United States
kS^laMIjk Environmental Protection
^J^iniiil m11 Agency
EPA/690/R-09/005F
Final
9-10-2009
Provisional Peer-Reviewed Toxicity Values for
Bromochloromethane
(CASRN 74-97-5)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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COMMONLY USED ABBREVIATIONS
BMD
Benchmark Dose
IRIS
Integrated Risk Information System
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELhec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
RfC
inhalation reference concentration
RfD
oral reference dose
UF
uncertainty factor
UFa
animal to human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete to complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL to NOAEL uncertainty factor
UFS
subchronic to chronic uncertainty factor
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
BROMOCHLOROMETHANE (CASRN 74-97-5)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (U.S. EPA) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1)	U.S. EPA's Integrated Risk Information System (IRIS).
2)	Provisional Peer-Reviewed Toxicity Values (PPRTVs) used in U.S. EPA's Superfund
Program.
3)	Other (peer-reviewed) toxicity values, including
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in U.S. EPA's IRIS. PPRTVs are developed according to a
Standard Operating Procedure (SOP) and are derived after a review of the relevant scientific
literature using the same methods, sources of data, and Agency guidance for value derivation
generally used by the U.S. EPA IRIS Program. All provisional toxicity values receive internal
review by two U.S. EPA scientists and external peer review by three independently selected
scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multiprogram consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all U.S. EPA programs, while PPRTVs are developed
specifically for the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a 5-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV documents conclude that
a PPRTV cannot be derived based on inadequate data.
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and Resource Conservation and Recovery Act (RCRA) program offices are advised to
carefully review the information provided in this document to ensure that the PPRTVs used are
appropriate for the types of exposures and circumstances at the Superfund site or RCRA facility
in question. PPRTVs are periodically updated; therefore, users should ensure that the values
contained in the PPRTV are current at the time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV document and understand the strengths
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and limitations of the derived provisional values. PPRTVs are developed by the U.S. EPA
Office of Research and Development's National Center for Environmental Assessment,
Superfund Health Risk Technical Support Center for OSRTI. Other U.S. EPA programs or
external parties who may choose of their own initiative to use these PPRTVs are advised that
Superfund resources will not generally be used to respond to challenges of PPRTVs used in a
context outside of the Superfund Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the U.S. EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
IRIS (U.S. EPA, 2008) does not report an RfD or RfC for bromochloromethane. The
Chemical Assessments and Related Activities (CARA) list (U.S. EPA, 1991, 1994a) includes a
Health and Environmental Effects Profile (HEEP) (U.S. EPA, 1985), a Health and
Environmental Effects Document (HEED) (U.S. EPA, 1990), and a Drinking Water Health
Advisory (DWHA; U.S. EPA, 1989) for bromochloromethane. Although the HEEP
(U.S. EPA, 1985) concluded that data were inadequate to support quantitative risk assessment,
the HEED (U.S. EPA, 1990) subchronic and chronic oral RfD values (1 and 0.1 mg/kg-day,
respectively) were derived by route-to-route extrapolation from inhalation data using a model no
longer recommended for long-term steady-state exposures. The DWHA derived a chronic oral
RfD of 0.01 mg/kg-day from the same inhalation data used by the HEED—but with a UF of
10,000 rather than 1000. The DWHA RfD of 0.01 mg/kg-day is included on the Drinking Water
Standards and Health Advisories list (U.S. EPA, 2006). The Agency for Toxic Substances and
Disease Registry (ATSDR, 2008) has not produced a Toxicological Profile for
bromochloromethane, and no Environmental Health Criteria Document is available from the
World Health Organization (WHO, 2008). The American Conference of Governmental
Industrial Hygienists (ACGIH, 2007) recommends a Threshold Limit Value (TLV) of 200 ppm
for bromochloromethane based on CNS effects. The National Institute of Occupational Safety
and Health (NIOSH) recommended exposure limit (REL) and the Occupational Safety and
Health Administration (OSHA) permissible exposure limit (PEL) are also 200 ppm
(1050 mg/m3) (NIOSH, 2005; OSHA, 2008). On IRIS (U.S. EPA, 2008), bromochloromethane
is assigned to cancer Weight-of-Evidence Group D (not classifiable as to human carcinogenicity)
based on inadequate human and animal data. The source document for this assessment, which
was verified 01/10/1991, is the HEED (U.S. EPA, 1990). The carcinogenicity of
bromochloromethane has not been assessed by the International Agency for Research on Cancer
(IARC, 2008) or the National Toxicology Program (NTP, 2005, 2008).
Literature searches were conducted from the 1960s through December 2007 for studies
relevant to the derivation of provisional toxicity values for bromochloromethane. Databases
searched include MEDLINE, TOXLINE (Special), BIOSIS, TSCATS/TSCATS 2, CCRIS,
DART/ETIC, GENETOX, HSDB, RTECS, and Current Contents. An updated literature search
was conducted using PubMed through November 2008.
