S-EPA
United States
Environmental Protection
Agency
EPA/690/R-21/005F | August 2021 | FINAL
Provisional Peer-Reviewed Toxicity Values for
l-Bromo-2-Chloroethane
(CASRN 107-04-0)
U.S. EPA Office of Research and Development
Center for Public Health and Environmental Assessment
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A United States
Environmental Protection
%#UI JTT,Agency
EPA/690/R-21/005F
August 2021
https://www.epa.gov/pprtv
Provisional Peer-Reviewed Toxicity Values for
1 -Bromo-2-Chloroethane
(CASRN 107-04-0)
Center for Public Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Jeffry L. Dean II, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
CONTRIBUTOR
Laura M. Carlson, PhD
Center for Public Health and Environmental Assessment, Research Triangle Park, NC
Roman Mezencev, PhD
Center for Public Health and Environmental Assessment, Washington, DC
SCIENTIFIC TECHNICAL LEAD
Jeffry L. Dean II, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
J. Phillip Kaiser, PhD, DABT
Center for Public Health and Environmental Assessment, Cincinnati, OH
Q. Jay Zhao, PhD, MPH, DABT
Center for Public Health and Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
Andrew Kraft, PhD
Center for Public Health and Environmental Assessment, Washington, DC
Paul G. Reinhart, PhD, DABT
Center for Public Health and Environmental Assessment, Research Triangle Park, NC
PRIMARY EXTERNAL REVIEWERS
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
li
1 -Bromo-2-chloroethane
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PPRTV PROGRAM MANAGEMENT
Teresa L. Shannon
Center for Public Health and Environmental Assessment, Cincinnati, OH
J. Phillip Kaiser, PhD, DABT
Center for Public Health and Environmental Assessment, Cincinnati, OH
Questions regarding the content of this PPRTV assessment should be directed to the U.S. EPA
Office of Research and Development (ORD) Center for Public Health and Environmental
Assessment (CPHEA) website at https://ecomments.epa.gov/pprtv.
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1 -Bromo-2-chloroethane
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS v
BACKGROUND 1
QUALITY ASSURANCE 1
DISCLAIMERS 1
QUESTIONS REGARDING PPRTVs 2
1. INTRODUCTION 3
2. REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER) 7
2.1. HUMAN STUDIES 10
2.1.1. Oral Exposures 10
2.1.2. Inhalation Exposures 10
2.2. ANIMAL STUDIES 10
2.2.1. Inhalation Exposures 10
2.2.2. Oral Exposures 10
2.3. OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 10
2.3.1. Acute Toxicity in Animals 10
2.3.2. Genotoxicity 11
2.3.3. Absorption, Distribution, Metabolism, and Excretion Studies 17
3. DERIVATION OI PROVISIONAL VALUES 18
3.1. DERIVATION OF PROVISIONAL REFERENCE DOSES 18
3.2. DERIVATION OF PROVISIONAL REFERENCE CONCENTRATIONS 18
3.3. SUMMARY OF NONCANCER PROVISIONAL REFERENCE VALUES 18
3.4. CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR 19
3.5. DERIVATION OF PROVISIONAL CANCER RISK ESTIMATES 20
APPENDIX A. SCREENING NONCANCER PROVISIONAL VALUES 21
APPENDIX B. BACKGROUND AND METHODOLOGY FOR THE SCREENING
EVALUATION OF POTENTIAL CARCINOGENICITY 54
APPENDIX C. RESULTS OF THE SCREENING EVALUATION OF POTENTIAL
CARCINOGENICITY 63
APPENDIX D. REFERENCES 91
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COMMONLY USED ABBREVIATIONS AND ACRONYMS
a2u-g
alpha 2u-globulin
LD50
median lethal dose
ACGIH
American Conference of Governmental
LOAEL
lowest-observed-adverse-effect level
Industrial Hygienists
MN
micronuclei
AIC
Akaike's information criterion
MNPCE
micronucleated polychromatic
ALD
approximate lethal dosage
erythrocyte
ALT
alanine aminotransferase
MOA
mode of action
AR
androgen receptor
MTD
maximum tolerated dose
AST
aspartate aminotransferase
NAG
7V-acetyl-P-D-glucosaminidase
atm
atmosphere
NCI
National Cancer Institute
ATSDR
Agency for Toxic Substances and
NO A F.I.
no-observed-adverse-effect level
Disease Registry
NTP
National Toxicology Program
BMD
benchmark dose
NZW
New Zealand White (rabbit breed)
BMDL
benchmark dose lower confidence limit
OCT
ornithine carbamoyl transferase
BMDS
Benchmark Dose Software
ORD
Office of Research and Development
BMR
benchmark response
PBPK
physiologically based pharmacokinetic
BUN
blood urea nitrogen
PCNA
proliferating cell nuclear antigen
BW
body weight
PND
postnatal day
CA
chromosomal aberration
POD
point of departure
CAS
Chemical Abstracts Service
PODadj
duration-adjusted POD
CASRN
Chemical Abstracts Service registry
QSAR
quantitative structure-activity
number
relationship
CBI
covalent binding index
RBC
red blood cell
CHO
Chinese hamster ovary (cell line cells)
RDS
replicative DNA synthesis
CL
confidence limit
RfC
inhalation reference concentration
CNS
central nervous system
RfD
oral reference dose
CPHEA
Center for Public Health and
RGDR
regional gas dose ratio
Environmental Assessment
RNA
ribonucleic acid
CPN
chronic progressive nephropathy
SAR
structure-activity relationship
CYP450
cytochrome P450
SCE
sister chromatid exchange
DAF
dosimetric adjustment factor
SD
standard deviation
DEN
diethylnitrosamine
SDH
sorbitol dehydrogenase
DMSO
dimethylsulfoxide
SE
standard error
DNA
deoxyribonucleic acid
SGOT
serum glutamic oxaloacetic
EPA
Environmental Protection Agency
transaminase, also known as AST
ER
estrogen receptor
SGPT
serum glutamic pyruvic transaminase,
FDA
Food and Drug Administration
also known as ALT
FEVi
forced expiratory volume of 1 second
SSD
systemic scleroderma
GD
gestation day
TCA
trichloroacetic acid
GDH
glutamate dehydrogenase
TCE
trichloroethylene
GGT
y-glutamyl transferase
TWA
time-weighted average
GSH
glutathione
UF
uncertainty factor
GST
glutathione-S'-transfcrase
UFa
interspecies uncertainty factor
Hb/g-A
animal blood-gas partition coefficient
UFC
composite uncertainty factor
Hb/g-H
human blood-gas partition coefficient
UFd
database uncertainty factor
HEC
human equivalent concentration
UFh
intraspecies uncertainty factor
HED
human equivalent dose
UFl
LOAEL-to-NOAEL uncertainty factor
i.p.
intraperitoneal
UFS
subchronic-to-chronic uncertainty factor
IRIS
Integrated Risk Information System
U.S.
United States of America
IVF
in vitro fertilization
WBC
white blood cell
LC50
median lethal concentration
Abbreviations and acronyms not listed on this page are defined upon first use in the
PPRTV document.
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1 -Bromo-2-chloroethane
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DRAFT PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
l-BROMO-2-CHLOROETHANE (CASRN 107-04-0)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant
scientific literature using established U.S. Environmental Protection Agency (U.S. EPA)
guidance on human health toxicity value derivations.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
Currently available PPRTV assessments can be accessed on the U.S. EPA's PPRTV
website at https://www.epa.gov/pprtv. PPRTV assessments are eligible to be updated on a 5-year
cycle and revised as appropriate to incorporate new data or methodologies that might impact the
toxicity values or affect the characterization of the chemical's potential for causing adverse
human-health effects. Questions regarding nomination of chemicals for update can be sent to the
appropriate U.S. EPA Superfund and Technology Liaison (https://www.epa.gov/research/fact-
sliects-regional-science).
QUALITY ASSURANCE
This work was conducted under the U.S. EPA Quality Assurance (QA) program to ensure
data are of known and acceptable quality to support their intended use. Surveillance of the work
by the assessment managers and programmatic scientific leads ensured adherence to QA
processes and criteria, as well as quick and effective resolution of any problems. The QA
manager, assessment managers, and programmatic scientific leads have determined under the
QA program that this work meets all U.S. EPA quality requirements. This PPRTV was written
with guidance from the CPHEA Program Quality Assurance Project Plan (PQAPP), the QAPP
titled Program Quality Assurance Project Plan (PQAPP) for the Provisional Peer-Reviewed
Toxicity Values (PPRTVs) and Related Assessments/Documents (L-CPAD-0032718-QP), and the
PPRTV development contractor QAPP titled Quality Assurance Project Plan—Preparation of
Provisional Toxicity Value (PTV) Documents (L-CPAD-0031971-QP). As part of the QA
system, a quality product review is done prior to management clearance. A Technical Systems
Audit may be performed at the discretion of the QA staff.
All PPRTV assessments receive internal peer review by at least two CPHEA scientists
and an independent external peer review by at least three scientific experts. The reviews focus on
whether all studies have been correctly selected, interpreted, and adequately described for the
purposes of deriving a provisional reference value. The reviews also cover quantitative and
qualitative aspects of the provisional value development and address whether uncertainties
associated with the assessment have been adequately characterized.
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
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limitations of the data. All users are advised to review the information provided in this document
to ensure that the PPRTV used is appropriate for the types of exposures and circumstances at the
site in question and the risk management decision that would be supported by the risk
assessment.
Other U.S. EPA programs or external parties who may choose to use PPRTVs are
advised that Superfund resources will not generally be used to respond to challenges, if any, of
PPRTVs used in a context outside of the Superfund program.
This document has been reviewed in accordance with U.S. EPA policy and approved for
publication. Mention of trade names or commercial products does not constitute endorsement or
recommendation for use.
QUESTIONS REGARDING PPRTVs
Questions regarding the content of this PPRTV assessment should be directed to the
U.S. EPA ORD CPHEA website at https://ecomments.epa.gov/pprtv.
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1. INTRODUCTION
l-Bromo-2-chloroethane (CASRN 107-04-0) belongs to the class of compounds known
as halogenated alkanes. l-Bromo-2-chloroethane currently has no commercial uses, but small
amounts may be imported and used for research and development (U.S. EPA. 2015b). It is listed
under the U.S. Environmental Protection Agency (U.S. EPA) Toxic Substances Control Act
(TSCA) Significant New Use Rule (SNUR), which requires notification of the U.S. EPA prior to
manufacturing, importing, or processing of a chemical substance for a significant new use
(e.g., commercial purpose) (U.S. HP A. 2015c). Former uses of 1 -bromo-2-chloroethane include
as a solvent for cellulose esters and ethers, in organic synthesis, and as a fumigant for fruits and
vegetables (Lewis and Hawlev. 2007). l-Bromo-2-chloroethane is listed on TSCA's public
inventory (U.S. HP A. 2015a). but it is not registered with Europe's Registration, Evaluation,
Authorisation and Restriction of Chemicals (REACH) program (ECHA. 2015).
l-Bromo-2-chloroethane can be produced by the reaction of bromine and chlorine on
ethylene gas (Lewis and Hawlev. 2007). However, it is no longer produced in the United States
because of potential carcinogenic activity based on its in vitro mutagenicity and the
carcinogenicity of the structurally similar chemicals 1,2-dibromoethane and 1,2-dichloroethane
(U.S. HP A. 2015b).
The empirical formula for l-bromo-2-chloroethane is C2H4BrCl, and its structure is
shown in Figure 1. Table 1 summarizes its physicochemical properties. l-Bromo-2-chloroethane
is a clear, colorless liquid with a sweet chloroform-like odor at room temperature (NOAA.
2015). Its high vapor pressure indicates that it will exist solely as a vapor in the atmosphere.
Given its vapor pressure and moderate estimated Henry's law constant, it is likely to volatilize
from either dry or moist soil surfaces and from water surfaces. The high water solubility and low
soil adsorption coefficient indicate that it will have the potential to leach to groundwater or
undergo runoff after a rain event. However, volatilization to the atmosphere is expected to be the
main transport pathway. Estimated hydrolysis half-lives of 3 and 32 years at pH 8 and 7,
respectively, indicate that hydrolysis is not likely to be an important fate process.
Br
Figure 1. l-Bromo-2-Chloroethane (CASRN 107-04-0) Structure
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Table 1. Physicochemical Properties of l-Bromo-2-Chloroethane (CASRN 107-04-0)
Property (unit)
Value
Physical state
Liquid
Boiling point (°C)
107a
Melting point (°C)
-16.33
Density (g/cm3)
1.63 (predicted average)3
Vapor pressure (mm Hg at 20°C)
33.13
pH (unitless)
NA
pKa (unitless)
NA
Solubility in water (mol/L)
4.79 x 10-2 a
Octanol-water partition coefficient (log Kow)
1.86 (predicted average)3
Henry's law constant (atm-m3/mol at 25°C)
9.09 x l0-4a
Soil adsorption coefficient Koc (L/kg)
55.1 (predicted average)3
Atmospheric OH rate constant (cm3/molecule-sec at 25°C)
3.22 x 10 13 (predicted average)3
Atmospheric half-life (days)
42 (estimated)0
Relative vapor density (air = 1)
4.94b
Molecular weight (g/mol)
1433
Flash point (closed cup, °C)
NA
aU.S. EPA CompTox Chemicals Dashboard (as of June 2021;
https://comptox.epa.gOv/dashboard/dsstoxdb/results7searcliFDTXSID4024775#properties).
bNOAA (2015).
CU.S. EPA (2012).
NA = not applicable.
No toxicity values are available for l-bromo-2-chloroethane from U.S. EPA or other
agencies/organizations (see Table 2).
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Table 2. Summary of Available Toxicity Values for l-Bromo-2-Chloroethane
(CASRN 107-04-0)
Source3
Value
Notes
Referenceb
Noncancer
IRIS
NV
NA
U.S. EPA (2020c)
HEAST
NV
NA
U.S. EPA (201 lb)
DWSHA
NV
NA
U.S. EPA (2018)
ATSDR
NV
NA
ATSDR (2018)
IPCS
NV
NA
IPCS (2020)
CalFPA
NV
NA
CalEPA (2019)
OSHA
NV
NA
OSHA (2020a): OSHA (2020b)
NIOSH
NV
NA
NIOSH (2018)
ACGIH
NV
NA
ACGIH (2020)
HEEP
NV
NA
U.S. EPA (1985)
Cancer
IRIS
NV
NA
U.S. EPA (2020c)
HEAST
NV
NA
U.S. EPA (2011b)
DWSHA
NV
NA
U.S. EPA (2018)
NTP
NV
NA
NTP (2016a)
IARC
NV
NA
IARC (2018)
CalEPA
NV
NA
CalEPA (2019)
ACGIH
NV
NA
ACGIH (2020)
aSources: ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic
Substances and Disease Registry; CalEPA = California Environmental Protection Agency; DWSHA = Drinking
Water Standards and Health Advisories; HEAST = Health Effects Assessment Summary Tables; HEEP = Health
and Environmental Effects Profile; IARC = International Agency for Research on Cancer; IPCS = International
Programme on Chemical Safety; IRIS = Integrated Risk Information System; NIOSH = National Institute for
Occupational Safety and Health; NTP = National Toxicology Program; OSHA = Occupational Safety and Health
Administration.
bReference date is the publication date for the database and not the date the source was accessed.
NA = not applicable; NY = not available.
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Non-date-limited literature searches were conducted in November 2017 and updated in
May 2021, for studies relevant to the derivation of provisional toxicity values for
l-bromo-2-chloroethane (CASRN 107-04-0). Searches were conducted using U.S. EPA's Health
and Environmental Research Online (HERO) database of scientific literature. HERO searches
the following databases: PubMed, TOXLINE1 (including TSCATS1), and Web of Science. The
following resources were searched outside of HERO for health-related values: American
Conference of Governmental Industrial Hygienists (ACGIH), Agency for Toxic Substances and
Disease Registry (ATSDR), California Environmental Protection Agency (CalEPA), Defense
Technical Information Center (DTIC), European Centre for Ecotoxicology and Toxicology of
Chemicals (ECETOC), European Chemicals Agency (ECHA), U.S. EPA Chemical Data Access
Tool (CDAT), U.S. EPA ChemView, U.S. EPA Integrated Risk Information System (IRIS),
U.S. EPA Health Effects Assessment Summary Tables (HEAST), U.S. EPA Office of Water
(OW), International Agency for Research on Cancer (IARC), U.S. EPA TSCATS2/TSCATS8e,
U.S. EPA High Production Volume (HPV), Chemicals via IPCS INCHEM, Japan Existing
Chemical Data Base (JECDB), Organisation for Economic Cooperation and Development
(OECD) Screening Information Data Sets (SIDS), OECD International Uniform Chemical
Information Database (IUCLID), OECD HPV, National Institute for Occupational Safety and
Health (NIOSH), National Toxicology Program (NTP), Occupational Safety and Health
Administration (OSHA), and World Health Organization (WHO).
'Note that this version of TOXLINE is no longer updated
(https://www.nlm.nih. gov/databases/download/toxlinesubset.html'): therefore, it was not included in the literature
search update from May 2021.
1 -Bromo-2-chloroethane
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2. REVIEW OF POTENTIALLY RELEVANT DATA
(NONCANCER AND CANCER)
As shown in Tables 3 A and 3B, there are no potentially relevant short-term, subchronic,
chronic, developmental, or reproductive toxicity studies of l-bromo-2-chloroethane in humans or
animals exposed by oral or inhalation routes. The phrase "statistical significance" or the term
"significant," used throughout the document, indicates ap-value of < 0.05 unless otherwise
noted.
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Table 3A. Summary of Potentially Relevant Noncancer Data for l-Bromo-2-Chloroethane (CASRN 107-04-0)
Number of Male/Female, Strain, Species, Study
Category
Type, Reported Doses, Study Duration
Dosimetry
Critical Effects
Reference
Notes
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
ND = no data.
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Table 3B. Summary of Potentially Relevant Cancer Data for l-Bromo-2-Chloroethane (CASRN 107-04-0)
Category
Number of Male/Female, Strain, Species, Study
Type, Reported Doses, Study Duration
Dosimetry
Critical Effects
Reference
Notes
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
ND = no data.
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2.1. HUMAN STUDIES
2.1.1. Oral Exposures
No human studies following oral exposure to l-bromo-2-chloroethane have been
identified.
2.1.2. Inhalation Exposures
No human studies following inhalation exposure to l-bromo-2-chloroethane have been
identified.
2.2. ANIMAL STUDIES
2.2.1. Oral Exposures
No animal studies following oral exposure to l-bromo-2-chloroethane have been
identified.
2.2.2. Inhalation Exposures
No animal studies following inhalation exposure to l-bromo-2-chloroethane have been
identified.
2.3. OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Toxicity data for l-bromo-2-chloroethane are limited to acute lethality values reported in
secondary sources, an acute oral hepatotoxicity study, an acute intraperitoneal (i.p.) injection
study, and genotoxicity studies.
2.3.1. Acute Toxicity in Animals
An oral median lethal dose (LDso) value of 64 mg/kg was identified for
1 -bromo-2-chloroethane in rats [Frear (1969) as cited in NLM (2016)1; no further data regarding
acute oral toxicity were reported. Valade (1957), as cited in U.S. EPA (1985). reported a
30-minute median lethal concentration (LCso) value of 15,000-25,000 mg/m3 for
l-bromo-2-chloroethane in unspecified laboratory animals. This study also indicated that acute
inhalation of "several alkyl halides" caused ataxia in dogs, rats, and guinea pigs; however, it is
unclear whether these halides included l-bromo-2-chloroethane.
Moody et al. (1980) treated male Sprague Dawley rats with 1 -bromo-2-chloroethane via
gavage and found decreases in cytochrome P450 (CYP450) content of hepatic microsomes to
51% of controls, as well as alterations in relative content of fatty acids within hepatic
microsomes 18 hours after exposure to a single dose (0.15 mL/kg). A high correlation between
CYP450 loss and decreased arachidonic acid, increased linoleic acid, and increased oleic acid
was observed.
Significant mortality was observed in male B6C3F1 mice (5/11 treated animals) at
24 hours following a single i.p. injection of 1.5 mmol/kg (215 mg/kg) of
l-bromo-2-chloroethane. Statistically significant increases in serum sorbitol dehydrogenase
(SDH), alanine aminotransferase (ALT), and blood urea nitrogen (BUN) and relative liver and
kidney weights were also observed at this dose (Storer and Conollv. 1983). No mortalities or
liver or kidney effects were noted at <1 mmol/kg (143 mg/kg); no other endpoints were
evaluated.
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2.3.2. Genotoxicity
Overview: Studies evaluating the potential genotoxicity of l-bromo-2-chloroethane are
summarized below (see Table 4 for details). Available data indicate that l-bromo-2-chloroethane
and/or its metabolites display genotoxic, mutagenic, clastogenic, and deoxyribonucleic acid
(DNA) damaging activity.
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Table 4. Summary of l-Bromo-2-Chloroethane (CASRN 107-04-0) Genotoxicity
Endpoint
Test System
Doses/
Concentrations
Tested
Results
without
Activation3
Results with
Activation3
Comments
References
(comments)
Genotoxicity studies in prokaryotic organisms
Mutation
Salmonella typhimurium
strains TA1535, TA1537,
TA1538, TA98, and
TA100
0, 1.6, 3.0,4.7,6.8,
8.1 |imol/platc
+
(TA1535,
TA100)
(TA1537,
TA1538,
TA98)
+
(TA1535,
TA100)
(TA1537,
TA1538,
TA98)
A concentration-dependent increase in revertants
was observed in TA1535 and TA100 with or
without metabolic activation (rat liver S9 fractions).
The addition of S9 activation did not significantly
increase the mutagenic response.
Barber et al. (1981)
Mutation
S. typhimurium strains
TA1530, TA1535, and
TA1538
0-15 |imol/platc
+
(TA1530,
TA1535)
(TA1538)
NT
A concentration-dependent increase in revertants
was observed without metabolic activation.
Brem et al. (1974)
Mutation
S. typhimurium strains
TA100 and TA98
0, 33, 100, 200,
333, 667, 1,000,
1,500,
2,000 (ig/plate
+
(TA100,
TA98)
+
(TA100)
(TA98)
In TA100, the number of revertants was increased
>twofold at >667 (ig/plate without metabolic
activation and >333 (ig/plate with metabolic
activation. In TA98, the number of revertants was
increased >twofold at >333 (ig/plate without
metabolic activation.
NTP (1990)
Mutation
S. typhimurium strains
TA100 and TA102
NR
+
(see
comments)
Preincubation assay. It is unclear from the abstract
whether or not metabolic activation was used.
Hughes et al. (1987)
(abstract only)
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Table 4. Summary of l-Bromo-2-Chloroethane (CASRN 107-04-0) Genotoxicity
Endpoint
Test System
Doses/
Concentrations
Tested
Results
without
Activation3
Results with
Activation3
Comments
References
(comments)
Mutation
S. typhimurium strains
TA1535/pK233-2 (empty
plasmid)
TA1535/DM11 (bacterial
dichloromethane
dehalogenase)
TA1535/GST 5-5
(rat GST)
TA1535/GST T1
(human GST)
0-10.0 nM
(DM11);
0-150 nM
(GST 5-5, GST Tl,
and control plasmid
pK233-2)
(pK233-2)
+
(DM11,
GST 5-5,
GST Tl)
Metabolic activation was achieved using
S. typhimurium TA1535 cells expressing
mammalian theta-class GSH transferases (rat
GST 5-5 or human GST Tl) or a bacterial
dichloromethane dehalogenase (DM11).
A concentration-dependent increase in revertants
was observed for each of the enzymes induced; an
increase in revertants was not observed in TA1535
with the expression plasmid only. The numbers of
revertants/nM per plate for GST 5-5, GST Tl, and
DM11 were 45, 3.3, and 2,200, respectively. It was
<0.1 for the plasmid only.
