EPA/690/R-22/001F | September 2022 | FINAL
United States
Environmental Protection
Agency
xvEPA
Provisional Peer-Reviewed Toxicity Values for
c/s-1,2-Dichloroethylene (c/s- 1,2-DCE)
(CASRN 156-59-2)
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-22/001F
September 2022
https://www.epa.gov/pprtv
Provisional Peer-Reviewed Toxicity Values for
cis-1,2-Dichloroethylene (cis-1,2-DCE)
(CASRN 156-59-2)
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
Allison L. Phillips, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
CONTRIBUTORS
Lucina E. Lizarraga, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
Chelsea A. Weitekamp, PhD
Center for Public Health and Environmental Assessment, Research Triangle Park, NC
SCIENTIFIC TECHNICAL LEAD
Lucina E. Lizarraga, PhD
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
Jeffry L. Dean II, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
Roman Mezencev, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
PRIMARY EXTERNAL REVIEWERS
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
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.
in
cis-1,2-Dichloroethylene
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS v
BACKGROUND 1
QUALITY ASSURANCE 1
DISCLAIMERS 2
QUESTIONS REGARDING PPRTVs 2
1. INTRODUCTION 3
2. REVIEW OF POTENTIALLY RELEVANT DATA FOR DERIVATION OF NONCANCER
AND CANCER INHALATION REFERENCE VALUES 8
2.1. OTHER DATA (SHORT TERM TESTS, OTHER EXAMINATIONS) 8
2.1.1. Supporting Animal Studies 16
2.1.2. Genotoxicity 18
2.1.3. Metabolism/Toxicokinetic Studies 19
3. DERIVATION 01 PROVISIONAL VALUES 21
3.1. DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 21
3.2. SUMMARY OF NONCANCER PROVISIONAL REFERENCE VALUES 21
3.3. CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR 21
3.4. DERIVATION OF PROVISIONAL CANCER RISK ESTIMATES 22
APPENDIX A. SCREENING NONCANCER PROVISIONAL VALUES 23
APPENDIX B. REFERENCES 70
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cis-1,2-Dichloroethylene
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COMMONLY USED ABBREVIATIONS AND ACRONYMS
a2u-g
alpha 2u-globulin
IVF
in vitro fertilization
ACGIH
American Conference of Governmental
LC50
median lethal concentration
Industrial Hygienists
LD50
median lethal dose
AIC
Akaike's information criterion
LOAEL
lowest-observed-adverse-effect level
ALD
approximate lethal dosage
MN
micronuclei
ALT
alanine aminotransferase
MNPCE
micronucleated polychromatic
AR
androgen receptor
erythrocyte
AST
aspartate aminotransferase
MOA
mode of action
atm
atmosphere
MTD
maximum tolerated dose
ATSDR
Agency for Toxic Substances and
NAG
7V-acetyl-P-D-glucosaminidase
Disease Registry
NCI
National Cancer Institute
BMC
benchmark concentration
NOAEL
no-observed-adverse-effect level
BMCL
benchmark concentration lower
NTP
National Toxicology Program
confidence limit
NZW
New Zealand White (rabbit breed)
BMD
benchmark dose
OCT
ornithine carbamoyl transferase
BMDL
benchmark dose lower confidence limit
ORD
Office of Research and Development
BMDS
Benchmark Dose Software
PBPK
physiologically based pharmacokinetic
BMR
benchmark response
PCNA
proliferating cell nuclear antigen
BUN
blood urea nitrogen
PND
postnatal day
BW
body weight
POD
point of departure
CA
chromosomal aberration
PODadj
duration-adjusted POD
CAS
Chemical Abstracts Service
QSAR
quantitative structure-activity
CASRN
Chemical Abstracts Service registry
relationship
number
RBC
red blood cell
CBI
covalent binding index
RDS
replicative DNA synthesis
CHO
Chinese hamster ovary (cell line cells)
RfC
inhalation reference concentration
CL
confidence limit
RfD
oral reference dose
CNS
central nervous system
RGDR
regional gas dose ratio
CPHEA
Center for Public Health and
RNA
ribonucleic acid
Environmental Assessment
SAR
structure-activity relationship
CPN
chronic progressive nephropathy
SCE
sister chromatid exchange
CYP450
cytochrome P450
SD
standard deviation
DAF
dosimetric adjustment factor
SDH
sorbitol dehydrogenase
DEN
diethylnitrosamine
SE
standard error
DMSO
dimethylsulfoxide
SGOT
serum glutamic oxaloacetic
DNA
deoxyribonucleic acid
transaminase, also known as AST
EPA
Environmental Protection Agency
SGPT
serum glutamic pyruvic transaminase,
ER
estrogen receptor
also known as ALT
FDA
Food and Drug Administration
SSD
systemic scleroderma
FEVi
forced expiratory volume of 1 second
TCA
trichloroacetic acid
GD
gestation day
TCE
trichloroethylene
GDH
glutamate dehydrogenase
TWA
time-weighted average
GGT
y-glutamyl transferase
UF
uncertainty factor
GSH
glutathione
UFa
interspecies uncertainty factor
GST
g 1 ii ta t h i o nc - V-1 ra ns fc ra sc
UFc
composite uncertainty factor
Hb/g-A
animal blood-gas partition coefficient
UFd
database uncertainty factor
Hb/g-H
human blood-gas partition coefficient
UFh
intraspecies uncertainty factor
HEC
human equivalent concentration
UFl
LOAEL-to-NOAEL uncertainty factor
HED
human equivalent dose
UFS
subchronic-to-chronic uncertainty factor
i.p.
intraperitoneal
U.S.
United States of America
IRIS
Integrated Risk Information System
WBC
white blood cell
Abbreviations and acronyms not listed on this page are defined upon first use in the
PPRTV document.
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EPA/690/R-22/001F
PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
C/5-l,2-DICHLOROETHYLENE (CASRN 156-59-2) [NONCANCER INHALATION
VALUES]
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 eComments Chemical Safety website at
https://ecomments.epa.gov/chemicalsafetv/.
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.
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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
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
cis-1,2-Dichloroethylene (cis- 1,2-DCE; CASRN 156-59-2) belongs to the class of
compounds known as halogenated alkenes. cis- 1,2-DCE is an isomer of dichloroethylene.
Mixtures of czs-l,2-DCE with its isomer, transA ,2-dichloroethylene {trans- 1,2-DCE), have
several commercial uses. 1,2-DCE mixtures are used in the production of other chlorinated
compounds and for solvent vapor and surface cleaning (Dreher et al.. 2014; Mertens. 2000;
ATS DR. 1996). 1,2-DCEs are also used as foam blowing additives, as refrigerants, and in
silicone etching (Dreher et al.. 2014). Other reported uses of 1,2-DCEs include low temperature
solvent extraction for organic materials such as waxes, resins, dyes, perfumes, lacquers, and
thermoplastics and extraction of oil and fats from fish and meat (Dreher et al .. 2014; Mertens.
2000). cis-1,2-DCE can be produced directly by chlorinating acetylene (Mertens, 2000).
1,2-DCEs are also produced as a byproduct of chlorinated compound production (Mertens.
2000). cis-1,2-DCE is listed on the U.S. EPA nonconfidential Toxic Substances Control Act
(TSCA) inventory (U.S. EPA. 2021c) and is registered with Europe's Registration, Evaluation,
Authorisation and Restriction of Chemicals (REACH) program (ECU A. 2020).
The empirical formula for cz's-l,2-DCE is C2H2CI2, and its structure is shown in
Figure 1. Table 1 summarizes the physicochemical properties of cis- 1,2-DCE. cis-1,2-DCE is a
clear, colorless liquid with a sharp, ether-like odor (Nl.M. 202 Ig; ATS DR. 1996). Given its high
vapor pressure, cis- 1,2-DCE is expected to exist solely as a vapor in the atmosphere. Its vapor
pressure and moderate Henry's law constant indicate that it will likely volatilize from either dry
or moist soil surfaces and from water surfaces. The high water solubility and low soil adsorption
coefficient indicate that cis- 1,2-DCE will have the potential to leach to groundwater or undergo
runoff after a rain event.
/^=\
f"' I
iJ
Figure 1. cis-l,2-DCE (CASRN 156-59-2) Structure
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Table 1. Physicochemical Properties of cis-1,2-DCE (CASRN 156-59-2)
Property (unit)
Value3
Molecular formula (unitless)
C2H2CI2
Molecular weight (g/mol)
96.94
Physical state
Liquidb
Physical properties
Clear, colorless, ether-like odor
Boiling point (°C)
54.4
Melting point (°C)
-64.9
Density (g/cm3 at 20°C)
1.24 (predicted)
Vapor density (at boiling point and 760 mm Hg)
3.54 g/Lb
Vapor pressure (mm Hg)
200b
Water solubility (mol/L)
0.0493
Log Kow
1.86
pKa (unitless)
NA
Henry's law constant (atm-nvVmole)
0.00673
Flash point (°C)
10.3 (predicted)
Auto flammability (°C)
460b
Viscosity (cp at 20°C)
0.456
Refractive index (at 25°C/D)
1.45 (predicted)
Dielectric constant
NA
aData were extracted from the U.S. EPA CompTox Chemicals Dashboard (cis-1.2-dichlorocthvlcnc.
CASRN 156-59-2. https://comptox.epa.gov/dashboard/dsstoxdb/results?search 1)1X511)21)241)30. Accessed on
May 12, 2021). All values are experimental averages unless otherwise specified.
' Data are from NLM (202 Ig).
cis- 1,2-DCE = 6/.V- 1.2-dichlorocthylcnc: NA = not applicable; U.S. EPA = U.S. Environmental Protection Agency.
A summary of available toxicity values for cis- 1,2-DCE from U.S. EPA and other
agencies/organizations is provided in Table 2.
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Table 2. Summary of Available Toxicity Values for cis- 1,2-DCE
(CASRN 156-59-2)
Source/Parameterab
Value (applicability)
Notes
Study
Observing
Critical Effect
Reference
Noncancer
IRIS (RfC)
NV
Information reviewed but
value not derived
U.S. EPA
(2010)
IRIS (RfD)
0.002 mg/kg-d
Based on increased
relative kidney weight in
male rats
McCaulev et al.
(1995);
McCaulev et al.
(1990)
PPRTV (subchronic
p-RfD)
0.02 mg/kg-d
Based on increased
relative kidney weight in
male rats
McCaulev et al.
(1995);
McCaulev et al.
(1990)
U.S. EPA
(2011c)
DWSHA (RfD)
0.002 mg/kg-d
NA
U.S. EPA
(2018a)
HEAST (subchronic
RfD)
NV
NA
U.S. EPA
(2011b)
ATSDR (MRL, oral
acute)
1 mg/kg-d
Based on decreased RBC
counts and hematocrit
levels in female rats
exposed for 14 d
McCaulev et al.
(1990)
ATSDR (1996)
ATSDR (MRL, oral
intermediate)
0.3 mg/kg-d
Based on decreased
hematocrit levels in male
rats and decreased
hemoglobin levels in rats
of both sexes exposed for
90 d
McCaulev et al.
(1990)
CalEPA (ADD)
0.00125 mg/kg-d
Based on increased
relative kidney weights in
male rats exposed for 90 d
McCaulev et al.
(1995)
CalEPA (2018)
AEGL (AEGL-1)
10 min: 140 ppm
30 min: 140 ppm
60 min: 140 ppm
4 h: 140 ppm
8 h: 140 ppm
Based on ocular irritation
in humans
Lehmann and
Schniidt-Kehl
U.S. EPA
(2018b. 2008)
(1936)
AEGL (AEGL-2)
10 min: 500 ppm
30 min: 500 ppm
60 min: 500 ppm
4 h: 340 ppm
8 h: 230 ppm
Based on narcosis in rats
(4 and 8 h) or anesthetic
effects in humans (10, 30,
and 60 min)
Hunt et al.
(1993)
AEGL (AEGL-3)
10 min: 850 ppm
30 min: 850 ppm
60 min: 850 ppm
4 h: 620 ppm
8 h: 310 ppm
Based on a no-effect level
for death in rats (4 and
8 h) or dizziness,
intracranial pressure, and
nausea in humans (10, 30,
and 60 min)
Kellv (1999)
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Table 2. Summary of Available Toxicity Values for cis- 1,2-DCE
(CASRN 156-59-2)
Source/Parameterab
Value (applicability)
Notes
Study
Observing
Critical Effect
Reference
ACGIH (TLV-TWA)0
200 ppm
Based on CNS
impairment and eye
irritation
Lehmann and
Schmidt-KeM
(1936)
ACGIH (2020)
OSHA (PEL)0
200 ppm (790 mg/m3)
8-h TWA for general
industry, construction, and
shipyard employment
OSHA (2020a.
2020b. 2020c)
NIOSH (REL)°
200 ppm (790 mg/m3)
TWA for up to a 10-h
workday during a 40-h
workweek
NIOSH (2019)
NIOSH (IDLH)0
1,000 ppm
Based on acute inhalation
toxicity data in humans
von Oettineen
(1955. 1937)
NIOSH (2019.
2014)
Cancer
IRIS (WOE)
Inadequate information to
assess carcinogenic
potential
NA
U.S. EPA
(2010)
DWSHA (WOE)
Inadequate information to
assess carcinogenic
potential
NA
U.S. EPA
(2018a)
HEAST
NV
NA
U.S. EPA
(2011b)
NTP
NV
NA
NTP (2016)
IARC
NV
NA
IARC (2021)
CalFPA
NV
NA
CalEPA (2021)
ACGIH0
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;
IARC = International Agency for Research on Cancer; IRIS = Integrated Risk Information System;
NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program;
OSHA = Occupational Safety and Health Administration; PPRTV = Provisional Peer-Reviewed Toxicity Value.
Parameters: ADD = acceptable daily dose; AEGL = acute exposure guideline level; IDLH = immediately
dangerous to life or health concentrations; MRL = minimum risk level; PEL = permissible exposure level;
p-RfD = provisional reference dose; REL = recommended exposure limit; RfC = reference concentration;
RfD = reference dose; TLV = threshold limit value; TWA = time-weighted average; WOE = weight of evidence.
°Values are for 1,2-dichloroethylene (unspecified mixed isomer) and are not specific for 1.2-c/.v-DCE.
dMcCaulev et at (1990) (unpublished report) was subsequently published as McCaulev et al. (1995).
cis- 1,2-DCE = cis- 1,2-dichloroethylene; CNS = central nervous system; NA = not applicable; NV = not available;
RBC = red blood cell.
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Non-date-limited literature searches were conducted in October 2017 and updated most
recently in July 2022 for studies relevant to the derivation of provisional toxicity values for
cz's-l,2-DCE (CASRN 156-59-2). 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 additional 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
International Programme on Chemical Safety (IPCS) INCHEM, Japan Existing Chemical Data
Base (JECDB), Organisation for Economic Co-operation 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 July 2022.
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2. REVIEW OF POTENTIALLY RELEVANT DATA FOR DERIVATION OF
NONCANCER AND CANCER INHALATION REFERENCE VALUES
No short-term, subchronic, or chronic studies; developmental or reproductive toxicity
studies; or carcinogenicity studies of c/s-1,2-DCE in humans or animals conducted by inhalation
exposure were identified.