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REVIEW OF PERTINENT DATA
Human Studies
Three male firefighters who used bromochloromethane as a fire-extinguishing agent
reported gastrointestinal disturbances (e.g., vomiting, stomach pains) and manifestations of CNS
involvement (e.g., headache, loss of consciousness) (Rutstein, 1963).
Animal Studies
Oral Exposure
No information was located regarding effects of subchronic or chronic oral exposure to
bromochloromethane in laboratory animals.
Inhalation Exposure
Torkelson et al. (1960) exposed groups of 20 male and 20 female rats (strain not
reported) to nominal bromochloromethane concentrations of 0, 500, or 1000 ppm for
7 hours/day, 5 days/week, for 79-82 exposures in 114 days. The actual average concentrations
were 490 ppm (2593 mg/m3) and 1010 ppm (5345 mg/m3). Appearance, activity, body-weight
gain, and survival were evaluated throughout treatment. Gross pathology, relative organ weights
(lungs, heart, liver, kidneys, spleen, and testes), and histopathology (organs that were weighed,
pancreas and adrenals) were evaluated at termination. Hematological evaluations of 10 females
exposed to 0 or 1010 ppm and blood bromide and blood nitrogen (urea nitrogen and nonprotein
nitrogen) determinations of 3 rats/sex from all groups were also conducted at termination.
Although not reported as statistically significant, mean body weight was reduced 10-12% in
both groups of treated male rats relative to controls. At 490 and 1010 ppm, relative liver weight
was increased in males (12.6 and 30.1% higher than controls) and females (14.2 and 36.1%
higher than controls). Other effects attributed to treatment include liver histopathology in
females at 490 ppm (slight bile duct epithelial proliferation, slight portal fibrosis, occasional
vacuolization) and both sexes at 1010 ppm (effects similar to those at 490 ppm, as well as cloudy
swelling and frequent vacuolization), and increased relative kidney weights in both sexes at
1010 ppm. Incidences of liver lesions were not reported. Blood bromide levels were elevated in
both sexes at both exposure concentrations, but the effects typical of bromism (apathy, obesity,
inactivity) were not observed. Based on increased liver weight and liver histopathology, this
study identifies a LOAEL of 490 ppm (2593 mg/m3) and no NOAEL in rats.
Torkelson et al. (1960) also exposed groups of 10 female rats (strain not reported) to
nominal bromochloromethane concentrations of 0 or 400 ppm for 7 hours/day, 5 days/week, for
"3
135 exposures in 195 days. The actual average concentration was 370 ppm (1958 mg/m ).
Air-exposed and unexposed control groups were used. Evaluations of appearance, activity, body
weight, survival, pathology, blood bromide and blood nitrogen were conducted as in the
114-day rat study. Hematological examinations were not performed. The only reported effect
was an increase in relative liver weight (10.4% higher than unexposed controls). This study
establishes a LOAEL of 370 ppm (1958 mg/m3) based on increased relative liver weight and no
NOAEL in rats.
Torkelson et al. (1960) also exposed groups of 10 female mice (strain not reported) to
"3
bromochloromethane at 0, 490, or 1010 ppm (2593 or 5345 mg/m ) for 7 hours/day,
5 days/week, for 79-82 exposures in 114 days. Evaluations of appearance, activity, body
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weight, survival and pathology were conducted as in the 114-day rat study. Blood bromide and
blood nitrogen determinations and hematological examinations were not performed. Decreased
body weight and increased relative liver and kidney weights occurred at exposures >490 ppm.
Final average body weight in the 490- and 1010-ppm female mice was 26.7 and 10.0% less than
controls, respectively. Relative liver weight in the 490- and 1010-ppm female mice was 20.8 and
37.8% higher than controls, respectively. Relative kidney weight was increased 25% relative to
controls in both the 490- and 1010-ppm female mice. No microscopic lesions were observed in
either liver or kidneys. Based on decreased body weight, and increased relative liver and kidney
"3
weights, this study identifies a LOAEL of 490 ppm (2593 mg/m ) and no NOAEL in mice.