Wheeler et al. (2001)
Mutation
S. typhimurium strain
TA100
0-4.0 mM
+
+
Metabolic activation was tested either with rat GSH
added or rat GSH + rat liver cytosol (S100). The
number of revertants following GSH + S100
activation was increased almost fourfold over GSH
only or without a metabolizing system.
van Bladeren et al.
(1981)
DNA damage
(SOS lumu
chromotest)
S. typhimurium strains
TA1535/pSK1002
(empty plasmid)
NM5004
(rat GST 5-5 and umuC-
lac Z operon)
0-0.5 mM
(pSK1002)
+
(NM5004)
Strain NM5004 was generated by introducing a
plasmid ,V. typhimurium TA1535 cells containing
both rat GSH transferase (GST 5-5) cDNA and the
umuC-lac Z operon.
1-1)111 gene expression was increased in a
dose-dependent manner for NM5004 at
noncytotoxic concentrations. Cytotoxicity was
observed at >0.25 mM in the NM5004 strain.
Shimada et al.
(1996)
13
1 -Bromo-2-chloroethane
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EPA/690/R-21/005F
Table 4. Summary of l-Bromo-2-Chloroethane (CASRN 107-04-0) Genotoxicity
Endpoint
Test System
Doses/
Concentrations
Tested
Results
without
Activation3
Results with
Activation3
Comments
References
(comments)
DNA damage
(SOS lumu
chromotest)
S. typhimurium strains
TA1535/pSK1002
(empty plasmid)
NM5004
(rat GST 5-5 and
umuC-lac Z operon)
0-0.1 mM
(pSK1002)
+
(NM5004)
Strain NM5004 was generated as describe above by
Shimada et al. (1996).
1-1)111 gene expression was increased in a
dose-dependent manner for NM5004 at
noncytotoxic concentrations. Cytotoxicity was
observed at 0.1 mM in the NM5004 strain.
Oda et al. (1996)
Genotoxicity studies in nonmammalian eukaryotic organisms
Mitotic
malsegregation
Aspergillus nidulans
diploid strain PI
0, 6.0, 12.0, 18.0,
24.0 mM
+
+
The number of malsegregations was significantly
elevated at >12.0 mM; survival was <50% at
>18.0 mM.
Crebelli et al. (1995)
Mitotic
recombination
(wing-spot test)
Drosophila melanogaster
(fir3 x mwh); 48-h
inhalation exposure
0, 0.31 ng/L
+
+
The tested concentration was based on the
calculated LC50. The frequency of wing spots at the
LC50 was significantly elevated by 17-fold
compared with controls.
Chroust et al. (2006)
Genotoxicity studies in mammalian cells in vitro
HGPRT
mutation
(6-thioguanine
resistance)
CHO cells
+S9: 0,0.05, 0.1,
0.2,0.3,0.4,0.5,
0.6, 0.7, 0.8,
1.0 mM;
-S9: 0,0.5, 1,2,3,
4, 6, 8 mM
+
+
A concentration-dependent increase in mutants was
observed with and without metabolic activation; the
mutagenic activity was fourfold greater with
metabolic activation (rat liver S9 mix) than without
S9. Enhancement by S9 mix did not occur when the
NADPH pool was reduced (via omission of NADP
from the S9 fraction). Cell survival (relative to
untreated control) was reduced by >50% at 6 mM
without S9 and 1 mM with S9.
I an and Hsie (1981)
CAs
CHL cells
0.1-0.5 mg/mL
(6 h; ±S9)
0.5-3.0 mg/mL
(24 h; -S9)
0.5-4.0 mg/mL
(48 h); -S9
+
(24 h; 48 h)
(6 h)
+
(6 h)
NA
Japan Chemical
Industry
Ecology-Toxicology
Information Center
(1996) as cited in
NLM (2005)
14
1 -Bromo-2-chloroethane
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Table 4. Summary of l-Bromo-2-Chloroethane (CASRN 107-04-0) Genotoxicity
Endpoint
Test System
Doses/
Concentrations
Tested
Results
without
Activation3
Results with
Activation3
Comments
References
(comments)
Genotoxicity studies in mammals in vivo
DNA damage
(DNA unwinding
assay)
Male B6C3F1 mice
(six/group); single i.p.
injection; sacrifice 4 h
after exposure; hepatic
cell nuclei were harvested
0, 0.5, 0.75,
1.0 mmol/kg
+
+
l-Bromo-2-chloroethane induced 8.9, 15.8, and
24.7% reduction in double-stranded DNA in liver
cells harvested from mice exposed to 0.5, 0.75, and
1.0 mM/kg (72, 107, and 143 mg/kg), respectively,
compared with control.
Storer and Conollv
(1983)
a+ = positive; ± = weakly positive; - = negative.
CA = chromosomal aberration; cDNA = complementary DNA; CHL = Chinese hamster lung; CHO = Chinese hamster ovary (cell line cells); DNA = deoxyribonucleic
acid; GSH = glutathione; GST = g 1 utathionc-V-1ransfcrasc: HGPRT = hypoxanthine-guanine phosphoribosyltransferase; i.p. = intraperitoneal; LC50 = median lethal
concentration; NA = not applicable; NADP = nicotinamide adenine dinucleotide phosphate; NADPH = reduced form of NADP; NR = not reported, NT = not tested.
15
1 -Bromo-2-chloroethane
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EPA/690/R-21/005F
l-Bromo-2-chloroethane is mutagenic in bacterial and mammalian cells in vitro, both
with and without metabolic activation (Wheeler et al.. 2001; N I P. 1990; Hughes et al.. 1987;
Barber et al.. 1981; Tan and Hsie- 1981; van Bladeren et al.. 1981; Brem et al.. 1974). Addition
of glutathione-^-transferases (GST) or glutathione (GSH) with or without SI00 into Salmonella
typhimurium bacterial test systems enhanced mutagenicity, indicating that GSH conjugation
results in the formation of mutagenic metabolites (Wheeler et al.. 2001; van Bladeren et al ..
1981). In the Chinese hamster ovary cell/hypoxanthine-guanine phosphoribosyl transferase
(CHO/HGPRT) system, mutagenicity was enhanced in the presence of an S9 metabolic
activation fraction; this enhancement did not occur when nicotinamide adenine dinucleotide
phosphate (NADP) was omitted from the S9 fraction, suggesting that CYP450 enzymes could be
involved in the increased metabolic activation (Tan and Hsie. 1981).
Chromosomal damage and mitotic malsegregation/recombination have been induced by
l-bromo-2-chloroethane in mammalian cells and nonmammalian eukaryotic organisms.
l-bromo-2-chloroethane induced chromosomal aberrations (CAs) in Chinese hamster lung
(CHL) cells, both in the presence and absence of a metabolic activation system, in a study by the
Japan Chemical Industry Ecology-Toxicology Information Center, available only as a brief
summary in the Chemical Carcinogenesis Research Information System (CCRIS) (NI.M. 2005).
l-Bromo-2-chloroethane also induced mitotic malsegregation in Aspergillus nidulans (('rebelli et
al.. 1995) and mitotic recombination in Drosophila melanogaster (Chroust et al.. 2006).
DNA damage has been reported in bacterial cells exposed to l-bromo-2-chloroethane in
the presence of GSTs (Oda et al.. 1996; Shimada et al.. 1996). DNA damage was assessed in the
SOSlumu test system, which measures the induction of DNA damage responsive umuC gene
expression by cellular P-galactosidase activity produced by an umuC-lac Z fusion gene. Shimada
et al. (1996) constructed a strain of S. typhimurium for use in the SOS lumu test system that
possessed enhanced GST activity by introducing a rat GST 5-5 cDNA plasmid into
S. typhimurium TA1535 (resulting in strain NM5004). Expression of the umuC gene was not
increased in the tester TA1535 strain containing only the empty plasmid (pSK1002), but it was
increased in a dose-related manner in the NM5004 strain expressing rat GST. These data suggest
that GSH conjugates of l-bromo-2-chloroethane were DNA-reactive intermediates.
DNA damage was also observed in liver cells from male B6C3F1 mice following a single
i.p. dose of 1 -bromo-2-ch 1 oroethane at greater than or equal to 0.5 mmol/kg (72 mg/kg) (Storer
and Conollv. 1983). Liver cell nuclei harvested from exposed mice showed a dose-related
decrease in the percentage of double-stranded DNA observed (indicating a dose-related increase
in DNA damage), as assessed by an alkaline DNA unwinding/hydroxylapatite batch
chromatography method.
In summary, l-bromo-2-chloroethane displayed mutagenic activity among in vitro
models employing bacterial and mammalian cells, and this mutagenic activity was increased
concomitantly with an increase in GSH conjugation (Wheeler et al.. 2001; N I P. 1990; Hughes et
al.. 1987; Tan and Hsie. 1981; van Bladeren et al.. 1981; Brem et al .. 1974). Increased CYP450
activity (as suggested by manipulating NADP levels within the S9 fraction) promoted elevated
mutagenicity in a CHO/HGPRT model system, indicating a potential role for CYP450 in the
mutagenicity resulting from 1 -bromo-2-chloroethane metabolism (Tan and Hsie, 1981).
Chromosomal aberrations and mitotic malsegregation were increased in both nonmammalian
eukaryotic organisms and mammalian cell model systems (Chroust et al.. 2006; NLM. 2005;
Crebelli et al.. 1995). Lastly, the induction of DNA damage in bacterial systems, as well as in in
16
1 -Bromo-2-chloroethane
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EPA/690/R-21/005F
vivo liver cells of male B6C3F1 mice, occurred in a dose-dependent manner after
1 -bromo-2-chloroethane exposure (Oda et al.. 1996; Shimada et al.. 1996; Storer and Conollv.
1983).
2.3.3. Absorption, Distribution, Metabolism, and Excretion Studies
Available in vivo and in vitro data indicate that l-bromo-2-chloroethane is metabolized
by a GSH conjugation pathway (Jean and Reed. 1992; Marchand and Reed. 1989). GSH
conjugation was demonstrated in vivo by the detection of »S'-(2-chloroethyl)glutathione (CEG)
and its hydrolysis product, »S'-(2-hydroxyethyl)glutathione (HEG), in the bile of
bile-duct-cannulated rats following intravenous (i.v.) injection with 75 mg/kg
1 -bromo-2-chloroethane (Marchand and Reed. 1989). The total amount of CEG detected in bile
was 2% of the administered dose. Marchand and Reed (1989) suggested that the low levels of
CEG detected in bile may result from rapid conversion of CEG to other metabolites (e.g., HEG)
or intrahepatic transport of CEG into plasma rather than bile. Data from the structurally similar
dihaloalkanes 1,2-dichloroethane and 1,2-dibromoethane indicate that once formed, CEG will
cyclize to form an electrophilic episulfonium ion in vivo, which subsequently binds to DNA
[reviewed by Guengerich (1994) and Dekant and Vamvakas (1993)1.
In isolated rat hepatocytes, l-bromo-2-chloroethane was metabolized to HEG,
»S'-(carboxyinethyl)glutathione (CMG), and S,S'-( 1,2-ethanediyl)bis(glutathione) (EDG)
conjugates. HEG was produced in the largest amounts, followed by EDG and CMG (Jean and
Reed. 1992). HEG and EDG are products of direct GSH conjugation (EDG results from
conjugation at both carbon atoms), whereas CMG is formed after an initial oxidation to
2-haloacetaldehyde metabolites (Jean and Reed. 1992). Formation of GSH conjugates was
concomitant with intracellular GSH depletion, measured as an 84% decrease in intracellular
GSH levels in response to l-bromo-2-chloroethane treatment. The addition of extracellular GSH
into the incubation medium increased the formation of EDG conjugates by 179% (Jean and
Reed, 1992). Combined, these data suggest that GSH conjugation is a primary and likely
rate-limiting step in the metabolic activation of l-bromo-2-chloroethane.
No data are available on the absorption, distribution, or excretion of
1 -bromo-2-chloroethane.
17
1 -Bromo-2-chloroethane
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3. DERIVATION OF PROVISIONAL VALUES
3.1. DERIVATION OF PROVISIONAL REFERENCE DOSES
No studies have been identified regarding toxicity of l-bromo-2-chloroethane to humans
by oral exposure. Animal studies of oral exposure to l-bromo-2-chloroethane are limited to acute
studies of inadequate design, duration, and scope to support derivation of a subchronic or chronic
provisional reference dose (p-RfD). As a result of the limitations of the available oral toxicity
data for l-bromo-2-chloroethane, subchronic and chronic p-RfDs are not derived directly.
Instead, screening subchronic and chronic p-RfDs are derived in Appendix A using an alternative
analogue approach. Based on the overall analogue approach presented in Appendix A,
l,2-dibromo-3-chloropropane is selected as the most appropriate analogue for
l-bromo-2-chloroethane for deriving a screening subchronic and chronic p-RfD (see Table 5).
3.2. DERIVATION OF PROVISIONAL REFERENCE CONCENTRATIONS
No studies have been identified on the toxicity of l-bromo-2-chloroethane to humans by
inhalation exposure. Animal studies of inhalation exposure to l-bromo-2-chloroethane are
limited to a single acute lethality study of inadequate design, duration, and scope to support
derivation of a subchronic or chronic provisional reference concentrations (p-RfCs). Due to lack
of adequate inhalation toxicity data for l-bromo-2-chloroethane, subchronic and chronic p-RfCs
are not derived directly. Instead, screening subchronic and chronic p-RfCs are derived in
Appendix A using an alternative analogue approach. Based on the overall analogue approach
presented in Appendix A, l,2-dibromo-3-chloropropane is selected as the most appropriate
analogue for l-bromo-2-chloroethane for deriving a screening subchronic and chronic p-RfC
(see Table 5).
3.3. SUMMARY OF NONCANCER PROVISIONAL REFERENCE VALUES
The noncancer screening provisional reference values for l-bromo-2-chloroethane are
summarized in Table 5.
18
1 -Bromo-2-chloroethane
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EPA/690/R-21/005F
Table 5. Summary of Noncancer Reference Values for
l-Bromo-2-Chloroethane (CASRN 107-04-0)
Toxicity Type
(units)
Species/
Sex
Critical
Effect
p-Reference
Value
POD
Method
POD
UFc
Principal Study
Screening
subchronic p-RfD
(mg/kg-d)
Rabbit/M
Reduced
germ cell
number
1 x 1(T3
NOAEL
(HED)
0.3
(based on
analogue POD)
300
Foote et al. (1986a, b)
as cited in U.S. EPA
(2006)
Screening
chronic p-RfD
(mg/kg-d)
Rabbit/M
Reduced
germ cell
number
1 x 1(T4
NOAEL
(HED)
0.3
(based on
analogue POD)
3,000
Foote etal. (1986a, b)
as cited in U.S. EPA
(2006)
Screening
subchronic p-RfC
(mg/m3)
Rabbit/M
Testicular
toxicity
6 x 1(T4
NOAEL
(HEC)
0.17
(based on
analogue POD)
300
Rao et al. (1982) as
cited in U.S. EPA
(2006)
Screening
chronic p-RfC
(mg/m3)
Rabbit/M
Testicular
toxicity
6 x 1(T5
NOAEL
(HEC)
0.17
(based on
analogue POD)
3,000
Rao et al. (1982) as
cited in U.S. EPA
(2006)
HEC = human equivalent concentration; HED = human equivalent dose; M = male(s);
NOAEL = no-observed-adverse-effect level; POD = point of departure; p-RfC = provisional reference
concentration; p-RfD = provisional reference dose; UFC = composite uncertainty factor.
3.4. CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
Although the scientific literature provides information on the mutagenicity and
genotoxicity of l-bromo-2-chloroethane, no studies have been conducted to directly assess its
carcinogenicity. Under the U.S. EPA Cancer Guidelines (U.S. EPA. 2005). there is "Inadequate
Information to Assess the Carcinogenic Potential" of l-bromo-2-chloroethane (see Table 6).
Within the current U.S. EPA Cancer Guidelines (U.S. EPA. 2005). there is no standard
methodology to support the identification of a weight-of-evidence (WOE) descriptor and
derivation of provisional cancer risk estimates for data-poor chemicals using an analogue
approach. In the absence of an established framework, a screening evaluation of potential
carcinogenicity is provided using the methodology described in Appendix B. This evaluation
determined that there was a qualitative level of concern for potential carcinogenicity for
l-bromo-2-chloroethane (see Appendix C).
19
1 -Bromo-2-chloroethane
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EPA/690/R-21/005F
Table 6. Cancer WOE Descriptor for l-Bromo-2-Chloroethane (CASRN 107-04-0)
Possible WOE Descriptor
Designation
Route of Entry (oral,
inhalation, or both)
Comments
"Carcinogenic to Humans"
NS
NA
No human data are available.
"Likely to Be Carcinogenic
to Humans "
NS
NA
No adequate chronic-duration animal cancer
bioassays are available.
"Suggestive Evidence of
Carcinogenic Potential"
NS
NA
No adequate chronic-duration animal cancer
bioassays are available.
"Inadequate Information to
Assess Carcinogenic
Potential"
Selected
Both
No studies are available assessing the
carcinogenic potential of
l-bromo-2-chloroethane in humans or
animals.
"Not Likely to Be
Carcinogenic to Humans"
NS
NA
No evidence of noncarcinogenicity is
available. No adequate chronic-duration
animal cancer bioassays are available.
NA = not applicable; NS = not selected; WOE = weight of evidence.
3.5. DERIVATION OF PROVISIONAL CANCER RISK ESTIMATES
The absence of suitable data precludes development of cancer risk estimates for
l-bromo-2-chloroethane (see Table 7).
Table 7. Summary of Cancer Risk Estimates for
l-Bromo-2-Chloroethane (CASRN 107-04-0)
Toxicity Type (units)
Cancer Risk
Species/Sex Tumor Type Estimate Principal Study
Screening p-OSF (mg/kg-d) 1
NDr
Screening p-IUR (|ig/m3) 1
NDr
NDr = not determined; p-IUR = provisional inhalation unit risk; p-OSF = provisional oral slope factor.
20
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EPA/690/R-21/005F
APPENDIX A. SCREENING NONCANCER PROVISIONAL VALUES
Due to the lack of evidence described in the main Provisional Peer-Reviewed Toxicity
Value (PPRTV) document, it is inappropriate to derive provisional toxicity values for
l-bromo-2-chloroethane. However, some information is available for this chemical, which
although insufficient to support derivation of a provisional toxicity value under current
guidelines, may be of limited use to risk assessors. In such cases, the Center for Public Health
and Environmental Assessment (CPHEA) 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 provisional reference values 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 could be more uncertainty associated with
deriving an appendix screening toxicity value than for a value presented in the body of the
assessment. Questions or concerns about the appropriate use of screening values should be
directed to the CPHEA.
APPLICATION OF AN ALTERNATIVE ANALOGUE APPROACH
The analogue approach allows for the use of data from related compounds to calculate
screening values when data for the compound of interest are limited or unavailable. Details
regarding searches and methods for analogue analysis are presented in Wang et al. (2012). Three
types of potential analogues (structural, metabolic, and toxicity-like) are identified to facilitate
the final analogue chemical selection. The analogue approach may or may not be route-specific
or applicable to multiple routes of exposure. All information was considered together as part of
the final weight-of-evidence (WOE) approach to select the most suitable analogue both
toxicologically and chemically.
Structural Analogues
An initial analogue search focused on the identification of structurally similar chemicals
with toxicity values from the Integrated Risk Information System (IRIS), PPRTVs, Agency for
Toxic Substances and Disease Registry (ATSDR), or California Environmental Protection
Agency (CalEPA) databases to leverage the body of well-characterized chemical-class
information. As described in Wang et al. (2012). structural similarity for analogues is evaluated
using the National Library of Medicine's (NLM's) ChemlDplus database (ChemlDplus, 2021)
and the Organisation for Economic Co-operation and Development (OECD) Toolbox. Both
structural similarity approaches were used to calculate structural similarity using the Tanimoto
method. Three structural analogues to l-bromo-2-chloroethane that have oral and/or inhalation
toxicity values were identified: 1,2-dibromoethane (U.S. HP A. 2004). 1,2-dichloroethane (U.S.
EPA. 2010). and l,2-dibromo-3-chloropropane (U.S. EPA. 2006. 2003). Table A-1 summarizes
the analogues' physicochemical properties and similarity scores. ChemlDplus similarity scores
were available only for 1,2-dibromoethane (92%) and 1,2-dichloroethane (68%). OECD
Quantitative Structure-Activity Relationship (QSAR) pairwise toolbox similarity scores were
similar for all three candidate analogues (24—33%) and the target chemical. The target compound
and all candidate analogues are expected to be bioavailable by oral and inhalation routes (based
on water solubility and Kow values). A range of vapor pressure values (0.580-78.9 mm Hg at
25°C) is identified for l-bromo-2-chloroethane and relevant analogue chemicals, suggesting that
these compounds may exhibit differences in volatility. All of the candidate analogues are
considered appropriate structural analogues based on the approach described in Wang et al.
(2012).
21
1 -Bromo-2-chloroethane
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EPA/690/R-21/005F
Table A-l. Physicochemical Properties of l-Bromo-2-Chloroethane (CASRN 107-04-0)
and Candidate Analogues3
Property
1-Bromo-
2-Chloro ethane
1,2-Dibromoethane
1,2-Dichloro ethane
1,2-Dibromo-
3-Chloropropane
(2R and 2S Isomers)
Structure
/-v ...Br
cr v
...Br
Br
cr
a^Y^Br
Br
CASRN
107-04-0
106-93-4
107-06-2
96-12-8
Molecular weight
143
188
99
236
OECD QSAR Toolbox
similarity score (%)b
100
33
33
24
ChemlDplus similarity
score (%)°
100
92
68
NV
Melting point (°C)
-16.3
9.8
-35.3
6.04
Boiling point (°C)
107
132
83.2
196
Vapor pressure
(mmHgat25°C)
33.1
11.2
78.9
0.580
Henry's law constant
(atm-m3/mole at 25°C)
9.09 x 10-4
6.50 x 10-4
1.18 x 10-3
2.93 x lO"4
(predicted)
Water solubility
(mol/L)
4.79 x 10-2
2.11 x 10-2
8.68 x lO"2
4.71 x 10~3
Octanol-water partition
coefficient (log Kow)
1.86 (predicted)
1.96
1.48
2.96
aData represent average values as reported on the U.S. EPA's CompTox Chemicals Dashboard unless otherwise
specified (https ://comptox. epa. gov/dashboard/dsstoxdb/results?search=DTXSID4024775#properties). Data
accessed June 2021.
bOECD (2018).
cChemIDplus advanced similarity scores (ChemlDplus. 20211.
NV = not available; OECD Organisation for Economic Co-operation and Development; QSAR = quantitative
structure-activity relationship.
Metabolic Analogues
Table A-2 summarizes available toxicokinetic data for l-bromo-2-chloroethane and the
structurally similar compounds identified as candidate analogues.
Absorption, Distribution, and Excretion
No data are available to describe the absorption, distribution, or excretion of
l-bromo-2-chloroethane. Oral absorption is rapid and extensive for all three candidate analogue
compounds (U.S. EPA. 2004; AT SDR. 2001; Gingell etal.. 1987). Absorption is also rapid and
extensive following inhalation exposure to 1,2-dibromoethane and 1,2-dichloroethane (U.S.
EPA. 2004; ATSDR. 2001). There are no data available on the rate or extent of absorption
following inhalation exposure to l,2-dibromo-3-chloropropane. Widespread distribution to
multiple organs and excretion primarily in the urine has been demonstrated for all three
candidate analogue compounds (U.S. EPA. 2004; ATSDR. 2001; Gingell et at.. 1987).