2.1. OTHER DATA (SHORT TERM TESTS, OTHER EXAMINATIONS)
Data for cis- 1,2-DCE are limited to a single acute inhalation study, oral studies, injection
studies, and studies on 1,2-DCE mixtures containing both the cis- and trans- 1,2-DCE isomers.
The findings from relevant studies are briefly summarized in the text below. More detailed
descriptions of the individual studies are provided in Table 3.
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Table 3. Supporting Animal Studies of cis-l,2-DCEa
Test
Materials and Methods
Results
Conclusions
References
Supporting studies in animals following inhalation exposure
Acute
(cis isomer)
Rats (5/sex/group; strain not
specified) were exposed to
cis-1,2-DCE vapor concentrations
of 0, 12,100, 13,500, 15,700, or
23,200 ppm (equivalent to 0,
47,900, 53,400, 62,200, and
91,900 mg/m3) for 4 h. Animals
were observed for 14 d.
No deaths occurred at 47,900 mg/m3. 4/10 rats died at
53,400 mg/m3, and 10/10 animals died in the two
highest dose groups.
During exposure, animals were prostrate, with eyes
open, and unresponsive to alerting stimulus. Animals
that survived exhibited irregular respiration
immediately after exposure and slight to severe
weight loss for 1 d after exposure.
RatLCso (4 h) = 13,700 ppm
(54,320 mg/m3).
DuPont Haskell Lab
(1999)
Supporting studies in animals following oral exposure
Acute
(cis and trans isomers)
Male Holtzman rats (3-4/group)
were administered single oral
doses of 0, 400, or 1,500 mg/kg
c/'s-l,2-DCE or trans- 1,2-DCE in
corn oil via gavage. At 20 h after
dosing, liver G6P, tyrosine
transaminase and ALP activities,
and plasma ALP and ALT
activities were measured.
Results for cis isomer: f liver ALP at >400 mg/kg;
i liver tyrosine transaminase and G6P at
1,500 mg/kg; J, plasma ALT at 1,500 mg/kg.
Results for trans isomer: f liver G6P at 400 mg/kg
(only); { liver tyrosine transaminase at 1,500 mg/kg.
Limited evidence of liver effects
for cis-1,2-DCE at >400 mg/kg,
unlike trans-1,2-DCE. at
1,500 mg/kg c/s-l,2-DCE:
t liver ALP, [ plasma ALT
suggesting that the cis isomer
elicits a slightly greater
biochemical response than the
trans isomer at this dose.
Jenkins et al. (1972)
Acute
(cis and trans isomers)
Male Sprague Dawley rats (6/dose)
were administered single oral
doses of 0, 26, or 51 mmol/kg
c/s-1,2-DCE (-2,500 or
5,000 mg/kg) by gavage in sesame
seed oil. Levels of liver GSH and
plasma ALT, AST, and SDH
activity were measured after 24 h.
Results for cis isomer: f liver GSH (19 and 28%) and
t serum SDH (57 and 56.5%) at 2,500 and
5,000 mg/kg, respectively; t serum AST (56%) at
5,000 mg/kg; no change in serum ALT. Two animals
in the 5,000 mg/kg group died.
Results for trans isomers: No significant changes in
enzyme levels. One treated animal died.
Limited evidence of liver effects
for cis-1,2-DCE at
>2,500 mg/kg, with no response
from trans-1,2-DCE.
Mcmillan (1986).
dissertation
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Table 3. Supporting Animal Studies of cis-l,2-DCEa
Test
Materials and Methods
Results
Conclusions
References
Short-term
(cis isomer)
Sprague Dawley rats (10/sex/dose)
were administered 0, 1.0, 3.0, 10.0,
or 20.0 mmol/kg c/'s-l,2-DCE (~0,
97, 291, 970, and 1,940 mg/kg-d)
by gavage for 14 d.
Animals were monitored for
mortality, clinical signs of toxicity,
food and water intake, serum
chemistry, hematology, organ
weights, and histopathology.
The percent changes of select endpoints compared
with controls in males and females at 97, 291, 970,
and 1,940 mg/kg-d, respectively, are reported. Results
shown are statistically significant except where noted
asNS.
Females:
t Absolute liver weisht
21%, 24%, 35%, 44%
t Relative liver weisht
15%, 18%, 29%, 39%
t Absolute kidnev weisht
11% (NS), 11% (NS), 20%, 16%
t Relative kidnev weisht
5% (NS), 5% (NS), 14%, 12%
J. Hematocrit
8% (NS), 11%, 11%, 11%
t Cholesterol
15% (NS), 17% (NS), 25% (NS), 40%
No significant changes in hemoglobin, RBC
counts, or plasma AST levels.
Males:
t Absolute liver weisht
12% (NS), 19% (NS), 28%, 26%
t Relative liver weisht
16%, 18%, 33%, 38%
t Absolute kidnev weisht
4% (NS), 16% (NS), 21% (NS), 5% (NS)
t Relative kidnev weisht
7% (NS), 15% (NS), 21% (NS), 15% (NS)
i Absolute spleen weight; (7%) in high-dose
males. No significant changes in RBC parameters
or plasma AST levels.
Limited evidence for an effect
on liver (increased organ
weights) in males and females at
>97 mg/kg-d.
Limited evidence for an effect
on the kidney (increased organ
weights) in females at
>970 mg/kg-d.
Hematological changes were
small in magnitude, not clearly
related to dose, and within the
normal range of variation (U.S.
EPA. 2010).
McCaulev et al.
(1995); McCaulev et
al. (1990)
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Table 3. Supporting Animal Studies of cis-l,2-DCEa
Test
Materials and Methods
Results
Conclusions
References
Subchronic
(cis isomer)
Sprague Dawley rats (10/sex/dose)
were administered 0, 0.33, 1, 3, or
9 mmol/kg-d cis-1,2-DCE (~0, 32,
97, 291, and 872 mg/kg-d) by
gavage for 90 d.
Animals were monitored for
mortality, clinical signs of toxicity,
food and water intake, serum
chemistry, hematology, organ
weights, and histopathology.
The percent changes of select endpoints in males and
females at 32, 97, 291, and 872 mg/kg-d,
respectively, are reported. Results shown are
statistically significant except where noted as NS.
Females:
t Absolute liver weisht
3% (NS), 11% (NS), 15% (NS), 24%
t Relative liver weisht
3% (NS), 14%, 19%, 30%
t Absolute kidnev weisht
3% (NS), 16% (NS), 17% (NS), 17% (NS)
t Relative kidnev weisht
3% (NS), 20% (NS), 23% (NS), 23% (NS)
J. Hemoslobin
3% (NS), 5% (NS), 6%, 4% (NS)
J. Hematocrit
4% (NS), 6% (NS), 10%, 8%
J. RBC counts
3% (NS), 4% (NS), 8%, 6% (NS)
t Absolute (13%) and t relative (17%) thymus
weight in high-dose females.
Males:
t Absolute liver weisht
6% (NS), 13% (NS), 5% (NS), 15% (NS)
t Relative liver weisht
11% (NS), 15%, 17%, 32%
t Absolute kidnev weisht
9% (NS), 17% (NS), 7% (NS), 14% (NS)
t Relative kidnev weisht
14%, 19%, 19%, 27%
J. Hemoslobin
5% (NS), 3% (NS), 6%, 6%
LOAEL = 32 mg/kg-d based on
increased relative kidney
weights in male rats.
Limited evidence for an effect
on liver (increased organ
weights) in males and females at
>97 mg/kg-d.
Hematological changes were
small in magnitude, not clearly
related to dose, within the
normal range of variation (U.S.
EPA. 2010). and oossiblv
reflective of increased water
intake observed in the treated
rats.
McCaulev et al.
(1995); McCaulev et
al. (1990)
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Table 3. Supporting Animal Studies of cis-l,2-DCEa
Test
Materials and Methods
Results
Conclusions
References
J. Hematocrit
6% (NS), 6%, 9%, 9%
No statistically significant changes inRBC counts.
Supporting studies in animals via other routes
Acute (i.p.)
(cis and trans isomers)
Male Sprague Dawley rats (6/dose)
were administered single i.p. doses
of 0, 21, or 26 mmol/kg
as-1,2-DCE (-2,000 and
2,500 mg/kg) or 0, 20, or
25 mmol/kg lrans-\ ,2-DCE
(-1,900 and 2,300 mg/kg) in
sesame seed oil. Levels of liver
GSH and plasma ALT, AST, and
SDH activities were measured
after 24 h.
In a separate time-course study
performed with 2,500 mg/kg
trans- 1,2-DCE administered i.p.,
serum enzyme activities were
measured at 2, 4, 8, 12, and 24 h
postdosing. Liver histopathology
was also characterized.
Results for cis isomer: Dose-related increases in AST
and SDH, statistically significant at >2,000 mg/kg.
No change in GSH. One animal died at the high dose.
Results for trans isomer: Dose-related decrease in
liver GSH, significant at 2,300 mg/kg. No significant
changes in plasma ALT, AST, or SDH. Two animals
died at the high dose.
Results for trans isomer time-course: Plasma ALT,
AST, and SDH peaked around 4 h postdosing,
returning to near normal by 12 h. Histopathology
indicated signs of necrosis. The extent was maximal
at 4-8 h, decreasing to 24 h.
Evidence of liver effects (serum
chemistry) for cis-1,2-DCE at
>2,000 mg/kg 24 h postdosing.
Evidence of liver effects (serum
chemistry, necrosis) for
/raws-1,2-DCE at 2,500 mg/kg
4 h postdosing.
Mcmillan (1986).
dissertation
Acute (i.p.)
(cis and trans isomers)
Wistar rats (4/sex/group) were
treated i.p. with 0 or 7.5 mmol/kg
(730 mg/kg) of cis- or
/raws-1,2-DCE for 4 consecutive
days. Animals were sacrificed 24 h
after the last dose. Body-weight
change was recorded, and liver,
spleen, and thymus weights were
measured.
Results for cis isomer: Statistically significant
decreased body-weight gain (-9%) was observed in
males but not females; no significant changes in
relative liver, spleen, or thymus organ weights in
either sex.
Results for trans isomer: Statistically significant
decreased body-weight gain (-4%) was observed in
males but not females; no significant changes in
relative liver, spleen, or thymus organ weights in
either sex.
No effect on relative liver
weight at 730 mg/kg 24 h after
dosing on 4 consecutive days,
even with significant decrease in
body-weight gain.
Hanioka et al. (1998)
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Table 3. Supporting Animal Studies of cis-l,2-DCEa
Test
Materials and Methods
Results
Conclusions
References
Acute (i.p.)
(cis and trans isomers)
Wistar rats (4-6/group) were given
single i.p. doses of 0 or 500 mg/kg
c/'s-1,2-DCE or trans- 1,2-DCE in
corn oil. Initial body weights were
measured at the start of the
treatment, and body, liver, and
lung weights were measured 24 h
postdosing.
cis isomer results: Statistically significant loss in
body weight occurred in treated animals. An increase
in relative liver weight (9.4%) was observed but did
not reach statistical significance. No changes in
relative lung weights were observed.
trans isomer results: A decrease in body weight and
an increase in relative liver weight (11%) were not
statistically significant. No changes in relative lung
weights were observed.
Marginal increase in relative
liver weight at 500 mg/kg 24 h
after a single dose of either
cis- or trans- 1,2-DCE, even with
body weights reduced.
Nakahama et al.
(2000)
Acute (i.p.)
(cis and trans isomers)
Male Swiss mice (10/dose) were
administered single i.p. doses of 0,
128, 1,280, or 2,560 mg/kg of
c/s-1,2-DCE orO, 1,280, 2,560, or
5,120 mg/kg of trans-1,2-DCE in
corn oil. Kidney function was
assessed by measuring protein and
glucose levels in urine.
Histopathological examinations of
proximal convoluted tubules were
performed in groups of five mice
at the mid dose.
4/10 (cis isomer) and 5/10 (trans isomer) animals
died in the high-dose groups. Deaths occurred within
24 h and appeared to be due to narcosis. In the low-,
mid-, and high-dose groups, 2/10, 2/10, and 3/6 (cis
isomer) and 0/10, 1/10, and 3/5 (trans isomer)
surviving animals, respectively, had increased urinary
protein (>100 mg% of protein, as indicated by a
Combistix standard color chart). In controls,
32/60 had no protein, 23/60 had trace amounts of
protein, 5/60 had 30 mg%, and 0/60 had 100 mg%.
None of the treated mice or controls had elevated
glucose. No swelling or necrosis of the proximal
convoluted tubules was observed (0/5 mice) for either
isomer at the mid dose.
The study authors considered
these results to show limited
evidence of nephrotoxicity for
cis- 1,2-DCE or ;ra«.v-1.2-DCE.
Plaa and Larson
(1965)
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Table 3. Supporting Animal Studies of cis-l,2-DCEa
Test
Materials and Methods
Results
Conclusions
References
Supporting mixture studies
Short-term (inhalation)
(mixture [58% cis. 42%
trans isomer])
Rats (10/sex) were exposed whole
body to a 1,2-DCE vapor
concentration of 1,000 ppm
(-1,980 mg/m3) for 7 h/d, 5 d/wk
for 14 d. Untreated and air-only
control groups were included.
Endpoints included body weights,
select organ weights, serum
chemistry (BUN, ALP, ALT), and
hematology.
t Relative kidney (males, 6.4%) and liver weights
(both sexes <5%).
Limited evidence for an effect
on the liver and kidney
(increased organ weights) at
1,980 mg/m3.
Dow Chemical (1994)
Subchronic (inhalation)
(mixture [58% cis, 42%
trans isomer])
Rats (24-35 at low dose; 12/sex at
high dose) were exposed whole
body to 1,2-DCE vapor
concentrations of 500 or
1,000 ppm (-1,980 or
3,970 mg/m3) for 7 h/d, 5 d/wk for
6 mo. Untreated and air-only
control groups were included.
Endpoints included body weights,
select organ weights, serum
chemistry (BUN, ALP, ALT), and
hematology.
t Relative kidney weights in males (9 and 16%) at
1,980 and 3,960 mg/m3. Relative kidney weights in
females were increased by 18 and 9%, respectively,
but were not statistically significant.
t Relative liver weights (19 and 23%, females only)
at both exposure levels.
Limited evidence of liver and
kidney effects (increased organ
weights) at 1,980 mg/m3.
Dow Chemical (1994)
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Table 3. Supporting Animal Studies of cis-l,2-DCEa
Test
Materials and Methods
Results
Conclusions
References
Short-term (oral)
(mixture [50:50])
Male Sprague Dawley rats
(6/group) were administered 0 or
5 mmol/kg-d (equivalent to
approximately 485 mg/kg-d) of a
50:50 mixture of cis- and
trans- 1,2-DCE by gavage in
sesame seed oil for 14 d.
Endpoints included body weights,
food consumption, hematology,
clinical chemistry, select organ
weights, and histopathology; liver
GSH analysis was performed.
t Relative kidney weights (13%).
