (10 to extrapolate from
animals to humans and 10 to protect sensitive Individuals).
The NOEL from the NTP (1985) subchronlc study Is based on a statistical
difference (Fisher Exact test) between two groups of 10 rats. Because group
sizes were 10 and because the control Incidence of liver effects was
relatively high (4/10) the power to detect a real difference in effect was
low. The observation of 7/10 male rats affected at 15 mg/kg, 5 days/week
(10.7 mg/kg/day) compared with 8/10 at 30 mg/kg, 5 days/week (21.4
mg/kg/day) also Indicates that although the 30 mg/kg dose may be a
statistical NOEL In this study, the 30 mg/kg dose, and lower doses may still
result 1n a biologically significant effect.
It 1s not clear If U.S. EPA (1987a) considered the Borzelleca and
Carchman (1982) study for RfD derivation. In this mult1generat1on study,
ICR mice were provided with drinking water (1:1000, emulphorrwater) contain-
ing dibromochloromethane at 0, 0.1, 1.0 or 4 mg/ma (0, 100, 1000 or 4000
ppm) for three generations. A dose-related Increase In the Incidence and
0116d -51- 03/24/89
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severity of IWer lesions was observed 1n FO and F,b mice treated for
<27 weeks. The liver lesions ranged from slight yellow-gray color,
presumably from fat accumulation, to enlarged livers with gray and black
discoloration with large nodules. Histologlc examinations were not
completed. Incidences of gross liver lesions were 0/15, 5/20, 16/23 and
22/22 In FQ mice treated at 0 (vehicle control), 0.1, 1.0 and 4.0 mg/ml,
and 0/30, 7/39, 24/38, 20/20 1n Flb mice treated at 0, 0.1, 1.0 and 4.0
mg/mlt. At 0.1 mg/ml, liver lesion Incidences were significantly
Increased compared with vehicle controls by the Fisher Exact test (analysis
completed at SRC) in FQ mice (p=0.0447) and in F,. mice (p=0.008). The
0.1 mg/ml (100 ppm) concentration can be transformed to a dose of 19
mg/kg/day by multiplying the 100 ppm concentration by a dally mouse water
Intake of 0.0057 i/day and dividing by a mouse body weight of 0.03 kg
(U.S. EPA, 1982b).
In contrast to the Borzelleca and Carchman (1982) study, no liver
effects were observed 1n B6C3F1 mice in the NTP (1985) subchronlc bloassay
at gavage doses of 125 mg/kg dlbromochloromethane, possibly because of
differences In vehicle (corn oil vs. emulphor In water), method of dosing
(gavage vs. drinking water) and strain (B6C3F1 vs. ICR).
The subchronlc oral studies concerning the toxicity of dlbromochloro-
methane all have limitations so that no single study Is the best candidate
for RQ derivation. The Borzelleca and Carchman (1982) drinking water study,
which did not Include histopathologlc examinations, provides evidence of
effects on the liver at a dose of 19 mg/kg/day. Although the NTP (1985)
subchronlc study, limited by small numbers of animals, identified a
statistical NOEL, the liver effects at all doses seemed to be dose-related.
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Based on the 21.4 mg/kg/day rat NOAEL, a subchronic RfD of 0.2 mg/kg/day or
10 mg/day for a 70 kg human can be derived by dividing the NOAEL by an
uncertainty factor of 100: 10 to extrapolate from animals to humans and 10
to protect sensitive Individuals.
Confidence In the subchronic oral RfD Is medium based on this study.
Supporting studies published by NTP did not contain adequate reproductive or
tetatology bloassays which resulted In a medium confidence rating of the
data base.
8.2.2.2. CHRONIC EXPOSURES — In the 2-year study by Tobe et al.
(1982), male and female Wistar SPF rats were fed mlcroencapsulated dlbromo-
chloromethane In the diet at concentrations that provided doses of 10, 39 or
210 mg/kg/day for males and 17, 66 or 350 mg/kg/day for females. Because
the study only reported hematologlcal and serum biochemical parameters and
gross necropsy observations from nine rats/sex/dose group at 18 months and
seven rats/sex/dose group at 24 months, the results are not conclusive. The
study reported a dose-related Increase In gross liver lesions that was more
severe In male rats. Liver effects (yellow liver and transparent lobules)
were observed In "some" low-dose male rats, Indicating that dlbromochloro-
methane 1n the diet at a dose of 10 mg/kg/day for 2 years may result In mild
effects on the liver but definitive conclusions must await the final
analysis and report.