22
1 -Bromo-2-chloroethane
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EPA/690/R-21/005F
Table A-2. Comparison of Available ADME Data for l-Bromo-2-Chloroethane (CASRN 107-04-0) and Candidate Analogues
Parameter
l-Bromo-2-Chloroethane
1,2-Dibromoethane
1,2-Dichloroethane
l,2-Dibromo-3-Chloropropane
(2R and 2S isomers)
Structure
,Br
cr ^
...Br
Br
,CI
CI
a-x^Y^Br
Br
CASRN
107-04-0
106-93-4
107-06-2
96-12-8
Absorption
Rate and extent of oral
absorption
ND
Rat:
rapid and extensive (Cmax within
30 min; >80% of dose absorbed)
Rat:
rapid and extensive (Cmax within
15 min; >80% of dose absorbed)
Rat:
rapid and extensive (Cmax within
5-40 min; >80% of dose
absorbed)
Rate and extent of
inhalation absorption
ND
Rat:
rapid and extensive (Cmax within
20 min; 40 to <60% of dose
absorbed)
Rat:
rapid and extensive (Cmax within
1-3 h; >80% of dose absorbed)
ND
Human blood-gas
partition coefficient3
29.2
ND
19.5
ND
Rat blood-gas partition
coefficient3
52.7
119
30.4
ND
Distribution
Extent of distribution
ND
Rat and mouse:
wide distribution to multiple
organs; covalent binding to tissues
(kidney, stomach, liver, and testis
after oral exposure; nasal mucosa,
liver, lung, kidney, and small
intestine after i.p. injection)
Rat:
wide distribution to multiple
organs; transplacental distribution
was demonstrated
Rat:
wide distribution to multiple
organs; Vd = 4.98 L/kg (oral)
23
1 -Bromo-2-chloroethane
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Table A-2. Comparison of Available ADME Data for l-Bromo-2-Chloroethane (CASRN 107-04-0) and Candidate Analogues
Parameter
l-Bromo-2-Chloroethane
1,2-Dibromoethane
1,2-Dichloroethane
l,2-Dibromo-3-Chloropropane
(2R and 2S isomers)
Metabolism—oxidation by CYP450
Primary reactive
metabolites
By analogy to 1,2-dibromoethane
and 1,2-dichloroethane:
(1) 2-bromo-acetaldehyde;
(2) 2-chloro-acetaldehyde
0
X
X = Br, CI
By analogy to 1,2-dibromoethane
and 1,2-dichloroethane:
(3) HBr, HC1
Demonstrated:
(1) 2-bromo-acetaldehyde
0
A
Br
Demonstrated:
(2) HBr
Demonstrated:
(1) 2-chloro-acetaldehyde
0
CI
Demonstrated:
(2) HC1
Demonstrated:
(1) 2-bromoacrolein
o
(2) 2-chloro-3-(bromomethyl)
oxirane
5
Br.
CI
(3) l-bromo-3-chloroacetone
0
Demonstrated:
(4) HBr, HC1
24
1 -Bromo-2-chloroethane
-------
EPA/690/R-21/005F
Table A-2. Comparison of Available ADME Data for l-Bromo-2-Chloroethane (CASRN 107-04-0) and Candidate Analogues
Parameter
l-Bromo-2-Chloroethane
1,2-Dibromoethane
1,2-Dichloroethane
l,2-Dibromo-3-Chloropropane
(2R and 2S isomers)
Potential role in toxicity
By analogy to 1,2-dibromoethane
and 1,2-dichloroethane:
(1) Forms DNA adducts
(2) Lipid peroxidation
(3) Protein binding
Demonstrated:
(1) Forms DNA adducts
(2) Lipid peroxidation
(3) Protein binding
Demonstrated:
(1) Forms DNA adducts
(2) Lipid peroxidation
(3) Protein binding
Demonstrated:
(1) 2-bromoacrolein and
2-chloro-3-(bromomethyl) oxirane
are direct-acting mutagens in
Salmonella
(2) 2-bromoacrolein forms DNA
adducts
Metabolism—GSH conjugation1"
Primary reactive
metabolites
Inferred from CEG as primary
GSH conjugate:
(1) HBr released during GSH
conjugation (HC1 released in
minor amounts)
By analogy to 1,2-dichloroethane:
(2) Reactive episulfonium ion
formed following cyclization of
GSH adduct
cr .p>
0 C f'" H O
A JL JL ,n_ a
HO' ^ N ^ Oh
nh2 h 0
Inferred from BEG as GSH
conjugate:
(1) HBr released during GSH
conjugation
Demonstrated:
(2) Reactive episulfonium ion
formed following cyclization of
GSH adduct
& >
o r h o
HO l-T Y - OH
NH; H 0
Inferred from CEG as GSH
conjugate:
(1) HC1 released during GSH
conjugation
Demonstrated:
(2) Reactive episulfonium ion
formed following cyclization of
GSH adduct
cr>
0 0 r H C
NHj H 0
Inferred from CBPG as primary
GSH conjugate:
(1) HBr released during GSH
conjugation (HC1 released in
minor amounts)
Demonstrated:
(2) Reactive episulfonium ion
formed following cyclization of
GSH adduct
,Ci
Bf k,
0 0 r H 0
NH- H 0
25
1 -Bromo-2-chloroethane
-------
EPA/690/R-21/005F
Table A-2. Comparison of Available ADME Data for l-Bromo-2-Chloroethane (CASRN 107-04-0) and Candidate Analogues
Parameter
l-Bromo-2-Chloroethane
1,2-Dibromoethane
1,2-Dichloroethane
l,2-Dibromo-3-Chloropropane
(2R and 2S isomers)
Potential role in toxicity
By analogy to all potential
analogues:
(1) Forms DNA adducts
By analogy to 1,2-dibromoethane
and l,2-dibromo-3-chloropropane:
(2) Causes DNA damage in cells
including spermatocytes
Demonstrated:
(3) Mutagenicity among
genotoxicity assays mediated by
GSH activity
Demonstrated:
(1) Forms DNA adducts,
(2) Causes DNA damage in
hepatocytes and spermatocytes
(unscheduled DNA synthesis)
Demonstrated:
(1) Forms DNA adducts,
(2) Binds to protein and DNA in
kidney and liver
Demonstrated:
(1) Forms DNA adducts,
(2) Causes DNA damage in
multiple tissues including kidneys
and testes (unscheduled DNA
synthesis),
(3) DNA strand breaks in
spermatocytes,
(4) DNA damage is correlated
with tissue injury at higher doses
Excretion
Half-life in blood (h)
ND
ND
Rat, oral:
<1
Rat, oral:
2.64
Route of excretion
ND
Rat, oral:
60 to <80% urine
<20% feces
<20% exhaled air (form not
indicated)
Rat, oral:
60 to <80% urine
<20% feces
20 to <40% excreted unchanged in
exhaled air
Rat, inhalation:
>80% urine
<20% feces
<20% as CO2 in exhaled air
Rat, oral:
40 to <60% urine
<20% feces
20 to <40% exhaled air (<1%
unmetabolized; 20% as CO2)
26
1 -Bromo-2-chloroethane
-------
EPA/690/R-21/005F
Table A-2. Comparison of Available ADME Data for l-Bromo-2-Chloroethane (CASRN 107-04-0) and Candidate Analogues
Parameter
l-Bromo-2-Chloroethane
1,2-Dibromoethane
1,2-Dichloroethane
l,2-Dibromo-3-Chloropropane
(2R and 2S isomers)
References
Gueneerich (1994); Dekatit and
U.S. EPA (2004): Gareas et al.
ATSDR (2001); Gareas et al.
Gueneerich (1994); van
Yamvakas (1993); Jean and Reed
(1992): Gareas etal. (1989):
Marchand and Reed (1989);
Gueneerich et al. (1987); van
(1989); Gueneerich et al. (1987);
NTP (2021)
(1989); Gueneerich et al. (1987)
Beerendonk et al. (1994); Dekatit
and Yamvakas (1993); Humohrevs
etal. (1991); Pearson etal. (1990);
Doira et al. (1988); Omichinski et
Bladeren et al. (1981); Wheeler et
al. (2001); Shimadaetal. (1996)
al. (1988a): Omichinski et al.
(1988b): Gineell et al. (1987):
Gueneerich et al. (1987)
aValues represent means in the case of multiple studies.
bMetabolism information was categorized as: (1) experimentally demonstrated, (2) inferred from other experimental data for the same compound, or (3) by analogy to
experimental data for a different compound.
ADME = absorption, distribution, metabolism, and excretion; BEG = .S'-(2-bromocthvl)glutathionc: Br = bromine; CBPG = ,S'-(3-chloro-2-bromopropyl) glutathione;
CEG = .S'-(2-chlorocth\i)glutathionc: Cmax = maximum concentration; CI = chlorine; CO2 = carbon dioxide; CYP450 = cytochrome P450; DNA = deoxyribonucleic acid;
GSH = glutathione; HBr = hydrogen bromide; HC1 = hydrogen chloride; i.p. = intraperitoneal; ND = no data; I '1 = volume of distribution.
27
1 -Bromo-2-chloroethane
-------
EPA/690/R-21/005F
Metabolism
Each of the candidate analogue compounds is metabolized by a cytochrome P450
(CYP450) oxidation pathway and a direct glutathione (GSH) conjugation pathway. Contributions
from both pathways are presumed by analogy for the target compound as well; however,
experimental data for l-bromo-2-chloroethane (the target compound) are available only for the
GSH conjugation pathway. Formation of a reactive episulfonium ion occurs, or is expected to
occur, for all compounds. Although metabolic pathways are similar among the target chemical
and potential analogues, available data indicate that the rate of GSH conjugation and the specific
products of oxidative metabolism differ between compounds.
Studies suggest that GSH conjugation leads to the formation of reactive intermediates for
the target compound and potential analogues. As discussed in the "Absorption, Distribution,
Metabolism, and Excretion" (ADME) section in the main document, l-bromo-2-chloroethane
was metabolized to S-(2-chloroethy 1 )glutathione (CEG) in bile-duct-cannulated rats (Marchand
and Reed. 1989). GSH conjugation to CEG is also suggested by formation of
S-(2--hydroxyethyl)glutathione (HEG), a hydrolysis product of CEG, in isolated rat hepatocytes
(Jean and Reed. 1992). Metabolic studies with 1,2-dichloroethane (which also forms CEG by
GSH conjugation) report that once formed, CEG cyclizes to form an electrophilic episulfonium
ion in vivo, which subsequently binds to deoxyribonucleic acid (DNA) [reviewed by Guengerich
(1994); Dekant and Vamvakas (1993)1. Similar electrophilic metabolites (i.e., episulfonium ions)
were also produced following GSH conjugation to 1,2-dibromoethane to form
»S'-(2-bromoethyl)gl utathi one (BEG) and to l,2-dibromo-3-chloropropane to form
»S'-(3-chloro-2-bromopropyl) glutathione (CBPG), also resulting in DNA and protein binding and
subsequent damage to DNA (NIP. 2021; U.S. EPA. 2004; ATS DR. 2001; Guengerich. 1994;
van Beerendonk et at., 1994; Dekant and Vamvakas, 1993; Pearson et at., 1990; Dohn et at.,
1988; Omichinski eta!., 1988b; Omichinski et at.. 1988a; Guengerich eta!.. 1987). The rate of
GSH conjugation is anticipated to be faster for the brominated compounds compared with
1,2-dichloroethane because of the increased relative reactivity of the bromine versus the chlorine
leaving group. This is demonstrated by the initial GSH conjugation products identified for both
1-bromo-2-chloroethane and the proposed analogue l,2-dibromo-3-chloropropane. When both
chlorine and bromine substituents are present, GSH conjugation occurs preferentially at the
brominated site (yielding CEG and CBPG, respectively) (Dekant and Vamvakas. 1993; Jean and
Reed. 1992; Humphreys et a!.. 1991; Marchand and Reed. 1989). The concomitant release of
hydrogen bromide (HBr) (with minor release of hydrogen chloride [HC1]) is inferred (i.e., not
experimentally demonstrated) by the preference for GSH conjugation at the brominated site.
Halogen reactivity (i.e., bromine vs. chlorine) is expected to have less influence on the rate of the
cyclization reaction that occurs subsequent to GSH conjugation, because the reacting centers are
held in close proximity to each other, resulting in rapid formation of the episulfonium ion from
the GSH adduct in all cases.
Oxidative metabolites differ among the candidate analogue compounds.
CYP450-mediated oxidation of 1,2-dibromoethane and 1,2-dichloroethane results in the
production of haloacetaldehyde metabolites that can cause lipid peroxidation and bind to cellular
proteins and DNA (NTP. 2021; U.S. EPA. 2004; ATSDR. 2001). HBr and HC1 are released
during the formation of the haloacetaldehyde metabolite (NTP. 1991; van Bladeren et a!.. 1981).
Although not experimentally demonstrated, this pathway is expected for the target compound as
well, based on analogy to the candidate analogue compounds. Oxidative metabolism of
l,2-dibromo-3-chloroethane produces three primary metabolites (2-bromoacrolein,
2-chloro-3-[bromomethy 1 ] oxirane, 1 -bromo-3-chloroacetone) (Pearson et a!.. 1990; Dohn et a!..
28
1 -Bromo-2-chloroethane
-------
EPA/690/R-21/005F
1988; Omichinski et al.. 1988b). none of which can be produced by oxidation of the target
compound due to structural constraints. Both HBr and HC1 are released during the formation of
2-bromoacrolein, while only HBr is released during the formation of 2-chloro-3-(bromomethyl)
oxirane and 1 -bromo-3-chloroacetone (Omichinski et al.. 1988b). 2-Bromoacrolein and
2-chloro-3-(bromomethyl) oxirane are electrophilic and have been shown to be clastogenic and
direct-acting mutagens in Salmonella (van Beerendonk et al.. 1994; Pearson et al.. 1990).
2-Bromoacrolein has also been demonstrated to bind to DNA, and the resulting adducts have
been characterized (van Beerendonk et al.. 1994).
Because of the preference for relative reactivity of the bromine versus the chlorine
leaving group during GSH conjugation, 1,2-dibromoethane and l,2-dibromo-3-chloropropane
are favored as metabolic analogues over 1,2-dichloroethane. Assuming that both CYP450
oxidation and GSH conjugation are equally relevant to the toxicity of the target compound,
1,2-dibromoethane is the most appropriate choice as a metabolic analogue. If the GSH
conjugation pathway predominates in its relevance to toxicity, l,2-dibromo-3-chloropropane
may be a more appropriate metabolic analogue.
Toxicity-Like Analogues—Oral
Table A-3 summarizes available oral toxicity values for l-bromo-2-chloroethane and the
compounds identified as potential structural analogues.
29
1 -Bromo-2-chloroethane
-------
EPA/690/R-21/005F
Table A-3. Comparison of Available Oral Toxicity Data for l-Bromo-2-Chloroethane
(CASRN 107-04-0) and Candidate Analogues
Parameter
1-Bromo-
2-Chloroethane
1,2-Dibromoethane
1,2-Dichloroethane
1,2-Dibromo-
3-Chloropropane
Structure
Br
CI
,Bf
Bl^
,-v XI
cr
ci^Y^"Br
Br
CASRN
107-04-0
106-93-4
107-06-2
96-12-8
Repeated-dose toxicity—subchronic
POD (mg/kg-d)
NA
NA
58
0.7
POD type
NA
NA
LOAEL
NOAEL
Subchronic UFC
NA
NA
3,000 (UFa, UFd,
UFh, UFl)
300 (UFa, UFd, UFh)
Subchronic p-RfD
(mg/kg-d)
NA
NA
2 x 10-2
2 x 10-3
Critical effects3
NA
NA
Increased absolute
kidney weight in
female rats
Male reproductive
toxicity (reduced
germ cell number)
Species
NA
NA
Rat
Rabbit
Duration
NA
NA
13 wk
10 wk
Route (method)
NA
NA
Drinking water
Drinking water
Source
NA
NA
U.S. EPA (2010)
U.S. EPA (2006)
Repeated-dose toxicity—chronic
POD (mg/kg-d)
NA
27
58
0.7
POD type
NA
I.OAF.I. (ADJ)
LOAEL
NOAEL
Chronic UFC
NA
3,000 (UFa, UFd,
UFh, UFl)
10,000 (UFa, UFd,
UFh, UFl, UFs)
3,000 (UFa, UFd,
UFh, UFs)
Chronic RfD/p-RfD
(mg/kg-d)
NA
9 x 10-3
6 x 10-3
(screening)
2 x 10-4
Critical effects3
NA
Liver peliosis,
testicular atrophy, and
adrenal cortical
degeneration
Increased absolute
kidney weight in
female rats
Testicular toxicity
(reduced germ cell
number)
Species
NA
Rat (M and F)
Rat
Rabbit
Duration
NA
49 wk (M);
61 wk(F)
13 wk
10 wk
Route (method)
NA
Gavage in corn oil
(5 d/wk)
Drinking water
Drinking water
Source
NA
U.S. EPA (2004)
U.S. EPA (2010)
U.S. EPA (2006)
30
1 -Bromo-2-chloroethane
-------
EPA/690/R-21/005F
Table A-3. Comparison of Available Oral Toxicity Data for l-Bromo-2-Chloroethane
(CASRN 107-04-0) and Candidate Analogues
l-Bromo-
1,2-Dibromo-
Parameter
2-Chloroethane
1,2-Dibromoethane
1,2-Dichloroethane
3-Chloropropane
Acute oral lethality data
Rat oral LD5o (mg/kg)
64
55-420
670-967
170
Toxicity at rat LD5o
NR
NR
NR
NR
Source
U.S. EPA (2020b):
U.S. EPA (2020b):
U.S. EPA (2020a)
U.S. EPA (2020b)
U.S. EPA (1985)
U.S. EPA (2004)
aExposure-response arrays were prepared to illustrate the dose-response relationship for testicular, kidney, and liver
effects across the candidate analogue compounds (Figures A-l, A-2, and A-3, respectively).
ADJ = duration adjusted; F = female(s); LD50 = median lethal dose; LOAEL = lowest-observed-adverse-effect
level; M = male(s); NA = not applicable; NOAEL = no-observed-adverse-effect level; NR = not reported;
POD = point of departure; p-RfD = provisional reference dose; RfD = oral reference dose; UFa = interspecies
uncertainty factor; UFC = composite uncertainty factor; UFD = database uncertainty factor; UFH = intraspecies
uncertainty factor; UFL = LOAEL-to-NOAEL uncertainty factor; UFS = subchronic-to-chronic uncertainty factor.
No repeated-dose oral toxicity data are available for l-bromo-2-chloroethane. Acute
toxicity data are limited to a reported median lethal dose (LD50) of 64 mg/kg-day in rats; no
further information was provided [Frear (1969) as cited in NLM (2016)1.
Oral toxicity values are available for 1,2-dibromoethane, 1,2-dichloroethane, and
l,2-dibromo-3-chloropropane (see Table A-3), and the data supporting these values are extensive
[as cited in U.S. EPA (2010. 2006. 2004)1. The target organs of toxicity for these potential
analogues include the testis, kidney, and liver (see exposure-response arrays in Figures A-l, A-2,
and A-3). After review of the available data for candidate analogues, testicular effects are
identified as the most sensitive toxicity target after exposure to l,2-dibromo-3-chloropropane and
1,2-dibromoethane.
Testicular effects occurred at the lowest oral doses for 1,2-dibromoethane and
l,2-dibromo-3-chloropropane and are identified as being among the critical effects for derivation
of provisional reference dose (p-RfD) values for both compounds (see Table A-3, Figure A-l). In
support of this endpoint, epidemiological studies of l,2-dibromo-3-chloropropane-exposed
production workers, farmers and pesticide applicators have demonstrated impaired testicular
function (decreased spermatogenesis and sperm count and altered sperm morphology) in exposed
humans. The testicular toxicity of l,2-dibromo-3-chloropropane is known to be mediated
exclusively by the GSH conjugation pathway because the inhibition of this pathway completely
abrogated the observed testicular effects (Omichinski et at.. 1988a; Soderlund et at.. 1988).
Reactive episulfonium metabolites are well known to bind to DNA and promote increased rates
of DNA damage. Within the context of the l,2-dibromo-3-chloropropane database, reactive
episulfonium metabolites were observed to produce increased amounts of testicular DNA
damage, promote testicular necrosis and atrophy at higher doses (Soderlund et at.. 1988). and in
turn, impair spermatogenesis and prolong oligospermia (Meistrich et at.. 2003). This same
sequence of events is likely to occur for 1,2-dibromoethane and l-bromo-2-chloroethane, which
are anticipated to undergo GSH conjugation at similar rates to l,2-dibromo-3-chloropropane due
to the presence of bromine leaving groups in all three compounds. This reaction leads to
31
1 -Bromo-2-chloroethane
-------
EPA/690/R-21/005F
formation of the reactive episulfonium metabolites that are implicated in testicular toxicity. The
absence of testicular toxicity following exposure to 1,2-dichloroethane (see Figure A-l) may be
attributable to reduced episulfonium formation secondary to the expected slower rate of GSH
conjugation resulting from lower reactivity of the chlorine leaving group relative to bromine
(see "Metabolic Analogues" section for more details).
In the absence of repeated-exposure oral toxicity data for l-bromo-2-chloroethane, there
is no information with which to clearly identify or rule out candidate analogues based on toxicity
comparisons. However, based on the expected formation of the episulfonium ion following
metabolism of l-bromo-2-chloroethane, the mechanism of action for the critical testicular effects
following exposure to l,2-dibromo-3-chloropropane (and by analogy 1,2-dibromoethane) is
plausible for l-bromo-2-chloroethane as well.
32
1 -Bromo-2-chloroethane
-------
EPA 690 R-21 005F
Figure A-l. Testicular Effects Following Oral Exposure to 1,2-Dichloroethane (1,2-DCE), 1,2-Dibromoethane (1,2-DBE), or
l,2-Dibromo-3-Chloropropane (l,2-DB-3-CP) [reviewed by U.S. EPA (2010. 2006. 2004)1
33
1 -Bromo-2-chloroethane
-------
EPA 690 R-21 005F
10000
1000
i?
o
Q
E
"O
<
100
10
0.1
Figure A-2. Kidney Effects Following Oral Exposure to 1,2-Dichloroethane (1,2-DCE), 1,2-Dibromoethane (1,2-DBE), or
l,2-Dibromo-3-Chloropropane (l,2-DB-3-CP) [reviewed by U.S. EPA (2010. 2006. 2004)1
T—1
-M
fU
^r
-M
fU
-M
>
Q_
Q_
¦
l—
ro
fU
ro
I—
I—
-------
EPA 690 R-21 005F
10000
1000
"O
j?
w>
E
Q
"C
E
Tj
<
100
10
• Dose ahove LOAEL
¦ LOAEL
~ NOAEL
ODose below NOAEL
-d-
o.i
1,2-DCE
Subchronic
'Y Liver weight
1,2-DB-
3-CP
1,2-DCE
Subchronic
1,2-DB-
S-CP
Liver lesions
1,2-DBE
l,2-DB-3-CP
Chronic
Figure A-3. Liver Effects Following Oral Exposure to 1,2-Dichloroethane (1,2-DCE), 1,2-Dibromoethane (1,2-DBE), or
l,2-Dibromo-3-Chloropropane (l,2-DB-3-CP) [reviewed by U.S. EPA (2010. 2006. 2004)1
35
1 -Bromo-2-chloroethane
-------
EPA 690 R-21 005F
Toxicity-Like Analogues—Inhalation
Table A-4 summarizes available inhalation toxicity values for the compounds identified
as potential structural analogues for l-bromo-2-chloroethane.