No significant changes in RBC or other hematology
parameters. No clinical chemistry or histopathology
findings.
Limited evidence of kidney
effect (increased kidney weight).
Mcmillan (1986).
dissertation
Subchronic (oral)
(mixture [50:50])
Male Sprague Dawley rats
(6/group) were administered 0 or
5 mmol/kg-d (equivalent to
approximately 485 mg/kg-d) of a
50:50 mixture of cis- and
trans- 1,2-DCE by gavage in
sesame seed oil for 30 d.
Endpoints included body weights,
food consumption, hematology,
clinical chemistry, select organ
weights, and histopathology; liver
GSH analysis was performed.
t Relative liver weight (19%), f relative lung weight
(14%), I RBC (6%), I hemoglobin (5%), and
i hematocrit (5%).
No effect on relative kidney weight. No biologically
significant changes in serum chemistry. No
histopathology was observed.
Limited evidence of effect on
liver (increased organ weight).
Mcmillan (1986).
dissertation
aSeveral studies conducted experiments on both cis- and trans- 1,2-DCE isomers. When appropriate, results for both isomers are reported.
t = statistically significantly increased; [ = statistically significantly decreased; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate
aminotransferase; BUN = blood nitrogen urea; C7.v-1.2-DCE = c/'s-l,2-dichloroethylene; G6P = glucose-6-phosphate; GSH = glutathione; i.p. = intraperitoneal; LC50 = median
lethal concentration; NS = not statistically significant; RBC = red blood cell; SDH = sorbitol dehydrogenase; trans- 1,2-DCE = trans-1.2-dichloroethvlcnc.
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2.1.1. Supporting Animal Studies
Inhalation Studies (Acute)
The only available inhalation study on cz's-1,2-DCE is a lethality study reporting a 4-hour
median lethal concentration (LC50) in rats of 54,320 mg/m3 (DuPont Haskell Lab. 1999).
Oral Studies (Acute)
Two studies, one detailed in a dissertation (Mcmillan. 1986). were located in which rats
were administered single gavage doses (ranging from 400 to 5,000 mg/kg) of cz's-1,2-DCE or
trans- 1,2-DCE and evaluated for serum markers of liver toxicity (e.g., serum alkaline
phosphatase [ALP], aspartate aminotransferase [AST], alanine aminotransferase [ALT]) and
liver enzyme activities (e.g., glucose-6-phosphatase, tyrosine transaminase, and glutathione
[GSH]) (Mcmillan, 1986; Jenkins et at., 1972). Both studies reported evidence of liver toxicity
following dosing with cis- 1,2-DCE, with a greater response in animals dosed with cis- 1,2-DCE
compared with the trans isomer.
Oral Studies (Short-Term and Subchronic Studies)
McCaulev et al. (1990) and McCaulev et al. (1995) conducted 14- and 90-day gavage
studies in Sprague Dawley rats; these are the only short-term and subchronic oral studies
available for cis- 1,2-DCE. The unpublished report described in McCaulev et al. (1990) was
subsequently published as McCaulev et al. (1995). Although errors in the documentation of
doses and other minor inconsistencies were noted between the two documents, they were not
considered to compromise the reliability of the findings and doses presented herein were
confirmed by the study authors.2
In the short-term gavage study (McCaulev et al., 1995; McCaulev et al.. 1990),
Sprague Dawley rats (10/sex/dose) were administered cz's-1,2-DCE in corn oil (at doses of 0, 97,
291, 970, or 1,940 mg/kg-day) for 14 days; doses as reported by U.S. EPA (2010). Several
gavage-related deaths (2/10 males and 3/10 females) and clinical signs, including excessive clear
secretions about the nose and/or mouth and agitation followed by lethargy and ataxia, were
reported at the 1,940 mg/kg-day dose level. At the high dose, male body weights were
significantly reduced by approximately 10%. Compared with controls, significant increases in
water consumption were observed, particularly in the highest dose groups (20-35% higher), and
water consumption per body weight was significantly increased for females in all treatment
groups and for males at 1,940 mg/kg-day. The main observed effects included statistically
significant, dose-related increases in relative liver weights in both sexes (males: 16—38%;
females 15—39%) and increased absolute liver weights in females in all dose groups (by
21-44%) and in males at 970 and 1,940 mg/kg-day (by 28 and 26%, respectively). Relative and
absolute kidney weights were statistically significantly increased in females at 970 and
1,940 mg/kg-day (by 14 and 12% and by 20 and 16%, respectively), but the increases were not
dose-related. No statistically significant increases in kidney weights were observed in males,
although increases were >10% in magnitude in several dose groups. In high-dose males, absolute
spleen weights were statistically significantly decreased from control by approximately 7%.
Supporting clinical chemistry changes were limited to significantly increased cholesterol levels
; Doses in the McCaulev et al. (1995) study were incorrectly reported and converted from mmol/kg-day to
mg/kg-day. In addition, the doses for the acute- and subchronic study as presented in the 1995 published paper were
reversed (i.e., the doses listed for the 14-day study are for the 90-day study and vice-versa). The doses presented
here reflect the correctly converted doses (confirmed by the study author) (U.S. EPA, 2010).
16
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(by 25-40%) in both males and females in the highest dose groups. There were no statistically
significant changes in plasma AST levels. Serum ALT and lactate dehydrogenase (LDH) levels
were also measured, but the results were not reported in the study. Other serum chemistry
changes (blood urea nitrogen [BUN], creatinine, phosphorus, calcium, and glucose) were
generally small in magnitude, not dose-related, or not consistent between sexes. Hematocrit
levels in females were statistically significantly decreased in the three highest dose groups, but
the changes were small (11%) and did not increase with dose. No significant changes in
hemoglobin or red blood cell (RBC) counts were observed; no other significant hematological
changes (i.e., white blood cell [WBC] counts) were observed in females and no statistically
significant hematological changes were observed in males. No gross or histopathological
findings accompanying any organ-weight changes were observed.
In the 90-day study, groups of Sprague Dawley rats (10/sex/dose) were administered
cz'5-1,2-DCE in corn oil via gavage at doses of 0, 32, 97, 291, or 872 mg/kg-day3 for 90 days
(McCaulev et al.. 1995; McCaulev et al.. 1990); doses as reported by U.S. EPA (2010). No
compound-related deaths or clinical signs were observed, but an increase in water intake (as a
percentage of body weight) occurred at the higher dose levels. Reductions in male body weights
(10-11%) at 291 and 872 mg/kg-day did not reach statistical significance. Similar to the 14-day
study, the liver and kidney were identified as main target organs. Relative liver weights were
statistically significantly increased over controls in a dose-related manner in both sexes (by
3-32%), and absolute liver weights were significantly increased in high-dose females (by 24%).
Absolute liver weights in males were not significantly different from controls. Relative kidney
weights in males were significantly increased, compared with controls, in all dose groups (by
14-27%)). Increased relative kidney weights in females and absolute kidney weight changes in
both sexes were not statistically significant, but the magnitudes of change were >10% in most
dose groups (see Table 3). In high-dose females, absolute and relative thymus weights were
statistically significantly increased, compared with controls (by 13 and 17%, respectively).
Statistically significant clinical chemistry changes were sporadic or not adverse. In females,
hemoglobin and RBC levels were significantly decreased (by 6 and 8%, respectively) at
291 mg/kg-day (but not in the high-dose group), and reduced hematocrit levels (by 10 and 8%,
respectively) were measured at 291 and 872 mg/kg-day. In males, significant decreases in
hemoglobin occurred in the 291 and 872 mg/kg-day groups and hematocrit levels were decreased
in the 97, 291, and 872 mg/kg-day groups. However, the changes were small (6—9% decreases)
and not clearly related to dose (see Table 3). An analysis by U.S. EPA (2010) showed that the
observed values were within the normal range of variation. These endpoints could have been
affected by increased water intake observed in the higher dose groups. No treatment-related
gross or histological lesions were observed. Increased relative kidney weight in male rats was
selected as the critical effect for deriving the subchronic provisional reference dose (p-RfD) for
cz5-1,2-DCE in the PPRTV assessment and the chronic reference dose (RfD) in the c/.s- l ,2-DCE
IRIS assessment (see Table 2 and Table A-7) (U.S. HP A. 2011c. 2010).
'The administered doses in McCaulev et al. (1995) were reported as 0, 0.33, 1,3, and 9 mmol/kg-day that, when
converted to mg/kg-day, are 0, 32, 97, 291, and 872 mg/kg-day, respectively. McCaulev et al. (1995). however,
reported the converted doses incorrectly as 0, 10, 32, 98, and 206 mg/kg-day. The doses presented here are the
correctly calculated doses of doses of 0, 32, 97, 291, and 872 mg/kg-day, as reported in McCaulev et al. (1990)
(confirmed by the study author) (U.S. EPA. 2010).
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Injection Studies
An acute injection study in rats reported in a dissertation (Mcmillan. 1986) showed dose-
related increases in plasma AST and sorbitol dehydrogenase (SDH) activities 24 hours after
single intraperitoneal (i.p.) injections of 0, -2,000, and 2,500 mg/kg cz's-1,2-DCE. Although a
single i.p. dose of-1,900 and 2,300 mg/kg trans- 1,2-DCE did not show effects at 24 hours,
time-course experiments performed with 2,500 mg/kg of the trans isomer as part of the same
study did show the following effects: serum ALT, AST, and SDH activities peaked 4 hours
postdosing, subsequently declining to near-normal levels; necrosis also was observed (maximal
at 4-8 hours). Nakahama et al. (2000) found only marginal nonsignificant increases in relative
liver weights (by 9.4-11%) in rats 24 hours after a single 500 mg/kg i.p. injection of either
cis- or trans- 1,2-DCE, even though body weights were reduced by both isomers. Similarly, there
was no effect on relative liver weight in rats injected on 4 consecutive days with 730 mg/kg of
either cis- or trans- 1,2-DCE, despite significant decreases in body-weight gain with both isomers
(Hanioka et al.. 1998). Mice injected with 128—5,120 mg/kg of cis- or trans-1,2-DCE showed
weak nephrotoxicity (increased urinary protein) in a study that also assessed urinary glucose
levels and included histopathological examinations of proximal convoluted tubules (Piaa and
Larson. 1965).
Mixture Studies
Several studies on 1,2-DCE mixtures containing both the cis and trans isomer are
reviewed in U.S. EPA (2010). In many cases, the isomer compositions were not reported or were
unknown, making the determination of the potential contribution of the cis isomer to the
observed effects difficult. Select studies where compositions were reported are detailed in
Table 3. In general, mixture studies (both inhalation and oral) identify the liver and kidney as
primary target organs, which is consistent with observations from studies on the cis- and
trans-1,2-DCE isomers alone. In an unpublished report, Dow Chemical (1994) performed a
series of inhalation experiments using a 1,2-DCE mixture composed of 58% cz's-1,2-DCE and
42% trans- 1,2-DCE in rats (rabbits, guinea pigs, and beagle dogs were also tested, but group
sizes were small and no statistical analysis was done) (U.S. EPA. 2010). This included a
preliminary 14-day study, followed by a 6-month inhalation study in which rats were exposed to
1,2-DCE vapor concentrations of 0, 500, or 1,000 ppm (equivalent to -1,980 or 3,970 mg/m3). In
the 6-month study, exposure concentration-related increases in relative kidney weights (by 9 and
16%) in males and relative liver weights (by 19 and 23%) in females at 1,980 and 3,970 mg/m3,
respectively, were statistically significant. In an oral mixture study described in a dissertation
(Mcmillan. 1986). a statistically significant increase in relative kidney weights (by 13%) was
reported in male Sprague Dawley rats administered 485 mg/kg-day 1,2-DCE (a 50:50 mixture of
cis- and trans- 1,2-DCE) via gavage for 14 days. In a follow-up 30-day study at the same dose,
relative liver weights in the treatment group were significantly increased by 19%, compared with
controls (Mcmillan. 1986).
2.1.2. Genotoxicity
The genotoxicity of cis- 1,2-DCE has been evaluated in numerous in vitro studies and in a
limited number of in vivo assays in both mammalian and nonmammalian systems summarized in
U.S. EPA (2010). No new genotoxicity studies on cis-1,2-DCE were identified. Overall
cz's-1,2-DCE is generally negative for genotoxicity. cis-1,2-DCE was negative in six reverse
mutation studies in Salmonella typhimurium and two studies for deoxyribonucleic acid (DNA)
damage in Escherichia coli. Results from gene conversion, reverse mutation, or mitotic
recombination studies in Saccharomyces cerevisiae were mixed. One study reported positive
18
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EPA/690/R-22/001F
results in S. cerevisiae D7 both with and without metabolic activation, but results were negative
in three other studies (U.S. EPA. 2010). No chromosomal aberrations or evidence of sister
chromatid exchange (SCE) were observed in Chinese hamster lung (CHL) cells, with or without
activation, in two separate studies. Negative results were also reported for chromosomal
aberrations (CAs) in one study in Chinese hamster ovary (CHO) cells, but results were
inconclusive for SCE in this study. In vivo, cz's-1,2-DCE was mutagenic in two of three available
host-mediated assays in mice, produced CAs in one of two available mouse bone marrow assays,
and was negative for SCE. Additional details can be found in the U.S. EPA (2010) IRIS
toxicological review for cz's- 1,2-DCE.
2.1.3. Metabolism/Toxicokinetic Studies
Experimental data show inhaled cz's-1,2-DCE to be well-absorbed through the lungs, a
result consistent with the blood-air partition coefficients estimated in humans and rats for this
chemical (9.2-9.8 and 21.6, respectively) (Gargas et al.. 1989). Closed-chamber gas uptake
studies in rats indicate an initial first phase of gas uptake to equilibrium that took approximately
2 hours and left approximately 50% of the gas remaining in the chamber (Filser and Bolt 1979).
Further uptake was dependent on the velocity of metabolism and showed a logarithmic (first-
order) decline in chamber levels of cz's- 1,2-DCE when the initial exposure concentration was low
(500 ppm). At a higher exposure concentration (1,000 ppm), equilibrium is followed by a phase
showing a linear (zero-order) decline, suggesting saturation of metabolism at the higher
concentrations. The equilibrium constant Keq for cz's-1,2-DCE is 20, approximately double that
for the trans isomer (Keq = 11.5), indicating that uptake of cis-1,2-DCE is ~2-fold higher, which
is consistent with the rodent blood-gas partition coefficients of 21.6 and 9.58 for cis- and
trans-1,2-DCE, respectively (Filser and Bolt. 1979; Bonse et al.. 1975). No studies quantifying
the rate or extent of cis- 1,2-DCE uptake following oral or dermal exposure were located.
No studies were identified that investigated the tissue distribution of c/.s-l ,2-DCE in the
body. Tissue:air partition coefficients determined for rat tissues ex vivo were 15.3 for liver,
6.09 for muscle, and 227 for fat (Gargas et al.. 1988). suggesting that cis-1,2-DCE in the blood
will be distributed to the liver and will accumulate preferentially in fat.
