United States
kS^laMIjk Environmental Protection
^J^iniiil m11 Agency
EPA/690/R-07/003F
Final
9-20-2007
Provisional Peer Reviewed Toxicity Values for
1 -Bromo-2-chloroethane
(CASRN 107-04-0)
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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Acronyms and Abbreviations
bw	body weight
cc	cubic centimeters
CD	Caesarean Delivered
CERCLA	Comprehensive Environmental Response, Compensation and
Liability Act of 1980
CNS	central nervous system
cu.m	cubic meter
DWEL	Drinking Water Equivalent Level
FEL	frank-effect level
FIFRA	Federal Insecticide, Fungicide, and Rodenticide Act
g	grams
GI	gastrointestinal
HEC	human equivalent concentration
Hgb	hemoglobin
i.m.	intramuscular
i.p.	intraperitoneal
IRIS	Integrated Risk Information System
i.v.	intravenous
IUR	inhalation unit risk
kg	kilogram
L	liter
LEL	lowest-effect level
LOAEL	lowest-observed-adverse-effect level
LOAEL(ADJ)	LOAEL adjusted to continuous exposure duration
LOAEL(HEC)	LOAEL adjusted for dosimetric differences across species to a human
m	meter
MCL	maximum contaminant level
MCLG	maximum contaminant level goal
MF	modifying factor
mg	milligram
mg/kg	milligrams per kilogram
mg/L	milligrams per liter
MRL	minimal risk level
MTD	maximum tolerated dose
MTL	median threshold limit
NAAQS	National Ambient Air Quality Standards
NOAEL	no-ob served-adverse-effect level
NOAEL(ADJ)	NOAEL adjusted to continuous exposure duration
NOAEL(HEC)	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
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PBPK
physiologically based pharmacokinetic
ppb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor
l^g
microgram
[j,mol
micromoles
voc
volatile organic compound
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9-20-2007
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
1-BROMO-2-CHLOROETHANE (CASRN 107-04-0)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude
that a PPRTV cannot be derived based on inadequate data.
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
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It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
l-Bromo-2-chloroethane is not listed in the Integrated Risk Information System (IRIS)
database (U.S. EPA, 2007) or the Health Effects Assessment Summary Tables (HEAST) (U.S.
EPA, 1997). There is no Agency for Toxic Substances and Disease Registry (ATSDR)
Toxicological Profile on l-bromo-2-chloroethane (ATSDR, 2006). Standards or guidelines were
not identified for l-bromo-2-chloroethane from the American Conference of Governmental
Industrial Hygienists (ACGIH, 2001, 2006) or the National Institute for Occupational Safety and
Health (NIOSH, 2006). The Occupational Safety and Health Administration (OSHA) have not
developed a permissible exposure limit (PEL) for l-bromo-2-chloroethane (OSHA, 2006).
Assessments for l-bromo-2-chloroethane are not available from other major toxicological data
sources, including the National Toxicology Program (NTP, 2006), the World Health
Organization (WHO, 2006), or the International Agency for Research on Cancer (IARC, 2006).
Literature searches were performed to identify relevant information for l-bromo-2-
chloroethane, without date limitations, in 2007 in the following databases: TOXLINE,
MEDLINE, CANCERLIT, RTECS, HSDB, TSCATS, CCRIS, GENETOX, EMIC,
EMICBACK, DART, and ETICBACK.
The toxicology of l-bromo-2-chloroethane has not been extensively studied or reported
in the scientific literature. Mutagenicity studies using the Ames test in Salmonella typhimurium
have reported positive results for l-bromo-2-chloroethane in the absence of a metabolic
activation system. Chromosomal aberrations have been reported in in vitro assays using Chinese
hamster lung (CHL) cells in the presence and absence of metabolic activation. Several reports
examining the metabolism of l-bromo-2-chloroethane have found that this compound is
conjugated to glutathione, resulting in the formation of S-(2-hydroxyethyl)glutathione (HEG), S-
(carboxymethyl)glutathione (CMG), S,S'-(l,2-ethanediyl)bis(glutathione) (GEG) and S-(2-
chloroethyl)glutathione (CEG) reactive conjugates. The metabolism of l-bromo-2-chloroethane
2

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9-20-2007
to reactive glutathione conjugates is evidenced by in vitro assays that utilize umuC gene
induction and resulting P-galactosidase activity as indication of DNA damage. In these assays,
Salmonella typhimurium NM5004 has been modified for enhanced expression of glutathione S-
transferase activity (original strain TA1535 with a plasmid expressing rat glutathione S-
transferase 5-5), resulting in increased DNA damage compared to the original strain when treated
with l-bromo-2-chloroethane. Genetic assays for mitotic chromosome malsegregation in the
diploid strain PI of Aspergillus nidulans produced evidence of significantly increased frequency
of abnormal colonies caused by l-bromo-2-chloroethane.