Torkelson et al. (1960) also exposed groups of 10 male and 10 female guinea pigs (strain
"3
not reported) to bromochloromethane at 0, 490, or 1010 ppm (2593 or 5345 mg/m ) for
7 hours/day, 5 days/week, for 79-82 exposures in 114 days. Evaluations of appearance, activity,
body weight, survival, and pathology were conducted as in the 114-day rat study. Hematological
examinations were conducted on 3 females from each group. Final body weight was decreased
at 490 and 1010 ppm in males (16.8 and 18.8% less than controls) and females (8.4 and
12.8%) less than controls). Other effects attributed to treatment included increased relative liver
weight in both sexes at >490 ppm, increased relative kidney weight in males at >490 ppm,
increased number of circulating leukocytes (primarily neutrophils; additional details not
reported) in females at >490 ppm, and testicular effects in males at 1010 ppm. The testicular
effects include reduced relative testes weight and histopathological changes consisting of
decreased spermatogenesis in the tubules and fibrosis in numerous tubules with only germinal
epithelium remaining in the other tubules. No microscopic lesions were observed in either liver
or kidneys. Blood bromide levels were elevated in both sexes at both exposure concentrations.
Based on reduced body weight, increased relative liver and kidney weights and neutrophilia, this
"3
study identifies a LOAEL of 490 ppm (2593 mg/m ) and no NOAEL in guinea pigs.
Torkelson et al. (1960) also exposed groups of 2 male and 2 female rabbits (strain not
"3
reported) to bromochloromethane at 0, 490, or 1010 ppm (2593 or 5345 mg/m ) for 7 hours/day,
5 days/week, for 79-82 exposures in 114 days. Evaluations of appearance, activity, body
weight, survival and pathology were conducted as in the 114-day rat study. Blood bromide and
blood nitrogen were determined in all rabbits except one 490-ppm female. Hematological
examinations were not performed. Liver weights appeared to be elevated in both sexes at both
exposure concentrations, but the small number of rabbits precluded definitive analysis. Results
of the blood-nitrogen determinations were not reported. The histological examinations showed
testicular changes (decreased spermatogenesis with replacement fibrosis in the tubules) in one of
the males at 1010 ppm. Blood-bromide levels were elevated in both sexes at both exposure
levels. The small number of animals precludes identification of a NOAEL or LOAEL.
Torkelson et al. (1960) also exposed one male and one female dog (strain not reported) to
bromochloromethane at 0 or 370 ppm (1958 mg/m3) for 7 hours/day, 5 days/week, for
135 exposures in 195 days. Evaluations of appearance, activity, body weight, survival, blood
bromide, blood nitrogen, and hematology were conducted as in the 114-day rat study.
Pathological examinations were not performed. The only reported effect was elevated blood
bromide levels. The small number of animals and lack of histopathology data preclude
identification of a NOAEL or LOAEL.
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MacEwen et al. (1966) exposed groups of 50 male and 50 female albino rats (descendants
of germ-free Wistar rats) to nominal bromochloromethane concentrations of 500 or 1000 ppm
for 6 hours/day, 5 days/week, for a total of 124 exposures conducted over 6 months. Actual
measured concentrations averaged 515 and 1010 ppm (2725 and 5345 mg/m3). There were
50 chamber-air-exposed male rats that served as controls; no female controls were used. Body
weight, survival, and serum bromide levels were evaluated throughout the treatment period.
After 2 and 4 months of exposure, groups of 10 rats in each treatment group and 5 control rats
were subjected to white blood cell count and clinical chemistry determinations and sacrificed for
organ weight and histological examinations. These endpoints were evaluated in the remaining
rats at termination of treatment. The clinical chemistry tests consisted of serum aspartate
aminotransferase (AST or SGOT), alanine aminotransferase (ALT or SGPT), total protein,
albumin, and albumin/globulin (A/G) ratio. It is not specified whether organs other than liver,
kidneys, and spleen were weighed and histologically examined. The only effect observed was
significantly decreased body-weight gain in male rats exposed to concentrations >515 ppm, the
magnitude of which increased with dose and duration of exposure. Final average body weight in
the male rats was 9.5 and 12.8% lower than controls at 515 and 1010 ppm, respectively. Blood
bromide levels were increased at both exposure concentrations throughout the treatment period.
The investigators indicated that similar levels of blood bromide in humans may produce mild
sedation. The investigators also suggested that lethargy (observed during the first few weeks of
the study), altered eating habits, and altered metabolic activity may have been responsible for the
reduction in body-weight gain. Based on reduced body-weight gain, this study identifies a
LOAEL of 515 ppm (2725 mg/m3) and no NOAEL in rats. However, chronic murine pneumonia
was a prominent finding in both treated and control rats and may have had an effect on the
reported findings.
MacEwen et al. (1966) also exposed groups of 4 male and 4 female beagle dogs to
0, 515, or 1010 ppm (2725 and 5345 mg/m3) for 6 hours/day, 5 days/week, for a total of
124 exposures conducted over 6 months. Toxicity was evaluated, as in the rat study, with the
addition of other clinical chemistry tests (serum LDH, sodium, potassium, and calcium).