Studies in vitro using liver microsomes indicate that metabolism of c/.s- l ,2-DCE is
initiated upon the binding of cis- 1,2-DCE to the heme moiety of hepatic microsomal cytochrome
P450s (CYP450s) (Costa and Ivanetich. 1984. 1982). Upon activation, presumably by CYP2E1
(in hepatic tissue), c/.s- l ,2-DCE is metabolized to an unstable epoxide intermediate that
rearranges to form 2,2-dichloracetaldehyde, which is enzymatically converted to
2,2-dich 1 oroethanol and 2,2-dichloroacetic acid (DCA) by alcohol dehydrogenase (Nakaiima.
1997; Costa and Ivanetich. 1984; Henschler and Bonse. 1979; Bonse et al.. 1975).
2,2-Dichloroethanol appears to be the major metabolite, with smaller amounts of DCA formed
(Costa and Ivanetich. 1984; Bonse et al .. 1975). The rate of cis-1,2-DCE metabolite production
appears to be faster and the total amount of metabolites produced is greater than for the trans
isomer (by approximately 4-25 times) (Costa and Ivanetich, 1984). Although CYP2E1 is likely
the primary CYP450 responsible for cz's-1,2-DCE metabolism, other CYP450s could also be
involved. For example, in vitro inhibition studies by Costa and Ivanetich (1984) indicated that
cytochrome P448, which is induced by P-naphthoflavone, appeared to play a slight, but
significant, role in the binding and metabolism of c/.s- l ,2-DCE, Studies indicate that both
cis- and trans- 1,2-DCE (or their metabolites) can inhibit CYP450 enzymes via irreversible
binding (i.e., suicide inactivation), with trans-\ ,2-DCE overall being the more potent inhibitor
19
cis-1,2-Dichloroethylene
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EPA/690/R-22/001F
(U.S. EPA. 2008; Nakahama et al.. 2000; Hanioka et al.. 1998; Lilly et al.. 1998; Mathews et al..
1998; Barton et al.. 1995; Ctewett and Andersen. 1994; Costa and Ivanetich. 1984; Freundt and
Macholz, 1978, 1972). The irreversible binding is anticipated to result in competitive inhibition
of the metabolism of other CYP450 substrates in vitro. The zero-order turnover velocity (Vmax)
of CVS-1,2-DCE was determined to be 2.4 mg/hour-kg (Filser and Bolt. 1979). The Vmax was later
determined to be 3.0 mg/hour-kg by Gargas et al. (1988) and to be 3.34 mg/hour-kg after
compensating for enzyme inhibition and resynthesis (Gargas et al.. 1990). Metabolic rates
increased under conditions of fasting or chronic ethanol intake ( Nakaiima. 1997).
Data on the elimination of c/s-1,2-DCE are limited. Biphasic elimination with an initial
rapid elimination from blood followed by a second, only slightly slower, phase of elimination
from highly perfused tissues was suggested from a single study in humans (Pleil and Lindstrom,
1997). Elimination rate constants based on concentrations in exhaled breath over time were
estimated for two volunteers exposed in a 10-minute shower to cis-1,2-DCE from contaminated
well water (exposure concentrations were 20.4-28.4 |ig/L and 84-125 |ig/m3 measured in water
and air, respectively). The elimination half-lives, corresponding to the two phases of elimination
were 0.82 and 8.96 minutes, respectively, in the first volunteer, and 2.37 and 29.33 minutes,
respectively, in the second volunteer (Pleil and Lindstrom, 1997). Elimination of the metabolite,
DC A, has not been specifically evaluated in the context of exposure to cis- 1,2-DCE but the
downstream metabolism of DCA and subsequent elimination have been reviewed in the
Toxicological Review of Dichloroacetic Acid (U.S. EPA. 2003). DCA is ultimately expected to
be metabolized to produce glyoxylate that can be further processed to form oxalate, which is
excreted in urine or reduced to form glycolic acid. DCA can also be broken down into carbon
dioxide (Costa and Ivanetich. 1984, 1982). Trace amounts of 2,2-dichloroethanol are expected to
be ultimately exhaled (U.S. EPA, 2010).
A physiologically based pharmacokinetic (PBPK) model is available for inhaled
cis-1,2-DCE in rats, as described in U.S. EPA (2010). but does not include a compartment to
account for oral exposure and has not been extended to humans. U.S. EPA (2010) concluded that
"Since this PBPK model was not calibrated with human data, it cannot be scaled allometrically
to humans, whose liver CYP2E1 activity, resynthesis rate, and sensitivity to inhibition differ
from those in rats. Given the current state of knowledge, this PBPK model is not useful for
estimating the human equivalent dose (HED) from the available animal data for cis- or
trans- 1,2-DCE." Because oral exposure is not accounted for, the model cannot be used for
route-to-route extrapolation.
20
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3. DERIVATION OF PROVISIONAL VALUES
3.1. DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
No adequate studies were located regarding toxicity of cz's-1,2-DCE to humans or animals
via inhalation exposure. Chronic (U.S. EPA. 2010) and subchronic (U.S. EPA. 2011c) oral
toxicity values based on renal effects in a subchronic rat study are available for cz's- 1,2-DCE;
however, the available PBPK model for cz's- 1,2-DCE is not suitable for route-to-route
extrapolation or estimation of HEDs. As a result of the limitations of the available inhalation
toxicity data for cz's- 1,2-DCE, subchronic and chronic provisional reference concentrations
(p-RfCs) were 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, trans- 1,2-DCE was selected as the most appropriate analogue for
cz's-1,2-DCE for deriving screening subchronic and chronic p-RfCs (see Table 4).
3.2. SUMMARY OF NONCANCER PROVISIONAL REFERENCE VALUES
Table 4 presents a summary of noncancer references values.
Table 4. Summary of Noncancer Risk Estimates for cis- 1,2-DCE
(CASRN 156-59-2)a
Toxicity Type
(units)
Species/
Sex
Critical Effect
p-Reference
Value
POD
Method
POD
(HEC)
UFc
Principal Study
Screening
subchronic
p-RfC (mg/m3)
Rat/M
Decreased
lymphocyte
counts
4 x KT1
BMCLisd
109 (based
on analogue
POD)
300
Kellv (1998) as
cited in U.S. EPA
(2020)
Screening
chronic p-RfC
(mg/m3)
Rat/M
Decreased
lymphocyte
counts
4 x 10-2
BMCLisd
109 (based
on analogue
POD)
3,000
Kellv (1998) as
cited in U.S. EPA
(2020)
BMCL = benchmark concentration lower confidence limit; c7.v-1.2-DCE = c/.v-l .2-dichloroethvlcnc: HEC = human
equivalent concentration; M = male(s); NDr = not determined; POD = point of departure; p-RfC = provisional
reference concentration; p-RfD = provisional reference dose; SD = standard deviation; UFC = composite
uncertainty factor.
3.3. CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
Under the U.S. EPA Cancer Guidelines (U.S. EPA. 2005). there is "Inadequate
Information to Assess the Carcinogenic PotentiaF of cis- 1,2-DCE by oral or inhalation exposure
(see Table 5).
21
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EPA/690/R-22/001F
Table 5. Cancer WOE Descriptor for cis-l,2-DCE (CASRN 156-59-2)
Possible WOE Descriptor
Designation
Route of Entry (oral,
inhalation, or both)
Comments
"Carcinogenic to humans "
NS
NA
No human carcinogenicity data were
identified to support this descriptor.
"Likely to be carcinogenic
to humans "
NS
NA
No human or animal carcinogenicity data
were identified to support this descriptor.
"Suggestive evidence of
carcinogenic potential"
NS
NA
No human or animal carcinogenicity data
were identified to support this descriptor.
"Inadequate information to
assess carcinogenic
potential"
Selected
Both
This descriptor is selected due to the lack
of any studies evaluating carcinogenicity of
cis- 1,2-DCE.
"Not likely to be
carcinogenic to humans"
NS
NA
No evidence of noncarcinogenicity was
available.
cis- 1,2-DCE = 6/ v- 1.2-dichloroctln lcnc: NA = not applicable; NS = not selected; WOE = weight of evidence.
3.4. DERIVATION OF PROVISIONAL CANCER RISK ESTIMATES
Table 6 presents a summary of cancer risk estimates. No human or animal studies of
carcinogenicity are available for cis- 1,2-DCE. Tests for genotoxicity were primarily negative.
Thus, the database for c/.s- l ,2-DCE provides inadequate information to assess carcinogenic
potential.
Table 6. Summary of Cancer Risk Estimates for cis- 1,2-DCE
(CASRN 156-59-2)
Toxicity Type
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF (mg/kg-d) 1
NDr
p-IUR (mg/m3) 1
NDr
cis- 1,2-DCE = 6/v- 1.2-dichloroctln lcnc: NDr = not determined; p-IUR = provisional inhalation unit risk;
p-OSF = provisional oral slope factor.
22
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EPA/690/R-22/001F
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 inhalation toxicity values for
cis-1,2-dichloroethylene (cis-1,2-DCE), However, some information is available for this
chemical, which although insufficient to support deriving a provisional toxicity value under
current guidelines, may be of 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 the
derivation of 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 (METHODS)
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.
The analogue identification approach of Wang et al. (2012) was expanded to collect a
more comprehensive set of candidate analogues for the compounds undergoing a
U.S. Environmental Protection Agency (U.S. EPA) PPRTV screening-level assessment. As
described below, this method includes application of a variety of tools and methods for
identifying candidate analogues that are similar to the target chemical based on chemical
structure and key features; metabolic relationships; or related toxic effects and mechanisms of
action.
To identify structurally related compounds, an initial pool of analogues is identified using
automated tools, including ChemlDplus (ChcmlDplus. 2021). CompTox Chemicals Dashboard
(U.S. HP A. 2019). and Organisation for Economic Co-operation and Development (OECD)
Quantitative Structure-Activity Relationship (QSAR) Toolbox (OECD. 2022). Additional
analogues identified as ChemlDplus-related substances, parent, salts, and mixtures, and
Comptox-related substances are considered. Comptox GenRA analogues are collected when
available using the methods available on the publicly available GenRA Beta version, which may
include Morgan fingerprints, Torsion fingerprints, ToxPrints and ToxCast, Tox21, and ToxRef
data. For compounds that have very few analogues identified by structural similarity using a
similarity threshold of 0.8 or 80%, substructure searches in the QSAR Toolbox may be
performed, or similarity searches may be rerun using a reduced similarity threshold (e.g., 70 or
60%). The compiled list of candidate analogues is batch run through the CompTox Chemicals
Dashboard where QSAR-ready simplified molecular-input line-entry system (SMILES) are
23
cis-1,2-Dichloroethylene
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EPA/690/R-22/001F
collected and toxicity data availability are determined (e.g., from the Agency for Toxic
Substances and Disease Registry [ATSDR], Office of Environmental Health Hazard Assessment
[OEHHA), California Environmental Protection Agency [CalEPA], U.S. EPA Integrated Risk
Information System [IRIS], PPRTVs). The batch output information is then uploaded into the
Chemical Assessment Clustering Engine (C hem ACE) (U.S. EPA. 201 la), which clusters the
chemicals based on chemical fragments and displays the toxicity data availability for each
candidate. The ChemACE output is reviewed by an experienced chemist, who narrows the list of
structural analogues based on known or expected structure-toxicity relationships, reactivity, and
known or expected metabolic pathways.
Toxicokinetic studies identified from the literature searches performed for this PPRTV
assessment were used to identify metabolic analogues (metabolites and metabolic precursors).
Metabolites were also identified from the two OECD QSAR Toolbox metabolism simulators (in
vivo rat metabolism simulator and rat liver S9 metabolism simulator). Targeted PubMed
searches were conducted to identify metabolic precursors and other compounds that share any of
the observed or predicted metabolites identified for the target chemical. Metabolic analogues are
then added to the pool of candidate analogues and toxicity data availability is determined
(e.g., from ATSDR, OEHHA, CalEPA, U.S. EPA IRIS, PPRTVs).
In vivo toxicity data for the target chemical (if available from the literature searches) are
evaluated to determine whether specific or characteristic toxicity was observed
(e.g., cholinesterase inhibition, inhibition of oxidative phosphorylation). In addition, in vitro
mechanistic data identified from the literature searches or obtained from tools including GenRA,
ToxCast/Tox21, and Comparative Toxicogenomics Database (CTD) (Davis et at.. 2021) were
evaluated for this purpose. Data from CompTox Chemicals Dashboard ToxCast/Tox21 are
collected to determine bioactivity of the target chemical in in vitro assays that may indicate
potential mechanism(s) of action. The GenRA option within the Dashboard also offers an option
to search for analogues based on similarities in activity in ToxCast/Tox21 in vitro assays. Using
the ToxCast/Tox21 bioactivity data, nearest neighbors identified with similarity indices of
>0.5 may be considered potential candidate analogues. The CTD (Davis et at.. 2021) is searched
to identify compounds with gene interactions similar to interactions induced by the target
chemical; compounds with gene interactions similar to the target chemical (with a similarity
index >0.5) may be considered potential candidate analogues. These compounds are then added
to the pool of candidate analogues, and toxicity data availability is determined (e.g., from
ATSDR, OEHHA, CalEPA, U.S. EPA IRIS, PPRTVs).
The tools used for the expanded analogue searches were selected because they are
publicly available, which allows for transparency and reproducibility of the results, and because
they are supported by U.S. and OECD agencies, updated regularly, and widely used. The
application of a variety of different tools and methods to identify candidate analogues serves to
minimize the limitations of any individual tool with respect to the pool of chemicals included,
chemical fragments considered, and methods for assessing similarity. Further, the inclusion of
techniques to identify analogues based on metabolism and toxicity or bioactivity expands the
pool of candidates beyond those based exclusively on structural similarity.
24
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EPA/690/R-22/001F
ANALOGUE SEARCH PROCESS
The initial analogue search focused on the identification of chemicals structurally similar
to cz's-1,2-DCE using the U.S. EPA CompTox Chemicals Dashboard (Tanimoto method)
[successor to the DSSTox, one of the tools discussed in Wang et al. (2012)1. C hem ID Plus
(method not described) [also discussed in Wang et al. (2012)1. and the more recently developed
OECD Toolbox (Dice method). The GenRA module (Beta version) in the Dashboard was
employed to identify structural analogues but was not functional for this compound (returned an
error message due to insufficient data availability). Results of the search are presented in
Table A-l. Eight unique structural analogues were identified, based on a similarity threshold
criterion of 80%. One identified analogue (vinyl chloride-d3, CASRN 6745-35-3) was excluded
because it is a deuterated compound (replacing a chemical's nondeuterated hydrogens
(i.e., protium or hydrogen-1) with deuterium can alter the chemical"s toxicokinetics) (Foster.
1984).