Despite the evidence that l-bromo-2-chloroethane is mutagenic, genotoxic and
aneugenic, no toxicology bioassays in laboratory animals by either oral or inhalation routes of
exposure have been located. Data from toxicology bioassays using subchronic or chronic
exposure protocols are necessary in order to derive provisional toxicity values such as inhalation
reference concentrations, oral reference doses, inhalation unit risk estimates, and oral cancer
slope factors. Therefore, provisional toxicity values cannot be derived for l-bromo-2-
chloroethane based on the reported literature. However, a "screening" level evaluation of the
carcinogenic potency of l-bromo-2-chloroethane is provided in the Appendix, which is based
upon comparative genotoxicity (e.g. mutagenicity) to two closely related dihaloalkane
carcinogens (1,2-dibromoethane and 1,2-dichloroethane). Furthermore, Phase II (conjugative)
metabolism of l-bromo-2-chloroethane is similar to that of both 1,2-dibromoethane and 1,2-
dichloroethane.
The major pathway of l-bromo-2-chloroethane metabolism is via glutathione conjugation
to the formation of S-(2-chloroethyl)glutathione (CEG) and the subsequent elimination of
chloride to form an episulfonium ion. This reactive intermediate has been identified as a major
metabolite involved in the genotoxicity and carcinogenicity of 1,2-dichloroethane (1,2-DCE) and
1,2-dibromoethane (1,2-DBE). 1,2-DCE and 1,2-DBE are classified as a B2 probable human
carcinogen (U.S. EPA, 1986) and as "likely to be carcinogenic to humans" (U.S. EPA, 1999),
respectively, in IRIS (U.S. EPA, 2007). The available toxicity database for 1,2-DBE is
extensive; and appropriately the IRIS file for 1,2-DBE contains a chronic oral RfD of 9E-3
mg/kg-d, inhalation RfC of 9E-3 mg/m3, cancer oral slope factor (OSF) of 2 (mg/kg-d)"1 (95%
upper bound), and cancer inhalation unit risk (IUR) of 6E-4 (|ig/m3)"' (95% upper bound). The
available toxicity database for 1,2-DCE is also extensive however only a cancer OSF of 9.1E-2
(mg/kg-d)"1 and a cancer IUR of 2.6E-5 (|ig/m3)"' are listed on the IRIS database.
REVIEW OF PERTINENT LITERATURE
Human Studies
No studies in humans were available that reported the toxicology of l-bromo-2-
chloroethane.
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9-20-2007
Animal Studies
No subchronic or chronic bioassays in laboratory animals were reported for l-bromo-2-
chloroethane by either oral or inhalation routes of exposure.
Genotoxicity
Mutagenicity of l-bromo-2-chloroethane was reported by Wheeler et al. (2001), Barber
et al. (1981), Brem et al. (1974), and Hughes et al. (1987). Wheeler et al. (2001) transformed
Salmonella typhimurium TA 1535 with recombinant plasmid DNA constructs containing rat or
human theta class glutathione-S-transferases (GST 5-5 or GST Tl, respectively), or a bacterial
dichloromethane dehalogenase (DM11). The transformed Salmonella typhimurium were then
used in a modified Ames assay to evaluate the relative mutation rates of various dihalogenated
alkanes including l-bromo-2-chloroethane. This assay indicated that l-bromo-2-chloroethane
was positive for mutagenicity and that the relative rate of bacterial reversion was related to the
different classes of GST (Wheeler et al., 2001). Barber et al. (1981) used the Ames Salmonella
typhimurium assay both with and without metabolic activation (rat liver S9) to evaluate the
mutagenicity of l-bromo-2-chloroethane. This assay gave positive results in strains TA1535 and
TA100 but negative results in TA98; the addition of rat liver S9 did not have a significant effect.