Table A-4. Comparison of Available Inhalation Toxicity Data for
l-Bromo-2-Chloroethane (CASRN 107-04-0) and Candidate Analogues
Parameter
1-Bromo-
2-Chloroethane
1,2-Dibromoethane
1,2-Dichloroethane
1,2-Dibromo-
3-Chloropropane
Structure
,-Br
ci- -
,Br
Br' -
... ,CI
cr -
Br
CASRN
107-04-0
106-93-4
107-06-2
96-12-8
Repeated-dose toxicity—subchronic
POD (mg/m3)
NA
NA
22
0.17
POD type
NA
NA
LOAEL (ADJ)
NOAF.L (HEC)
Subchronic UFC
NA
NA
300 (UFd, UFh, UFl)
100 (UFa, UFd, UFh)
Subchronic p-RfC
(mg/m3)
NA
NA
7 x 10-2
2 x 10-3
Critical effects3
NA
NA
Neurobehavioral
impairment (impaired
visual-motor
reactions)
Testicular effects
(decreased absolute
testis-weight, atrophy,
loss of spennatogenic
elements in
seminiferous tubules)
Species
NA
NA
Human
Rabbit
Duration
NA
NA
No information on
length of employment
or duration of
exposure was
reported; treated as
subchronic in the
PPRTV assessment
14 wk
Route (method)
NA
NA
Inhalation
(occupational)
Inhalation
(whole body; 6 h/d,
5 d/wk)
Source
NA
U.S. EPA (2004)
U.S. EPA (2010)
U.S. EPA (2006);
U.S. EPA (2003)
Repeated-dose toxicity—chronic
POD (mg/m3)
NA
2.8
22
0.17
POD type
NA
BMCLio (HEC)
LOAEL (ADJ)
NOAF.L (HEC)
Chronic UFC
NA
300 (UFa, UFd, UFh)
3,000 (UFd, UFh,
UFl, UFs)
1,000 (UFa, UFd,
UFh, UFs)
Chronic RfC/p-RfC
(mg/m3)
NA
9 x 10-3
7 x 10-3
2 x 10-4
36
1 -Bromo-2-chloroethane
-------
EPA/690/R-21/005F
Table A-4. Comparison of Available Inhalation Toxicity Data for
l-Bromo-2-Chloroethane (CASRN 107-04-0) and Candidate Analogues
Parameter
1-Bromo-
2-Chloroethane
1,2-Dibromoethane
1,2-Dichloroethane
1,2-Dibromo-
3-Chloropropane
Critical effects3
NA
Suppurative
inflammation of nasal
cavity in female mice
Neurobehavioral
impairment (impaired
visual-motor
reactions)
Testicular effects
(decreased absolute
testis weight, atrophy,
loss of spermatogenic
elements in
seminiferous tubules)
Species
NA
Mouse
Human
Rabbit
Duration
NA
78 wk (M)
90-106 wk (F)
No information on
length of employment
or duration of
exposure was
reported; treated as
subchronic in the
PPRTV assessment
14 wk
Route (method)
NA
Inhalation
(whole body; 6 h/d,
5 d/wk)
Inhalation
(occupational)
Inhalation
(whole body; 6 h/d,
5 d/wk)
Source
NA
U.S. EPA (2004)
U.S. EPA (2010)
U.S. EPA (2006):
U.S. EPA (2003)
Acute inhalation lethality data
LC50 (mg/m3)
15,000-25,000
(30-min; unspecified
species)
-1,500 (9 h; rat)
7,758 (4 h; rat)
ND
Source
U.S. EPA (1985)
U.S. EPA (2004)
U.S. EPA (2020a)
U.S. EPA (2020b)
aExposure-response arrays were prepared to illustrate the dose-response relationship for testicular, kidney, liver,
and respiratory tract effects in experimental animal inhalation studies across the candidate analogue compounds
(see Figures A-4, A-5, A-6, and A-7, respectively).
ADJ = duration adjusted; BMCLio = 10% benchmark concentration lower confidence limit; F = female(s);
HEC = human equivalent concentration; LC50 = median lethal concentration;
LOAEL = lowest-observed-adverse-effect level; M = male(s); NA = not applicable; ND = no data;
NOAEL = no-observed-adverse-effect level; POD = point of departure; PPRTV = provisional peer-reviewed
toxicity value; p-RfC = provisional reference concentration; RfC = inhalation reference concentration;
UFa = interspecies uncertainty factor; UFC = composite uncertainty factor; UFD = database uncertainty factor;
UFh = intraspecies uncertainty factor; UFL = LOAEL-to-NOAEL uncertainty factor; UFS = subchronic-to-chronic
uncertainty factor.
37
1 -Bromo-2-chloroethane
-------
EPA/690/R-21/005F
No repeated-exposure inhalation toxicity data are available for l-bromo-2-chloroethane.
Acute inhalation toxicity data are limited to a single study by Valade et al. (1957) as cited in U.S.
EPA (19851 which reports a 30-minute median lethal concentration (LCso) value of
15,000-25,000 mg/m3 in unspecified laboratory animals. This study also indicates that acute
inhalation of "several alkyl halides" caused ataxia in dogs, rats, and guinea pigs; however, it is
unclear whether these halides included l-bromo-2-chloroethane.
Inhalation toxicity values are available for 1,2-dichloroethane, 1,2-dibromoethane, and
l,2-dibromo-3-chloropropane (see Table A-4), and the data supporting these values are extensive
[reviewed by U.S. EPA (2010. 2006. 2004. 2003)1. Target organs and systems of toxicity for
potential analogues include the testis, kidney, liver, nervous system, and respiratory tract
(see exposure-response arrays in Figures A-4, A-5, A-6, and A-7). Although neurobehavioral
impairment was observed following occupational exposure to 1,2-dichloroethane (impaired
visual-motor reactions in two of three tests), an exposure-response array was not prepared for
this endpoint because no additional neurobehavioral studies were identified for any candidate
analogue in humans or laboratory animals. No information is available regarding the potential
mode of action (MOA) for the observed neurobehavioral effects in humans or animals. Upon
review of the available inhalation toxicity data, testicular and respiratory effects are identified as
the most sensitive toxicity endpoints among the candidate analogues.
Epidemiology studies of l,2-dibromo-3-chloropropane-exposed production workers,
farmers, and pesticide applicators have demonstrated impaired testicular function (decreased
spermatogenesis and sperm count and altered sperm morphology) in exposed humans. Testicular
effects were identified as critical effects for assessment of l,2-dibromo-3-chloropropane
inhalation toxicity in animal studies. A comparison of rat, mouse, and rabbit data indicates that
the rabbit is the most sensitive of these species for testicular effects (by both inhalation and oral
exposure). Oral data indicate that testicular toxicity of l,2-dibromo-3-chloropropane is mediated
exclusively by the GSH conjugation pathway (Omichinski et al.. 1988a; Soderlund et al.. 1988).
This is likely the case also for 1,2-dibromoethane and l-bromo-2-chloroethane, which are
anticipated to undergo GSH conjugation at similar rates because of the expected similar
reactivity of the bromine leaving groups. This reaction leads to the formation of the reactive
episulfonium ion metabolites that are implicated in testicular toxicity (see "Toxicity-Like
Analogues—Oral" section above for more details).
Inhalation exposure to the candidate analogues 1,2-dibromoethane and
l,2-dibromo-3-chloropropane in rats and mice produced respiratory tract lesions, with nasal
effects occurring at lower concentrations than lesions observed in the bronchial, bronchiolar, and
alveolar regions. Respiratory lesions may result, at least in part, from the production of HBr
(from both CYP450 oxidation and GSH conjugation) in the respiratory tract. Nasal irritation has
been observed in volunteers and laboratory animals exposed to HBr gas (NRC. 2014). By
analogy, HBr formation and respiratory lesions may also be expected to occur for the
l-bromo-2-chloroethane target compound. In contrast, 1,2-dichloroethane does not produce nasal
or other respiratory tract lesions following inhalation exposure. This may be partially explained
by the slower release of chlorine relative to bromine during GSH conjugation, resulting in a
reduced rate of generation of HC1 in the respiratory tract of exposed animals (relative to HBr
from the other compounds). The lack of effect by 1,2-dichloroethane supports the hypothesized
role of HBr in the observed respiratory effects.
38
1 -Bromo-2-chloroethane
-------
EPA/690/R-21/005F
Other cytotoxic mechanisms may contribute to the nasal toxicity of 1,2-dibromoethane;
these include lipid peroxidation and/or protein binding induced by anticipated or experimentally
determined metabolites (e.g., 2-bromoacetaldehyde) (U.S. EPA. 2004). By analogy, formation of
2-bromoacetaldehyde and subsequent nasal and/or respiratory lesions may also be expected to
occur for the l-bromo-2-chloroethane target compound.
In the absence of repeated-exposure inhalation toxicity data for l-bromo-2-chloroethane,
there is no information with which to clearly identify or rule out candidate analogues based on
toxicity comparisons. However, based on the expected formation of the episulfonium ion
following metabolism of l-bromo-2-chloroethane, the mechanism of action for testicular toxicity
following exposure to l,2-dibromo-3-chloropropane (and by analogy 1,2-dibromoethane) is
plausible for l-bromo-2-chloroethane. Based on the expected formation of HBr and
2-bromoacetaldehyde following metabolism of l-bromo-2-chloroethane, respiratory toxicity is
also plausible for l-bromo-2-chloroethane.
39
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Figure A-4. Testicular Effects Following Inhalation Exposure to 1,2-Dichloroethane (1,2-DCE), 1,2-Dibromoethane (1,2-DBE), or
l,2-Dibromo-3-Chloropropane (l,2-DB-3-CP) [reviewed by U.S. EPA (2010. 2006. 2004. 2003)1
40
1 -Bromo-2-chloroethane
-------
EPA 690 R-21 005F
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l,2-Dibromo-3-Chloropropane (l,2-DB-3-CP) [reviewed by U.S. EPA (2010. 2006. 2004. 2003)1
41
1 -Bromo-2-chloroethane
-------
EPA 690 R-21 005F
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Figure A-6. Liver Effects Following Inhalation Exposure to 1,2-Dichloroethane (1,2-DCE), 1,2-Dibromoethane (1,2-DBE), or
l,2-Dibromo-3-Chloropropane (l,2-DB-3-CP) [reviewed by U.S. EPA (2010. 2006. 2004. 2003)1
42
1 -Bromo-2-chloroethane
-------
EPA 690 R-21 005F
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Figure A-7. Respiratory Tract Effects Following Inhalation Exposure to 1,2-Dichloroethane (1,2-DCE), 1,2-Dibromoethane
(1,2-DBE), or l,2-Dibromo-3-Chloropropane (l,2-DB-3-CP) [reviewed by U.S. EPA (2010. 2006. 2004. 2003)1
43
1 -Bromo-2-chloroethane
-------
EPA/690/R-21/005F
Weight-of-Evidence Approach
To select the best analogue chemical based on all of the information described within the
three analogue similarity tiers prescribed in Wang et al. (20121 the following considerations are
used in a weight-of-evidence (WOE) approach: (1) lines of evidence from U.S. EPA assessments
are preferred; (2) biological and toxicokinetic data are preferred over the structural similarity
scores; (3) lines of evidence that indicate pertinence to humans are preferred; (4) chronic studies
are preferred over subchronic studies when selecting an analogue for a chronic value;
(5) chemicals with more sensitive toxicity values may be favored; and (6) if there are no clear
indications as to the best analogue chemical based on the other considerations, then the candidate
analogue with the highest structural similarity scores may be preferred.
Oral
The WOE approach used to select the analogue compound for l-bromo-2-chloroethane is
based on mechanistic and metabolism considerations related to the most sensitive critical effect
(i.e., testicular toxicity). Unlike 1,2-dibromoethane and l,2-dibromo-3-chloropropane,
1,2-dichloroethane is not a testicular toxicant. This may be explained by differences in the rate
and extent of GSH adduct formation due in part to differences in the chemical reactivity of the
brominated versus the chlorinated compounds. 1,2-Dibromoethane will react more rapidly with
GSH than 1,2-dichloroethane because bromide is a better chemical leaving group in comparison
to the chloride. That is, the C-Br bond is more readily cleaved than is the C-Cl bond. The results
of this difference are demonstrated by the metabolic products and GSH adducts formed by
l-bromo-2-chloroethane and l,2-dibromo-3-chloropropane. In both cases, bromine is
preferentially displaced when both C-Br and C-Cl bonds are available. The only
GSH-conjugated product detected from l-bromo-2-chloroethane metabolism was CEG, and
episulfonium products of l,2-dibromo-3-chloropropane contain chlorine, indicating that bromine
was preferentially released during metabolism (Dekant and Vamvakas. 1993; Jean and Reed.
1992; Humphreys et al.. 1991; Marchand and Reed. 1989). These data suggest that from the
available identified potential analogue chemicals, chemicals with a bromine leaving group are
expected to be more relevant as an analogue for l-bromo-2-chloroethane. The presence of this
group is expected to significantly influence the rate of GSH conjugation (and ultimately the rate
of toxic moiety production) over analogues containing chlorine leaving groups.
By analogy, l-bromo-2-chloroethane can be expected to form the same episulfonium ion
that is formed from 1,2-dibromoethane and 1,2-dichloroethane after GSH conjugation (see
Table A-2). In the initial reaction, bromine will be preferentially displaced from
l-bromo-2-chloroethane. Although this compound and 1,2-dichloroethane are both expected to
lead to the same initial adduct, l-bromo-2-chloroethane is expected to react faster because of the
presence of a bromide versus chloride leaving group, leading to a higher localized concentration
of the proximal toxicant. Therefore, the rate of initial adduct formation is expected to be more
similar to 1,2-dibromoethane and l,2-dibromo-3-chloropropane than to 1,2-dichloroethane.
Available data suggest that the cyclization of the GSH adducts for each respective analogue is
rapid and immediate, and that this step (leading to the production of the toxic episulfonium ion
moiety) is not likely to be the rate-limiting step in the metabolism of the parent chemicals.
Given the demonstrated significance of the presence of a bromide leaving group in
metabolism and expected toxicity, l-bromo-2-chloroethane, 1,2-dibromoethane, and
44
1 -Bromo-2-chloroethane
-------
EPA/690/R-21/005F
l,2-dibromo-3-chloropropane were determined to be more appropriate analogues compared with
1,2-dichloroethane. Ultimately, l,2-dibromo-3-chloropropane is selected as the most appropriate
analogue compound for both subchronic and chronic effects because the demonstrated testicular
effect of this chemical on sperm is the most sensitive measure of toxicity among the favored
brominated analogues.
Inhalation
The WOE approach used to select the analogue compound for l-bromo-2-chloroethane is
based on mechanistic considerations related to sensitive effects for the candidate brominated
analogues following inhalation exposure (i.e., testicular toxicity and respiratory effects). The
absence of testicular and respiratory tract effects for 1,2-dichloroethane may be explained, at
least in part, by a decrease in the rate and extent of GSH conjugation (i.e., bromine is a better
chemical leaving group than chlorine), leading to a lower localized concentration of proximal
toxicants (i.e., episulfonium ion, HC1). l-Bromo-2-chloroethane can be expected to form both
the reactive episulfonium metabolite (responsible for testicular effects) and HBr (which may
contribute to respiratory lesions) at a similar rate as 1,2-dibromoethane and
l,2-dibromo-3-chloropropane. Both 1,2-dibromoethane and l,2-dibromo-3-chloropropane
release HBr during GSH conjugation, and this is expected to occur for l-bromo-2-chloroethane.
As described above, the rate of GSH conjugation among brominated compounds, rapid
cyclization of GSH conjugates to generate reactive episulfonium ions, and the release of HBr
during GSH conjugation suggest that the brominated analogues are more appropriate surrogate
chemicals for l-bromo-2-chloroethane than 1,2-dichloroethane. However, these characteristics
do not provide a means to sufficiently differentiate amongst the brominated analogues.
Ultimately, l,2-dibromo-3-chloropropane is selected as the analogue compound for both
subchronic and chronic inhalation exposure because the demonstrated effect of this chemical on
sperm is among the most sensitive measures of toxicity among the favored brominated
analogues, and the relevance of this endpoint to humans is supported by the observation of
similar effects in exposed workers (U.S. EPA. 2006).
NONCANCER ORAL TOXICITY VALUES
Derivation of a Screening Subchronic Provisional Reference Dose
Based on the overall analogue approach presented in this PPRTV assessment,
l,2-dibromo-3-chloropropane is selected as the analogue for l-bromo-2-chloroethane for
deriving a screening subchronic p-RfD. The study used for the U.S. EPA subchronic p-RfD for
l,2-dibromo-3-chloropropane was a 10-week reproductive study in rabbits [Foote et al.
(1986a, b) as cited in U.S. EPA (2006)1 described as follows:
Groups of 6 male Dutch rabbits were exposed to drinking water that
provided reportedDBCP intakes of 0, 0.94, 1.88, 3.75, 7.5 or 15.0 mg/kg on
5 days/week (0, 0.7, 1.3, 2.7, 5.4 or 10.7 mg/kg-day) for 10 weeks (Foote et al.,
1986a, 1986b). General health, body weight, semen quality, and libido were
evaluated throughout the study. Assessments of fertility (mated with untreated
females) and serum levels of reproductive hormones (follicle stimulation
hormone, luteinizing hormone and testosterone) were performed during the last
week of the study. Endpoints evaluated following sacrifice at the end of the study
45
1 -Bromo-2-chloroethane
-------
EPA/690/R-21/005F
included organ weights (liver, kidneys, testes, epididymides, accessory sex
glands), quantitative histology of testes and epididymides, and sperm morphology
and forward motility and morphology. There were no statistically significant
(p < 0.05) changes in any of the study endpoints at 0.7 mg/kg-day. Effects
observed at higher doses included dose-related reductions in numbers of all germ
cell types within Stage I seminiferous tubular cross sections (significantly reduced
numbers of spermatogonia and preleptotene spermatocytes at >1.3 mg/kg-day,
pachytene spermatocytes at >2.7 mg/kg-day, and round spermatids at
>5.4 mg/kg-day) (Table 1 [in U.S. EPA 2006\). Other effects included dose-
related significantly reduced numbers of leptotene primary spermatocytes per
Sertoli cell at >2.7 mg/kg-day, and significantly reduced mean diameter of
seminiferous tubules and increased percentage of sperm with abnormal tails at
>5.4 mg/kg-day (Table 2 [in U.S. EPA 2006\). Testis weight and volume, and
sperm production (number of seminiferous tubules with round or elongating
spermatids), output (ejaculate volume times sperm concentration) and motility
were reduced, and serum FSH level was increased, at 10.7 mg/kg-day (Table 3 [in
U.S. EPA 2006]./ Fertility was not affected at any dose level, as assessed by
number of males producing young, number or percentage of live births, total
number of young, average litter size, and gestation length. The results
summarized above are based on comparisons of mean data from the treated and
control groups. Regression analyses showed highly significant correlations
between DBCP dosage and essentially all of the testicular responses. The findings
of this study indicate that rabbits are more sensitive than rats to testicular effects
of DBCP. This study identified a NOAEL of 0.7 mg/kg-day and LOAEL of
1.3 mg/kg-day for reproductive toxicity in male rabbits.
The critical effect in this study was testicular toxicity in male rabbits; the
no-observed-adverse-effect level (NOAEL) of 0.7 mg/kg-day was used as the point of departure
(POD) for l,2-dibromo-3-chloropropane (U.S. EPA. 2006) and is adopted as the analogue POD
for the current assessment of l-bromo-2-chloroethane.
For the current assessment, the NOAEL of 0.7 mg/kg-day was converted to a human
equivalent dose (HED) according to current (U.S. HP A. 2011c) guidance. In Recommended Use
of Body Weight3/4 as the Default Method in Derivation of the Oral Reference Dose (U.S. EPA.
2011c). the Agency endorses body-weight scaling to the 3/4 power (i.e., BW3'4) as a default to
extrapolate toxicologically equivalent doses of orally administered agents from all laboratory
animals to humans for the purpose of deriving an RfD from effects that are not portal-of-entry
effects.
Following U.S. EPA (2011c) guidance, the POD for testicular effects in male rabbits is
converted to an HED by applying a dosimetric adjustment factor (DAF) derived as follows:
46
1 -Bromo-2-chloroethane
-------
EPA/690/R-21/005F
DAF = (BWa1 4 - BWh14)
where
DAF = dosimetric adjustment factor
BWa = animal body weight
BWh = human body weight
Using a reference BWa of 2.86 kg for rabbits and a reference BWh of 70 kg for humans
(U.S. EPA. 1988). the resulting DAF is 0.45. Applying this DAF to the NOAEL of
0.7 mg/kg-day yields a POD (HED) as follows:
POD (HED) = NOAEL (mg/kg-day) x DAF
= 0.7 mg/kg-day x 0.45
= 0.3 mg/kg-day
The U.S. EPA (2006) sub chronic p-RfD for l,2-dibromo-3-chloropropane was derived
using a composite uncertainty factor (UFc) of 300, reflecting 10-fold uncertainty factors for
interspecies extrapolation and intraspecies variability and a 3-fold uncertainty factor for database
uncertainties (UFa, UFh, and UFd, respectively). Wang et al. (2012) indicated that the
uncertainty factors typically applied in deriving a toxicity value for the selected analogue are the
same as those applied to the chemical of concern unless additional information is available. For
l-bromo-2-chloroethane, a UFa of 3 is applied because cross-species dosimetric adjustment was
performed, and a UFd of 10 was used to reflect the lack of repeated-dose toxicity data; the UFh
remained the same as for l,2-dibromo-3-chloropropane. Thus, the screening subchronic p-RfD
for l-bromo-2-chloroethane is derived using a UFc of 300.
Screening Subchronic p-RfD = Analogue POD (HED) UFc
= 0.3 mg/kg-day -^300
= 1 x 10"3 mg/kg-day
Table A-5 summarizes the uncertainty factors for the screening subchronic p-RfD for
1 -bromo-2-chloroethane.
47
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EPA/690/R-21/005F
Table A-5. Uncertainty Factors for the Screening Subchronic p-RfD for
l-Bromo-2-Chloroethane (CASRN 107-04-0)
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for uncertainty in characterizing the toxicokinetic or
toxicodynamic differences between rabbits and humans following l-bromo-2-chloroethane exposure.
The toxicokinetic uncertainty has been accounted for by calculating an HED through application of a
DAF as outlined in the U.S. EPA's Recommended Use of Body Weight4 as the Default Method in
Derivation of the Oral Reference Dose CU.S. EPA. 20110). Dosimetric adjustment calculations were
performed on the POD for the selected analogue, l,2-dibromo-3-chloropropane.
UFd
10
A UFd of 10 is applied to reflect database limitations for l,2-dibromo-3-chloropropane and the
absence of repeated-dose toxicity data for l-bromo-2-chloroethane.
UFh
10
A UFh of 10 is applied for interindividual variability to account for human-to-human variability in
susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of l-bromo-2-chloroethane in humans.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is a NOAEL.
UFs
1
A UFS of 1 is applied because a subchronic study was selected as the principal study for the
subchronic assessment.
UFC
300
Composite uncertainty factor = UFA x UFD x UFH x UFL x UFS.
DAF = dosimetric adjustment factor; HED = human equivalent dose; LOAEL = lowest-observed-adverse-effect
level; NOAEL = no-observed-adverse-effect level; POD = point of departure; p-RfD = provisional reference dose;
UF = uncertainty factor; UFA = interspecies uncertainty factor; UFC = composite uncertainty factor;
UFd = database uncertainty factor; UFH = intraspecies uncertainty factor; UFL = LOAEL-to-NOAEL uncertainty
factor; UFS = subchronic-to-chronic uncertainty factor.
Derivation of a Screening Chronic Provisional Reference Dose
l,2-Dibromo-3-chloropropane is also selected as the analogue for
l-bromo-2-chloroethane for deriving a screening chronic p-RfD. The key study and calculation
of the POD (HED) are described above for the subchronic p-RfD. The uncertainty factors used
for the screening subchronic p-RfD (UFa of 3, UFh of 10, and UFd of 10) are applied, and a UFs
of 10 is applied to account for extrapolation from a subchronic to a chronic duration (consistent
with the UFs applied during the derivation of the chronic p-RfD for
l,2-dibromo-3-chloropropane). Thus, the screening chronic p-RfD for l-bromo-2-chloroethane is
derived using a UFc of 3,000.
Screening Chronic p-RfD = Analogue POD (HED) UFc
= 0.3 mg/kg-day ^ 3,000
= 1 x 10"4 mg/kg-day
Table A-6 summarizes the uncertainty factors for the screening chronic p-RfD for
1 -bromo-2-chloroethane.