The NTP (1985) bloassay reported a dose-related Increase In fatty
changes and ground-glass cytoplasmlc changes In the livers of F344 rats
treated orally with dlbromochloromethane at doses of 40 or 80 mg/kg, 5 days/
week for 104 weeks. In B6C3F1 mice treated at 50 or 100 mg/kg, 5 days/week
for 105 weeks, fatty metamorphosis of the liver was Increased at both dose
levels (NTP, 1985). Liver necrosis and kidney nephrosls were also observed
1n treated male mice, while an Increased Incidence of calcification of the
0116d -53- 04/12/89
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liver was observed 1n high-dose female mice. Hepatocellular adenomas and
carcinomas were significantly Increased at both doses In female mice, and
hepatocellular carcinomas were significantly Increased in high-dose male
mice. Because of a dosing error that killed low-dose male mice, there were
Insufficient numbers available for analysis of neoplasms.
The lowest dose resulting In a noncarclnogenlc effect In the chronic NTP
(1985) study is the 40 mg/kg dose in rats, which Is transformed to 28.6
mg/kg/day by multiplying by 5/7 days. Because this dose Is higher than
doses resulting In effects In subchronlc studies It Is not being considered
for derivation of a chronic oral RfO.
According to U.S. EPA (1987a), the NTP (1985) subchronlc study In male
rats Identifies a LOAEL at 60 mg/kg, 5 days/week (42.9 mg/kg/day) and a NOEL
at 30 mg/kg, 5 days/week (21.4 mg/kg/day). This NOEL Is based on a statis-
tical difference (Fisher Exact test) between two groups of 10 rats. Because
group sizes were 10 and because the Incidence In control rats of liver
effects was relatively high (4/10), the power to detect a real difference In
effect was low. The observation of 7/10 male rats affected at 15 mg/kg, 5
days/week (10.7 mg/kg/day) compared with 8/10 at 30 mg/kg, 5 days/week (21.4
mg/kg/day) also Indicates that although the 30 mg/kg dose may be a statisti-
cal NOEL 1n this study, <30 mg/kg may still result 1n a biologically signi-
ficant effect. U.S. EPA (1987a) based the chronic RfD on the statistical
subchronlc NOEL (21.4 mg/kg/day) rather than the chronic rat LOAEL (28.6
mg/kg/day) because of "the slightly greater confidence In the subchronlc
NOEL versus the chronic LOAEL that was associated wUh several adverse
effects." Dividing the statistical subchronlc NOEL of 21.4 mg/kg/day by an
uncertainty factor of 1000 (10 to extrapolate from a subchronlc study, 10 to
extrapolate from human data and 10 to protect sensitive humans), a chronic
oral RfD of 0.02 mg/kg/day or 2 mg/day for a 70 kg human was derived.
0116d -54- 04/12/89
-------
According to U.S. EPA (1987a), confidence In the 0.02 mg/kg/day RfO 1s
medium because of a Tack of adequate reproductive or teratology bloassays.
It is not clear from U.S. EPA (1987a) if the teratogeniclty (Ruddlck et al.t
1983) or the multigeneration (Borzelleca and Carchman, 1982} studies
summarized in this document were overlooked or If they were reviewed and
considered inadequate.