The authors concluded that l-bromo-2-chloroethane is a direct-acting base-pair mutagen. Brem
et al. (1974) reported that l-bromo-2-chloroethane was positive for mutagenicity in Ames
Salmonella typhimurium strains TA1530 and TA1535 without the addition of a metabolic
activation system. Hughes et al. (1987) reported that l-bromo-2-chloroethane was positive in
strains TA100 and TA102.
Studies of in vitro chromosomal aberrations caused by l-bromo-2-chloroethane were
reported by the Japan Chemical Industry Ecology-Toxicology Information Center (1996). This
study was reported and briefly summarized in the Chemical Carcinogenesis Research
Information System (CCRIS). Chinese hamster lung (CHL) cells were assayed for in vitro
chromosomal aberrations induced by l-bromo-2-chloroethane. The results were positive in the
presence and absence of a metabolic activation system (liver S9 from rats pretreated with sodium
phenobarbital and 5,6-benzoflavone).
Genotoxicity of l-bromo-2-chloroethane using the SOS/umu test system was reported by
Oda et al. (1996) and Shimada et al. (1996). DNA damage in the SOS/umu test system caused
an induction of umuC gene expression, which was measured by cellular P-galactosidase activity
produced by a umuClac Z fusion gene. These researchers constructed a strain of Salmonella
typhimurium for use in the SOS/umu test system that possessed enhanced glutathione S-
transferase (GST) activity by introducing a rat glutathione S-transferase 5-5 cDNA plasmid into
Salmonella typhimurium TA1535 (resulting in strain NM5004). The SOS/umu test strain with
the enhanced GST activity caused a greater induction of P-galactosidase activity in response to 1-
bromo-2-chloroethane treatment than the SOS/umu test strain without enhanced GST. These
results indicated that l-bromo-2-chloroethane mutagenicity was increased in the presence of
GST activity. Therefore, this study suggested that glutathione (GSH) conjugates of l-bromo-2-
chloroethane were DNA-reactive intermediates.
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Van Bladeren et al. (1981) tested the mutagenicity of l-bromo-2-chloroethane in
Salmonella typhimurium TA100 without exogenous metabolic activation, with GSH or with
GSH and 100,000 x g supernatant (SI00) from rat liver. The addition of GSH had little effect on
the mutagenic activity of l-bromo-2-chloroethane. However, the presence of GSH and the 100S
fraction (which contains GST activity) resulted in a considerable increase (~4-fold) in mutagenic
activity. These results confirmed that glutathione conjugation caused the formation of mutagenic
metabolites.
Crebelli et al. (1995) evaluated various halogenated hydrocarbons for chromosome
malsegregation, mitotic arrest and lethality in the mold, Aspergillus nidulans. l-Bromo-2-
chloroethane exhibited a bell-shaped dose-response curve for chromosome malsegregation that
was typical of aneuploidogens, which are able to disturb chromosome distribution in the range of
concentrations where mitotic growth is affected but not arrested.
Mutation induction in the Chinese hamster ovary cell/hypoxanthine-guanine
phosphoribosyl transferase (CHO/HGPRT) system was reported by Tan and Hsie (1981). Tan
and Hsie (1981) reported that l-bromo-2-chloroethane was mutagenic and cytotoxic in this test
system. The presence of an S9 metabolic activation fraction increased cytotoxicity and
mutagenicity. When NADP was omitted from the S9 fraction, these increases were abolished
indicating that cytochrome P450 enzymes were involved in the increased metabolic activation.
Storer and Conolly (1983) assessed hepatic DNA damage in male B6C3F1 mice treated
with l-bromo-2-chloroethane using an alkaline DNA unwinding/hydroxylapatite batch
chromatography method. A single i.p. dose of 0.5 mmol/kg of l-bromo-2-chloroethane or 1,2-
dibromoethane produced similar levels of DNA damage.
Other Studies
Moody et al. (1980) treated male Sprague-Dawley rats with l-bromo-2-chloroethane and
found decreases in cytochrome P450 content of hepatic microsomes to 51% of controls, as well
as alterations in relative content of fatty acids. A high correlation between cytochrome P450 loss
and decreased arachidonic acid, increased linoleic acid, and increased oleic acid was observed.