Evaluations were performed on two treated and one control dog (sex not specified), after 2 and
4 months, and on the remaining dogs at termination of treatment. The only effect attributable to
treatment was increased serum bromide levels at both concentrations. This study identifies a
NOAEL of 1010 ppm (5345 mg/m3) and no LOAEL in dogs.
Svirbely et al. (1947) exposed groups of 20 male rats (strain not reported) to a nominal
bromochloromethane concentration of 1000 ppm for 7 hours/day, 5 days/week, for a total of
67 exposures conducted over 14 weeks. The measured concentration was reported to be
generally 11% lower than the calculated value (i.e., approximately 890 ppm or 4710 mg/m3). An
equal number of unexposed animals served as controls. Body-weight gain and survival were
evaluated throughout the exposure period, and histology and bromide levels in blood and brain
were evaluated at termination of treatment. The investigators do not indicate whether the
histological examinations were performed on tissues other than liver, kidney, and spleen. Effects
consisted of a "slight" increase in hemosiderin in the spleen (additional details not reported) and
increased concentrations of bromide in the blood and brain. Based on hemosiderosis in the
"3
spleen, this study identifies a LOAEL of 890 ppm (4710 mg/m ) in rats. However, confidence in
this LOAEL is low due to poor reporting of results.
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Svirbely et al. (1947) also exposed three male rabbits (strain not reported) to
approximately 890-ppm (4710 mg/m3) bromochloromethane for 7 hours/day, 5 days/week, for a
total of 67 exposures conducted over 14 weeks (Svirbely et al., 1947). An equal number of
unexposed animals served as controls. Toxicity was evaluated as in the rat study with the
addition of hematological examinations at "regular" intervals. Hematological endpoints
consisted ofRBC count, hemoglobin concentration, hematocrit value, reticulocyte count, and
total and differential WBC counts. The only effects attributed to treatment were increased blood
and brain bromide levels. The small number of animals and poor reporting of results precludes
identification of a NOAEL or LOAEL.
Svirbely et al. (1947) also exposed two female dogs (strain not reported) to
"3
approximately 890-ppm (4710 mg/m ) bromochloromethane for 7 hours/day, 5 days/week, for a
total of 67 exposures (Svirbely et al., 1947) conducted over 14 weeks. An equal number of
unexposed animals served as controls. Toxicity was evaluated as in the rats and rabbits with the
addition of liver function evaluation (bromsulfalein excretion) and urinalysis (pH, specific
gravity, sugar, albumin, urobilin, and urobilinogen) at "regular" intervals and blood inorganic
bromide determinations throughout the treatment period. Effects consisted of a "slight" increase
in hemosiderin in the spleen and kidneys, increased fat in the kidneys, and increased bromide
levels in the blood and brain. The small number of animals and poor reporting of results
precludes identification of a NOAEL or LOAEL.
Highman et al. (1948) exposed 100 strain-A mice (sex not reported, age 2 months) and
45 C3H mice (sex not reported, age 3-7 months) to bromochloromethane at 1000 ppm
(5292 mg/m3). Use of a control group is not indicated. Exposures were administered
5 times/week with occasional long rest periods of unspecified frequency and duration when
necessary—as indicated by mortality and abnormal general condition. Surviving strain-A mice
each received a total of 64 exposures of 3-7 hours in a period of approximately 5 months, and
surviving C3H mice each received a total of 49 exposures of 3-7 hours in a period of 4 months.
Most of the mice (numbers not reported) died at unspecified, irregular intervals during
treatment, and some died—or were sacrificed—at unspecified intervals following treatment. A
total of 21 mice (one Strain A and 20 C3H) survived until terminal sacrifice at 13-16 months of
age. Histological examinations were conducted on mice that were sacrificed and some (number
unspecified) that died. The mice that died during exposure generally showed slight fatty changes
in the liver and kidneys. Extensive tubular necrosis of the inner zone of the renal cortex was
observed in two strain-A mice that died during the fourth daily exposure. Several other mice that
died during exposure showed coagulation or karyorrhectic necrosis of a few isolated liver cells.
No treatment-related effects were observed in the mice that survived until terminal sacrifice.
Confidence in this study is low due to the lack of control data, unclear exposure schedule, and
poor reporting of results.
Other Studies
Acute and Short-term Oral Toxicity
Groups of five rats were fed (apparently by gavage) an unspecified range of single doses
of bromochloromethane in corn oil (Torkelson et al., 1960). Observation for 14 days showed
that all rats survived a dose of 5000 mg/kg and all rats died within 24 hours after a dose of
7000 mg/kg. Pathological examinations were not conducted.
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Groups of 10 mice were fed (apparently by gavage) single doses of 500-4400 mg/kg
bromochloromethane in olive oil (Svirbely et al., 1947). The LD50 (6-day observation) was
approximately 4300 mg/kg. Clinical signs showing dose-related CNS depression were observed
at >500 mg/kg, but the lowest dose producing death was not reported. Pathological examinations
were not conducted.