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Table A-6. Uncertainty Factors for the Screening Chronic p-RfD for
l-Bromo-2-Chloroethane (CASRN 107-04-0)
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for uncertainty in characterizing the toxicokinetic or
toxicodynamic differences between rabbits and humans following l-bromo-2-chloroethane exposure.
The toxicokinetic uncertainty has been accounted for by calculating an HED through application of a
DAF as outlined in the U.S. EPA's Recommended Use of Body Weight4 as the Default Method in
Derivation of the Oral Reference Dose CU.S. EPA. 201 lc). Dosimetric adjustment calculations were
performed on the POD for the selected analogue, l,2-dibromo-3-chloropropane.
UFd
10
A UFd of 10 is applied to reflect database limitations for l,2-dibromo-3-chloropropane and the
absence of repeated-dose toxicity data for l-bromo-2-chloroethane.
UFh
10
A UFh of 10 is applied for interindividual variability to account for human-to-human variability in
susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of l-bromo-2-chloroethane in humans.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is a NOAEL.
UFS
10
A UFS of 10 is applied because a subchronic study was selected as the principal study for the chronic
assessment.
UFC
3,000
Composite uncertainty factor = UFA x UFD x UFH x UFL x UFS.
DAF = dosimetric adjustment factor; HED = human equivalent dose; LOAEL = lowest-observed-adverse-effect
level; NOAEL = no-observed-adverse-effect level; POD = point of departure; p-RfD = provisional reference dose;
UF = uncertainty factor; UFA = interspecies uncertainty factor; UFC = composite uncertainty factor;
UFd = database uncertainty factor; UFH = intraspecies uncertainty factor; UFL = LOAEL-to-NOAEL uncertainty
factor; UFS = subchronic-to-chronic uncertainty factor.
NONCANCER INHALATION TOXICITY VALUES
Derivation of a Screening Subchronic Provisional Reference Concentration
Based on the overall analogue approach presented in this PPRTV assessment,
l,2-dibromo-3-chloropropane is selected as the most appropriate analogue for
l-bromo-2-chloroethane for deriving a screening subchronic p-RfC. The study used for the
subchronic p-RfC for l,2-dibromo-3-chloropropane was a 14-week study in rabbits [Rao et al.
(1982) as cited in U.S. EPA (2006)1. U.S. EPA (2006) described the study as follows:
In rabbits, reproductive toxicity was evaluated in groups of 10 New
Zealand white males (age 6 months) that were exposed to 0, 0.1, 1 or 10 ppm (0,
0.94, 9.4 or 94 mg/m3) vapor for 6 hours/day, 5 days/week for 14 weeks, and
observed for the following 32 weeks (0, 0.1 and 1 ppm groups) or 38 weeks
(10ppm group) (Rao et al., 1982). The 10ppm rabbits were exposedfor only
8 weeks due to high mortality (apparently from pneumonia). Body weight and
hematological and clinical chemistry parameters were evaluated, but no exposure
related changes were found. No gross lesions were found in the lungs or upper
respiratory tract, but these tissues were not examined histologically. Semen was
collected during the exposure and recovery periods to assess sperm motility,
viability and counts. The average sperm count of the 10-ppm rabbits was
significantly less than that of the controls after 7 weeks of exposure, and remained
49
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EPA/690/R-21/005F
decreasedfor the duration of the exposure and observation periods. At 1 ppm
(9.4 mg/m3), sperm counts were significantly reduced, compared with controls,
from weeks 11 to 13 of exposure. At 0.1 ppm (0.94 mg/m3), sperm counts were
sporadically lower than control values (significantly reduced at only one interim
time point). The percentage of live sperm in the semen of the 10 ppm (94 mg/m3)
rabbits was also significantly reduced compared to controls during weeks 8-26.
Rabbits exposed to 1 ppm (9.4 mg/m3), but not those exposed to 0.1 ppm
(0.94 mg/m3), exhibited significant decreases in the percentage of live sperm
during weeks 6, 12 and 13. From the 8th week of exposure onward, the 10-ppm
(94 mg/m3) rabbits had a marked decrease in the percentage of progressively
motile sperm; no consistent statistically significant decreases in this endpoint
were found at <1 ppm (9.4 mg/m3) (Table 4 [in U.S. EPA 2006]).
Abnormal spermatozoa within the seminiferous tubules were counted in
3-4 rabbits per group; the percentage of abnormal sperm at 14 weeks was 5% in
controls, 10% at 0.1 ppm (0.94 mg/m3), and 18% at 1 ppm (9.4 mg/m3).
To assess the effects ofDBCP on fertility in the rabbits, exposed males
were mated to unexposedfemales at study weeks 14 and 41 (Rao et al., 1982)
(Tables 5, 6 [in U.S. EPA 2006]). There were no effects on the libido of the
exposed male rabbits during week 14, based on percentages of males (78-100%)
that copulated with unexposed females. Five of the 10 males exposed to 10 ppm
were infertile (none of the females that they were mated with became pregnant).
The mean number of implantations/litter in the 1 ppm (9.4 mg/m3) group was
significantly less than that of the control group. During week 41 (27 weeks
post-exposure), all rabbits exposed to 0.1 or 1 ppm (0.94 or 9.4 mg/m3) DBCP
produced normal litters, and 2 of the 5 infertile males exposed to 10 ppm
(94 mg/m3) recovered (sperm counts increased) and produced normal litters.
Serum levels of follicle stimulating hormone (FSH) were significantly elevated at
14 weeks in the males exposed to 1 ppm (9.4 mg/m3) and at 46 weeks in the males
exposed to 10 ppm (94 mg/m3), but serum levels of testosterone were unchanged
(Table 7 [in U.S. EPA 2006]). The increases in serum FSH were consistent with
the decreases in sperm count. Gross pathologic examinations showed small testes
size in rabbits exposed to 1 or 10 ppm. Testes weight was significantly decreased
to 50% of control values (week 14) in the group exposed to 1 ppm (9.4 mg/m3)
and to 75% of control values (week 8) in the group exposed to 10 ppm.
Histological examinations showed reproductive system effects that included
atrophy of the testes, epididymides, and accessory sex glands, including the
prostate. The testicular atrophy was severe, as characterized by nearly complete
or complete loss of spermatogenic elements in nearly all seminiferous tubules.
Following the recovery period, tubular regeneration was observed in the testes of
some 10 ppm (94 mg/m3) rabbits (3/5 had regeneration such that 25% of the
seminiferous tubules appeared normal). At 1 ppm, testicular recovery was
reported to be nearly complete in some rabbits (incidences not given). The testes
of the 0.1 ppm rabbits appeared normal. The lack of exposure-related adverse
testicular and fertility effects at 0.1 ppm indicates that this study identified a
50
1 -Bromo-2-chloroethane
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EPA/690/R-21/005F
NOAEL of 0.1 ppm (0.94 mg/m3) andLOAEL of 1 ppm (9.4 mg/m3) for
reproductive effects in rabbits.
The critical effect in this study was testicular toxicity in male rabbits; the NOAEL of
0.94 mg/m3 was used as the POD for l,2-dibromo-3-chloropropane. The U.S. EPA (2006)
calculated a POD (human equivalent concentration [HEC]) according to U.S. EPA (1994)
guidance for Category 3 gases by adjusting intermittent exposure levels to a continuous exposure
basis (U.S. HP A. 2002) and multiplying the result by a ratio of the animal blood-gas partition
coefficient (concentration ^ concentration) for l,2-dibromo-3-chloropropane to the human
blood-gas partition coefficient (concentration ^ concentration) for l,2-dibromo-3-chloropropane.
Because blood-air partition coefficients for l,2-dibromo-3-chloropropane are unknown, a default
value of 1 was assigned.
POD (HEC) = NOAEL (mg/m3) x (hours exposed/24 hours) x
(days/week exposed/7 days) x (animal blood-gas partition
coefficient ^ human blood-gas partition coefficient)
= 0.94 mg/m3 x (6/24) x (5/7) x 1
= 0.17 mg/m3
The POD (HEC) of 0.17 mg/m3 derived for 1,2-dibromo-3-chloropropane by U.S. EPA
(2006) is adopted as the analogue POD (HEC) for the current assessment of
1 -bromo-2-chloroethane.
The U.S. EPA (2006) sub chronic p-RfC for l,2-dibromo-3-chloropropane was derived
using a UFc of 100 to account for uncertainties due to interspecies extrapolation (UFa = 3),
intraspecies variability (UFn = 10), and database uncertainties (UFd = 3) (U.S. HP A. 2006).
Wang et al. (2012) indicated that the uncertainty factors typically applied in deriving a toxicity
value for the chemical of concern are the same as those applied to the analogue unless additional
information is available. Because no repeated-exposure inhalation toxicity data are available for
l-bromo-2-chloroethane, a UFd of 10 is used; other UF values remain the same as for
l,2-dibromo-3-chloropropane. Thus, the screening subchronic p-RfC for
l-bromo-2-chloroethane is derived using a UFc of 300, reflecting a UFa of 3, a UFh of 10, and a
UFd of 10.
Screening Subchronic p-RfC = Analogue POD (HEC) ^ UFc
= 0.17 mg/m3 ^ 300
= 6 x 10"4 mg/m3
Table A-7 summarizes the uncertainty factors for the screening subchronic p-RfC for
1 -bromo-2-chloroethane.
51
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EPA/690/R-21/005F
Table A-7. Uncertainty Factors for the Screening Subchronic p-RfC for
l-Bromo-2-Chloroethane (CASRN 107-04-0)
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for uncertainty associated with extrapolating from animals
to humans when cross-species dosimetric adjustment (HEC calculation) is performed. Dosimetric
adjustment calculations were performed on the POD for the selected analogue,
1,2-dibromo-3 -chloropropane.
UFd
10
A UFd of 10 is applied to reflect database limitations for l,2-dibromo-3-chloropropane and the
absence of repeated-exposure toxicity data for l-bromo-2-chloroethane.
UFh
10
A UFh of 10 is applied for interindividual variability to account for human-to-human variability in
susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of l-bromo-2-chloroethane in humans.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is a NOAEL.
UFS
1
A UFS of 1 is applied because a subchronic study was selected as the principal study for the
subchronic assessment.
UFC
300
Composite uncertainty factor = UFA x UFD x UFH x UFL x UFS.
HEC = human equivalent concentration; LOAEL = lowest-observed-adverse-effect level;
NOAEL = no-observed-adverse-effect level; POD = point of departure; p-RfC = provisional reference
concentration; UF = uncertainty factor; UFA = interspecies uncertainty factor; UFC = composite uncertainty factor;
UFd = database uncertainty factor; UFH = intraspecies uncertainty factor; UFL = LOAEL-to-NOAEL uncertainty
factor; UFS = subchronic-to-chronic uncertainty factor.
Derivation of a Screening Chronic Provisional Reference Concentration
l,2-Dibromo-3-chloropropane is also selected as the analogue for
l-bromo-2-chloroethane for deriving a screening chronic p-RfC. The key study and calculation
of the POD (HEC) are described above for the subchronic p-RfC. The uncertainty factor values
used for the screening subchronic p-RfC (UFa of 3, UFh of 10, and UFd of 10) are applied, and a
UFs of 10 is applied to account for extrapolation from a subchronic to a chronic duration
(consistent with the UFs applied during the derivation of the chronic RfC for
1,2-dibromo-3-chloropropane) (U.S. EPA. 2003). Thus, the screening chronic p-RfC for
l-bromo-2-chloroethane is derived using a UFc of 3,000.
Screening Chronic p-RfC = Analogue POD (HEC) UFc
0.17 mg/m3-3,000
= 6 x 10"5 mg/m3
Table A-8 summarizes the uncertainty factors for the screening chronic p-RfC for
1 -bromo-2-chloroethane.
52
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EPA/690/R-21/005F
Table A-8. Uncertainty Factors for the Screening Chronic p-RfC for
l-Bromo-2-Chloroethane (CASRN 107-04-0)
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for uncertainty associated with extrapolating from animals to
humans when cross-species dosimetric adjustment (HEC calculation) is performed. Dosimetric
adjustment calculations were performed on the POD for the selected analogue,
1,2-dibromo-3 -chloropropane.
UFd
10
A UFd of 10 is applied to reflect database limitations for l,2-dibromo-3-chloropropane and the
absence of repeated-exposure toxicity data for l-bromo-2-chloroethane.
UFh
10
A UFh of 10 is applied for interindividual variability to account for human-to-human variability in
susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of l-bromo-2-chloroethane in humans.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is a NOAEL.
UFS
10
A UFS of 10 is applied because a subchronic study was selected as the principal study for the chronic
assessment.
UFC
3,000
Composite uncertainty factor = UFA x UFD x UFH x UFL x UFS.
HEC = human equivalent concentration; LOAEL = lowest-observed-adverse-effect level;
NOAEL = no-observed-adverse-effect level; POD = point of departure; p-RfC = provisional reference
concentration; UF = uncertainty factor(s); UFA = interspecies uncertainty factor; UFC = composite uncertainty
factor; UFD = database uncertainty factor; UFH = intraspecies uncertainty factor; UFL = LOAEL-to-NOAEL
uncertainty factor; UFS = subchronic-to-chronic uncertainty factor.
53
1 -Bromo-2-chloroethane
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EPA 690 R-21 005F
APPENDIX B. BACKGROUND AND METHODOLOGY FOR THE SCREENING
EVALUATION OF POTENTIAL CARCINOGENICITY
For reasons noted in the main Provisional Peer-Reviewed Toxicity Value (PPRTV)
document, there is inadequate information to assess the carcinogenic potential of
l-bromo-2-chloroethane. However, information is available for this chemical which, although
insufficient to support a weight-of-evidence (WOE) descriptor and derivation of provisional
cancer risk estimates under current guidelines, may be of limited use to risk assessors. In such
cases, the Center for Public Health and Environmental Assessment (CPHEA) summarizes
available information in an appendix and develops a "screening evaluation of potential
carcinogenicity." Appendices receive the same level of internal and external scientific peer
review as the provisional cancer assessments in PPRTVs to ensure their appropriateness within
the limitations detailed in the document. Users of the information regarding potential
carcinogenicity in this appendix should understand that there could be more uncertainty
associated with this evaluation than for the cancer WOE descriptors presented in the body of the
assessment. Questions or concerns about the appropriate use of the screening evaluation of
potential carcinogenicity should be directed to the CPHEA.
The screening evaluation of potential carcinogenicity includes the general steps shown in
Figure B-l. The methods for Steps 1 through 8 apply to any target chemical and are described in
this appendix. Chemical-specific data for all steps in this process are summarized in Appendix C.
STEP 1
Use automated tools
to identify an initial
list of structural
analogues with
genotoxicity and/or
carcinogenicity data
STEP 4
Summarize ADME
data from targeted
literature searches.
Identify metabolites
likely related to
genotoxic and/or
carcinogenic alerts
Apply expert
judgment to refine
the list of analogues
(based on
physicochemical
properties, ADME,
and mechanisms of
toxicity)
Compare
experimental
genotoxicity data (if
any) for the target
and analogue
compounds
STEP 5
Summarize cancer
data and MOA
information for
analogues
STEP 8
Assign qualitative
level of concern for
carcinogenicity based
on evidence
integration (potential
concern or
inadequate
information)
Use computational
tools to identify
common structural
alerts and SAR
predictions for
genotoxicity and/or
carcinogenicity
Integrate evidence
streams
Figure B-l. Steps Used in the Screening Evaluation of Potential Carcinogenicity
54 l-Bromo-2-chloroethane
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EPA 690 R-21 005F
STEP 1. USE OF AUTOMATED TOOLS TO IDENTIFY STRUCTURAL ANALOGUES
WITH CARCINOGENICITY AND/OR GENOTOXICITY DATA
ChemACE Clustering
The U.S. EPA's Chemical Assessment Clustering Engine [ChemACE; U.S. EPA
(2011a)1 is an automated tool that groups (or clusters) a user-defined list of chemicals based on
chemical structure fragments. The methodology used to develop ChemACE was derived from
U.S. EPA's Analog Identification Methodology (AIM) tool, which identifies structural analogues
for a chemical based on common structural fragments. ChemACE uses the AIM structural
fragment recognition approach for analogue identification and applies advanced queries and
user-defined rules to create the chemical clusters. The ChemACE cluster outputs are available in
several formats and layouts (i.e., Microsoft Excel, Adobe PDF) to allow rapid evaluation of
structures, properties, mechanisms, and other parameters, which are customizable based on an
individual user's needs. ChemACE clustering has been successfully used with chemical
inventories for identifying trends within a series of structurally similar chemicals, demonstrating
structural diversity in a chemical inventory, and detecting structural analogues to fill data gaps
and/or perform read-across.
For this project, ChemACE is used to identify potential structural analogues of the target
compound that have available carcinogenicity assessments and/or carcinogenicity data. An
overview of the ChemACE process is shown in Figure B-2.
Create and curate an
inventory of chemicals with
carcinogenicity
assessments and/or cancer
data
Cluster the target
compound with the
chemical inventory using
ChemACE
Identify structural
analogues for the target
compound from specific
ChemACE clusters
lists:
Figure B-2. Overview of ChemACE Process
The chemical inventory was populated with chemicals from the following databases and
Carcinogenic Potency Database [CPDB; CPDB (2011)1
Agents classified by the International Agency for Research on Cancer (IARC)
monographs (IARC. 2018)
National Toxicology Program (NTP) Report on Carcinogens [ROC; NTP (2016a)1
NTP technical reports (NTP. 2017)
Integrated Risk Information (IRIS) carcinogens (U.S. EPA. 2017)
California EPA Prop 65 list (CalEPA. 2020)
European Chemicals Agency (ECHA) carcinogenicity data available in the Organisation
for Economic Co-operation and Development (OECD) Quantitative Structure-Activity
Relationship (QSAR) Toolbox (OECD. 2018)
PPRTVs for Superfund (U.S. EPA. 2020d)
55
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EPA/690/R-21/005F
In total, 2,123 distinct substances were identified from the sources above. For the purpose
of ChemACE clustering, each individual substance needed to meet the following criteria:
1) Substance is not a polymer, metal, inorganic, or complex salt because ChemACE is not
designed to accommodate these substances;
2) Substance has a CASRN or unambiguous chemical identification; and
3) Substance has a unique Simplified Molecular Input Line Entry System (SMILES)
notation (encoded molecular structure format used in ChemACE) that can be identified
from one of these sources:
a. Syracuse Research Corporation (SRC) and Distributed Structure-Searchable Toxicity
(DSSTox) database lists of known SMILES associated with unique CASRNs (the
combined lists contained >200,000 SMILES) or
b. ChemlDplus, U.S. EPA Chemicals Dashboard, or internet searches.
Of the initial list of 2,123 substances, 201 were removed because they did not meet one
of the first two criteria, and 155 were removed because they did not meet the third. The final
inventory of substances contained 1,767 unique compounds.
Two separate ChemACE approaches were compared for clustering of the chemical
inventory. The restrictive clustering approach, in which all compounds in a cluster contain all of
the same fragments and no different fragments, resulted in 208 clusters. The less restrictive
approach employed the following rules for remapping the chemical inventory:
• treat adjacent halogens as equivalent, allowing fluorine (F) to be substituted for chlorine
(CI), CI for bromine (Br), Br for iodine (I);
• allow methyl, methylene, and methane to be equivalent;
• allow primary, secondary, and tertiary amines to be equivalent; and
• exclude aromatic thiols (removes thiols from consideration).
Clustering using the less restrictive approach (Pass 2) resulted in 284 clusters. ChemACE
results for clustering of the target chemical within the clusters of the chemical inventory are
described in Appendix C.
Analogue Searches in the OECD QSAR Toolbox (Dice Method)
The OECD QSAR Toolbox (Version 4.1) is used to search for additional structural
analogues of the target compound. There are several structural similarity score equations
available in the toolbox (Dice, Tanimoto, Kulczynski-2, Ochiai/Cosine, and Yule). Dice is
considered the default equation. The specific options that are selected for the performance of this
search include a comparison of molecular features (atom-centered fragments) and atom
characteristics (atom type, count hydrogens attached, and hybridization). Chemicals identified in
these similarity searches are selected if their similarity scores exceeded 50%.
The OECD QSAR Toolbox Profiler is used to identify those structural analogues from
the Dice search that have carcinogenicity and/or genotoxicity data. Nine databases in the OECD
QSAR Toolbox (Version 4.1) provide data for carcinogenicity or genotoxicity (see Table B-l).
Analogue search results for the target chemical are described in Appendix C.
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Table B-l. Databases Providing Carcinogenicity and Genotoxicity Data in the OECD
QSAR Toolbox (Version 4.1)
Database Name
Toolbox Database Description3
CPDB
The CPDB provides access to bioassay literature with qualitative and quantitative
analysis of published experiments from the general literature (through 2001) and from
the NCI/NTP (through 2004). Reported results include bioassays in rats, mice,
hamsters, dogs, and nonhuman primates. A calculated carcinogenic potency (TD5o) is
provided to standardize quantitative measures for comparison across chemicals. The
CPDB contains 1,531 chemicals and 3,501 data points.
ISSCAN
The ISSCAN database provides information on carcinogenicity bioassays in rats and
mice reported in sources including NTP, CPDB, CCRIS, and IARC. This database
reports a carcinogenicity TD5o. There are 1,149 chemicals and 4,518 data points
included in the ISSCAN database.
ECHA CHEM
The ECHA CHEM database provides information on chemicals manufactured or
imported in Europe from registration dossiers submitted by companies to ECHA to
comply with the REACH Regulation framework. The ECHA database includes
9,229 chemicals with almost 430,000 data points for a variety of endpoints including
carcinogenicity and genotoxicity. ECHA does not verily the information provided by
the submitters.
ECVAM Genotoxicity and
Carcinogenicity
The ECVAM Genotoxicity and Carcinogenicity database provides genotoxicity and
carcinogenicity data for Ames positive chemicals in a harmonized format. ECVAM
contains in vitro and in vivo bacteria mutagenicity, carcinogenicity, CA,
CA/aneuploidy, DNA damage, DNA damage and repair, mammalian culture cell
mutagenicity, and rodent gene mutation data for 744 chemicals and 9,186 data points.
ISSCTA
ISSCTA provides results of four types of in vitro cell transformation assays including
Syrian hamster embryo cells, mouse BALB/c 3T3, mouse C3H/10T1/2, and mouse
Bhas 42 assays that inform nongenotoxic carcinogenicity. ISSCTA consists of
352 chemicals and 760 data points.
Bacterial mutagenicity
ISSSTY
The ISSSTY database provides data on in vitro Salmonella typhimurium Ames test
mutagenicity (positive and negative) taken from the CCRIS database in TOXNET. The
ISSSTY database provides data for 7,367 chemicals and 41,634 data points.
Genotoxicity OASIS
The Genotoxicity OASIS database provides experimental results for mutagenicity
results from "Ames tests (with and without metabolic activation), in vitro chromosomal
aberrations and MN and MLA evaluated in vivo and in vitro, respectively." The
Genotoxicity OASIS database consists of 7,920 chemicals with 29,940 data points
from 7 sources.
Micronucleus OASIS
The Micronucleus OASIS database provides experimental results for in vivo bone
marrow and peripheral blood MNT CA studies in blood erythrocytes, bone marrow
cells, and polychromatic erythrocytes of humans, mice, rabbits, and rats for
557 chemicals.
57
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Table B-l. Databases Providing Carcinogenicity and Genotoxicity Data in the OECD
QSAR Toolbox (Version 4.1)
Database Name
Toolbox Database Description3
ISSMIC
The ISSMIC database provides data on the results of in vivo MN mutagenicity assays
to detect CAs in bone marrow cells, peripheral blood cells, and splenocytes in mice and
rats. Sources include TOXNET, NTP, and the Leadscope FDA CRADA Toxicity
Database. The ISSMIC database includes data for 563 chemicals and 1,022 data points.
'Descriptions were obtained from the OECD QSAR Toolbox documentation | Version 4.1; OECD (2018)1.