The metabolism of l-bromo-2-chloroethane was studied by Marchand and Reed (1989),
Jean and Reed (1992), Dekant and Vamvakas (1993), and Guengerich (1994). Marchand and
Reed (1989) evaluated the formation of S-(2-chloroethyl)glutathione (CEG) and other reactive
glutathione conjugates in the bile of male Sprague-Dawley rats treated with l-bromo-2-
chloroethane. These rats were injected i.v. with 0 or 75 mg/kg, and bile was collected from
cannulated bile ducts. CEG was secreted into bile for 3 hours following dosing, with peak
excretion at one hour. The total amount of CEG detected in bile was 2% of the administered
dose. HEG, a CEG hydrolysis product, was also detected. Jean and Reed (1992) investigated
the metabolism of l-bromo-2-chloroethane in freshly isolated rat hepatocytes. l-Bromo-2-
chloroethane was metabolized to S-(2-hydroxyethyl)glutathione (HEG), S-
(carboxymethyl)glutathione (CMG), and S,S'-(l,2-ethanediyl)bis(glutathione) (GEG) conjugates.
HEG was produced in the largest amounts, followed by GEG and CMH. Formation of these
GSH conjugates was concomitant with intracellular GSH depletion, measured as an 84% loss
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9-20-2007
due to l-bromo-2-chloroethane treatment. The addition of extracellular GSH into the incubation
medium increased the formation of GEG conjugates by 179%.
As described previously, l-bromo-2-chloroethane is metabolized to CEG. 1,2-
dichloroethane is also metabolized to CEG, and is classified by U.S. EPA (2007) as a "B2;
probable human carcinogen" according to the 1986 Cancer Guidelines (U.S. EPA, 1986). The
current hypothesis for the carcinogenic mode of action for 1,2-dichloroethane is that CEG forms
an electrophilic episulfonium ion by elimination of chloride (Dekant and Vamvakas, 1993;
Guengerich, 1994). This episulfonium ion is believed to be the ultimate intermediate that is
responsible for binding DNA and inducing genotoxicity (Dekant and Vamvakas, 1993). CEG
reacts with guanosine to form S-[2-(N7-guanyl)ethyl]glutathione, which is a mutagenic DNA
adduct inducing primarily G:C to A:T transitions (Dekant and Vamvakas, 1993). The
corresponding mercapturic acid, S-(2-chloroethyl)-L-cysteine, is a potent mutagen in Salmonella
typhimurium TA100 and also induces high rates of DNA repair in cultured cells (Dekant and
Vamvakas, 1993). Both S-(2-chloroethyl)-L-cysteine and CEG are nephrotoxic metabolites in
rats.
These metabolism experiments confirm that glutathione conjugation is the major pathway
of l-bromo-2-chloroethane metabolism. In addition, studies by van Bladeren et al. (1981), Oda
et al. (1996) and Shimada et al. (1996) corroborate the hypothesis that l-bromo-2-chloroethane
mutagenicity is mediated by reactive glutathione conjugates.
DERIVATION OF PROVISIONAL CHRONIC AND SUBCHRONIC ORAL RfDS AND
INHALATION RfCs FOR l-BROMO-2-CHLOROETHANE
Oral reference doses and inhalation reference concentrations were not derived for 1-
bromo-2-chloroethane due to lack of appropriate information.
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR
l-BROMO-2-CHLOROETHANE
Although the scientific literature provides information on the mutagenicity and
genotoxicity of l-bromo-2-chloroethane, no studies have been conducted to assess its
carcinogenicity. Oral slope factors and inhalation unit risks were not developed due to lack of
appropriate information. However, a "screening" level evaluation of the carcinogenic potency of
l-bromo-2-chloroethane is provided in the Appendix.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2001. Documentation
of the threshold limit values for chemical substances. 7th Edition. Cincinnati, OH.
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ACGIH (American Conference of Governmental Industrial Hygienists). 2006. TLVs® and
BEIs®: Threshold Limit Values for Chemical Substances and Physical Agents, Biological
Exposure Indices. Cincinnati, OH.
ATSDR (Agency for Toxic Substances and Disease Registry). 2006. Toxicological Profile
Information Sheet. Available at http://www.atsdr.cdc.gov/toxpro2.html
Barber, E.D., W.H. Donish and K.R. Mueller. 1981. A procedure for the quantitative
measurement of the mutagenicity of volatile liquids in the ames Salmonella typhimurium
mammalian/microsome assay. Mutat. Res. 90(1):31-48.
Brem, H., A.B. Stein and H.S. Rosenkranz. 1974. The mutagenicity and DNA-modifying effect
of haloalkanes. Cancer Res. 34(10):2576-2579.