Unspecified numbers of Swiss mice were administered single gavage doses of
0-, 500-, 3000-, or 4000-mg/kg bromochloromethane in olive oil (Highman et al., 1948).
Histological examinations conducted <96 hours after treatment showed no significant changes at
500-mg/kg exposures. Effects occurred at exposures >3000 mg/kg that included death, fatty
degeneration of the liver and kidneys, and focal subcapsular necrosis and hydropic degeneration
of the liver.
A group of 32 Swiss mice was administered 3000-mg/kg-day bromochloromethane in
olive oil by gavage for 1-10 consecutive days (Highman et al., 1948). Several mice were
sacrificed after each of the 10 doses. Histological examination of mice that died or were
sacrificed showed fatty degeneration of the liver, kidneys and sometimes heart. Other hepatic
effects include subcapsular necrosis, hydropic degeneration and an increased number of
mononuclear periportal cells.
Acute and Short-term Inhalation Toxicity
LC50 values ranged from 2268-2995 ppm (12,000-15,850 mg/m3) for mice exposed to
bromochloromethane for 7 hours (Highman et al., 1948; Svirbely et al., 1947). No deaths
"3
occurred in rats exposed to bromochloromethane at 5000 ppm (26,460 mg/m ) for 7 hours,
although exposure to 10,000 ppm (52,920 mg/m3) for 4 hours resulted in 50-60% mortality
(Torkelson et al., 1960). Clinical signs indicative of CNS toxicity were observed in both species;
in mice, these include restlessness, muscular twitching, uncoordinated movements, labored
respiration, and narcosis (Svirbely et al., 1947). In rats, these included drowsiness and
unconsciousness (Torkelson et al., 1960).
"3
Histopathologic changes occurred in the liver of rats exposed to 1500 ppm (7938 mg/m )
for 7 hours, 5000 ppm (26,460 mg/m3) for 7 hours, 10,000 ppm (52,920 mg/m3) for 0.7 hours or
40,000 ppm (211,681 mg/m3) for 0.1 hours (Torkelson et al., 1960). The changes were
characterized as small vacuoles in the parenchyma not typical of fatty degeneration that are often
accompanied by increased liver weight. Mice that were exposed to bromochloromethane at
7-17 mg/L (7000-17,000 mg/m3 or 1323-3212 ppm) for 7 hours/day for 1-5 days had
histological changes that mainly included fatty degeneration in the liver and kidneys
(Highman et al., 1948).
Mutagenicity
A limited amount of information is available on the mutagenicity of
bromochloromethane. Bromochloromethane induced reverse mutations in Salmonella
typhimurium strains TA100 without metabolic activation (Simmon et al., 1977), strains TA100
and TA1535 (but not TA1950) without metabolic activation (Osterman-Golkar et al., 1983), and
strains TA97, TA98, TA100, and TA104 with and without metabolic activation (Strobel and
Grummt, 1987). Bromochloromethane also produced reverse mutations in Escherichia coli
strain WU361089 without metabolic activation, forward mutations in E. coli Sd-4 without
metabolic activation, and lambda prophage induction in E. coli K39 without metabolic activation
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(Osterman-Golkar et al., 1983). In mammalian cells, bromochloromethane induced sister
chromatid exchanges and chromosomal aberrations in cultured Chinese hamster embryonic lung
fibroblasts (Strobel and Grummt, 1987). In vivo genotoxicity studies of bromochloromethane
were not located.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL p-RfD VALUES FOR BROMOCHLOROMETHANE
No relevant subchronic or chronic oral studies of bromochloromethane were located. No
PBPK models suitable for route-to-route extrapolation from the inhalation exposure data were
found. Derivation of oral p-RfD values is not feasible.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION p-RfC VALUES FOR BROMOCHLOROMETHANE
Subchronic inhalation studies of bromochloromethane have been conducted with rats,
mice, guinea pigs, rabbits, and dogs (Highman et al., 1948; MacEwen et al., 1966;
Svirbely et al., 1947; Torkelson et al., 1960). The studies are old and reported incompletely.
Table 1 presents a summary of the available literature. Exposure concentrations ranged from
370-1010 ppm, and exposure durations were 6-7 hours/day, on a 5-days/week regimen, and
ranged from 14 weeks to approximately 6 months. The table includes the human equivalent
concentrations (HECs) calculated for the various studies. As only systemic effects were reported
in the existing studies, the U.S. EPA (1994b) default procedure for calculating a HEC for an
extrarespiratory effect from a vapor is used for all endpoints and studies (see Table 1).