As indicated in Section 8.2.2.1., the Borzelleca and Carchman (1982)
study observed liver effects in mice treated with dlbromochloromethane in
the drinking water at a dose of 19 mg/kg/day for <27 weeks. Considering a
dose of 19 mg/kg/day an effect level is supported by the Tobe et al. {1982}
study, which provided very limited evidence that mild liver effects may
occur in male rats treated chronically with dlbromochloromethane at doses as
low as 10 mg/kg/day, and the NTP (1985) subchronlc study, which observed
statistically nonsignificant Increases In liver effects at doses of 21.4 and
10.7 mg/kg/day. Based on the 19 mg/kg/day LOAEL (Borzelleca and Carchman,
1982), a chronic RfD of 0.02 mg/kg/day, or 2 mg/day for a 70 kg human can be
derived by dividing the LOAEL by an uncertainty factor of 1000. An
uncertainty factor of 10 Is not used to extrapolate from subchronlc to
chronic exposure because the Borzelleca and Carchman (1982) study was a
3-generat1on study, and the available toxidty data provide evidence that
the liver effects do not become significantly more severe with duration, and
that they are reversible after exposure ceases. The RfD derived for the
multigeneration study (Borzelleca and Carchman, 1982) Is similar to that
derived by U.S. EPA (1987a). However, based on adequate, toxlcologlcal
evaluations it 1s appropriate to recommend the RfD of 0.02 mg/kg/day (NTP,
1985; U.S. EPA, 1987a).
0116d -55- 04/12/89
-------
Confidence in the chronic oral RfD Is medium. As described for the
subchronic oral RfD, the confidence is based on medium confidence in the
study (NTP, 1985); confidence in the data base was considered medium because
of conflicts in the data base.
0116d -56- 04/12/89
-------
9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
U.S. EPA (1983) derived a chronic toxlclty RQ of TOO based on the 90-day
gavage study by Munson et al. (1978) in which suppression of hepatic and
splenic phagocytosis was observed 1n mice treated with dibromochloro-
methane at 12.5 mg/kg/day. Because this study 1s only available in abstract
form and additional more relevant studies are now available, the Munson et
al. (1978) study will not be considered for RQ derivation.
The toxlclty of dlbromochloromethane was discussed in Chapter 6, and the
data useful for RQ derivation are summarized in Table 9-1. The Tobe et al.
(1982) study was not considered adequate for RQ derivation because the study
examined only a few animals per dose group. The data Indicate that oral
exposure to dlbromochloromethane produces liver effects, with fatty livers
being observed In mice at doses >19 mg/kg/day (Borzelleca and Carchman,
1982) and in rats at doses >28.6 mg/kg/day (NTP, 1985). Reduced survival
was also reported in subchronlc studies at doses of 760 mg/kg/day 1n mice
{Borzelleca and Carchman, 1982) and 178.6 mg/kg/day 1n rats (NTP, 1985).
Reproductive effects (reduction 1n liter size, gestation Index and the
percentage of live born pups surviving until day 4) were also observed at
760 mg/kg/day In the Borzelleca and Carchman (1982) study, but because these
effects occurred at a dose that was associated with reduced survival,
reproductive effects are not considered for RQ derivation.
The derivations of CSs for dlbromochloromethane are presented 1n Table
9-2. The lowest equivalent human doses at which liver effects and decreased
survival were observed are 1.4 and 22.4 mg/kg/day, respectively. These
doses correspond to RV s of 3.2 for liver effects and 2.2 for death. The
most appropriate RV for the fatty liver effect Is 5 and the RV for
v 6
0116d
-57-
03/24/89
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03/24/89
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death is 10. Multiplication of the RV.s by the RV s yields CSs of 20
for liver effects and 22 for death. Because the CS for death (22) is the
highest, It is considered the basis for the RQ. The CS of 22, which
corresponds to an RQ of 100, 1s presented in Table 9-3.
9.2. BASED ON CARCINOGENICITY
Epidemiological data Indicate a possible association between trihalo-
methane levels in drinking water and Incidences of various types of cancer
(Crump and Guess, 1982). However, data available for evaluating the
carcinogenic potential of individual trlhalomethanes, including
dibromochloromethane, are Inadequate.
NTP (1985) conducted carcinogenicity bioassays of dibromochloromethane
In mice and rats. No evidence of carcinogenicity was observed in rats.