Crebelli, R., C. Andreoli, A. Carere et al. 1995. Toxicology of halogenated aliphatic
hydrocarbons: Structural and molecular determinants for the disturbance of chromosome
segregation and the induction of lipid peroxidation. Chemico-Biological Interactions.
98(2): 113-129.
Dekant, W. and S. Vamvakas. 1993. Glutathione-dependent bioactivation of xenobiotics.
Xenobiotica. 23(8):873-887.
Guengerich, F.P. 1994. Metabolism and genotoxicity of dihaloalkanes. In: Anders, M.W. and
W. Dekant, eds. Advances in pharmacology; conjugation-dependent carcinogenicity and toxicity
of foreign compounds. Vol. 27. London, United Kingdom, Academic Press, Inc., p. 211-236.
Hughes, T.J., D.S Simmons, L.G. Monteith et al. 1987. Mutagenicity of 31 organic compounds
in a modified preincubation ames assay with salmonella-typhimurium strains talOO and tal02.
Presented at 18th annual meeting of the Environmental Mutagen Society. April; San Francisco,
CA; Environ. Mutagen. 9(SUPPL. 8):49.
IARC (International Agency for Research on Cancer). 2006. IARC search page. Available at
http ://www.i arc, fr/i ndex. html
Japan Chemical Industry Ecology-Toxicology Information Center. 1996. Mutagenicity test data
of existing chemical substances based on the toxicity investigation of the industrial safety and
health law. Unpublished report, as cited in CCRIS.
Jean, P. A. and D.J. Reed. 1992. Utilization of glutathione during 1,2-dihaloethane metabolism
in rat hepatocytes. Chem. Res. Toxicol. 5(3):386-391.
Marchand, D.H. and D.J. Reed. 1989. Identification of the reactive glutathione conjugate S-(2-
chloroethyl)glutathione in the bile of l-bromo-2-chloroethane-treated rats by high-pressure
liquid chromatography and precolumn derivatization with ortho-phthalaldehyde. Chem. Res.
Toxicol. 2(6):449-454.
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Moody, D.E., J.L. James and E.A. Smuckler. 1980. Cytochrome P-450 lowering effect of alkyl
halides, correlation with decrease in arachidonic acid. Biochem. Biophys. Res. Commun.
97(2):673-679.
NIOSH (National Institute for Occupational Safety and Health). 2006. Online NIOSH Pocket
Guide to Chemical Hazards. Available at http://www.cdc.gov/niosh/npg
NTP (National Toxicology Program). 2006. Management Status Report. Available at
http://ntp-server.niehs.nih.gov/
Oda, Y., H. Yamazaki, R. Thier et al. 1996. A new Salmonella typhimurium NM5004 strain
expressing rat glutathione S-transferase 5-5: use in detection of genotoxicity of dihaloalkanes
using an SOS/umu test system. Carcinogenesis. 17(2):297-302.
OSHA (Occupational Safety and Health Administration). 2006. OSHA Standard 1910.1000
Table Z-l. Part Z, Toxic and Hazardous Substances. Available at
http://www.osha.gov/pls/oshaweb/owadisp.show docuinent'.'p table=STANDARDS&p id=9992
Shimada, T., H. Yamazaki, Y. Oda et al. 1996. Activation and inactivation of carcinogenic
dihaloalkanes and other compounds by glutathione S-transferase 5-5 in Salmonella typhimurium
tester strain NM5004. Chem. Res. Toxicol. 9(l):333-340.
Storer, R.D. and R.B. Conolly. 1983. Comparative in vivo genotoxicity and acute
hepatotoxicity of three 1,2-dihaloethanes. Carcinogenesis. 4(11): 1491-1494.
Tan, E.L. and A.W. Hsie. 1981. Mutagenicity and cytotoxicity of haloethanes as studied in the
CHO hypoxanthine guanine phosphoribosyl transferase system. Mutat. Res. 90(2): 183-192.
U.S. EPA. 1986. Guidelines for Carcinogen Risk Assessment. Federal Register 51(185):33992-
34003. Available at: http://epa.gov/iris/backgr-d.htm
U.S. EPA. (1999) Guidelines for carcinogen risk assessment - review draft. Risk Assessment
Forum. U.S. Environmental Protection Agency. Washington, D.C. http://epa.gov/iris/backgr-
d.htm
U.S. EPA. 1997. Health Effects Assessment Summary Tables. Annual Update. FY-1997.