"3
The Torkelson et al. (1960) study establishes a LOAELhec of 540 mg/m in rats, female
mice and guinea pigs based primarily on liver histopathology in rats, and a decrease in
body-weight and increase in kidney weight in the other species. Other studies establish
LOAELhec values of 487 and 981 mg/m3 in rats based on decreased body weight (MacEwen et
al., 1966) and splenic hemosiderosis (Svirbely et al., 1947), respectively. The LOAELhec of
487 mg/m3 in rats (MacEwen et al., 1966) is discounted because of the chronic pneumonia,
unrelated to bromochloromethane exposure, seen in control and treated animals alike. In
addition to the aforementioned studies, Torkelson et al. (1960) also performed a longer
"3
experiment that identified a LOAELhec of 395 mg/m for increased relative liver weight in rats,
which was selected as the POD for the subchronic p-RfD. The data are insufficiently reported
for benchmark concentration analysis.
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Table 1. Summary of Inhalation Noncancer Dose-Response Information
Species
Sex
Exposure
Concentration
(ppm)
Exposure
NOAEL
(mg/m3)
LOAEL
(mg/m3)
NOAELhec3
(mg/m3)
LOAEL|||.;c''
(mg/m3)
Responses
Reference
Subchronic Exposure
Rat
M,F
0, 500, or 1000 (0,
490, 1010 measured;
0, 2593, or 5345
mg/m3)
7hr/d, 5 d/wk, for
79-82 exposures in
114 days
None
2593
None
540
Increased relative liver wt.;
Liver pathology (slight bile
duct epithelial proliferation,
slight portal fibrosis,
occasional vacuolization)
Torkelson et al.,
1960
Rat
F
0, 370 (0,
1958 mg/m3)
7 hr/d, 5 d/wk, for
135 exposures in
195 days
None
1958
None
395
Increased relative liver wt
Torkelson et al.,
1960
Rat
M,F
0,515, and 1010
(0, 2725, and
5345 mg/m3)
6 hr/d, 5 d/wk, for
6 months
None
2725
None
487
Reduced body-weight gain;
Chronic murine pneumonia
was a prominent finding in
both treated and control rats
MacEwen et al.,
1966
Rat
M
0 or 890 (0 or
4710 mg/m3)
7 hr/d, 5 d/wk, for
14 weeks for a total
of 67 exposures
None
4710
None
981
Hemosiderosis in the spleen
Svirbely et al.,
1947
Mouse
F
0, 490, or 1010 (0,
2593, or
5345 mg/m3)
7 h/d, 5 d/wk, for
79-82 exposures in
114 days
None
2593
None
540
Decreased body weight and
increased kidney weights
Torkelson et al.,
1960
Mouse
NRb
1000 (5292 mg/m3)
Unclear and poorly
reported
Cannot determine effect levels due to poorly reported experimental design, including
use of controls, exposure regiment and results
Highman et al.,
1948
Guinea
Pig
M,F
0, 490, or 1010 (0,
2593. or
5345 mg/m3)
7 h/d, 5 d/wk, for
79-82 exposures in
114 days
None
2593
None
540
Reduced body weight,
increased kidney weights and
neutrophilia
Torkelson et al.,
1960
Rabbit
M,F
0, 490, or 1010 (0,
2593, or
5345 mg/m3)
7 h/d, 5 d/wk, for
79-82 exposures in
114 days
Small numbers of animals preclude reliable determination of effect levels
Torkelson et al.,
1960
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Table 1. Summary of Inhalation Noncancer Dose-Response Information
Species
Sex
Exposure
Concentration
(ppm)
Exposure
NOAEL
(mg/m3)
LOAEL
(mg/m3)
NOAELhec3
(mg/m3)
LO A E L| 11.( ¦
(mg/m3)
Responses
Reference
Rabbit
M
0 or 890 (0 or
4710 mg/m3)
7 hours/day,
5 days/week for
14 weeks for a total
of 67 exposures
Small numbers of animals and poor reporting preclude reliable determination of effect
levels
Svirbely et al.,
1947
Dog
M,F
0, 370 (0,
1958 mg/m3)
7 hr/d, 5 d/wk for
135 exposures in
195 days
Small numbers of animals and lack of histopathology preclude reliable determination
of effect levels
Torkelson et al.,
1960
Dog
M,F
0,515, and 1010
(0, 2725, and
5345 mg/m3)
6 hours/day,
5	days/week for
6	months
5345
None
954
None
None
MacEwen et al.,
1966
Dog
F
0 or 890 (0 or
4710 mg/m3)
7 hours/day,
5 days/week for
14 weeks for a total
of 67 exposures
Small numbers of animals and poor reporting preclude reliable determination of effect
levels
Svirbely et al.,
1947
aExposure concentration adjusted to human equivalent concentration (HEC) based on exposure regimen (number of hours/day and days/week) and U.S. EPA (1994b)
methodology for extrarespiratory effects of a vapor:
NOAELadj = NOAEL x (hours exposure per day/24)(days exposure per week/7)
NOAELhec = NOAELadj x (Hb/g)A/(Hb/g)H
where (Hb/g)A/(Hb/g)H = rat-to-human blood:air partition coefficient ratio. A default ratio of 1 is used because a Hb/g value for
bromochloromethane was located for rats (41.5 [Gargas et al., 1986]), but not for humans
bNR = Not Reported
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Subchronic p-RfC
The LOAELhec of 395 mg/m3 for increased relative liver weight in rats
(Torkelson et al., 1960) was used to derive the subchronic p-RfC.