CA = chromosomal aberration; CCRIS = Chemical Carcinogenesis Research Information System;
CPBD = Carcinogenic Potency Database; CRADA = Cooperative Research and Development Agreement;
DNA = deoxyribonucleic acid; ECHA = European Chemicals Agency; ECVAM = European Centre for the
Validation of Alternative Methods; FDA = Food and Drug Administration; IARC = International Agency for
Research on Cancer; ISSCAN = Istituto Superiore di Sanita Chemical Carcinogen; ISSCTA = Istituto Superiore di
Sanita Cell Transformation Assay; ISSMIC = Istituto Superiore di Sanita Micronucleus; ISSSTY = Istituto
Superiore di Sanita Salmonella typhimurium; ML A = mouse lymphoma gene mutation assay; MN = micro nuclei;
MNT = micronucleus test; NCI = National Cancer Institute; NTP = National Toxicology Program;
OECD = Organisation for Economic Co-operation and Development; QSAR = quantitative structure-activity
relationship; REACH = Registration, Evaluation, Authorisation and Restriction of Chemicals; TD5o = median toxic
dose.
STEPS 2-5. ANALOGUE REFINEMENT AND SUMMARY OF EXPERIMENTAL
DATA FOR GENOTOXICITY, TOXICOKINETICS, CARCINOGENICITY, AND
MODE OF ACTION
The outcome of the Step 1 analogue identification process using ChemACE and the
OECD QSAR Toolbox is an initial list of structural analogues with genotoxicity and/or
carcinogenicity data. Expert judgment is applied in Step 2 to refine the list of analogues based on
physicochemical properties; absorption, distribution, metabolism, and excretion (ADME); and
mechanisms of toxicity. The analogue refinement process is chemical specific and is described in
Appendix C. Steps 3, 4, and 5 (summary of experimental data for genotoxicity, toxicokinetics,
carcinogenicity, and mode of action [MOA]) are also chemical specific (see Appendix C for
further details).
STEP 6. STRUCTURAL ALERTS AND STRUCTURE-ACTIVITY RELATIONSHIP
PREDICTIONS FOR l-BROMO-2-CHLOROETHANE AND ANALOGUES
Structural alerts (SAs) and predictions for genotoxicity and carcinogenicity are identified
using six freely available structure-based tools (described in Table B-2).
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Table B-2. Tools Used to Identify Structural Alerts and Prediction of Carcinogenicity and
Genotoxicity
Name
Description3
OECD QSAR
Toolbox
(Version 4.1)
Seven OECD QSAR Toolbox profiling methods were used, including:
• Carcinogenicity (genotox and nongenotox) alerts by ISS (Version 2.3); updated version of
the module originally implemented in Toxtree. It is a decision tree for estimating
carcinogenicity, based on 55 SAs (35 from the Toxtree module and 20 newly derived).
• DNA alerts for Ames by OASIS (Version 1.4); based on the Ames mutagenicity TIMES
model, uses 85 SAs responsible for interaction of chemicals with DNA.
• DNA alerts for CA and MNT by OASIS (Version 1.1); based on the DNA reactivity of the
CAs TIMES model, uses 85 SAs for interaction of chemicals with DNA.
• In vitro mutagenicity (Ames test) alerts by ISS (Version 2.3); based on the Mutagenicity
module in Toxtree. It is a decision tree for estimating in vitro (Ames test) mutagenicity,
based on a list of 43 SAs relevant for the investigation of chemical genotoxicity via DNA
adduct formation.
• In vivo mutagenicity (MN) alerts by ISS (Version 2.3); based on the ToxMic rulebase in
Toxtree. The rule base has 35 SAs for in vivo MN assay in rodents.
• OncoLogic Primary Classification (Version 4.0); "developed by LMC and OECD to mimic
the structural criteria of chemical classes of potential carcinogens covered by the
U.S. EPA's OncoLogic Cancer Expert System for Predicting the Carcinogenicity
Potential" for categorization purposes only, not for predicting carcinogenicity. It is
applicable to organic chemicals with at least one of the 48 alerts specified.
• Protein binding alerts for CAs by OASIS (Version 1.3); based on 33 SAs for interactions
with specific proteins including topoisomerases, cellular protein adducts, etc.
OncoLogic
(Version 7)
OncoLogic is a tool for predicting the potential carcinogenicity of chemicals based on the
application of rules for SAR analysis, developed by experts. Results may range from "low" to
"high" concern level.
ToxAlerts
ToxAlerts is a platform for screening chemical compounds against SAs, developed as an
extension to the OCHEM svstem (httos://ochem.eu). Onlv "approved alerts" were selected,
which corresponds to a moderator approved the submitted data. A list of the ToxAlerts found
for the chemicals screened in the preliminary batch is below:
• Genotoxic carcinogenicity, mutagenicity
o Aliphatic halide (general)
o Aliphatic halide (specific)
o Aliphatic halogens
o Aromatic amine (general)
o Aromatic amine (specific)
o Aromatic amines
o Aromatic and aliphatic substituted primary alkyl halides
o Aromatic nitro (general)
o Aromatic nitro (specific)
o Aromatic nitro groups
o Nitroarenes
o Nitro-aromatic
o Primary and secondary aromatic amines
o Primary aromatic amine, hydroxyl amine and its derived esters or amine-generating
group
• Nongenotoxic carcinogenicity
o Aliphatic halogens
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Table B-2. Tools Used to Identify Structural Alerts and Prediction of Carcinogenicity and
Genotoxicity
Name
Description3
ToxRead
(Version 0.9)
ToxRead is a tool designed to assist in making read-across evaluations reproducible. SAs for
mutagenicity are extracted from similar molecules with available experimental data in its
database. Five similar compounds were selected for this project. The rule sets included:
• Benigni/Bossa as available in Toxtree (Version 1)
• S ARpy rules extracted by Politecnico di Milano, with the automatic tool SARpy
• IRFMN rules extracted by human experts
• CRS4 rules extracted by CRS4 with automatic tools
Toxtree
(Version 2.6.13)
Toxtree estimates toxic hazard by applying a decision tree approach. Chemicals were queried
in Toxtree using the Benigni/Bossa rulebase for mutagenicity and carcinogenicity. If a
potential carcinogenic alert based on any QS AR model or if any SA for genotoxic and
nongenotoxic carcinogenicity was reported, then the prediction was recorded as a positive
carcinogenicity prediction for the test chemical. The output definitions from the tool manual
are listed below:
• SA for genotoxic carcinogenicity (recognizes the presence of one of more SAs and
specifies a genotoxic mechanism)
• SA for nongenotoxic carcinogenicity (recognizes the presence of one or more SAs, and
specifies a nongenotoxic mechanism)
• Potential Salmonella typhimurium TA100 mutagen based on QSAR
• Unlikely to be a S. typhimurium TA100 mutagen based on QSAR
• Potential carcinogen based on QSAR (assigned according to the output of QSAR8 aromatic
amines)
• Unlikely to be a carcinogen based on QSAR (assigned according to the output of QSAR8
aromatic amines)
• Negative for genotoxic carcinogenicity (no alert for genotoxic carcinogenicity)
• Negative for nongenotoxic carcinogenicity (no alert for nongenotoxic carcinogenicity)
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Table B-2. Tools Used to Identify Structural Alerts and Prediction of Carcinogenicity and
Genotoxicity
Name
Description3
VEGA
VEGA applies several QSARs to a given chemical, as described below:
• Mutagenicity (Ames test) CONSENSUS model: a consensus assessment is performed
based on predictions of the VEGA mutagenicity models (CAESAR, SARpy, ISS, and
&-NN)
• Mutagenicity (Ames test) model (CAESAR): integrates two models, one is a trained SVM
classifier, and the other is for FN removal based on SAs matching
• Mutagenicity (Ames test) model (SARpy/IRFMN): rule-based approach with 112 rules for
mutagenicity and 93 for nonmutagenicity, extracted with SARpy software from the original
training set from the Caesar model; includes rules for both mutagenicity and
nonmutagenicity
• Mutagenicity (Ames test) model (ISS): rule-based approach based on the work of Benigni
and Bossa (ISS) as implemented in the software Toxtree Version 2.6
• Mutagenicity (Ames test) model (&-NN/read-across): performs a read-across and provides a
qualitative prediction of mutagenicity on S. typhimurium (Ames test)
• Carcinogenicity model (CAESAR): Counter Propagation Artificial neural network
developed using data for carcinogenicity in rats extracted from the CPDB database
• Carcinogenicity model (ISS): built implementing the same alerts Benigni and Bossa (ISS)
implemented in the software Toxtree 2.6
• Carcinogenicity model (IRFMN/Alternative Non-Testing Methods Assessed for REACH
Substances [ANTARES]): a set of rules (127 SAs), extracted with the SARpy software
from a data set of 1,543 chemicals obtained from the carcinogenicity database of European
Union-funded project ANT ARES
• Carcinogenicity model (IRFMN/ISSCAN-CGX): based on a set of rules (43 SAs) extracted
with the SARpy software from a data set of 986 compounds; the data set of carcinogenicity
of different species was provided bv Kirkland et al. (2005)
aThere is some overlap between the tools. For example, OncoLogic classification is provided by the QS AR
Toolbox, but the prediction is available only through OncoLogic, and alerts or decision trees were used in or
adapted from several models (e.g., Benigni and Bossa alerts and Toxtree decision tree).
ANT ARES = Alternative Non-Testing Methods Assessed for REACH Substances; CA = chromosomal aberration;
CAESAR = Computer-Assisted Evaluation of industrial chemical Substances According to Regulations;
CONSENSUS = consensus assessment based on multiple models (CAESAR, SARpy, ISS, and &-NN);
CPDB = Carcinogenic Potency Database; CRS4 = Center for Advanced Studies, Research and Development in
Sardinia; DNA = deoxyribonucleic acid; FN = false negative; IRFMN = Istituto di Ricerche Farmacologiche Mario
Negri; ISS = Istituto Superiore di Sanita; ISSCAN-CGX = Istituto Superiore di Sanita Chemical Carcinogen;
/i'-NN = ^-nearest neighbor; LMC = Laboratory for Mathematical Chemistry; MN = micronucleus;
MNT = micronucleus test; OCHEM = Online Chemical Monitoring Environment; OECD = Organisation for
Economic Co-operation and Development; QSAR = quantitative structure-activity relationship;
REACH = Registration, Evaluation, Authorisation and Restriction of Chemicals; SA = structural alert;
S AR = structure-activity relationship; SVM = support vector machine; TIMES = The Integrated MARKEL-EFOM
System; VEGA = Virtual models for property Evaluation of chemicals within a Global Architecture.
The tool results for the target and analogue compounds are provided in Appendix C.
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STEP 7. EVIDENCE INTEGRATION FOR SCREENING EVALUATION OF
l-BROMO-2-CHLOROETHANE CARCINOGENICITY
Available data across multiple lines of evidence from Steps 1-6 (outlined above) are
integrated to determine the qualitative level of concern for potential carcinogenicity of the target
compound (Step 8). In the absence of information supporting carcinogenic portal-of-entry
effects, the qualitative level of concern for the target chemical should be considered applicable to
all routes of exposure.
Evidence integration for the target compound is provided in Appendix C.
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APPENDIX C. RESULTS OF THE SCREENING EVALUATION OF POTENTIAL
CARCINOGENICITY
STEP 1. USE OF AUTOMATED TOOLS TO IDENTIFY STRUCTURAL ANALOGUES
WITH CARCINOGENICITY AND/OR GENOTOXICITY DATA
U.S. EPA's Chemical Assessment Clustering Engine (ChemACE) clustering was
performed as described in Appendix B. Using the most restrictive clustering rules (where
ChemACE assigns a unique definition for each fragment, ensuring that each chemical submitted
for clustering appears in only one ChemACE cluster), l-bromo-2-chloroethane appeared in
Cluster 67, which did not contain any other compounds. Using the less restrictive clustering
option, ChemACE treats adjacent halogens as equivalent fragments, resulting in the inclusion of
l-bromo-2-chloroethane in multiple clusters. Using the more permissive fragment definition,
halogens (i.e., bromine [Br] and chlorine [CI]) in the structures could be swapped in the
clustering scheme and appear in more than one cluster. Five clusters (15, 31, 34, 49, and 152)
contain l-bromo-2-chloroethane and a total of 38 other halogenated chemicals (see Table C-l
below). All of these clusters contain halogenated alkanes with chain lengths of 1-3 carbon atoms
and 1-6 halogen substituents.
Table C-l. Clusters Containing l-Bromo-2-Chloroethane (CASRN 107-04-0) and the
Associated Fragments
Cluster
Fragments
15
Cl-R or F-R or Br-R
31
Cl-R or F-R or Br-R (but not Br-R only structures)
34
Cl-R or F-R or Br-R (but not F-R only structures)
49
Cl-R or F-R or Br-R or I-R
152
Cl-R or F-R or Br-R (but not Br-R or F-R only structures)
Br = bromine; CI = chlorine; F = fluorine; I = iodine; R = functional group (must be an aliphatic carbon
attachment).
The Organisation for Economic Co-operation and Development (OECD) Quantitative
Structure-Activity Relationship (QSAR) Toolbox Profiler was used to identify structural
analogues from the Dice analogue search with carcinogenicity and/or genotoxicity data (see
Step 1 methods in Appendix B). Only one analogue was identified in the Dice analogue search
(l-bromo-3-chloropropane); this compound was also identified by ChemACE. Refinement of
selection of final analogues is described below.
STEP 2. ANALOGUE REFINEMENT USING EXPERT JUDGMENT
Expert judgment was applied to refine the initial list of 38 potential analogues based on
physicochemical properties; absorption, distribution, metabolism, and excretion (ADME); and
mechanisms of toxicity.
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l-Bromo-2-chloroethane contains two halogen substituents with the following attributes:
(1) they are labile (easily displaced) leaving groups that can undergo nucleophilic substitution;
(2) they are attached to adjacent carbon atoms (1,2-substitution pattern); and (3) they are both
attached at primary carbon atoms (R-CH2-X). Each of these attributes influences the reactivity of
the molecule, its available metabolic pathways, and its potential bioactivity. Therefore,
compounds were considered potential analogues if they contain (1) two or more labile halogen
substituents; (2) halogens attached to adjacent, primary carbon atoms; and (3) no more than one
halogen per carbon atom.
Of the 38 chemicals identified as potential analogues by ChemACE clustering and the
OECD Toolbox analogue selection tool (Dice), 32 were not selected for further review, including
halogenated methanes, monohalogenated compounds, and compounds with more than one
halogen per carbon atom. Each of these attributes introduce significant differences in
bioavailability, reactivity, and applicable metabolic pathways relative to
1 -bromo-2-chloroethane.
The remaining six possible analogues for l-bromo-2-chloroethane are listed in Table C-2.
The existence of a cancer risk estimate and/or a weight-of-evidence (WOE) determination for
cancer is indicated for each analogue. All of the potential analogues were included in each of the
five clusters, except for 1,2-dibromoethane, which was excluded from Clusters 31 and 152.
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Table C-2. Summary of Cancer Assessment Information for Analogues of
l-Bromo-2-Chloroethane (CASRN 107-04-0)a
Analogue Name
(CASRN)
Cancer Risk Estimates
(if available)
WOE
Determinations
1,2-Dibromoethane (106-93-4)b
U.S. EPA (2004)—OSF. IUR
CalEPA (2011)—OSF. IUR
U.S. EPA (2004)—likelv
IARC (1999)—vrobablv (Group 2A)
NTP (2016c)—reasonably anticipated
CalFPA (2018)—known
1,2-Dichloroethane (107-06-2)b
U.S. EPA (1993)—OSF. IUR
CalFPA (1999b)—OSF
U.S. EPA (1993)—probable
IARC (1999)—possibly (Group 2B)
NTP (2016d)—reasonably anticipated
CalFPA (2018)—known
l-Bromo-3-chloropropane
(109-70-6)bc
Noned
None
1,2-Dichloropropane (78-87-5)b
U.S. EPA (2020c)—d-OSF. d-IUR
CalFPA (2004); CalEPA
(1999b)—OSF
U.S. EPA (2020c)—likelv
IARC (2017)—carcinosenic (Group 1)
CalFPA (2018)—known
1,2-Dibromo-3 -chloropropane
(96-12-8)b
U.S. EPA (2006)—d-OSF. d-IUR
CalFPA (2020)—OSF. IUR
U.S. EPA (2006)—likelv
IARC (1999)—possibly (Group 2B)
NTP (2016b)—reasonably anticipated
CalFPA (2018)—known
1,2,3-Trichloropropane (96-18-4)b
U.S. EPA (2009)—OSF
CalFPA (2009)—OSF
U.S. EPA (2009)—likelv
IARC (1995)—probably (Group 2A)
NTP (2016b)—reasonably anticipated
CalFPA (2018)—known
aGray shading indicates that there was not a cancer risk estimate and/or a WOE determination for cancer for that
analogue.
bFound by ChemACE.
°Found by Dice.
dNo cancer toxicity values are available; however, a 2-year inhalation bioassay in rats and mice with clear evidence
of carcinogenicity is available from the Japanese Industrial Safety and Health Association (Japan Industrial Safety
and Health Association. 2005a. b).
ChemACE = Chemical Assessment Clustering Engine; IUR = inhalation unit risk; OSF = oral slope factor;
p-IUR = provisional inhalation unit risk; p-OSF = provisional oral slope factor; WOE = weight of evidence.
l-Bromo-3-chloropropane, which lacks a cancer risk estimate or a WOE determination
for cancer (highlighted in gray in Table C-2), was not further considered as a potential analogue
for the screening evaluation of potential carcinogenicity of l-bromo-2-chloroethane. Compounds
selected for further consideration were 1,2-dibromoethane (1,2-DBE), 1,2-dichloroethane
(1,2-DCE), 1,2-dichloropropane (1,2-DCP), l,2-dibromo-3-chloropropane (l,2-DB-3-CP), and
1,2,3-trichloropropane (TCP).
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STEP 3. COMPARISON OF THE EXPERIMENTAL GENOTOXICITY DATA FOR
l-BROMO-2-CHLOROETHANE AND ANALOGUES
The genotoxicity data available for l-bromo-2-chloroethane are described in the "Other
Data" section in the main body of this report. Available data indicate that
l-bromo-2-chloroethane and/or its metabolites display genotoxic, mutagenic, clastogenic, and
deoxyribonucleic acid (DNA)-damaging activity. Genotoxicity data for the analogue compounds
have been extensively reviewed. A summary of the genotoxicity data for analogue halogenated
alkanes is provided in Table C-3. Overall data indicate that these analogues are mutagenic and
clastogenic, and capable of binding DNA and causing DNA damage.
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Table C-3. Comparison of Available Genotoxicity Data for l-Bromo-2-Chloroethane (CASRN 107-04-0) and Candidate
Analogues
1-Bromo-
1,2-Dibromo-
2-Chloroethane
1,2-Dibromoethane
1,2-Dichloro ethane
1,2-Dichloropropane
3-Chloropropane
1,2,3-Trichloropropane
Parameter
CASRN 107-04-0
CASRN 106-93-4
CASRN 107-06-2
CASRN 78-87-5
CASRN 96-12-8
CASRN 96-18-4
Mutagenicity
• Mutagenic in
• Mutagenic in
• Mutagenic in
• Mixed results in
• Mutagenic in
• Mutagenic in
Salmonella
S. typhimurium and
S. typhimurium;
S. typhimurium;
S. typhimurium
S. typhimurium with
typhimurium
Streptomyces
mixed results in
not mutagenic in E.
with and without
metabolic activation;
• Mutagenic in
coelicolor; mixed
E. coli; not
coli or
metabolic
not mutagenic in
mammalian cells in
results in
mutagenic in
S. coelicolor
activation
E. coli
vitro
Escherichia coli
S. coelicolor or
• Mutagenic in
• Induced sex-linked
• Not mutagenic in
• Mutagenic in
Bacillus subtilis
A. nidulans
recessive mutations
A. nidulans
Aspergillus
• Not mutagenic in
• Induced somatic
in D. melanogaster
• Induced somatic
nidulans
A. nidulans
mutations in
• Mutagenic in
mutations in
• Induced somatic
• Induced somatic
D. melanogaster,
mammalian cells
D. melanogaster
and sex-linked
and sex-linked
but not sex-linked
with and without
• Mutagenic in
recessive
recessive
recessive mutations
metabolic
mammalian cells with
mutations in
mutations
• Mutagenic in
activation
metabolic activation
Drosophila
• Mutagenic in
mammalian cells in
• Induced somatic
• Did not induce
melanogaster
mammalian cells in
vitro
mutations in mice
dominant lethal
• Mutagenic in
vitro
• Did not induce
(spot test)
mutations in rats
mammalian cells in
• Induced somatic
dominant lethal
• Induced dominant
vitro
mutations in mice
mutations in rats
lethal mutations in
• Did not induce
• Did not induce
• Did not induce
rats, but not mice
dominant lethal
dominant lethal
Pig-a or Gpt
mutations in mice
mutations in mice
mutations in mice
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Table C-3. Comparison of Available Genotoxicity Data for l-Bromo-2-Chloroethane (CASRN 107-04-0) and Candidate
Analogues
1-Bromo-
1,2-Dibromo-
2-Chloroethane
1,2-Dibromoethane
1,2-Dichloro ethane
1,2-Dichloropropane
3-Chloropropane
1,2,3-Trichloropropane
Parameter
CASRN 107-04-0
CASRN 106-93-4
CASRN 107-06-2
CASRN 78-87-5
CASRN 96-12-8
CASRN 96-18-4
Clastogenicity
• Induced CAs in
• Induced SCEs in
• Induced SCEs in
• Induced CAs and
• Induced CAs in
• Induced polyploidy in
mammalian cells in
mammalian cells in
mammalian cells in
SCEs in
mammalian cells in
mammalian cells in
vitro
vitro and in vivo
vivo
mammalian cells in
vitro and in vivo
vivo
• Induced mitotic
• Induced CAs and
• Induced MNs in
vitro
• Induced MNs in
• Induced MNs in
malsegregation/
MNs in
mammalian cells in
• Did not induce
mammalian cells in
mammalian cells in
aneuploidy in
mammalian cells in
vitro
MNs in
vivo
vitro, but not in vivo
A. nidulans
vitro, but not in
• Induced
mammalian cells in
• Induced SCEs in
• Induced CAs and
• Induced mitotic
vivo
chromosomal loss
vivo
mammalian cells in
SCEs in mammalian
recombination in
and mitotic
• Induced mitotic
vitro
cells in vitro
D. melanogaster
recombination in
recombination in
• Induced heritable
• Induced MN without
D. melanogaster
D. melanogaster,
translocation and
metabolic activation
• Induced
but not
mitotic
• Induced mitotic gene
aneuploidy and
Saccharomyces
recombination in
conversion in
mitotic segregation
cerevisiae
D. melanogaster
S. cerevisiae
aberrations in
• Did not induce
• Did not induce
A. nidulans; no
chromosomal
chromosomal
clear evidence of
abnormalities in
abnormalities in
aneuploidy in
A. nidulans
A. nidulans
mammalian cells in
vitro
DNA damage
• Induced DNA damage
• Induced DNA
• Induced DNA
• Induced DNA
• Induced DNA
• Induced DNA
and adducts
in mammalian cells in
damage/repair in
damage/repair in
damage/repair in
damage/repair in
damage/repair in
vivo
mammalian cells in
mammalian cells in
mammalian cells in
mammalian cells in
mammalian cells in
• Induced DNA damage
vitro and in vivo
vitro and in vivo
vitro and in vivo
vitro and in vivo
vitro and in vivo
i n S. typhimurium
• Forms DNA
adducts
• Equivocal DNA
damage detected
via comet assay in
rodent liver cells.