Office of Research and Development, Office of Emergency and Remedial Response,
Washington, DC. July 1997. EPA/540/R-97/036. NTIS PB97-921199.
U.S. EPA. 2007. Integrated Risk Information System (IRIS). National Center for
Environmental Assessment, Office of Research and Development, Washington, DC. Available
at: http://www.epa.gov/iris
Van Bladeren, P. J., D.D. Breimer, G.T. Rotteveel-Smijs et al. 1981. The relation between the
structure of vicinal dihalogen compounds and their mutagenic activation via conjugation to
glutathione. Carcinogenesis. 2:499-505.
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Wheeler, J.B., N.V. Stourman, R.N. Armstrong and F.P. Guengerich. 2001. Conjugation of
haloalkanes by bacterial and mammalian glutathione transferases: mono- and vicinal
dihalothanes. Chem. Res. Toxicol. 14:1107-1117.
WHO (World Health Organization). 2006. Online Catalogs for the Environmental Criteria
Series. Available at http://www.inchem.org/pages/ehc.html
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APPENDIX
Derivation of a Screening Value for l-Bromo-2-chloroethane (CASRN 107-04-0)
For reasons noted in the main PPRTV document, it is inappropriate to derive provisional
toxicity values directly from the available toxicity database for l-bromo-2-chloroethane.
However, mechanistic and kinetic information are available for this chemical which, although
insufficient to support derivation of provisional toxicity reference values 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 or, in
this specific case, adopts 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. In the OSRTI hierarchy, Screening Values are
considered to be below Tier 3, "Other (Peer-Reviewed) Toxicity Values."
Screening Values are intended for use in limited circumstances when no Tier 1, 2, or 3
values are available. Screening Values may be used, for example, to rank relative risks of
individual chemicals present at a site to determine if the risk developed from the associated
exposure at the specific site is likely to be a significant concern in the overall cleanup decision.
Screening Values are not defensible as the primary drivers in making cleanup decisions because
they are based on limited information. Questions or concerns about the appropriate use of
Screening Values should be directed to the Superfund Health Risk Technical Support Center.
The available toxicity database reveals an absence of animal data for l-bromo-2-
chloroethane. However, available in vitro studies in bacterial or mammalian cell cultures, which
are summarized in the primary section of this PPRTV document, indicate that l-bromo-2-
chloroethane is mutagenic, aneugenic, and genotoxic. Several of these in vitro studies included
evaluation of the closely related dihalogenated alkanes 1,2-dibromoethane (1,2-DBE) and/or 1,2-
dichloroethane (1,2-DCE), in addition to l-bromo-2-chloroethane. As such, the relative
mutagenic, aneugenic, and/or genotoxic activity of l-bromo-2-chloroethane could be directly
compared to 1,2-DBE and 1,2-DCE. Both 1,2-DBE and 1,2-DCE are found on IRIS (U.S. EPA,
2007). The available toxicity database for 1,2-DBE is extensive; and appropriately the IRIS file
for 1,2-DBE contains a chronic oral RfD of 9E-3 mg/kg-d, inhalation RfC of 9E-3 mg/m3, cancer
oral slope factor (OSF) of 2 (mg/kg-d)"1 (95% upper bound), and cancer inhalation unit risk
(IUR) of 6E-4 (|ig/m3)"' (95% upper bound) (U.S. EPA, 2007). The available toxicity database
for 1,2-DCE is also extensive however only a cancer OSF of 9.1E-2 (mg/kg-d)"1 and a cancer
IUR of 2.6E-5 (iig/m3)"1 are listed on the IRIS database (U.S. EPA, 2007). Therefore, while 1-
bromo-2-chloroethane does not have data sufficient for derivation of any provisional toxicity
value, cancer or non-cancer, it may be appropriate to estimate the carcinogenic potential of this
compound somewhere within the range of the closely related compounds 1,2-DBE and 1,2-DCE.