Subchronic p-RfC = LOAELhec UF
= 395 mg/m3 - 3000
= 0.1 or 1 x 10"1 mg/m3
The composite Uncertainty Factor (UF) is derived as follows:
•	A partial UFA of 3 was applied for interspecies extrapolation; this includes a factor of
1 for species differences in pharmacokinetic considerations (because a dosimetric
adjustment was used) and a factor of 3 for pharmacodynamic considerations.
•	A full UFh of 10 for extrapolation to sensitive humans was used to account for
potentially susceptible individuals in the absence of information on the variability of
response in humans.
•	A full UFd of 10 was used to account for database uncertainty; the database consists of
several old, poorly reported subchronic studies. The database lacks developmental and
reproductive toxicity studies.
•	A full UFl of 10 was applied to account for the use of a LOAEL as the point of
departure.
Confidence in the principal study is low. The study is old and incompletely reported. A
NOAEL is not identified. Confidence in the database is low because all of the subchronic
studies are very old and there are no developmental or reproductive toxicity data. Low
confidence in the subchronic p-RfC results.
Chronic p-RfC
Chronic toxicity testing of bromochloromethane has not been conducted and large
composite UF (3000) used in the derivation of the subchronic p-RfC precludes its use as the
basis for derivation of a chronic p-RfC. Therefore, derivation of a provisional chronic RfC is not
feasible. However, Appendix A presents a screening chronic p-RfC.
PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR BROMOCHLOROMETHANE
Weight-of-Evidence Descriptor
There are no human or animal carcinogenicity data for bromochloromethane. A limited
amount of in vitro genotoxicity data are available indicating that bromochloromethane is
mutagenic. Bromochloromethane induced mutations in S. typhimurium and E. coli
(Osterman-Golkar et al., 1983; Simmon et al., 1977; Strobel and Grummt, 1987), as well as sister
chromatid exchanges and chromosomal aberrations in Chinese hamster embryonic lung
fibroblasts (Strobel and Grummt, 1987). In accordance with current U.S. EPA cancer guidelines,
there is "Inadequate Information to Assess Carcinogenic Potential' in humans
(U.S. EPA, 2005).
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Quantitative Estimates of Carcinogenic Risk
Due to the lack of adequate data, it is neither possible nor appropriate to derive
quantitative estimates of carcinogenic risk for bromochloromethane for either oral (p-OSF) or
inhalation (p-IUR) exposures.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2007. 2007 Threshold
Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices.
ACGIH, Cincinnati, OH.
ATSDR (Agency for Toxic Substances and Disease Registry). 2008. Toxicological Profile
Information Sheet. U.S. Department of Health and Human Services, Public Health Service.
Online, http://www.atsdr.cdc.gov/toxpro2.html.
Gargas, M.L., H.J. Clewell and M.E. Andersen. 1986. Metabolism of inhaled dihalomethanes in
vivo: Differentiation of kinetic constants for two independent pathways. Toxicol. Appl.
Pharmacol. 82:211-223.
Highman, B., J.L. Svirbely, W.F. von Oettingen et al. 1948. Pathologic changes produced by
monochloromonobromomethane. Am. Med. Assoc. Arch. Pathol. 45:299-305.
IARC (International Agency for Research on Cancer). 2008. Search IARC Monographs.
Online. http://monoeraphs.iarc.fr/ENG/Monoeraphs/allmonos90.php.
MacEwen, J.D., J.M. McNerney, E.H. Vernot et al. 1966. Chronic inhalation toxicity of
chlorobromomethane. J. Occup. Med. 8:251-256.
NIOSH (National Institute for Occupational Safety and Health). 2005. NIOSH Pocket Guide to
Chemical Hazards. Index by CASRN. Online, http://www2.cdc.gov/nioshtic-2/nioshtic2.htm.
NTP (National Toxicology Program). 2005. 11th Report on Carcinogens. U.S. Department of
Health and Human Services, Public Health Service, National Institutes of Health, Research
Triangle Park, NC. Online, http://ntp-server.niehs.nih.eov.