Table A-l. Candidate Structural Analogues Identified for cis- 1,2-DCE
Tool (method)
Similarity
Threshold
Number of Analogues
Identified
Analogue (CASRN) Selected for Toxicity Value
Searchesb
Dashboard
(Tanimoto)
80%
4a
• trans- 1,2-DCE (156-60-5)
• 1,2-DCE, mixed isomers (540-59-0)
• Vinyl chloride (75-01-4)
OECD Toolbox
(Dice)
80%
3
• trans- 1,2-DCE (156-60-5)
• 1,2-DCE, mixed isomers (540-59-0)
• (lE,3Z)-l,4-Dichlorobuta-l,3-diene (3588-13-4)
ChemID Plus
(method not
described)
80%
5
• trans- 1,2-DCE (156-60-5)
• 1,2-DCE, mixed isomers (540-59-0)
• (Z)-l-Chloro-2-fluoroethene (2268-31-7)
• (E)-l-Chloro-2-fluoroethene (2268-32-8)
• l-Chloro-2-fluoroethene, mixed isomers (460-16-2)
aOne of the four was not selected for toxicity value searches because it is a deuterated compound (see text).
bBold shows compounds with inhalation toxicity values.
CIS- 1,2-DCE = 6/.V-1.2-dichlorocthylcnc: OECD = Organisation for Economic Cooperation and Development;
trans- 1,2-DCE = /ra«.v-1.2-dichlorocthylcnc.
The seven identified candidate structural analogues for cis- 1,2-DCE were searched for
inhalation toxicity values. Of these, inhalation toxicity values were located only for
trans-1,2-dichloroethylene (trails-] ,2-DCE; CASRN 156-60-5) and vinyl chloride
(CASRN 75-01-4).
Metabolites, metabolic precursors, and compounds that share metabolites with
cz's-1,2-DCE were also considered for analogues. As discussed in Section 2.1.3 in the main
document, the primary liver metabolites of cis- 1,2-DCE (based on in vitro studies using rat liver
microsomes) are dichloroacetaldehyde (CASRN 79-02-7), 2,2-dichloroethanol
(CASRN 598-38-9), and 2,2-dichloroacetic acid (DCA; CASRN 79-43-6) (Bonse et al.. 1975).
No information on metabolism in vivo was located, nor were data on metabolism in tissues other
25
cis-1,2-Dichloroethylene
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EPA/690/R-22/001F
than the liver. As hepatic metabolites have been identified and could be relevant to inhalation
exposure, they were considered candidate analogues. No inhalation toxicity values were
identified, however, for dichloroacetaldehyde, 2,2-dichloroethanol, or DCA.
PubMed searches (searching "cis-1,2-dichloroethylene" or "156-59-2" and "metabolite")
were conducted to identify metabolic precursors to cz's-1,2-DCE. No metabolic precursors
yielding cz's-1,2-DCE in vivo or in vitro were identified by this method. PubMed was also
searched to identify other compounds that are metabolized to dichloroacetaldehyde,
2,2-dichloroethanol, or DCA (searching the metabolite name or CASRN and "metabolite"). The
search identified four other compounds reportedly metabolized to one of the three cz's- 1,2-DCE
metabolites: 1,1 -dichloroethylene (1,1-DCE; CASRN 75-35-4) (Simmonds et al.. 2004);
trichloroethylene (TCE; CASRN 79-01-6) (Johnson et al.. 1998); and the organophosphate
pesticides, trichlorphon and dichlorvos (Yamano and Morita. 1992). The organophosphate
pesticides were not considered further as candidate analogues on the basis of unshared structural
properties with the target chemical (i.e., cz's-1,2-DCE is not an organophosphate.) In the
toxicological review for cz's- and trans-1,2-DCE, U.S. EPA (2010) reported that trans-1,2-DCE
is metabolized to the same compounds as is cz's-1,2-DCE; thus, it can be considered a potentially
relevant analogue on this basis, in addition to the structural similarity described above. Review
of the metabolism information in the U.S. EPA (201 Id) toxicological review for TCE also
showed that DCA, a known metabolite of cz's-l,2-DCE, can also be formed during metabolism of
three other compounds: tetrachloroethylene (Perc; CASRN 127-18-7); 1,1-dichloroethane
(CASRN 75-34-3); and 1,1,1,2-tetrachloroethane (CASRN 630-20-6). Among the six
nonorganophosphate compounds sharing metabolites with cz's-1,2-DCE, four chemicals
(i.e., trans- 1,2-DCE, Perc, 1,1-DCE, and TCE) have subchronic and/or chronic inhalation
toxicity values and were selected as candidate metabolic analogues. No inhalation toxicity values
were identified for 1,1-dichloroethane or 1,1,1,2-tetrachloroethane. Table A-2 summarizes the
candidate metabolic analogues for 1,2-DCE.
Table A-2. Candidate Metabolic Analogues of cis-1,2-DCE
Relationship to cis- 1,2-DCE
Compound3
CASRN
Metabolic precursor
None identified
Metabolite
Dichloroacetaldehyde
79-02-7
Dichloroacetic acid
79-43-6
2,2-Dichloroethanol
598-38-9
Shares common metabolite(s)
1,1 -Dichloroethane
75-34-3
1,1 -Dichloroethylene
75-35-4
Z/Y/rt.v-l,2-Dichlorocthylcnc
156-60-5
Trichlo roethy lene
79-01-6
1,1,1,2-T etrachloroethane
630-20-6
Tetrachloroethylene
127-18-4
aBold shows compounds with inhalation toxicity values.
cis- 1,2-DCE = as- 1.2-dichlorocthylcnc.
26
cz's-1,2-Dichloroethylene
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EPA/690/R-22/001F
In addition to structural and metabolic data, available toxicity and mechanistic data for
cz's-l,2-DCE were evaluated to identify candidate analogues. The GenRA option within the
Dashboard offers an option to search for analogues on the basis of similarities in activity in in
vitro assays in ToxCast/Tox21; however, for cis-1,2-DCE, the GenRA module returned an error
message. cz's-l,2-DCE was only active in one ToxCast/Tox21 assay (of 235) and was not active
in any EDSP21 assays (n = 22) or PubChem assays (n = 421). The single assay in which this
compound was active was TOX21_RT_HEK293_FLO_16hr_viability. The endpoint of this
assay (cell viability in human embryonic kidney cells) cannot be used to infer specific
mechanisms of toxicity. The CTD had no entry for cis- 1,2-DCE.
The toxicological data for cis- 1,2-DCE, described in Section 2 of the main document, do
not suggest any specific, characteristic toxicity that could be used to identify candidate
analogues. Repeat-dose gavage studies identified the liver and kidneys as target organs
(McCautev et al.. 1995; McCaulev et al.. 1990). The target organs of the oral study might or
might not be relevant to inhalation. The only inhalation study available, an unpublished acute
lethality study (DuPont Haskell Lab. 1999). reported weight loss and clinical signs of central
nervous system (CNS) depression (unresponsiveness, weakness, irregular respiration) at lethal
concentrations but did not evaluate liver or kidney effects. None of the effects identified in the
limited in vivo studies of cis- 1,2-DCE suggested a characteristic or unique mechanism of toxicity
that could be used to inform candidate analogue selection.
In summary, searches for structural, metabolic, and toxicity/mechanistic analogues for
cz'5-1,2-DCE yielded a total of 15 unique analogues: 7 structural analogues (excluding
1 deuterated compound) and 9 metabolism-related analogues (excluding 2 organophosphates),
1 of which is also a structural analogue (trans- 1,2-DCE). No analogues were identified on the
basis of having similar mechanisms or modes-of-action (MO As). Of the 15 identified candidates,
5 were found to have inhalation toxicity values: 1 structural analogue (vinyl chloride);
3 chemicals (1,1-DCE, Perc, and TCE) that share at least one common metabolite with the target
compound; and trans- 1,2-DCE, which is both a structural analogue and shares common
metabolites with the target chemical.
Structural/Physicochemical Properties Similarity Comparisons
Table A-3 summarizes the physicochemical properties of the analogues, cz's-1,2-DCE and
the candidate analogues are members of the volatile organic compounds (VOC) chemical class,
cw-1,2-DCE, trans- 1,2-DCE, and 1,1-DCE share the same molecular weight. Melting and
boiling points show that all of the compounds are liquids at room temperature except for vinyl
chloride, which is a gas. Based on the Henry's law constants and vapor pressures, all of the
compounds are expected to volatilize from water to air and from soil to air, respectively, and will
exist mostly in the vapor (gas) phase in the atmosphere, cis- 1,2-DCE and the candidate
analogues are soluble in water. Vinyl chloride, with one chlorine atom, is the most water-soluble
and has the lowest molecular weight and log Kow value of the group. Perc, with four chlorine
atoms, is the least water-soluble and has the highest molecular weight and log Kow value. The
target compound and all candidate analogues are expected to be bioavailable by the oral and
inhalation routes (based on vapor pressure, water solubility, and log Kow values). Overall,
trans- 1,2-DCE is the most similar candidate analogue to c/.s- l ,2-DCE based on structural and
physicochemical properties.
27
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EPA/690/R-22/001F
Table A-3. Physicochemical Properties of cis-1,2-DCE (CASRN 156-59-2)
and Candidate Analogues"
Chemical
cis-l,2-DCE
trans- 1,2-DCE
1,1-DCE
Perc
TCE
Vinyl
Chloride
Role
Target
Analogue
Analogue
Analogue
Analogue
Analogue
Structure
c:|/ \:i
CI
/
a
c, /'
C!
V
(Li
CI
CI\^D
C|-/:^CH2
CASRN
156-59-2
156-60-5
75-35-4
127-18-4
79-01-6
75-01-4
DTXSID
2024030
7024031
8021438
2021319
0021383
8021434
Molecular
weight (g/mol)
96.94
96.94
96.94
165.82
131.38
62.5
Melting point
(°C)
-64.9
-59.7
-122
-11.6
-83.5
-155
Boiling point
(°C)
54.4
52.0
32.5
121
87.0
-13.7
Vapor pressure
(mm Hg)
200b
33 lb
600
18.5
69.0
2,980
Henry's law
constant
(atm-m3/mole at
25°C)
0.00673
0.00673
0.0261
0.0177
0.00985
0.0278
Water solubility
(mol/L)
0.0493
0.0484
0.0235
0.00178
0.0100
0.0923
Octanol-water
partition
coefficient (log
K-ow)
1.86
1.86
2.13
3.40
2.51
1.46b
aData were extracted from the U.S. EPA CompTox Chemicals Dashboard:
c/.v-l .2-dichlorocthylcnc. CASRN 156-59-2;
https://comptox.epa.gov/dashboard/chemical/properties/DTXSID2024030; accessed May 12, 2021;
trans-1.2-dichlorocthylcnc. CASRN 156-60-5;
https://comptox.epa.gov/dashboard/chemical/properties/DTXSID7024031; accessed May 12, 2021;
1,1 -dichloroethylene (1,1-DCE), CASRN 75-35-4;
https ://comptox.epa. gov/dashboard/ehemical/properties/PTXSID802143 8: accessed May 12, 2021;
tetrachloroethylene (Perc), CASRN 127-18-4;
https://comptox.epa. gov/dashboard/chemical/properties/DTXSID2021319: accessed May 12, 2021;
trichloroethylene (TCE), CASRN 79-01-6;
https://comptox.epa.gov/dashboard/chemical/properties/DTXSID0021383; accessed May 12, 2021;
vinyl chloride, CASRN 75-01-4; https://comptox.epa.gov/dashboard/chemical/properties/DTXSID8021434:
accessed May 12, 2021; all presented values are experimental averages unless otherwise specified.
' Compound-specific PubChem records (NLM. 202Ig. h, i,j).
c/'s-1,2-DCE = els-1.2-dichlorocthylcnc: DCE = 1,1-dichloroethylene; DTXSID = DSSTox substance identifier;
Perc = tetrachloroethylene; TCE = trichloroethylene; trans- 1,2-DCE = trans-1.2-dichlorocthylcnc:
U.S. EPA = U.S. Environmental Protection Agency.
28
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EPA/690/R-22/001F
Structural alerts and toxicity predictions were identified using computational tools from
the OECD QSAR Toolbox profilers, ToxAlerts, Toxtree, and Patty's Toxicology, 6th Edition
(Bingham and Cohrssen, 2012). The model results for cis-1,2-DCE and its analogue compounds
are shown in Figure A-l. Concerns for protein binding, hepatotoxicity, developmental or
reproductive toxicity, and reactivity or metabolism of cz's-l,2-DCE and its analogues were
flagged when indicated by models within each predictive tool. Notably, cz's-1,2-DCE and
trans- 1,2-DCE share the same structure activity relationship (SAR) predictions across all
domains evaluated.
29
cis-1,2-Dichloroethylene
-------
EPA 690 R-22 00IF
Structural Category
Analogues (CASRN)
t/v-l,2-DCE
fr«/is-l,2-DCE
1,1-DCE
Perc
TCE
Vinyl Chloride
Source
(156-59-2)
(156-60-5)
(75-35-4)
(127-18-4)
(79-01-6)
(75-01-4)
Protein Binding
Protein binding (based on polarized alkenes with a halogen leaving
group (SN2) alert)—Organisation for Economic Cooperation and
Development (OECD)
OECD quantitative
structure-activity
relationship (QSAR)
Toolbox
Protein binding alerts identified (based on SN2 alert)
Toxtree
Protein binding (based on vinyl type compounds with electron
withdrawing groups (SN vinyl) alert)—OASIS
Hepatotoxicity
OECD QSAR Toolbox
Hepatotoxicity (based on halogenated aliphatic compounds
alert)—Hazard Evaluation Support System (HESS)
OECD QSAR Toolbox
Developmental/Reproductive Toxicity
Developmental or reproductive toxicant (based on alkene
structural alert)—Developmental and Reproductive Toxicity
(DART) scheme
OECD QSAR Toolbox
Metabolism/Reactivity
Cytochrome P450-mediated drug metabolism predicted (based on
the presence of sp2 hybridized carbon atom alert)
ToxAlerts
Reactive, unstable, toxic (based on alkyl halides alert)
ToxAlerts
Reactive, unstable, toxic (based on haloethylenes alert)
ToxAlerts
Reactive, unstable, toxic (based on acyclic gem-dihalosubstituted
carbon atom alert)
ToxAlerts
Reactive, unstable, toxic (based on polyhalogenated compounds
[only chlorine, bromine, and iodine])
ToxAlerts
Other
Unsaturated halogen hydrocarbons (general chemical class)
Bingham and Cohrssen
(2012)
~ Model results or structural alerts indicating concern for toxicity
~ Model results or structural alert indicating no concern for toxicity
Models with results are presented in the heat map (models without results were omitted).
Figure A-l. Structural Alerts for cis- 1,2-DCE and Candidate Analogues
30
cis-1,2-Dichloroethylene
-------
EPA/690/R-22/001F
c/s-1,2-DCE and all candidate analogues, except for 1,1-DCE, met criteria indicating
potential for protein binding by at least one model. The OECD QSAR Toolbox SN2 and SN
Vinyl at vinylic (sp2) carbon atom alerts are for protein binding through an SN2 type mechanism
with a halogen as a leaving group; however, these alerts have no chemicals reported in their
training set to compare with cis- 1,2-DCE and the candidate analogues.