• Forms DNA
adducts
• Forms DNA
adducts
• Forms DNA adducts
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Table C-3. Comparison of Available Genotoxicity Data for l-Bromo-2-Chloroethane (CASRN 107-04-0) and Candidate
Analogues
Parameter
1-Bromo-
2-Chloroethane
CASRN 107-04-0
1,2-Dibromoethane
CASRN 106-93-4
1,2-Dichloro ethane
CASRN 107-06-2
1,2-Dichloropropane
CASRN 78-87-5
1,2-Dibromo-
3-Chloropropane
CASRN 96-12-8
1,2,3-Trichloropropane
CASRN 96-18-4
Cell
transformation
ND
• Induced neoplastic
transformation in
mammalian cells
• Mixed results for
cell transformation
ND
• Induced neoplastic
transformation in
mammalian cells
• Induced neoplastic
transformation in
mammalian cells
References
See "Genotoxicity"
section in main
document for references
U.S. EPA (2004):
I ARC (1999)
Gwinn et al. (2011);
ATSDR (2001);
CalEPA (1999a);
I ARC (1999); U.S.
EPA (1993); Lebaron
et al. (2021)
I ARC (2017); U.S.
EPA (2020c);
CalEPA (1999b)
U.S. EPA (2006);
Clark and Snedeker
(2005); I ARC (1999)
U.S. EPA (2009); IARC
(1995)
CA = chromosomal aberration; DNA = deoxyribonucleic acid; MN = micronuclei; ND = no data; SCE = sister chromatid exchange.
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STEP 4. TOXICOKINETICS OF l-BROMO-2-CHLOROETHANE AND ANALOGUES
The toxicokinetics of l-bromo-2-chloroethane and potential analogues are briefly
described in Table C-4. Each of the candidate analogue compounds is metabolized by a CYP450
oxidation pathway and a direct glutathione (GSH) conjugation pathway (U.S. EPA. 2020c;
I ARC. 2017; CalEPA. 2009; U.S. EPA. 2009. 2006. 2004; ATSDR. 2001; I ARC. 1999. 1995).
Contributions from both pathways are presumed by analogy for l-bromo-2-chloroethane as well,
although experimental data for the target compound are available for the GSH conjugation
pathway only (Jean and Reed. 1992; Marchand and Reed. 1989).
Experimental data show that GSH conjugation leads to the formation of episulfonium
ions via cyclization of GSH adducts for 1,2-DBE, 1,2-DCE, l,2-DB-3-CP, and TCP (CalEPA.
2009; U.S. EPA. 2009. 2004; ATSDR. 2001; I ARC. 1995; Guengerich. 1994; van Beerendonk et
at.. 1994; Dekant and Vamvakas. 1993; Pearson et at.. 1990; Dohn et at.. 1988; Omichinski et
at.. 1988b; Omichinski et at.. 1988a; Guengerich et at.. 1987). Based on analogy and identified
glutathione-conjugated metabolites, episulfonium ion generation is also expected following GSH
conjugation of l-bromo-2-chloroethane (based on formation of »S'-[2-chloroethyl]glutathione
[CEG]) (Jean and Reed. 1992; Marchand and Reed. 1989) and 1,2-DCP (based on the formation
of ,S'-[2-hydroxypropyl]glutathione) (IARC. 2017).
No data are available for absorption, distribution, or excretion of
l-bromo-2-chloroethane. Experimental data indicate that all candidate analogues show rapid and
extensive absorption, wide distribution, and primary excretion in urine (U.S. EPA, 2020c; IARC,
2017; CalEPA. 2009; U.S. EPA. 2009. 2006. 2004; ATSDR. 2001; IARC. 1999. 1995).
70
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Table C-4. Summary of Toxicokinetic Data for l-Bromo-2-Chloroethane and Analogues
Compound
(CASRN)
Absorption, Distribution,
Excretion
Metabolism
References
1-Bromo-
2-chloroethane
(107-04-0)
ND
Primary metabolic pathways are oxidation by CYP450 (by analogy to
other dihaloalkanes) and GSH conjugation (demonstrated)
1. Primary metabolites formed via oxidation expected to be:
• 2-bromoacetaldehyde
• 2-chloroacetaldehyde
• HBr
• HC1
2. Primary metabolites formed via GSH conjugation:
• CEG, with HBr release (minor HC1 release)
• Inferred from other dihaloalkanes: CEG will cyclize to form
episulfonium ion
Gueneerich (1994); Dekatit
and Vamvakas (1993);
Jean and Reed (1992);
Gareas et al. (1989);
Marchand and Reed
(1989); Gueneerich et al.
(1987)
1,2-Dibromoethane
(106-93-4)
• Rapid and extensive
absorption (oral and
inhalation)
• Wide distribution
• Primary excretion in urine,
small amounts in feces and
exhaled air
Primary metabolic pathways are oxidation by CYP450 and GSH
conjugation
1. Primary metabolites formed via oxidation:
• 2-bromoacetaldehyde
• HBr
2. Primary metabolites formed via GSH conjugation:
• BEG, with HBr release
• Episulfonium ion (from cyclization of GSH adduct in BEG)
U.S. EPA (2004): Gareas
et al. (1989); Gueneerich et
al. (1987)
1,2-Dichloroethane
(107-06-2)
• Rapid and extensive
absorption (oral and
inhalation)
• Wide distribution
• Primary excretion in urine,
small amounts in feces and
exhaled air
Primary metabolic pathways are oxidation by CYP450 and GSH
conjugation
1. Primary metabolites formed via oxidation:
• 2-chloroacetaldehyde
• HC1
2. Primary metabolites formed via GSH conjugation:
• CEG, with HC1 release
• Episulfonium ion (from cyclization of GSH adduct in CEG)
ATSDR (2001); Gareas et
al. (1989); Gueneerich et
al. (1987)
71
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Table C-4. Summary of Toxicokinetic Data for l-Bromo-2-Chloroethane and Analogues
Compound
(CASRN)
Absorption, Distribution,
Excretion
Metabolism
References
1,2-Dichloropropane
(78-87-5)
• Readily absorbed (oral,
inhalation, dermal)
• Wide distribution, with
preferential disposition in
body fat at high exposures
• Rapid elimination, primarily
via urine with small amounts
via exhaled breath
(proportion increases with
increased exposure)
Primary metabolic pathway is oxidation by CYP2E1 followed by GSH
conjugation (or vice versa) to form:
• ,S'-(2-o.\opropyl)glutathione (identified)
• .S'-( l-carbo\\ etln l)glutathione (identified)
• .S'-(2-hydro\ypropyl)glutathionc (presumed based on cysteine-
conjugated urinary metabolite)
Presumed secondary pathways (based on identified metabolites and
known metabolism of similar haloalkanes)
• Formation of episulfonium ions from cyclization of GSH adduct in
.S'-(2-hydro\ypropyl)glutathionc
• Oxidative dechlorination, leading to formation of lactate and
release of carbon dioxide
I ARC (2017): U.S. EPA
(2020c)
1,2-Dibromo-
3-chloropropane
(96-12-8)
• Rapid and extensive
absorption (oral; no
inhalation data)
• Wide distribution
• Most excretion in urine,
some in exhaled air, small
amounts in feces
Primary metabolic pathways are oxidation by CYP450 and GSH
conjugation
1. Primary metabolites formed via oxidation:
• 2-chloro-3-(bromomethyl)oxirane
• l-bromo-3-chloroacetone
• HBr
• HC1
2. Primary metabolites formed via GSH conjugation:
• CBPG, with HBr release (minor HC1 release)
• Episulfonium ion (from cyclization of GSH adduct in CBPG)
Gueneerich (1994): van
Beerendonk et al. (1994):
Dekant and Yamvakas
(1993): Humotaevs et al.
(1991): Pearson et al.
(1990): Dohn etal. (1988):
Omictanski et al. (1988a):
Omictanski et al. (1988b):
Gineell et al. (1987):
Gueneerich et al. (1987)
72
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Table C-4. Summary of Toxicokinetic Data for l-Bromo-2-Chloroethane and Analogues
Compound
(CASRN)
Absorption, Distribution,
Excretion
Metabolism
References
1,2,3 -Trichloropropane
(96-18-4)
• Rapid and extensive
absorption (oral; no
inhalation data)
• Rapid distribution, initially
to adipose tissue, liver, and
kidney
• Primary excretion in urine,
smaller amounts in feces and
exhaled air
Primary metabolic pathways are oxidation by CYP450 and GSH
conjugation
1. Primary metabolites formed via oxidation:
• 1,3-dichloroacetone
• 2,3-dichloropropanal
• Chloroacrolein
• HC1
2. Primary metabolites formed via GSH conjugation:
• B-chlorothioether with HC1 release
• Episulfonium ion (from cyclization of GSH adduct in thioether)
CalEPA (2009): U.S. EPA
(2009); I ARC (1995)
BEG = .S'-(2-bromocthvl)glutathionc: CBPG = ,S'-(3-chloro-2-bromoprop\i) glutathione; CEG = .S'-(2-chlorocth\i)glutathionc: CYP450 = cytochrome P450;
GSH = glutathione; HBr = hydrogen bromide; HC1 = hydrogen chloride; ND = no data.
73
1 -Bromo-2-chloroethane
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EPA/690/R-21/005F
STEP 5. CARCINOGENICITY OF l-BROMO-2-CHLOROETHANE ANALOGUES
AND MODE-OF-ACTION DISCUSSION
U.S. EPA cancer WOE descriptors for l-bromo-2-chloroethane and analogue compounds
are shown in Tables C-5 (oral) and C-6 (inhalation). As noted in the PPRTV document, there is
"Inadequate Information to Assess the Carcinogenic Potential" of l-bromo-2-chloroethane. All
analogues are characterized as having evidence of carcinogenic potential. 1,2-DBE, 1,2-DCP,
l,2-DB-3-CP, and TCP were all classified as "Likely to be Carcinogenic to Humans" (U.S.
EPA. 2020c. 2009. 2006. 2004) under the 2005 or 1999 Guidelines for Carcinogen Risk
Assessment (U.S. EPA. 2005). 1,2-DCE is considered a "Probable Human Carcinogen" (U.S.
EPA, 1993) under the 1986 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1986). OSF
values varied by several orders of magnitude, with the highest potency value calculated for TCP
and the lowest (provisional) potency value for 1,2-DCP. IUR values also varied by several orders
of magnitude, with the highest potency value calculated for l,2-DB-3-CP (provisional) and the
lowest potency value for 1,2-DCP (provisional).
Several epidemiology studies in print shop workers in Japan reported a potential
correlation between exposure to 1,2-DCP (and other solvents) and cholangiocarcinoma, a rare
cancer of the bile duct (U.S. EPA, 2020c; I ARC, 2017). However, the population size is small in
most of these studies, and the workers were exposed to numerous other solvents, including
dichloromethane and 1,1,1-trichloroethane, as well as kerosene and printing ink, confounding
interpretation of the results. Some human epidemiology studies for 1,2-DCE, 1,2-DBE, and
l,2-DB-3-CP have found limited evidence of increased risk of certain cancers (e.g., lymphatic,
hematopoietic, pancreatic, and stomach cancer); however, due to multiple exposures in the
available studies, these data are inadequate to evaluate a relationship between human cancer and
exposure to a specific compound (NTP, 2016b, c, d; U.S. EPA, 2006, 2004; I ARC, 1999). No
human cancer data are available for TCP (NTP, 2016e; U.S. EPA, 2009).
All analogues are associated with tumor induction in animal bioassays (U.S. EPA, 2020c;
I ARC. 2017; NTP, 2016b. c, d, c; U.S. EPA. 2006. 2004; IARC. 1999. 1995; U.S. EPA. 1993).
These are briefly summarized below and in Table C-5 (oral) and Table C-6 (inhalation).
Common target organs and systems in rats and/or mice following exposure to analogues
include the liver, respiratory system, and mammary gland. All analogues induced hepatocellular
neoplasms (adenomas and/or carcinomas) following chronic oral exposure; liver tumors were
also increased following chronic inhalation exposure to 1,2-DCE. All analogues tested via the
inhalation route also induced respiratory tract tumors, including nasal cavity tumors (1,2-DBE,
1,2-DCP, l,2-DB-3-CP) and lung tumors (1,2-DBE, 1,2-DCE, 1,2-DCP, l,2-DB-3-CP). Lung
tumors were also observed following oral exposure to 1,2-DBE and 1,2-DCE. Mammary gland
tumors were increased following exposure to analogues via the oral route (1,2-DCE, 1,2-DCP,
l,2-DB-3-CP, TCP) and/or the inhalation route (1,2-DBE, 1,2-DCE, l,2-DB-3-CP).
The gastrointestinal, endocrine, and circulatory systems were also identified as cancer
targets for the majority of analogues. Most analogues induced tumors of the gastrointestinal
system following chronic oral exposure, including forestomach tumors (1,2-DBE, 1,2-DCE,
l,2-DB-3-CP, TCP); tongue, pharynx, and stomach tumors (l,2-DB-3-CP); oral cavity and
alimentary system tumors (TCP); and esophageal papillomas (1,2-DBE). Endocrine tumors
observed included thyroid tumors (1,2-DBE, 1,2-DCP) and pancreatic tumors (TCP) following
74
1 -Bromo-2-chloroethane
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EPA/690/R-21/005F
oral exposure and adrenal tumors (1,2-DBE and l,2-DB-3-CP) following inhalation exposure.
Hemangiosarcoma, most notably in the spleen, was observed following oral or inhalation
exposure to 1,2-DBE, oral exposure to 1,2-DCE, and inhalation exposure to 1,2-DCP.
Other tumor types were identified in only one or two of the analogues and therefore do
not represent common targets of the identified analogue chemicals (see Tables C-5 and C-6 for
more details). Observed tumors included female reproductive tumors (1,2-DCE, TCP), renal
tumors (TCP, l,2-DB-3-CP), malignant lymphoma (1,2-DCE), Harderian gland tumors (TCP,
1,2-DCP), Zymbal gland tumors (TCP), preputial gland tumors (TCP), mesothelioma of the
peritoneum (1,2-DCE), mesothelioma of the tunica vaginalis (1,2-DBA, l,2-DB-3-CP), and
subcutaneous tumors (1,2-DBE, 1,2-DCE).
U.S. EPA (2009) and U.S. EPA (2006) concluded that l,2-DB-3-CP and TCP are
carcinogenic through a mutagenic MO A, supported by experimental evidence of mutagenicity.
The U.S. EPA (2004) report did not make a formal determination regarding a carcinogenic MO A
for 1,2-DBE; however, available evidence suggested potential mutagenicity and/or DNA damage
as potential MO As. Available data for 1,2-DCP were considered inadequate for a formal MO A
analysis by U.S. EPA (2020c); however, DNA damage has been proposed as a potential
mechanism. The U.S. EPA (1993) report did not evaluate potential carcinogenic MOAs for
1,2-DCE, but experimental data indicate that the chemical is both DNA damaging and mutagenic
(see Step 3). Taken together, all analogues except 1,2-DCP have sufficient evidence of
mutagenicity (see Step 3) to indicate a potential common mutagenic MOA for halogenated
alkanes. Specifically, experimental data show that 1,2-DBE, 1,2-DCE, l,2-DB-3-CP, and TCP
form DNA-reactive episulfonium ions via cyclization of GSH adducts during metabolism. By
analogy, both 1,2-DCP and the target compound, l-bromo-2-chloroethane, are expected to form
episulfonium ions as well (see Table C-4). Data for 1,2-DCE indicate that although oxidative
metabolites appear to influence CAs, the formation of the episulfonium ion is likely the primary
mutagen (Gwinn et at., 2011). However, 1,2-DCP is not considered a potent mutagen, and
experimental data do not support the potential for GSH-mediated mutagenicity (U.S. HP A.
2020c: Akiba et al.. 2017; I ARC. 2017).
75
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Table C-5. Comparison of Available Oral Carcinogenicity Data for l-Bromo-2-Chloroethane (CASRN 107-04-0) and
Candidate Analogues
Type of Data
1-Bromo-
2-Chloroethane
CASRN 107-04-0
1,2-Dibromoethane
CASRN 106-93-4
1,2-Dichloroethane
CASRN 107-06-2
1,2-Dichloropropane
CASRN 78-87-5
1,2-Dibromo-
3-Chloropropane
CASRN 96-12-8
1,2,3-Trichloro-
propane
CASRN 96-18-4
Structure
/Br
cr
.Br
Br
Gl
cr
XH3
cr
CI
CI-^^Y^Br
Br
ci-^^y""01
CI
U.S. EPA WOE
characterization
"Inadequate
Information to
Assess
Carcinogenic
Potential"
(see Table 6)
"Likely to Be
Carcinogenic to
Humans "
"Probable Human
Carcinogen "
"Likely to Be
Carcinogenic to
Humans "
"Likely to Be
Carcinogenic to
Humans "
"Likely to Be
Carcinogenic to
Humans "
OSF (mg/kg-d) 1
NDr
2 (upper bound)3
9.1 x 10-2
3.7 x 10-2
(provisional)
Sxio1 (provisional)
3 x 101 (upper bound)b
Data set(s) used
for slope factor
derivation
NA
Forestomach tumors,
hemangiosarcomas,
and thyroid follicular
cell adenomas or
carcinomas in male
rats
Hemangiosarcoma in
male rats
Hepatocellular
adenoma or carcinoma
in male mice
Renal adenoma or
carcinoma in male rat
Alimentary system,
liver, Harderian gland,
and uterine tumors in
female mice
76
1 -Bromo-2-chloroethane
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EPA/690/R-21/005F
Table C-5. Comparison of Available Oral Carcinogenicity Data for l-Bromo-2-Chloroethane (CASRN 107-04-0) and
Candidate Analogues
Type of Data
1-Bromo-
2-Chloroethane
CASRN 107-04-0
1,2-Dibromoethane
CASRN 106-93-4
1,2-Dichloroethane
CASRN 107-06-2
1,2-Dichloropropane
CASRN 78-87-5
1,2-Dibromo-
3-Chloropropane
CASRN 96-12-8
1,2,3-Trichloro-
propane
CASRN 96-18-4
Other tumors
observed in
animal oral
bioassays
ND
Rat: forestomach,
thyroid, or liver
tumors and
hemangiosarcomas
(females)
Mouse: forestomach
and lung tumors,
esophageal papilloma
(female)
Rat: forestomach and
mammary gland
tumors
Mouse: lung, liver,
and uterus tumors;
malignant lymphoma
Rat: mammary gland
tumors (marginal
increase in females)
Mouse: liver tumors
(female), thyroid
tumors (female)
Rat: mammary gland
and kidney tumors
(female), liver tumors
(male), forestomach
and stomach tumors
(both)
Mouse: forestomach
and stomach tumors
Rat: alimentary system
and Zymbal gland
tumors (both);
pancreatic, preputial
gland, and kidney
tumors (males); clitoral
and mammary gland
tumors (females)
Mouse: alimentary
system, Harderian
gland, and liver tumors
(males)
Study doses
(mg/kg-d)
NA
TWA: 0, 38, 41
HEDb: 0, 11,22
TWA: 0, 47, 95
HED: 0, 4.46, 8.23
TWA: 0, 89.3, 179
HED: 0, 12.5, 25.1
TWA: 0, 0.24, 0.80,
2.39
HED: not reported per
dose (HED conversion
done after OSF
calculation)
0, 6, 20, 60
HED: not reported per
dose (HED conversion
done after BMD
modeling)
Route (method)
NA
Gavage in corn oil
(5 d/wk)
Gavage in corn oil
(5 d/wk)
Gavage in corn oil
(5 d/wk)
Diet
Gavage
Duration
NA
49 wk
78 wk, followed by
untreated observation
period up to 32 wk
103 wk
104 wk
2 yr; all high-dose
females sacrificed after
73 wk
POD type
NA
BMDLio (HED)
BMDL (linearized
multistage with time-
to-death analysis,
extra risk)
BMDLio (HED)
BMDLio (HED)
BMDLio (HED)
77
1 -Bromo-2-chloroethane
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EPA/690/R-21/005F
Table C-5. Comparison of Available Oral Carcinogenicity Data for l-Bromo-2-Chloroethane (CASRN 107-04-0) and
Candidate Analogues
Type of Data
1-Bromo-
2-Chloroethane
CASRN 107-04-0
1,2-Dibromoethane
CASRN 106-93-4
1,2-Dichloroethane
CASRN 107-06-2
1,2-Dichloropropane
CASRN 78-87-5
1,2-Dibromo-
3-Chloropropane
CASRN 96-12-8
1,2,3-Trichloro-
propane
CASRN 96-18-4
Source
NA
NTP (2016c): U.S.
EPA (2004)
NTP (2016d): U.S.
EPA (2020c): U.S.
EPA (2010)
U.S. EPA (2020c)
U.S. EPA (2006)
U.S. EPA (2009)
aAn upper bound on cancer risk was estimated by adding the central tendency risk estimates for the three tumor types and calculating an upper confidence limit
on the sum, using an estimate of the variance pooled across the three slope factors. The resulting (upper bound) slope factor was adjusted for daily exposure by
multiplying by 5 days/7 days and for lifetime exposure by dividing by (49 weeks/104 weeks).
'HED values were reported in the modeling section of U.S. EPA (2004) and appear to correlate with initial doses of 40 and 80 mg/kg-day, not TWA doses that
reflect lowered dose in the high-dose group.
BMD = benchmark dose; BMDL = benchmark dose lower confidence limit; BMDLio = 10% benchmark dose lower confidence limit; HED = human equivalent
dose; NA = not applicable; ND = no data; NDr = not determined; OSF = oral slope factor; POD = point of departure; TWA = time-weighted average;
WOE = weight of evidence.