NTP (National Toxicology Program). 2008. Management Status Report. Online.
http://ntp.niehs.nih.eov/index.cfm?obi ectid=78CC7E4C-F 1F6-975E-72940974DE301C3F.
OSHA (Occupational Safety and Health Administration). 2008. OSHA Standard 1910.1000
Table Z-l. Part Z, Toxic and Hazardous Substances. Online, http://www.osha-
slc.eov/OshStd data/1910 1000 TABLE Z-l.html.
Osterman-Golkar, S., S. Hussain, S. Walles et al. 1983. Chemical reactivity and mutagenicity of
some dihalomethanes. Chem. Biol. Interact. 46:121-130.
Rutstein, H.R. 1963. Acute chlorobromomethane toxicity. Arch. Environ. Health. 7:440-444.
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Simmon, V.F., K. Kauhanen and R.G. Tardiff. 1977. Mutagenic activity of chemicals identified
in drinking water. Dev. Toxicol. Environ. Sci. 2:249-258.
Strobel, K. and T. Grummt. 1987. Aliphatic and aromatic halocarbons as potential mutagens in
drinking water. Parti. Halogenated methanes. Toxicol. Environ. Chem. 13:205-221.
Svirbely, J.L., B. Highman, W.C. Alford et al. 1947. The toxicity and narcotic action of
mono-chloro-mono-bromo-methane with special reference to inorganic and volatile bromide in
blood, urine and brain. J. Ind. Hyg. Toxicol. 29:382-389.
Torkelson, T.R., F. Oyen and V.K. Rowe. 1960. The toxicity of bromochloromethane
(methylene chlorobromide) as determined on laboratory animals. Am. Ind. Hyg. Assoc. J.
21:275-286.
U.S. EPA (U.S. Environmental Protection Agency). 1985. Health and Environmental Effects
Profile for Bromochloromethanes. Prepared by the Environmental Criteria and Assessment
Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington,
DC.
U.S. EPA (U.S. Environmental Protection Agency). 1989. Drinking Water Health Advisory for
Bromochloromethane. Prepared by the Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Water, Washington, DC.
U.S. EPA (U.S. Environmental Protection Agency). 1990. Health and Environmental Effects
Document for Bromochloromethane. Prepared by the Environmental Criteria and Assessment
Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington,
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U.S. EPA (U.S. Environmental Protection Agency). 1991. Chemical Assessments and Related
Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. April.
U.S. EPA (U.S. Environmental Protection Agency). 1994a. Chemical Assessments and Related
Activities (CARA). Office of Health and Environmental Assessment, Washington, DC.
December.
U.S. EPA (U.S. Environmental Protection Agency). 1994b. Methods for Derivation of
Inhalation Reference Concentrations and Application of Inhalation Dosimetry. Office of
Research and Development, Washington, DC. EPA/600/8-90/066F.
U.S. EPA (U.S. Environmental Protection Agency). Guidelines for Carcinogen Risk Assessment
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Carcinogens. Risk Assessment Forum, Washington, DC. EPA/630/P-03/001F. Online.
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U.S. EPA (U.S. Environmental Protection Agency). 2008. Integrated Risk Information System
(IRIS). Online. Office of Research and Development, National Center for Environmental
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APPENDIX A. DERIVATION OF A SCREENING VALUE FOR
BROMOCHLOROMETHANE
For reasons noted in the main PPRTV document, it is inappropriate to derive a
provisional chronic inhalation toxicity values for bromochloromethane. However, information is
available for this chemical, which, although insufficient to support derivation of a provisional
chronic inhalation toxicity value, under current guidelines, may be of limited use to risk
assessors. In such cases, the Superfund Health Risk Technical Support Center summarizes
available information in an Appendix and develops a "Screening value." Appendices receive the
same level of internal and external scientific peer review as the PPRTV documents to ensure
their appropriateness within the limitations detailed in the document. Users of screening toxicity
values in an appendix to a PPRTV assessment should understand that there is considerably more
uncertainty associated with the derivation of an appendix screening toxicity value than for a
PPRTV presented in the body of the assessment. Questions or concerns about the appropriate
use of screening values should be directed to the Superfund Health Risk Technical Support
Center.
-2
A screening chronic p-RfC value of 0.04 mg/m can be derived from the subchronic
LOAELhec of 395 mg/m3 for increased relative liver weights in rats (Torkelson et al., 1960) by
dividing by a composite UF of 10,000. The composite UF consists of four full areas of
uncertainty (UFH, UFl, UFd, UFs) and a factor of 3 for UFA, reduced by convention for use of a
dosimetric inhalation exposure adjustment. The composite UF is 30,000 using standard risk
assessment methodologies (10 ><3 x 10 x 10 x 10 = 30,000); however, the composite UF has
been limited to 10,000 due to significant uncertainty.
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