The OECD QSAR Toolbox Hazard Evaluation Support System (HESS) model indicated
a concern for hepatotoxicity for cis- 1,2-DCE and all analogues. The structural alert applies to
halogenated aliphatic compounds that do not contain a ring. The OECD QSAR Toolbox HESS
model alert is based on data from 20 halogenated aliphatics, including the candidate analogue
trans- 1,2-DCE (CASRN 156-60-5). Chlorinated aliphatic compounds cause in vivo liver
necrosis by multiple mechanistic pathways, including oxidative metabolism and reductive
dehalogenation (Parkinson. 2001; O'Brien. 1988; Anders. 1985).
The OECD QSAR Toolbox Developmental and Reproductive Toxicity (DART) model
indicated a concern for developmental and/or reproductive toxicity for cis- 1,2-DCE and all
analogues based on the structural alert for small (CI-4), halo- and multihalo-alkenes. The alert is
derived from data on three chemicals: vinyl chloride (CASRN 75-01-4),
hexachloro-1,3-butadiene (CASRN 87-68-3), and 2-chloro-l,3-butadiene (CASRN 126-99-8).
The ToxAlerts tool showed potential for reactivity and/or metabolism for c/.s- l ,2-DCE
and all analogues based on at least one of four reported structural alerts: the presence of an alkyl
halide, haloethylene, acyclic gem-dihalosubstituted carbon atom, or polyhalogenated compound
containing at least four halogen (chlorine, bromine, iodine) atoms. Supporting documentation for
interpretation of these ToxAlerts is limited.
Toxicokinetic Similarity Comparisons
Table A-4 summarizes available toxicokinetic data for cis-1,2-DCE and the structurally
similar compounds identified as potential analogues, cis- 1,2-DCE and the candidate analogues
are rapidly and readily absorbed via inhalation, with the rate and extent of absorption influenced
by the concentration and duration of exposure, ventilation rates, cardiac output, body mass,
physical activity, and blood-air partition coefficients. Available data indicate that the inhalation
uptake of cis-1,2-DCE is ~2 times greater than that of the trans isomer (U.S. EPA, 2020, 2010;
ATS DR. 1996Y
31
cis-1,2-Dichloroethylene
-------
EPA/690/R-22/001F
Table A-4. ADME Data for cis-l,2-DCE (CASRN 156-59-2) and Candidate Analogues"
Chemical
CASRN
civ-1,2-DC E
156-59-2
trans-i ,2-DCE
156-60-5
1,1-DCE
75-35-4
Perc
127-18-4
TCE
79-01-6
Vinyl Chloride
75-01-4
Structure
a \i
CI
CI
CI
a
cl'vAC;
Role
Target
Analogue
Analogue
Analogue
Analogue
Analogue
DTXSID
2024030
7024031
8021438
2021319
0021383
8021434
Absorption
Rate and
extent of
inhalation
absorption
Humans: ND
Laboratory animals:
Rats exoosed to vaoor in
Humans:
Human subiects (n = 2)
Humans: ND
Laboratory animals:
Rats exoosed to vaoor
Humans:
Human subiects (n = 7)
Humans:
Human subiects
Humans:
Human subiects
exoosed to either vaoor
or aerosol (3.291 and
exoosed to vaoor in an
ODcn chamber (6.8 mg/m2
exoosed to vaoor
(376-1.080 mg/m- for
exoosed to vaoor bv
gas mask
a closed chamber (single
8.803 mg/m2 for 30 min)
(100. 300. 600. or
for 6 h)
30 min-5 h)
(7.5-60 mg/m- for
dose of
• 72-75% of inhaled
amount is absorbed via
lungs.
Laboratory animals:
Rats exoosed to vaoor in
a closed chamber (single
1.200 mg/m2 for 3 h)
• 64-100% of inhaled
amount is absorbed via
lungs.
• Peak levels in blood
occurred near the end of
the 6-h period.
Laboratory animals:
Rats exoosed via nose-
• 37-64% of inhaled
amount is absorbed
via lungs.
Human subiects (n = 5)
6 h)
• Retention
(difference between
inhaled and exhaled
air) averaged 42%,
with maximum
values reached
within 15 min.
Laboratory animals:
Rats exoosed to vaoor
(2.600-18.200 mg/m2
79-39.652 mg/m2)
• Rapid uptake from air
with substantial levels
in venous blood within
2 min and equilibrium
blood levels achieved
within 45 min (similar
pattern at
1,200 mg/m3, although
blood levels continued
slowly increasing
through exposure so
that equilibrium was
never achieved).
• At equilibrium during
the last 90 min of 3 -h
exposure, systemic
uptake was 72-77% at
100-600 mg/m3
(uptake decreased
from -60% to -50%
over the same time
period at
1,200 mg/m3).
• Rapid uptake from air
with equilibrium
achieved at ~2 h.
• Inhalation uptake
~2 times that of the
trans isomer (at
equilibrium, the ratio
of uptake to exhalation
was 20 for
cis vs. 11.5 for trans,
and this is consistent
with the partition
coefficients shown
below).
exoosed via inhalation
in a chamber
(537 mg/m- for 6 h)
dose of
79-39.652 mg/rf)
• Peak levels in blood
occurred after 1-2 h.
Laboratory animals:
Rats exoosed to vaoor
(273-2.730 mg/m2 for
• Rapid uptake from air
with equilibrium
achieved at ~1.5 h.
• Inhalation uptake
—1/2 that for cis isomer
(at equilibrium, the
ratio of uptake to
exhalation was 20 for
cis vs. 11.5 for trans,
and this is consistent
with the partition
coefficients shown
below).
onlv inhalation (340 or
3.400 me/m- for 2 h)
• Rapid uptake from air
with substantial levels in
arterial blood within
2 min; blood levels
increased throughout 2 h
exposure, with the rate
of increase higher at the
higher exposure level.
for 5 h)
• Equilibrium blood
levels achieved
within 30 min.
Rats exoosed to vaoor
in a closed svstem
(260 mg/m- for 1 h)
2 h)
• Rapid uptake from air
with substantial levels
in blood within 5 min
and equilibrium blood
levels achieved within
30 min.
• -40% of inhaled
[14C] absorbed via
the lungs.
32
cis-1,2-Dichloroethylene
-------
EPA/690/R-22/001F
Table A-4. ADME Data for cis-l,2-DCE (CASRN 156-59-2) and Candidate Analogues"
Chemical
CASRN
civ-1,2-DC E
156-59-2
?/y/m.v-1,2-DCE
156-60-5
1,1-DCE
75-35-4
Perc
127-18-4
TCE
79-01-6
Vinyl Chloride
75-01-4
Rate and
extent of
inhalation
absorption,
continued
• After the first 20 min of
exposure, when near-
steady-state levels in
exhaled breath were
reached, systemic uptake
was relatively constant
at -50% at 340 mg/m3
and -40% at
3,400 mg/m3.
• At equilibrium during
the last 60 min of 2-h
exposure, systemic
uptake was 69-71%.
Human
blood-gas
partition
coefficient
9.2-9.85
5.8-6.08
ND
10.3-19.8
8.1-11.7
1.16
Rodent
blood-gas
partition
coefficient
21.6
9.58
5
18.9-33.5
13.3-25.82
1.6-2.8
33
cis-1,2-Dichloroethylene
-------
EPA/690/R-22/001F
Table A-4. ADME Data for cis- 1,2-DCE (CASRN 156-59-2) and Candidate Analogues3
Chemical
CASRN
cis- 1,2-DCE
156-59-2
trans- 1,2-DCE
156-60-5
1,1-DCE
75-35-4
Perc
127-18-4
TCE
79-01-6
Vinyl Chloride
75-01-4
Distribution
Extent of
distribution
Humans and laboratory
animals: ND
Rat tissue homo senates
exposed to vapor
(793-1.586 mg/m-for
1-4 h)
• The tissue:air partition
coefficients
determined for rats in
vitro were 227 (fat),
15.3 (liver), and
6.09 (muscle),
suggesting distribution
to the liver and
preferentially to fat.
Isolated perfused livers
from female rats exposed
to vapor (180 mia
concentrations not
reported)
• Uptake 3 times faster
than for trans isomer,
consistent with
difference in partition
coefficients.
Humans and laboratory
animals: ND
Rat tissue homo senates
exposed to vapor
(793-1.586 mg/m-for
1-4 h)
• The tissue:air partition
coefficients
determined for rats in
vitro were 148 (fat),
8.96 (liver), and
3.52 (muscle),
suggesting distribution
to the liver and
preferentially to fat.
Isolated perfused livers
from female rats exposed
to vapor (180 mia
concentrations not
reported)
• Uptake 3 times slower
than for cis isomer,
consistent with
difference in partition
coefficients.
Humans: ND
Laboratory animals:
Rats exposed to vapor
(40 or 8.000 mg/m- for
72 h)
• Preferential
distribution to liver
and kidney, with only
small amounts of
[14C] in other tissues.
Humans and laboratory
animals:
• Distributed throughout
the body, with highest
concentrations in fat,
liver, brain, and kidney.
Rats exposed via nose-
only inhalation (340 or
3.400 mg/m- for 2 h)
• Accumulates in fat; only
slowly released from fat
with half-time of ~25 h.
Pregnant rats exposed to
vapor in a closed chamber
(136-6.782 mg/m- and for
1-6 h)
• Found in milk in
proportion to fat content
(higher in
rats vs. humans).
Pregnant mice exposed to
vapor (100 uCi for 10 min
or 1 h: maternal blood
concentrations
-230 umol/L immediately
following exposure)
• Crosses placenta;
distributes to fetus and
amniotic fluid.
• Crosses blood:brain
barrier.
Humans and
laboratory animals:
• Rapidly distributed to
brain, liver, lung, and
preferential
accumulation to fat.
• Found in milk.
• Crosses placenta;
detected in neonatal
blood.
Humans: ND
Laboratory animals:
Rats exposed to vapor
in a closed system
(256 mg/m- for 6 h)
• Rapidly distributed
throughout body,
with highest levels
in liver and kidney.
Pregnant rats exposed
to vapor (single dose
of 511. 1.789. or
3.067 mg/m- for
2.5 h)
• Crosses placenta;
distributes to fetus
and amniotic fluid.
Rats exposed to vapor
(12.781 mg/m-for
6 h/d. 5 d/wk for
7 wk)
• Not expected to
accumulate due to
rapid metabolism
and elimination.
34
cis-1,2-Dichloroethylene
-------
EPA/690/R-22/001F
Table A-4. ADME Data for cis-l,2-DCE (CASRN 156-59-2) and Candidate Analogues"
Chemical
civ-1,2-DC E
?/y/m.v-1,2-DCE
1,1-DCE
Perc
TCE
Vinyl Chloride
CASRN
156-59-2
156-60-5
75-35-4
127-18-4
79-01-6
75-01-4
Metabolism
Rate;
Humans: ND
Humans: ND
Humans and
Humans and laboratory
Humans and
Humans and
primary
laboratory animals:
animals:
laboratory animals:
laboratory animals:
reactive
Laboratory animals:
Laboratory animals:
• Rapid.
• Undergoes only limited
• Extensively
• Rapid.
metabolites
• Rapid.
• Rapid.
• Saturable.
metabolism (in humans,
metabolized.
• Saturable.
• Saturable.
• Saturable.
• CYP450-mediated
>80% of absorbed dose
• Saturable.
• CYP450-mediated
• CYP450-mediated
• CYP450-mediated
oxidation (primarily
[any route] eliminated as
• Two competing
oxidation (primarily
oxidation (primarily
oxidation (primarily
CYP2E1).
unchanged parent).
biotransformation
CYP2E1).
CYP2E1).
CYP2E1).
• Primary oxidation
• Saturable.
pathways:
• Primary oxidation
Isolated Dcrfuscd livers
Isolated Dcrfuscd livers
products are
• Two competing
(1) CYP450-
product is an
from female rats exposed
from female rats exposed
1,1 -dichloroethene-
biotransformation
mediated oxidation
unstable epoxide
to vaoor (180 mia
to vaoor (180 mia
epoxide (major),
pathways: (1) CYP450-
(primary) and
intermediate
concentrations not
concentrations not
2-chloroacetyl
mediated oxidation
(2) GSH conjugation
(2-chloroethylene
reported): liver
rcDortcd): liver
chloride (minor), and
(primary) and (2) GSH
of parent compound.
oxide) that
microsomes from male
microsomes from male
2,2-dichloro-
conjugation of parent
• CYP450-mediated
spontaneously
rats exDOsed in vitro
rats exposed in vitro
acetaldehyde (minor),
compound.
oxidation (primarily
rearranges to form
(7.2 mM for 30 mini
(7.2 mM for 30 min)
all of which undergo
• CYP450-mediated
CYP2E1): initial
2-chloro-
• Suicide inhibitor of
• Suicide inhibitor of
hydrolysis or
oxidation (primarily
product is unstable
acetaldehyde.
CYP450 (less potent
CYP450 (more potent
conjugation with
CYP2E1): initial
intermediate
• The epoxide and
than trans isomer).
than cis isomer).
GSH.
product is unstable
(TCE-O-P450
2-chloroacetaldehyd
• Primary oxidation
• Primary oxidation
• GSH conjugates are
intermediate
complex) that
e are both
product is an unstable
product is an unstable
catabolized in the
(Perc-Fe-O) that is
spontaneously
conjugated with
epoxide intermediate
epoxide intermediate
kidney to a variety of
converted to
rearranges to form
GSH to form
that spontaneously
that spontaneously
urinary elimination
trichloroacetyl chloride
chloral and unstable
cysteine derivatives
rearranges to form
rearranges to form
products.
(hydrolyzed to TCA
TCE oxide, which
that are excreted in
2,2-dichloro-
2,2-dichloro-
with further metabolism
then forms dichloro-
the urine.
acetaldehyde, which is
acetaldehyde, which is
to DCA) or oxalic acid,
acetyl chloride.
enzymatically
enzymatically
possibly via an unstable
Further metabolism
converted to
converted to
epoxide intermediate.
yields 2,2,2-trichloro-
2,2-dichloroethanol
2,2-dichloroethanol
ethanol, TCA, DCA,
(primarily) and DCA,
and DCA (primarily),
and oxalic acid.
which may undergo
which may undergo
oxidative
oxidative
dechlorination to
dechlorination to
glyoxylic acid.
glyoxylic acid.
35
cis-1,2-Dichloroethylene
-------
EPA/690/R-22/001F
Table A-4. ADME Data for cis-l,2-DCE (CASRN 156-59-2) and Candidate Analogues"
Chemical
CASRN
civ-1,2-DC E
156-59-2
?/y/m.v-1,2-DCE
156-60-5
1,1-DCE
75-35-4
Perc
127-18-4
TCE
79-01-6
Vinyl Chloride
75-01-4
Rate;
primary
reactive
metabolites,
continued
• Metabolite production
is faster and quantities
are greater than for the
trans isomer (by
4-25 times).
• Metabolites are not
thought to undergo
GSH conjugation to
any major extent.
• Metabolite production
is slower and
quantities are lower
than for the cis isomer
(by 4-25 times).
• Metabolites are not
thought to undergo
GSH conjugation to
any major extent.
• GSH conjugation: yields
trichlorovinyl cysteine,
which can be
bioactivated to form
reactive species and
DCA via beta-lyase or
flavin-containing
monooxygenases.