78
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EPA/690/R-21/005F
Table C-6. Comparison of Available Inhalation Carcinogenicity Toxicity Data for l-Bromo-2-Chloroethane
(CASRN 107-04-0) and Candidate Analogues
Type of Data
1-Bromo-
2-Chloroethane
CASRN 107-04-0
1,2-Dibromoethane
CASRN 106-93-4
1,2-Dichloro ethane
CASRN 107-06-2
1,2-Dichloro-
propane
CASRN 78-87-5
1,2-Dibromo-
3-Chloropropane
CASRN 96-12-8
1,2,3-Trichloro-
propane
CASRN 96-18-4
Structure
/Br
cr
/Br
Br
Xi
cr
XH3
cr
CI
CI-^^Y^Br
Br
ci^y^ci
CI
WOE
characterization
"Inadequate
Information to Assess
Carcinogenic
Potential"
(see Table 6)
"Likely to Be
Carcinogenic to
Humans "
"Probable Human
Carcinogen "
"Likely to Be
Carcinogenic to
Humans "
"Likely to Be
Carcinogenic to
Humans "
"Likely to Be
Carcinogenic to
Humans "
IUR (|ig/m3) 1
NDr
6 x 10~4 (upper
bound)3
2.6 x l(T5b
1.0 x 1(T6 (95%
upper bound)0
3.7 x 1(T6
(provisional)
6 x 10° (provisional)
NDr
Data set(s) used for
slope factor
derivation
NA
Nasal tumors (male
and female rats,
female mice),
hemangiosarcomas
(male and female
rats, female mice),
mesothelioma (male
rats), lung tumors
(female rats and
mice), mammary
tumors (female rats
and mice),
fibrosarcoma (female
mice)
Hemangiosarcoma
(oral study)3
Nasal cavity tumors
in male rats
Nasal cavity tumors
in male rats
NA
79
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Table C-6. Comparison of Available Inhalation Carcinogenicity Toxicity Data for l-Bromo-2-Chloroethane
(CASRN 107-04-0) and Candidate Analogues
Type of Data
1-Bromo-
2-Chloroethane
CASRN 107-04-0
1,2-Dibromoethane
CASRN 106-93-4
1,2-Dichloro ethane
CASRN 107-06-2
1,2-Dichloro-
propane
CASRN 78-87-5
1,2-Dibromo-
3-Chloropropane
CASRN 96-12-8
1,2,3-Trichloro-
propane
CASRN 96-18-4
Human
carcinogenicity data
ND
Available
occupational data
inadequate to
evaluate relationship
between 1,2-DBE
and cancer
Available
occupational data
inadequate to
evaluate relationship
between 1,2-DCE
and cancer
Elevated risk of
cholangiocarcinoma
in print shop workers
from several cohorts
exposed to 1,2-DCP
(and other
chlorinated solvents)
Available
occupational data
inadequate to
evaluate relationship
between
l,2-DB-3-CP and
cancer; no
associations between
gastric cancer or
leukemia and
l,2-DB-3-CP in
drinking water
(case-control)
ND
Other tumors
observed in animal
inhalation bioassays
ND
Rat: splenic
hemangiosarcoma,
adrenal tumors,
subcutaneous
mesenchymal tumor
Inhalation study
published since
derivation of IUR:
Rat: mammary gland
tumors, peritoneal
mesothelioma,
subcutaneous fibroma
Mouse: lung, liver,
and mammary gland
tumors (females)
Rats: nasal cavity
tumors (female)
Mice: Harderian
gland tumors (male),
lung tumors (female),
hemangiocarcinoma
(male)
Rats: nasal cavity,
pharynx, adrenal
gland, and mammary
gland tumors
(females), tongue
tumors (both),
mesothelioma
(males)
Mice: nasal and lung
tumor (both)
ND
80
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EPA/690/R-21/005F
Table C-6. Comparison of Available Inhalation Carcinogenicity Toxicity Data for l-Bromo-2-Chloroethane
(CASRN 107-04-0) and Candidate Analogues
Type of Data
1-Bromo-
2-Chloroethane
CASRN 107-04-0
1,2-Dibromoethane
CASRN 106-93-4
1,2-Dichloro ethane
CASRN 107-06-2
1,2-Dichloro-
propane
CASRN 78-87-5
1,2-Dibromo-
3-Chloropropane
CASRN 96-12-8
1,2,3-Trichloro-
propane
CASRN 96-18-4
Study concentrations
NA
Reported (ppm):
0, 10, 40
HECer (ppm):
0, 1.8, 7.1 (rat,
mouse)
HECet (ppm):
0, 0.36, 1.42 (male
rat, female mouse);
0, 0.25, 0.99 (female
rat)
HECpu (ppm)
0, 3.1, 12.3 (female
rat); 0, 5.8, 22.7
(female mouse)
HECtb (ppm)
0, 4.86, 19.2 (female
mouse)
TWA (mg/kg-d): 0,
47, 95
HED (mg/kg-d): 0,
4.46, 8.23
Analytical (ppm):
0, 80.2, 200.5, 500.2
HECet (mg/m3):
0, 16.2, 40.54, 101.1
Reported (ppm):
0, 0.6, 3
HECet (mg/m3):
0,0.23, 1.13
NA
Route (method)
NA
Inhalation (6 h/d;
5 d/wk)
Gavage in corn oil
(5 d/wk)b
Inhalation (6 h/d;
5 d/wk)
Inhalation (6 h/d;
5 d/wk)
NA
Duration
NA
79-104 wk
78 wk, plus untreated
observation period up
to 32 wk
104 wk
Control:
105-107 wk;
0.6 ppm: 103 wk plus
1-wk observation;
3 ppm: 84 wk plus
0-1-wk observation
NA
81
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Table C-6. Comparison of Available Inhalation Carcinogenicity Toxicity Data for l-Bromo-2-Chloroethane
(CASRN 107-04-0) and Candidate Analogues
Type of Data
1-Bromo-
2-Chloroethane
CASRN 107-04-0
1,2-Dibromoethane
CASRN 106-93-4
1,2-Dichloro ethane
CASRN 107-06-2
1,2-Dichloro-
propane
CASRN 78-87-5
1,2-Dibromo-
3-Chloropropane
CASRN 96-12-8
1,2,3-Trichloro-
propane
CASRN 96-18-4
POD type
NA
BMCLio (HEC)
BMDL (linearized
multistage with time-
to-death analysis,
extra risk)
BMCLio (HEC)
BMCLio (HEC)
NA
Source
NA
NTP (2016c): U.S.
EPA (2004)
NTP (2016d): U.S.
EPA (2010); U.S.
EPA (1993)
IARC (2017): U.S.
EPA (2020c)
NTP (2016b): U.S.
EPA (2006); IARC
(1995)
NTP (2016e): U.S.
EPA (2009)
aAn upper bound on cancer risk was estimated by using the multistage model with Poly-3 adjusted incidence data central tendency estimate for tumors at six
sites in two species.
bAvailable inhalation data in 1987 was inadequate to derive an IUR (no induction of tumors); therefore, data from oral studies used to derive IUR in 1987 (the
same major urinary metabolites and concentration from both oral and inhalation exposure) (Reitz et al.. 1982). The IUR was calculated from oral data, assuming
100% absorption and metabolism at the low dose. See findings from oral study in Table C-5.
"Inferred unit risk from negative inhalation study (Maltoni et al.. 1980).
l,2-DB-3-CP = l,2-dibromo-3-chloropropane; 1,2-DBE= 1,2-dibromoethane; 1,2-DCE= 1,2-dichloroethane; 1,2-DCP = 1,2-dichloropropane; BMCLio = 10%
benchmark concentration lower confidence limit; BMDL = benchmark dose lower confidence limit; ER = extrarespiratory; ET = extrathoracic; HEC = human
equivalent concentration; HED = human equivalent dose; IUR = inhalation unit risk; NA = not applicable; ND = no data; NDr = not determined; POD = point of
departure; PU = pulmonary; TB = tracheobronchial; TWA = time-weighted average; WOE = weight of evidence.
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STEP 6. STRUCTURAL ALERTS AND STRUCTURE-ACTIVITY RELATIONSHIP
PREDICTIONS FOR l-BROMO-2-CHLOROETHANE AND ANALOGUES
Structural alerts (SAs) and predictions for genotoxicity and carcinogenicity were
identified using computational tools as described in Appendix B. The model results for
l-bromo-2-chloroethane and its analogue compounds are shown in Table C-7. Concerns for
carcinogenicity and/or mutagenicity of l-bromo-2-chloroethane and its analogues were indicated
by several models within each predictive tool (see Table C-7). Table C-8 provides a list of the
specific SAs that underlie the findings of a concern for carcinogenicity or mutagenicity in
Table C-7.
OECD QSAR Toolbox models showed a concern for in vitro and in vivo mutagenicity
for l-bromo-2-chloroethane and all analogues based on structural alerts, a concern for CAs for
l-bromo-2-chloroethane, and concerns for all analogues based on protein binding alerts (see
Table C-7). OECD QSAR Toolbox models also showed a concern for mutagenicity, CAs, and
MN induction for l-bromo-2-chloroethane, 1,2-DBE, 1,2-DCE, and 1,2-DCP; no results were
reported for l,2-DB-3-CP or TCP. The ToxRead and VEGA models also indicated a concern for
mutagenicity for l-bromo-2-chloroethane and all analogues.
OECD QSAR Toolbox models showed a concern for carcinogenicity for
l-bromo-2-chloroethane and all analogues based on structural alerts (see Table C-8). The level of
carcinogenicity concern in OncoLogic was "moderate" for l-bromo-2-chloroethane and 1,2-DCE
based on SAR analysis only (haloalkanes and haloalkenes structural alert) and
1,2-dichloropropane based on experimental data and SAR analysis (haloalkanes and haloalkenes
structural alert). The level of carcinogenicity concern in OncoLogic was "high-moderate" for
1,2-DBE, l,2-DB-3-CP, and TCP based on experimental data and SAR analysis (haloalkanes and
haloalkenes structural alert). Two carcinogenicity models in VEGA showed concern for
carcinogenicity for l-bromo-2-chloroethane (ISS and IFRMN/ANTARES). The CAESAR and
IRFMN/ISSCAN-CGX models did not have reliable data for l-bromo-2-chloroethane. For
analogues, all four carcinogenicity models in VEGA showed concern for carcinogenicity for
1,2-DBE, 1,2-DCE, l,2-DB-3-CP, and TCP. For 1,2-DCP, the ISS and IRFMN/ISSCAN-CGX
models in VEGA showed concern for carcinogenicity, but the CAESAR and IRFMN/ANTARES
models showed no concern for carcinogenicity. The ToxAlerts tool showed concern for
nongenotoxic carcinogenicity for l-bromo-2-chloroethane and all analogues based on structural
alerts (aliphatic halogens). In contrast, the Toxtree tool indicated that there was no concern for
nongenotoxic carcinogenicity for l-bromo-2-chloroethane or any of its analogues.
The ToxAlerts and Toxtree tools showed a concern for genotoxic carcinogenicity for
l-bromo-2-chloroethane and all analogues based on various structural alerts (see Table C-8).
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Table C-7. Heat Map Illustrating the Structural Alert and SAR Prediction Results for
l-Bromo-2-Chloroethane (CASRN 107-04-0) and Analogues
Tool
Model3
l-Bromo-2-chloro ethane
1,2-Dibromoethane
1,2-Dichloroethane
1,2-Dichloropropane
l,2-Dibromo-3-chloropropane
1,2,3-Trichloropropane
Mutagenicity/genotoxicity alerts
OECD
QSAR
Toolbox
DNA alerts for Ames by OASIS
DNA alerts for CA and MNT by OASIS
In vitro mutagenicity (Ames test) alerts by ISS
In vivo mutagenicity (micronucleus) alerts by ISS
Protein binding alerts for CA by OASIS
ToxRead
ToxRead (mutagenicity)
VEGA
Mutagenicity (Ames test) CONSENSUS model—assessment
Mutagenicity (Ames test) model (CAESAR)—assessment
Mutagenicity (Ames test) model (SARpy/IRFMN)—assessment
Mutagenicity (Ames test) model (ISS)—assessment
Mutagenicity (Ames test) model (A-NN/read-across)—assessment
Carcinogenicity alerts
OECD
QSAR
Toolbox
Carcinogenicity (genotoxicity and nongenotoxicity) alerts by ISS
OncoLogic
OncoLogic (prediction of the carcinogenic potential of the chemical)
VEGA
Carcinogenicity model (CAESAR)—assessment
Carcinogenicity model (ISS)—assessment
Carcinogenicity model (IRFMN/ANTARES)—assessment
Carcinogenicity model (IRFMN/ISSCAN-CGX)—assessment
ToxAlerts
Aliphatic halogens (for nongenotoxic carcinogenicity)
Toxtree
Nongenotoxic carcinogenicity
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Table C-7. Heat Map Illustrating the Structural Alert and SAR Prediction Results for
l-Bromo-2-Chloroethane (CASRN 107-04-0) and Analogues
Tool
Model3
l-Bromo-2-chloro ethane
1,2-Dibromoethane
1,2-Dichloroethane
1,2-Dichloropropane
l,2-Dibromo-3-chloropropane
1,2,3-Trichloropropane
Combined alerts
ToxAlerts
Aliphatic halide (general) (for genotoxic carcinogenicity, mutagenicity)
Aliphatic halide (specific) (for genotoxic carcinogenicity, mutagenicity)
Aliphatic halogens (for genotoxic carcinogenicity, mutagenicity)
Aromatic and aliphatic substituted primary alkyl halides (for genotoxic
carcinogenicity, mutagenicity)
Structural alert for genotoxic carcinogenicity
Toxtree
Model results outside the applicability domain for
carcinogenicity/mutagenicity.
Model results or alerts indicating no concern for carcinogenicity/mutagenicity.
Model results outside the applicability domain for carcinogenicity/mutagenicity.
Model results or alerts indicating concern for carcinogenicity/mutagenicity.
aAll tools and models described in Appendix B were used. Models with results or alerts are presented in the heat
map (models without results were omitted).
ANT ARES = Alternative Non-Testing Methods Assessed for REACH Substances; CA = chromosomal aberration;
CAESAR = Computer-Assisted Evaluation of industrial chemical Substances According to Regulations;
CONSENSUS = consensus assessment based on multiple models (CAESAR, SARpy, ISS, and A-NN);
DNA = deoxyribonucleic acid; IRFMN = Istituto di Ricerche Fannacologiche Mario Negri; ISS = Istituto
Superiore di Sanita; ISSCAN-CGX = Istituto Superiore di Sanita Chemical Carcinogen; A-NN = A-nearest
neighbor; MNT = micronucleus test; OECD = Organisation for Economic Co-operation and Development;
QSAR = quantitative structure-activity relationship; REACH = Registration, Evaluation, Authorisation and
Restriction of Chemicals; SAR = structure-activity relationship; VEGA = Virtual models for property Evaluation
of chemicals within a Global Architecture.
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Table C-8. Structural Alerts for l-Bromo-2-Chloroethane (CASRN 107-04-0) and
Analogues
SA
Tool
Compounds
Haloalkanes and haloalkenes
OncoLogic
l-Bromo-2-chloroethanea,l,2-DBEb, l,2-DCE,a
1,2-DCPC, l,2-DB-3-CPb, TCPb
Aliphatic halogens
ToxAlerts
Toxtree
OECD QSAR Toolbox
l-Bromo-2-chloroethane, 1,2-DBE, 1,2-DCE,
1,2-DCP, l,2-DB-3-CP, TCP
Aliphatic halide
Aromatic and aliphatic substituted
primary alkyl halides
ToxAlerts
l-Bromo-2-chloroethane, 1,2-DBE, 1,2-DCE,
1,2-DCP, l,2-DB-3-CP, TCP
Vicinal dihaloalkanes
OECD QSAR Toolbox
l-Bromo-2-chloroethane, 1,2-DBE, 1,2-DCE,
1,2-DCP
Halogenated vicinal hydrocarbons
l-Bromo-2-chloroethane, 1,2-DBE, 1,2-DCE,
1,2-DCP, l,2-DB-3-CP, TCP
identified as moderate alert based on SAR analysis only.
identified as high-moderate alert based on experimental data and SAR analysis.
identified as moderate alert based on experimental data and SAR analysis.
l,2-DB-3-CP = l,2-dibromo-3-chloropropane; 1,2-DBE= 1,2-dibromoethane; 1,2-DCE= 1,2-dichloroethane;
1,2-DCP = 1,2-dichloropropane; OECD = Organisation for Economic Co-operation and Development;
QSAR = quantitative structure-activity relationship; SA = structural alert; SAR = structure-activity relationship;
TCP = 1,2,3-trichloropropane.
STEP 7. EVIDENCE INTEGRATION FOR SCREENING EVALUATION OF
l-BROMO-2-CHLOROETHANE CARCINOGENICITY
Table C-9 presents the data for multiple lines of evidence pertinent to the screening
evaluation of the carcinogenic potential of l-bromo-2-chloroethane.
86
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Table C-9. Integration of Evidence for l-Bromo-2-Chloroethane (CASRN 107-04-0) and Analogues
Evidence
Streams
1-Bromo-
2-Chloroethane
CASRN 107-04-0
1,2-Dibromoethane
CASRN 106-93-4
1,2-Dichloroethane
CASRN 107-06-2
1,2-Dichloropropane
CASRN 78-87-5
1,2-Dibromo-
3-Chloropropane
CASRN 96-12-8
1,2,3-Trichloro-
propane
CASRN 96-18-4
Structure
/Br
cr
/Br
Br
O
\
Q
/CH3
cr
CI
Br
ci-^y^ci
CI
Analogue
selection and
evaluation
(see Steps 1
and 2)
Target compound
Contains: (1) two
labile halogen
substituents;
(2) halogens
attached to adjacent,
primary carbon
atoms; and (3) no
more than one
halogen per carbon
atom
Contains: (1) two
labile halogen
substituents;
(2) halogens attached
to adjacent, primary
carbon atoms; and
(3) no more than one
halogen per carbon
atom
Contains: (1) two
labile halogen
substituents;
(2) halogens attached
to adjacent, primary
carbon atoms; and
(3) no more than one
halogen per carbon
atom
Contains: (1) two labile
halogen substituents;
(2) halogens attached to
adjacent, primary
carbon atoms; and
(3) no more than one
halogen per carbon atom
Contains: (1) three
labile halogen
substituents;
(2) halogens attached to
adjacent, primary
carbon atoms; and
(3) no more than one
halogen per carbon
atom
Contains: (1) three
labile halogen
substituents;
(2) halogens attached to
adjacent, primary
carbon atoms; and
(3) no more than one
halogen per carbon
atom
Experimental
genotoxicity
data
(see Step 3)
Mutagenic
Clastogenic
DNA damaging
Forms DNA adducts
Mutagenic
Clastogenic
DNA damaging
Forms DNA adducts
Induces cell
transformation
Mutagenic
Clastogenic
DNA damaging
Forms DNA adducts
Not a potent mutagen
Clastogenic
DNA damaging
Mutagenic
Clastogenic
DNA damaging
Forms DNA adducts
Induces cell
transformation
Mutagenic
Clastogenic
DNA damaging
Forms DNA adducts
Induces cell
transformation
ADME
evaluation
(see Step 4)
Oxidation (based on
analogy to other
dihaloalkanes) and
GSH conjugation
(demonstrated)
Expected to form
episulfonium ion
Common metabolic
pathways with other
haloalkanes
(oxidation and GSH
conjugation)
Forms episulfonium
ion
Common metabolic
pathways with other
haloalkanes
(oxidation and GSH
conjugation)
Forms episulfonium
ion
Common metabolic
pathways with other
haloalkanes (oxidation
and GSH conjugation)
Expected to form
episulfonium ion
Common metabolic
pathways with other
haloalkanes (oxidation
and GSH conjugation)
Forms episulfonium ion
Common metabolic
pathways with other
haloalkanes (oxidation
and GSH conjugation)
Forms episulfonium ion
87
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Table C-9. Integration of Evidence for l-Bromo-2-Chloroethane (CASRN 107-04-0) and Analogues
Evidence
Streams
1-Bromo-
2-Chloroethane
CASRN 107-04-0
1,2-Dibromoethane
CASRN 106-93-4
1,2-Dichloroethane
CASRN 107-06-2
1,2-Dichloropropane
CASRN 78-87-5
1,2-Dibromo-
3-Chloropropane
CASRN 96-12-8
1,2,3-Trichloro-
propane
CASRN 96-18-4
Cancer data
and MOAa
(see Step 5)
No data
Multisite carcinogen
in rats and mice
following oral or
inhalation exposure
Proposed MOA:
Mutagenicity and/or
DNA damage
Multisite carcinogen
in rats and mice
following oral or
inhalation exposure
Potential MOA:
Mutagenicity and/or
DNA damage
Liver tumors (mice) and
marginal increase in
mammary gland tumors
(rats) following oral
exposure; nasal tumors
(rats) and lung and
Harderian gland tumors
(mice) following
inhalation exposure
Proposed MOA: DNA
damage
Multisite carcinogen in
rats and mice following
oral exposure; primarily
respiratory tract cancer
(nasal, pharynx, lung)
following inhalation
exposure
MOA: mutagenicity
Multisite carcinogen in
rats and mice following
oral exposure; no
inhalation data
MOA: mutagenicity
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Table C-9. Integration of Evidence for l-Bromo-2-Chloroethane (CASRN 107-04-0) and Analogues
1-Bromo-
1,2-Dibromo-
1,2,3-Trichloro-
Evidence
2-Chloroethane
1,2-Dibromoethane
1,2-Dichloroethane
1,2-Dichloropropane
3-Chloropropane
propane
Streams
CASRN 107-04-0
CASRN 106-93-4
CASRN 107-06-2
CASRN 78-87-5
CASRN 96-12-8
CASRN 96-18-4
Common
ALERTS
ALERTS
ALERTS
ALERTS
ALERTS
ALERTS
structural
• Haloalkanes and
• Haloalkanes and
• Haloalkanes and
• Haloalkanes and
• Haloalkanes and
• Haloalkanes and
alerts and
haloalkenes
haloalkenes
haloalkenes
haloalkenes
haloalkenes
haloalkenes
SAR
• Aliphatic
• Aliphatic halogens
• Aliphatic halogens
• Aliphatic halogens
• Aliphatic halogens
• Aliphatic halogens
predictions
halogens
• Aliphatic halide
• Aliphatic halide
• Aliphatic halide
• Aliphatic halide
• Aliphatic halide
(see Step 6)
• Aliphatic halide
• Vicinal
• Vicinal
• Vicinal dihaloalkanes
• Halogenated vicinal
• Halogenated vicinal
• Vicinal
dihaloalkanes
dihaloalkanes
• Halogenated vicinal
hydrocarbons
hydrocarbons
dihaloalkanes
• Halogenated vicinal
• Halogenated vicinal
hydrocarbons
• Halogenated
hydrocarbons
hydrocarbons
SAR PREDICTIONS:
SAR PREDICTIONS:
vicinal
SAR PREDICTIONS:
Concerns for
Concerns for
hydrocarbons
SAR PREDICTIONS:
SAR
Concerns for
mutagenicity and
mutagenicity and
Concerns for
PREDICTIONS:
mutagenicity and
carcinogenicity in most
carcinogenicity in most
SAR
mutagenicity and
Concerns for
carcinogenicity in most
models; no concern for
models; no concern for
PREDICTIONS:
carcinogenicity in
mutagenicity and
models; no concern for
nongenotoxic
nongenotoxic
Concerns for
most models; no
carcinogenicity in
carcinogenicity in two
carcinogenicity in
carcinogenicity in
mutagenicity and
concern for
most models; no
of four VEGA models
Toxtree
Toxtree
carcinogenicity in
nongenotoxic
concern for
and no concern for
most models; no
carcinogenicity in
nongenotoxic
nongenotoxic
concern for
Toxtree
carcinogenicity in
carcinogenicity in
nongenotoxic
Toxtree
Toxtree
carcinogenicity in
Toxtree
Tor MOA descriptions, "MO A" was used if the U.S. EPA did a formal MOA evaluation and made a conclusion regarding cancer MOA(s); "proposed MO A"
was used if the U.S. EPA did not do formal MOA evaluation, but proposed possible MOAs; and "potential MOA" was used if the U.S. EPA did not discuss
potential MOAs but available experimental data suggest an MOA.
ADME = absorption, distribution, metabolism, excretion; DNA = deoxyribonucleic acid; GSH = glutathione; MOA = mode of action; SAR = structure-activity
relationship; VEGA = Virtual models for property Evaluation of chemicals within a Global Architecture.
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STEP 8. QUALITATIVE LEVEL OF CONCERN FOR l-BROMO-2-CHLOROETHANE
POTENTIAL CARCINOGENICITY
Table C-10 identifies the qualitative level of concern for potential carcinogenicity of
l-bromo-2-chloroethane based on the multiple lines of evidence described above. Due to lack of
information supporting carcinogenic portal-of-entry effects, the qualitative level of concern for
this chemical is considered to be applicable to all routes of exposure.
Table C-10. Qualitative Level of Concern for Carcinogenicity of
l-Bromo-2-Chloroethane (CASRN 107-04-0)
Level of Concern
Designation
Comments
Concern for potential
carcinogenicity
Selected
All analogues of l-bromo-2-chloroethane have carcinogenic potential
based on tumors observed in rodent studies. The U.S. EPA identified a
mutagenic MOA for l,2-DB-3-CP and TCP, and all analogues except
1,2-DCP are mutagenic (evidence is limited for 1,2-DCP). DNA damage
is also a potential MOA suggested for 1,2-DBE and 1,2-DCP, and
experimental evidence indicates that all analogues are DNA damaging
and all except 1,2-DCP form DNA adducts (no data for 1,2-DCP).
Common metabolic pathways exist between l-bromo-2-chloroethane
and the analogue compounds. l-Bromo-2-chloroethane and its
analogues have similar structural alerts (e.g., haloalkanes and
haloalkenes, aliphatic halogens, aliphatic halide, halogenated vicinal
hydrocarbons) and similar SAR predictions showing concern for
carcinogenicity and/ or genotoxicity.
Inadequate information
for assigning qualitative
level of concern
Not selected
NA
l,2-DB-3-CP = l,2-dibromo-3-chloropropane; 1,2-DBE = 1,2-dibromoethane; 1,2-DCP = 1,2-dichloropropane;
DNA = deoxyribonucleic acid; MOA = mode of action; NA = not applicable; SAR = structure-activity relationship;
TCP = 1,2,3-trichloropropane.
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