Because of a dosing error in male mice a number of low-dose males died, and
this group could not be evaluated for tumor Incidence. Hepatocellular
carcinomas were Increased in high-dose male mice. Increased Incidences of
hepatocellular adenomas and carcinomas 1n female mice provided evidence that
dibromochloromethane Is a carcinogen. Based on the positive results in
female mice, inconclusive mutagenlcity studies and discrepancies In observed
data relating structure activity to known carcinogens (chloroform,
bromodlchloromethane), U.S. EPA (1987a) considered dibromochloromethane to
be a Group C carcinogen.
The derivation of an F factor of 0.34 (mg/kg/day)"1 for dibromochloro-
methane Is presented In Table 9-4. This potency factor corresponds to
Potency Group 3. Substances with an EPA classification of C and a Potency
Group of 3 are ranked as a low hazard. The low hazard ranking corresponds
to a carclnogenlcity-based RQ of 100 for dibromochloromethane.
0116d -60- 03/24/89
-------
TABLE 9-3
Dlbromochloromethane
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 9.8 mg/day
Effect: death
Reference: NTP, 1985
RVd: 2.2
RVe: 10
Composite Score: 22
RQ: 100
*Equ1valent human dose
D1164 -61- 03/24/89
-------
TABLE 9-4
Derivation of Potency Factor (F) for Dlbromochloromethane
Reference:
Exposure Route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight:
Duration of treatment:
Duration of study:
Llfespan of animal:
Target organ:
Tumor type:
Experimental dose:
Transformed dose (mg/kg/day)
Tumor Incidence:
Unadjusted 1/E010:
Adjusted 1/ED10 (F factor):
NTP. 1985
oral
mouse
B6C3F1
fema1e
corn oil
0.035 kg (estimated from growth curve)
105 weeks
105 weeks
105 weeks
liver
hepatocellular adenomas and carcinomas
0, 50 or 100 mg/kg, 5 days/week
0, 35.71, 71.43
6/50, 10/49, 19/50
2.72443 (mg/kg/day)"1
0.3432566 (mg/kg/day)'1
0116d
-62-
03/24/89
-------
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traces In air. VII: Bromo- and bromocfiloromethanes In air over the Atlantic
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Cole, R.H., R.E. Frederick, R.P. Healy and R.G. Rolan. 1984. Preliminary
findings of the priority pollutant monitoring project of the Nationwide
Urban Runoff Program. J. Water Pollut. Control Fed. 56: 898-908.
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Substances In Water, L. Keith, Ed. Ann Arbor Science, Ann Arbor, HI.
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0116d -67- 03/24/89
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0116d -68- 03/24/89
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0116d -69- 03/24/89
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Heikes, D.L. 1987. Purge and trap method for determination of volatile
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0116d -70- 03/24/89
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0116d -71- 04/18/89
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Mattke, J.S., S.C. Tsai and M.B. Burch. 1981. ToxIcUy of trIhalomethanes
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0116d -72- 03/24/89
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0116d -73- 03/24/89
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Pelllzzarl, E.D., T.O. Hartwell, B.S.H. Harris, R.O. Waddell, D.A. WhHaker
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water quality changes during groundwater recharge 1n the Palo Alto baylands.
Water Res. 16: 1025-1035.
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0116d -74- 04/18/89
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Ruddick, J.A., D.C. Vllleneuve, I. Chu and V.E. Valll. 1983. A terato-
loglcal assessment of four trlhalomethanes 1n the rat. J. Environ. Scl.
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0116d -75- 03/24/89
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Stanley, J.S. 1986. Broad Scan Analysis of Human Adipose Tissue: Volume 1:
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0116d -76- 03/24/89
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Tobe, M., Y. Suzuki, K. Alda, et al. 1982. Studies on the chronic oral
tox1c1ty of trlbromomethane, dlbromochloromethane and bromodlchloromethane.
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1980. Monitoring of volatile halogenated organlcs: A survey of twelve
drinking waters from various parts of the world. Water Chlorlnatlon:
Environ. Impact Health Eff. 3: 39-53.
U.S. EPA. 1977. Computer print-out of non-confidential production data
from TSCA Inventory. OPTS, CIO, U.S. EPA, Washington, DC.