• GSH conjugation:
yields dichlorovinyl
cysteine, which can
be bioactivated to
form reactive species
via beta-lyase or
flavin-containing
monooxygenases.
Elimination
Elimination
half-time;
route of
elimination
Humans:
Humans (n = 2) cxooscd
Humans and
laboratory animals: ND
• The metabolite, DC A,
is expected to be
broken down to CO2
and exhaled, along
with trace amounts of
2,2-dichloroethanol.
Humans: ND
Laboratory animals:
Rats cxooscd to vaoor
Humans:
Human subiects (n = 6)
Humans:
Human subiects
Humans:
Human subiects
to vaoor in showers
cxooscd to vaoor (488 or
cxooscd singly or
exoosed to vaoor bv
(10 mia absorbed
977 mg/m- for 4 h)
seauentiallv to vaoor
gas mask
doses = 1.19-2.34 us)
(40 or 8.000 mg/m- for
• 80-100% of the total
absorbed dose was
exhaled as unchanged
parent compound in
three first-order phases
with half-lives of 12-16,
30-40, and 55-65 h.
• <2% excreted as
metabolites in urine,
primarily TCA.
OcciiDationallv cxooscd
humans (n= 13)
• Biological half-life of
Perc was ~6 d
Human subiects (n = 6)
cxooscd to vaoor in a
dynamic chamber (67.
136. or 271 me/m- for 6 h)
(267-2.042 mg/m- for
(7.5-60 mg/m-for
• Elimination half-times
of 0.82-2.37 min for
blood and
8.96-29.33 min for
highly perfused tissues
were estimated.
Laboratory animals:
ND
• The metabolite, DC A,
is expected to be
broken down to CO 2
and exhaled, along
with trace amounts of
2,2-dichloroethanol.
72 h)
• Rapid elimination
after inhalation
exposure, mostly as
metabolites in urine
with some unchanged
parent compound
exhaled in expired air.
• Elimination following
inhalation was
biphasic, with most
material eliminated in
rapid first phase;
elimination half-times
were 20 min and 4 h
for unchanged parent
compound in breath
and 3 and 20 h for
metabolites in urine.
4 h on 1-5 d)
• 11% of the absorbed
dose was exhaled
unchanged (half-time
~10 h), 2% was
exhaled as
trichloroethanol
(half-time ~20 h),
58% was eliminated
as urinary metabolites
(primarily
trichloroethanol and
its glucuronide with
half-time of ~10 h
and TCA with
half-time of ~52 h),
and 30% was
unaccounted for
(likely stored in
adipose tissue).
6 h)
• 5-7% of the
inhaled amount was
exhaled as
unchanged parent
compound.
Laboratory animals:
• Rapid elimination
after inhalation
exposure, primarily
as metabolites in
urine up to
metabolic
saturation, with
increasing
exhalation of
unchanged parent
compound above
saturation.
36
cis-1,2-Dichloroethylene
-------
EPA/690/R-22/001F
Table A-4. ADME Data for cis-l,2-DCE (CASRN 156-59-2) and Candidate Analogues"
Chemical
CASRN
civ-1,2-DC E
156-59-2
?/y/m.v-1,2-DCE
156-60-5
1,1-DCE
75-35-4
Perc
127-18-4
TCE
79-01-6
Vinyl Chloride
75-01-4
Elimination
half-time;
route of
elimination,
continued
Rats exoosed to vaoor
(793 me/m- for 6 h)
• Elimination half-times
were 45.6 h for TCA
and 14.1 hfor a
trichlorovinyl cysteine
derivative.
Laboratory animals:
• For some inhalation
exposures, rats excrete
more than humans as
urinary metabolites,
with shorter half-times
(11 hfor TCA and 7.5 h
for a trichlorovinyl
cysteine derivative at
68-271 mg/m3 for 6 h),
and mice more than rats
(62.5% of absorbed dose
from a 6-h inhalation
exposure of 68 mg/m3,
versus 18.7% in rats).
Rats cxooscd to vaoor
(68-4.080 me/m- for
6 hi
• Elimination is dose-
dependent (68% of
absorbed dose exhaled
as parent compound,
3.6% exhaled as CO2,
and 18.7% excreted as
metabolites in urine at
68 mg/m3 vs. 88, 0.7,
and 6%, respectively, at
4,080 mg/m3).
Laboratory animals:
Rats and mice exoosed
Rats exoosed to vaoor
(26-13.000 me/m- for
• 75% of absorbed dose
was excreted in urine,
6% in feces, 8% as
CO 2 in breath and 4%
as unchanged parent
compound in breath.
to vaoor (54 or
3.240 me/m- for 6 h)
6 h)
• In rats exposed for
6 h to 26 mg/m3,
70% of the initial
dose was recovered
in urine and 2%
was exhaled as the
parent compound.
Respective
recoveries were
56 and 12% at
2,600 mg/m3 and
27 and >50% at
13,000 mg/m3.
• Elimination half-
times were
20-30 minfor
parent compound in
breath and
4.1-4.6 hfor
metabolites in
urine.
• Recovery of [14C]
was 5% (9%) exhaled
as CO2, 63% (74%)
excreted in urine, and
7% (4%) in feces for
the low dose, with
similar results in both
species at the high
dose.
Rats exoosed to vaoor
(270-1.340 me/m-for
8 h)
• Elimination half-time
for oxidative
metabolites (total
trichloro compounds)
in urine was 14-17 h.
37
cis-1,2-Dichloroethylene
-------
EPA/690/R-22/001F
Table A-4. ADME Data for cis- 1,2-DCE (CASRN 156-59-2) and Candidate Analogues"
Chemical
CASRN
civ-1,2-DC E
156-59-2
?/y/m.v-1,2-DCE
156-60-5
1,1-DCE
75-35-4
Perc
127-18-4
TCE
79-01-6
Vinyl Chloride
75-01-4
PBPK
models
available
Yes
Yes
Yes
Yes
Yes
Yes
References
U.S. EPA (2003): Lillv et
U.S. EPA (2003): Lillv et
Dallas etal. (1983):
Chiu et al. (2007): Volkel
Dallas etal. (1991):
Kraiewski et al.
al. (1998): Pleil and
Lindstrom (1997);
Gareas et al. (1989);
al. (1998); Gareas et al.
(1989); Gareas et al.
(1988); Sato and
Jones and Hathwav
(1978); Mckenna et al.
(1978a): Mckenna et al.
et al. (1998); Bvczkowski
and Fisher (1994); Dallas
et al. (1994); Ghantous et
Pellizzari et al. (1982);
Monster etal. (1979a):
Astrand and Ovrum
(1980); Unevarv et al.
(1978): Bolt etal.
(1977): Bolt etal.
Gareas et al. (1988); Sato
Nakaiima (1987); Costa
(1978b): Mckenna et al.
al. (1986); Schumann et
(1976); Monster et al.
(1976); Watanabe et
and Nakaiima (1987);
and Ivanetich (1984.
(1977)
al. (1980); Monster et al.
(1976); Midler et al.
al. (1976): Withe v
Costa and Ivanetich
(1984. 1982); Filser and
Bolt (1979); Henschler
and Bonse (1977); Bonse
et al. (1975)
1982); Filser and Bolt
(1979); Henschler and
Bonse (1977); Bonse et
al. (1975); Lehtnann and
Schmidt-Kehl (1936)
(1979b): Peee et al.
(1979); Ikeda and
Imamura (1973)
(1974); Ikeda and
Imamura (1973); Laham
(1970)
(1976)
aWhen possible, exposure concentrations are reported in units of mg/m3 to enable interstudy comparisons. Concentrations reported in parts per million were converted to
mg/m3 using: concentration in ppm x molecular weight (g/mol)] ^ 24.45 (L/mol).
ADME = absorption, distribution, metabolism, and excretion; cis-1,2-DCE = cis-1.2-dichlorocthvlcne: CO2 = carbon dioxide; CYP450 = cytochrome P450;
DCA = 2,2-dichloroacetic acid; GSH = glutathione; ND = no data; Perc = tetrachloroethylene; PBPK = physiologically based pharmacokinetic; TCA = trichloroacetic
acid; TCE = trichloroethylene; trans-1,2-DCE = trans-1.2-dichloroetln lene.
38
cis-1,2-Dichloroethylene
-------
EPA/690/R-22/001F
No in vivo human or animal studies reporting distribution of cz's-l,2-DCE were identified
(U.S. EPA. 2020. 2010). Based on tissue:air partition coefficients and in vitro studies, cis- and
trans- 1,2-DCE are expected to distribute from the blood to the liver and preferentially to fat
(U.S. EPA. 2010). The fat, liver, and muscle tissue:air partition coefficients for cis-1,2-DCE are
~2-fold greater than those for the trans isomer, suggesting that the cis isomer is taken up more
efficiently by these tissues (U.S. EPA. 2010). For the candidate analogues with data, distribution
is rapid and widespread throughout the body, although differences in partitioning are observed.
Perc and TCE primarily accumulate in fat and are also found in milk, which has a high fat
content (ATSDR, 2019b, c; U.S. EPA, 2012. 201 Id). In contrast, the highest levels of 1,1-DCE
and vinyl chloride are found in the liver and kidneys, with only small amounts in other tissues
and little to no accumulation in fat (ATSDR. 2019a. 2006; U.S. EPA. 2002b. 2000). Perc, TCE,
and vinyl chloride have been shown to cross the placenta. Distribution to the placenta and the
fetus has not been evaluated for the other compounds (ATSDR. 2019a; U.S. EPA. 2010).
Similar to cis- 1,2-DCE, all of the candidate analogues undergo oxidative metabolism
mediated by cytochrome P450 (CYP450) enzymes (primarily CYP2E1), and metabolism is
saturable. For both cis- and trans- 1,2-DCE, the initial oxidation product is an unstable epoxide
intermediate that rearranges to form 2,2-dichloroacetaldehyde, which is then enzymatically
converted to 2,2-dichloroethanol and 2,2-dichloracetic acid (U.S. EPA. 2020. 2010). Comparing
cis- and trans- 1,2-DCE, quantitative differences in the rate and quantity of metabolites produced
have been noted, with the overall rate of metabolism faster and metabolite production greater for
the cis isomer by approximately 4-25 times (U.S. EPA. 2020. 2010; ATSDR. 1996). In addition,
the relative levels of metabolic products differ, so that 2,2-dichloroethanol is the major
metabolite for the cis isomer, while DCA is the more abundant metabolite for the trans isomer
(although due to the overall difference in metabolic rate, production of DCA from the cis isomer
is still greater). Both isomers are capable of irreversible inhibition (i.e., suicide inactivation) via
binding to the heme molecule on CYP450s, although c/.s- l ,2-DCE is a less potent inhibitor than
trans- 1,2-DCE (U.S. EPA. 2010). Distinct from the other compounds under consideration, the
downstream metabolites of the cis and trans isomers are not thought to undergo GSH
conjugation to any major extent. Oxidation of 1,1-DCE generates three products, including an
epoxide, and vinyl chloride oxidation generates an epoxide intermediate that rearranges to
2-chloroacetaldehyde; all of these products undergo hydrolysis and/or conjugation with GSH.
GSH conjugation has been shown to contribute to the detoxification of 1,1-DCE and vinyl
chloride (ATSDR. 2019a. 2006; U.S. EPA. 2002b. 2000). Perc and TCE are the only candidates
having a competing GSH conjugation pathway independent of CYP450 oxidation. Metabolites
from these GSH conjugation pathways can be bioactivated, yielding reactive species that
contribute to the toxicity of these two compounds (ATSDR. 2019b. c). Compared with
cz'5-1,2-DCE and to the other candidate analogues, less of the absorbed Perc is metabolized. In
humans, 80-100% of the absorbed Perc dose remained unmetabolized and was exhaled as the
parent compound (ATSDR. 2019a; U.S. EPA. 2012).
Elimination of czs-l,2-DCE is biphasic, with an initial rapid elimination from blood
(half-time of 0.82-2.37 minutes in humans) followed by a second only slightly slower phase of
elimination from highly perfused tissues (half-time of 8.96-29.33 minutes in humans) (U.S.
EPA, 2010). Based on structural and physicochemical similarity to the cis isomer, elimination of
trans- 1,2-DCE is also expected to be reasonably rapid, although potentially longer than that of
cz'5-1,2-DCE due to its slower rate of metabolism. Data in humans and/or laboratory animals
show rapid elimination (minutes to a few hours) following inhalation exposure to 1,1-DCE and
39
cis-1,2-Dichloroethylene
-------
EPA/690/R-22/001F
vinyl chloride (ATSDR. 2019a. 2006). Elimination half-times were significantly longer
(10 hours to a few days) for Perc and TCE, indicating delayed clearance, presumably due to
retention in fat (ATSDR, 2019b, c). For the candidate analogues with data, the primary routes of
elimination are as metabolites in urine and via exhalation of unchanged parent compound in
breath, with relative importance being dose dependent (increasing exhalation of unchanged
parent compound as the exposure level increases above metabolic saturation). Perc differs from
the other candidate analogues in that even at low exposure levels below metabolic saturation,
elimination occurs primarily by exhalation of parent compound, with lesser amounts excreted as
metabolites in the urine (ATSDR, 2019b).
Among the candidate analogues, trans- 1,2-DCE appears to be the closest metabolic
analogue to cz's-l,2-DCE on the basis of rapid uptake and similarities in distribution and
metabolism patterns. However, quantitative differences between the isomers, in uptake and in the
rate and quantity of metabolites produced, could have implications for relative toxicity of the two
compounds. Although Perc and TCE were identified as candidate analogues for cz's-l,2-DCE
based on the shared DCA metabolite, there are important differences between these candidate
analogues and cis- 1,2-DCE. Unlike c/.s- l ,2-DCE, which is rapidly metabolized, Perc undergoes
only limited metabolism. Additionally, metabolism of both Perc and TCE includes a direct GSH
conjugation pathway independent of CYP450 oxidation that yields reactive species thought to
contribute significantly to the toxicity of these two compounds (ATSDR, 2019b. c). Based on
these metabolic differences, Perc and TCE are less suitable metabolic analogues for cis- 1,2-DCE
than the other candidate analogues.
Toxicodynamic Similarity Comparisons
Table A-5 summarizes the inhalation toxicity values for the cis-1,2-DCE candidate
analogues, and Table A-6 shows a comparison of the inhalation toxicity data for the candidate
analogues in selected target organs/systems. Because inhalation data for cz's-1,2-DCE are limited
to an acute lethality study, oral data for cis- 1,2-DCE were also considered when making
comparisons across chemicals. Additional information, including more detailed discussions of
possible mechanisms of toxicity, can be found in recent assessments for these chemicals (U.S.
EPA, 2020; ATSDR, 2019a. b, c; U.S. EPA, 2012, 201 Id. 2010; ATSDR. 2006; U.S. EPA.
2002b. 2000; ATSDR. 1996).