The suitability of this assumption is based upon direct comparisons of the relative genotoxic
activity of 1,2-DBE, 1,2-DCE, and l-bromo-2-chloroethane (Table 1). As illustrated in Table 1,
1,2-DBE consistently has the highest activity for genotoxicity while 1,2-DCE is consistently the
lowest. Importantly, the genotoxic activity of l-bromo-2-chloroethane is consistently, based
upon available data, 5-10 fold greater than 1,2-DCE, but less than half of that of 1,2-DBE (Table
1). Furthermore, as stated in the main body of the PPRTV document, the metabolite profile for
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TABLE 1
Test System
Assay Type
Concentrations
Tested c
(M
Results
utants per plate)
Reference



1,2-1
QBE
l-Br-2-Cl
1,2-1
0CE

-S9
+S9
-S9
+S9
-S9
+S9
S. typhimurium
(TA1535,a 98,
100)
Bacterial reverse
mutation assay b
1,2-DBE: 14.1, 28.2, 56.4, 111.8
nmols/plate;
l-Br-2-Cl: 1.6, 3.0, 4.7, 6.8, 8.1 nmols/plate;
1,2-DCE: 31.8, 63.1, 128.2, 231.8
|imols/platc
2064
2406
973
720
73
75
Barber etal., 1981
S. typhimurium
(TA1530,
1535,a 1538)
Bacterial reverse
mutation assay b
10 |imols/platc
1438
NT
372
NT
54
NT
Bremetal., 1974
S. typhimurium
(TA1535)a
Bacterial reverse
mutation assay b
0-150 nM
(results here are expressed as revertants u\ f'
per plate)
85±6
NT
45±2
NT
7.1±0.3
NT
Wheeler et al.,
2001
Chinese
Hamster Ovary
(CHO) cells
HGPRT mutation
(6-thioguanine
resistance)b
0-4.0 mM 1,2-DBE
0-8.0 mM l-Br-2-Cl
0-60.0 mM 1,2-DCE
167
197
9
33
1
5
TanandHsie, 1981
Male B6C3F1
mice (single
i.p. injection)
in vivo/in vitro
alkaline DNA
unwinding assay
1,2-DBE: 0, 0.25, 0.5 mmol/kg;
l-Br-2-Cl: 0, 0.5, 0.75, 1.0 mmol/kg;
1,2-DCE: 0,1.0, 2.0, 3.0 mmol/kg
11.6 % decrease in
double stranded
DNA at 0.5 dose
level compared to
control
8.9 % decrease in
double stranded
DNA at 0.5 dose
level compared to
control
1.8 % decrease
in double
stranded DNA at
1.0 dose level
compared to
control
Storer and Conolly,
1983
aBolded numbers indicate the specific Salmonella typhimurium strain corresponding to the mutagenic activities presented in the results columns
bRelative mutation frequency of 1,2-dibromoethane (1,2-DBE), l-bromo-2-chloroethane (l-Br-2-Cl), and 1,2-Dichloroethane (1,2-DCE) in the absence (-S9) or
presence (+S9) of metabolic activation (e.g. S100 fraction of rat liver cytosol).
°Bolded numbers indicate the concentration or dose level at which an effect was compared among the three dihaloalkanes.
NT = not tested
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l-bromo-2-chloroethane is similar to 1,2-DBE and 1,2-DCE; of particular interest is that Phase II
metabolism of all three compounds involves formation of an episulfonium ion, which is
suspected of being the primary electrophilic target for DNA adduct formation (i.e. mutagen).
Collectively, the genotoxicity and kinetic data for l-bromo-2-chloroethane suggests this
compound as a potential carcinogen. And, although there are no animal studies available to
evaluate l-bromo-2-chloroethane carcinogenicity directly, ad hoc comparisons of in vitro
genotoxicity data to 1,2-DBE and 1,2-DCE, two known cancer-causing dihalogenated alkanes,
support the assumption that l-bromo-2-chloroethane may also be carcinogenic via the oral and
inhalation route. Considering that the genotoxic activity of l-bromo-2-chloroethane is more
closely related to 1,2-DBE than 1,2-DCE (Table 1), the current IRIS cancer OSF of 2E0
(mg/kg-day)1 and IUR of 6E-4 (jig/m3)"1 (U.S. EPA, 2004) for 1,2-DBE may serve as
conservative (surrogate) estimates of carcinogenicity for l-bromo-2-chloroethane.
Importantly, it should be noted that an estimation of non-cancer toxicity for l-bromo-2-
chloroethane based upon 1,2-DBE or 1,2-DCE data would be inappropriate as there currently
exist no known in vitro or in vivo non-cancer toxicity information for purposes of comparison.
REFERENCES
U.S. EPA. 2007. Integrated Risk Information System (IRIS). National Center for
Environmental Assessment, Office of Research and Development, Washington, DC. Accessed
August 10, 2007. http ://www. epa. gov/iri s
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