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Health Effect Assessment Chapters of the Consent Decree Water Criteria
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U.S. EPA. 1980b. Ambient Water Quality Criteria Document for Halo-
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U.S. EPA. 1982a. Errata: Halomethanes. Ambient Water Quality Criterion
for the Protection of Human Health. Prepared by the Office of Health and
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Dllfcd -77- 04/18/89
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U.S. EPA. 1982b. Subpart B - Maximum Contaminant levels. 40 CFR 141.12.
p. 315-316.
U.S. EHA. 1983. Reportable Quantity Document for Chlorodlbromomethane
(Dibromochloromethane). 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. p. 1-3.
U.S. EPA. 1984. Methodology and Guidelines for Ranking Chemicals Based on
Chronic Toxlclty Data. 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. 1985. Health and Environmental Effects Profile for Bromochloro-
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0116d -78- 04/18/89
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U.S. EPA. 1986c. Reference Values for Risk Assessment. Prepared by the
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0116d -79- 04/18/89
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Verschueren, K. 1983. Handbook of Environmental Data on Organic Chemicals,
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1980. Trlhalomethane levels In Canadian drinking water. In: Hydrocarbon
Halo. Hydrocarbon Aquatic Environ., B.K. Afghan and D. Mackay, Ed. Plenum
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0116d -80- 04/18/89
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Wilson, J.T., C.G. Enfleld, H.J. Dunlap, R.L. Cosby, O.A. Foster and L.B.
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Zeiger, E., B. Anderson, S. Haworth, T. Lawlor, K. Hortelmans and W. Speck.
1987. Salmonella mutagenlclty tests: III. Results from the testing of 255
chemicals. Environ. Mutagen. 9(9): 1-4, 12-18, 20, 43.
Zoeteman, B.C.J., E. DeGreef and F.J.J. Brlnkmann. 1981. Persistency of
organic contaminants In groundwater: Lessons from soil pollution Incidents
In The Netherlands. Scl. Total Environ. 21: 187-202.
0116d -81- 04/18/89
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APPENDIX A
LITERATURE SEARCHED
This HEED is based on data identified by computerized literature
searches of the following:
CHEMLINE
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXLIT
TOXLIT 65
RTECS
OHM TAOS
STORET
SRC Environmental Fate Data Bases
SANSS
AQU1RE
TSCAPP
NTIS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
HSDB
These searches were conducted In October 1987, and the following secondary
sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyg1en1sts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyg1en1sts).
1987. TLVs: Threshold Limit Values for Chemical Substances In the
Work Environment adopted by ACGIH with Intended Changes for
1987-1988. Cincinnati, OH. 114 p.
Clayton, G.O. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John Wiley and
Sons, NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 28. John Wiley and
Sons, NY. p. 2879-3816.
Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2C. John Wiley and
Sons, NY. p. 3817-5112.
0116d -82- 03/24/89
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Grayson, M. and D. Eckroth, Ed. 1978-1984. Kirk-Othmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, MA. 575 p.
IARC {International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. IARC, WHO, Lyons, France.
Jaber, H.M., W.R. Mabey, A.T. Lieu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
EPA 600/6-84-010. NTIS PB84-243906. SRI International, Menlo
Park, CA.
NTP (National Toxicology Program). 1987. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Reinhold Co., NY.
SRI (Stanford Research Institute). 1987. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report In the Special Review
Program, Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call 1n Programs.
Office of Pesticide Programs, Washington, DC.
USITC (U.S. International Trade Commission). 1986. Synthetic
Organic Chemicals. U.S. Production and Sales, 1985, USITC Publ.
1892, Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Reinhold Co., NY.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
0116d -83- 03/24/89
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In addition, approximately 30 compendia of aquatic toxldty data were
reviewed, Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson, W.tf. and M.T. Flnley. 1980. Handbook of Acute Toxldty
of Chemicals to Fish and Aquatic Invertebrates. Summaries of
loxldty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, F1sh and Wildlife
Serv. Res. Publ. 137, Washington. DC.
HcKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
0116d -84- 03/24/89
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