40
cis-1,2-Dichloroethylene
-------
EPA/690/R-22/001F
Table A-5. Comparison of Available Inhalation Toxicity Values for cis-l,2-DCE (CASRN 156-59-2) and Candidate
Analogues"
Chemical
CASRN
civ-1,2-DC E
156-59-2
?/y/m.v-1,2-DCE
156-60-5
1,1-DCE
75-35-4
Perc
127-18-4
TCE
79-01-6
Vinyl Chloride
75-01-4
Structure
CI
/C"2
"" I
CI Ci
CI
a
/
{;r"'*x^cH2
Role
Target
Analogue
Analogue
Analogue
Analogue
Analogue
DTXSID
2024030
7024031
8021438
2021319
0021383
8021434
Repeat-dose toxicity—
subchronic
POD (mg/m3)
NA
109
0.170
11.53
0.177 (1st study)
0.020 (2nd study)
2.56
POD type
NA
BMCLisdhec
BMCLiohec
LOAEL
HEC99 (based on
calculated idPODs)
LECiohec
Subchronic UFC
NA
300
(UFa = 3;UFh= 10;
UFd = 10)
30
(UFa = 3; UFh = 10)
300
(UFh = 10; UFL = 10;
MF = 3 for database
deficiencies)
1st study: 100
(UFl = 10;
UFa = 3.16;
UFh = 3.16)
2nd study: 10
(UFa = 10)
30
(UFa = 3; UFh = 10)
Subchronic p-RfC or
Intermediate MRL
(mg/m3)
NA
4 x 10-1
(screening)
4 x 10 3 (provisional)
4 x 10-2
2 x 10-3
(midpoint RfC from
two candidate RfCs)
8 x 10-2
Critical effects
NA
Decreased WBC and
lymphocyte counts
Atrophy in nasal
olfactory epithelium
Color vision loss
Decreased thymus
weight and fetal heart
malformations
Centrilobular
hypertrophy
Species
NA
Rat
Rat
Human
Mouse (1st study)
Rat (2nd study)
Rat
Duration
NA
90 d
14 wk
Average 106 mo
Simulation-52 wk (1st
study)
GDs 1-22 (2nd study)
From 10 wk prior to
mating through
lactation
41
cis-1,2-Dichloroethylene
-------
EPA/690/R-22/001F
Table A-5. Comparison of Available Inhalation Toxicity Values for cis-l,2-DCE (CASRN 156-59-2) and Candidate
Analogues"
Chemical
CASRN
civ-1,2-DC E
156-59-2
?/y/m.v-1,2-DCE
156-60-5
1,1-DCE
75-35-4
Perc
127-18-4
TCE
79-01-6
Vinyl Chloride
75-01-4
Route (method)
NA
Inhalation (whole
body)
Inhalation (whole
body)
Inhalation (worker
breathing zone)
Oral (drinking water)
Inhalation (whole
body)
Source
NA
U.S. EPA (2020)
ATSDR (2019a)
ATSDR (2019b)
ATSDR (2019c)
ATSDR (2006)
Repeat-dose toxicity—chronic
POD (mg/m3)
NA
109
6.9
15 (1st study)
56 (2nd study)
0.177 (1st study)
0.020 (2nd study)
2.5
POD type
NA
BMCLisdhec
BMCLhec
LOAEL
HEC99 (based on
calculated idPODs)
NOAELhec (based on
idPODs)
Chronic UFC
NA
3,000
(UFa = 3;UFh= 10;
UFd = 10; UFS = 10)
30
(UFa = 3; UFh = 10)
1,000
(UFh = 10; UFL = 10;
UFS = 10)
1st study: 100
(UFl = 10; UFA-Pk = 3;
UFn-pk = 3)
2nd study: 10
(UFa = 3; UFh = 3)
30
(UFa = 3; UFh = 10)
Chronic RfC/p-RfC or
chronic MRL
(mg/m3)b
NA
4 x 10-2
(screening)
2 x 10-1
4 x 10-2
(midpoint of the range
from two studies)
2 x 10-3
(midpoint RfC from
two candidate RfCs)
1 x 10-1
Critical effects
NA
Decreased WBC and
lymphocyte counts
Liver toxicity (fatty
change)
Cognitive and reaction
time changes and color
vision changes
Decreased thymus
weight and fetal heart
malformations
Liver cell
polymorphisms and
cysts
Species
NA
Rat
Rat
Human
Mouse (1st study)
Rat (2nd study)
Rat
Duration
NA
90 d
up to 18 mo
Mean 8.8 yr (1st
study); 15 yr (2nd
study)
Simulated 100 wk
(1st study);
GDs 1-22 (2nd study)
Lifetime
Route (method)
NA
Inhalation (whole
body)
Inhalation (whole
body)
Inhalation (workplace
exposure)
Oral (drinking water)
Oral (feed)
Source
NA
U.S. EPA (2020)
U.S. EPA (2002b)
ATSDR (2019b): U.S.
EPA (2012)
ATSDR (2019c): U.S.
EPA (201 Id)
U.S. EPA (2000)
42
cis-1,2-Dichloroethylene
-------
EPA/690/R-22/001F
Table A-5. Comparison of Available Inhalation Toxicity Values for cis-l,2-DCE (CASRN 156-59-2) and Candidate
Analogues"
Chemical
CASRN
civ-1,2-DCE
156-59-2
trans- 1,2-DCE
156-60-5
1,1-DCE
75-35-4
Perc
127-18-4
TCE
79-01-6
Vinyl Chloride
75-01-4
Acute inhalation lethality data (LCso)
Rat inhalation LC50
(mg/m3)
(lowest observed)
54,320
95,556
25,178
34,200
67,172
460,113
Mouse inhalation
LC50 (mg/m3)
(lowest observed)
65,500 (LClo)
NA
200
35,269
45,408
294,000
Source
NLM (2021b): Kellv
et al. (2000):
NLM (202Id): Kellv et
al. (2000); Lehmann
NLM (2021a): U.S.
EPA (2021a): Sieeel et
NLM (2021c): Pozzani
et al. (1959); Friberg et
NLM (2021e):
U.S. EPA CompTox
Chemicals Dashboard
(trichloroethylene,
CASRN 79-01-6);
httDS ://comDtox. ena.
NLM (202If): U.S.
EPA (2021b): Clark
Lehtnatm and
and Schmidt-KeM
al. (1971)
al. (1953)
and Tinston (1982)
Schmidt-KeM (1936)
(1936)
eov/dashboard/
dsstoxdb/results? search
=DTXSID0021383#
toxicitv-values:
accessed July 1, 2021
aU.S. EPA derived toxicity values are reported. In instances where no U.S. EPA toxicity value is available, ATSDR MRL values are shown. If U.S. EPA and ATSDR
values were the same, both sources are noted.
' For 1.1-DCE. the U.S. EPA chronic RFC is shown. However, a more recent ATSDR assessment (ATSDR. 201931 was done that reviewed new studies not available in
the U.S. EPA (2002b) Toxicological Review. One of these new studies was used to derive a chronic MRL of 2 x 10~3 mg/m3; POD = 0.67 mg/m3 (BMCLiohec);
UFC = 30; based on metaplasia in nasal olfactory epithelium in a 105-wk whole-body inhalation study in mice.
1,1-DCE = 1,1-dichloroethylene; ATSDR = Agency for Toxic Substances and Disease Registry; BMCL = benchmark concentration lower confidence limit;
BMCL io = 10% benchmark concentration lower confidence limit; cis- 1,2-DCE = cis-1.2-dichlorocthvlcnc: DTXSID = DSSTox substance identifier; GD = gestation day;
HEC = human equivalent concentration; HEC99 = 99th percentile human equivalent concentration; idPOD = internal dose points of departure; LC50 = median lethal
concentration; LClo = lowest lethal concentration; LEC10 = 10% lowest effect concentration; LOAEL = lowest-observed-adverse-effect level; MF = modifying factor;
MRL = minimal risk level; NA = not applicable; NOAEL = no-observed-adverse-effect level; p-RfC = provisional reference concentration; Perc = tetrachloroethylene;
pk = uncertainty based on pharmacokinetic component; POD = point of departure; RfC = reference concentration; SD = standard deviation; TCE = trichloroethylene;
/raws-1,2-DCE = /ra«s-l,2-dichloroethylene; UFA = interspecies uncertainty factor; UFC = composite uncertainty factor; UFD = database uncertainty factor;
UFh = intraspecies uncertainty factor; UFL = LOAEL uncertainty factor; UFS = subchronic-to-chronic uncertainty factor; U.S. EPA = U.S. Environmental Protection
Agency; WBC = white blood cell.
43
cis-1,2-Dichloroethylene
-------
EPA/690/R-22/001F
Table A-6. Comparison of Effects on Target Organs/Systems Following Short-term, Subchronic, and Chronic
Exposure to cis- 1,2-DCE (Oral) and Candidate Analogues (Inhalation)a'b
Target Organ/
System
civ-1,2-DC Ec
trans- 1,2-DCE
1,1-DCE
Perc
TCEd
Vinyl Chlorided
EffecteAg (species)
Liver
In 14- and 90-d studies
in rats (10/sex/dose;
Sprague Dawley)
exposed orally (gavage;
0-1,940 mg/kg-d; 97%
purity), relative
increases in liver
weight were observed
(3-39% increases). In
the 14-d study,
statistically significant
increases were
observed in both
absolute and relative
liver weights (15-21%)
in females and in
relative liver weights
(16%) in males at
>97 mg/kg-d. In the
90-d study, relative
liver weight increases
(14-15%) were
statistically significant
in both females and
males at >97 mg/kg-d.
Refer to Table 3 in the
main document for
more details.
(rat, oral, short-term
and subchronic)
In 8- and 16-wk studies in
rats (6 females/dose; SPR
Wistar) exposed to vapor
(793 mg/m3; 8 h/d,
5 d/wk), fatty
degeneration of the liver
lobule and Kupffer cells
were observed. In the
8-wk study, 3 of
6 exposed rats showed
slight changes in the liver
lobules and severe
changes in the Kupffer
cells, while severe fat
accumulation was also
noted in the Kupffer cells
in 1 of 6 controls. In the
16-wk study, 3 of
6 exposed rats showed
severe changes in liver
lobules and slight
changes in Kupffer cells
and 2 of the other
exposed rats showed
slight changes in both the
liver lobules and Kupffer
cells. Of the 6 controls,
2 also showed slight
changes in both the liver
lobules and Kupffer cells
in the 16-wk study.
(rat, inhalation,
subchronic and chronic)
In a 14-wk study, male
rats (10/sex/dose;
F344/N) exposed to
vapor (0-396 mg/m3;
6 h/d, 5 d/wk) exhibited
hepatic centrilobular
cytoplastic alterations at
>50 mg/m3.
(rat, inhalation, chronic)
In 6-, 12-, and 18-mo
studies, rats (86/group;
Sprague Dawley)
exposed to vapor
(40 and 160 mg/m3 for
the first 5 wk, then
100 and 300 mg/m3 for
the remainder; 6 h/d,
5 d/wk) exhibited
hepatocellular
midzonal fatty changes
at the high dose after
6 and 12 mo (males
and females), and at
the high dose at 18 mo
(females only); changes
were reversible.
(rat, inhalation,
chronic)h
In a population of 27 dry
cleaners (107 mg/m3 8-h
TWA exposure; 12-yr
mean duration) and
26 nonexposed laundry
workers, a higher
prevalence of diffuse
parenchymal changes was
observed among the
laundry workers
(67 vs. 38% in the control
group).
(human)
In a 30-d study, mice
(10-12/sex/dose; NMRI)
exposed to vapor
(0-1,017 mg/m3; 24 h/d,
continuous) exhibited liver
enlargement and
vacuolization of
hepatocytes at >61 mg/m3.
(mouse, inhalation,
short-term)
In a 30-d study, male
mice
(10-20/sex/dose;
NMRI) exposed to
vapor
(0-1,612 mg/m3;
24 h/d, continuous)
exhibited increased
liver weight and
increased BuChE
activity,
accompanied by
misshapen, enlarged
and vacuolated
hepatocytes at
>403 mg/m3 (in
female mice, these
effects occurred at
1,612 mg/m3).
(mouse, inhalation,
short-term)
In a 19-wk study in
rats (30/sex/dose;
Sprague Dawley)
exposed to vapor
(0-2,812 mg/m3;
6 h/d, 10 wk prior to
mating through
lactation),
centrilobular
hypertrophy was
observed in Fi female
rats at >26 mg/m3.
(rat, inhalation,
reproductive)'
44
cis-1,2-Dichloroethylene
-------
EPA/690/R-22/001F
Table A-6. Comparison of Effects on Target Organs/Systems Following Short-term, Subchronic, and Chronic
Exposure to cis- 1,2-DCE (Oral) and Candidate Analogues (Inhalation)a'b
Target Organ/
System
civ-1,2-DC Ec
?/y/«.s-1,2-DCE
1,1-DCE
Perc
TCEd
Vinyl Chlorided
Effectefg (species)
Liver,
continued
In a 12-d study, mice
(10/sex/dose; Ha[ICR])
exposed to vapor
(0-793 mg/m3; 6 h/d,
5 d/wk) exhibited
increased relative liver
weights (by 20-24%) at
>218 mg/m3. {mouse,
inhalation, short-term)
In a 5-d study, mice
(4-10 males/dose;
CD-I) exposed to vapor
(0-238 mg/m3;
22-23 h/d) exhibited
hepatocellular
degeneration at
>59 mg/m3.
(mouse, inhalation,
short-term)
45
cis-1,2-Dichloroethylene
-------
EPA/690/R-22/001F
Table A-6. Comparison of Effects on Target Organs/Systems Following Short-term, Subchronic, and Chronic
Exposure to cis- 1,2-DCE (Oral) and Candidate Analogues (Inhalation)a'b
Target Organ/
System
civ-1,2-DC Ec
trans- 1,2-DCE
1,1-DCE
Perc
TCEd
Vinyl Chlorided
Effect®'''8 (species)
Kidney
In 14- and 90-d
studies in rats
(10/sex/dose;
Sprague Dawley)
exposed orally
(gavage;
0-1,940 mg/kg-d;
97% purity), relative
increases in kidney
weight were observed
(12-27% increases).
In the 14-d study,
absolute and relative
kidney weights were
statistically
significantly increased
in females (14-20%)
at >970 mg/kg-d; in
males, increases in
absolute and relative
kidney weights did
not reach statistical
significance at any
dosing level
(97-1,940 mg/kg-d).
In a 90-d study in rats
(15/sex/dose; Crl:CD BR)
exposed to vapor
(793-15,860 mg/m3;
6 h/d, 5 d/wk; >99.4%
purity), increases in
relative kidney weights
for male and females
were <10% and not
generally dose-related.
(rat, inhalation,
subchronic)
In a 14-wk study, female
mice (10/sex/dose;
B6C3F1/N) exposed to
vapor (0-396 mg/m3;
6 h/d, 5 d/wk) exhibited
increased relative kidney
weights (by 11%) at
>25 mg/m3.
(mouse, inhalation,
chronic)
Enzyme changes
(| kidney
monooxygenase and
epoxide hydrolase
levels), tubular
alterations, and kidney
histopathology were
observed at higher
exposure levels.
In a population of 57 dry
cleaners (68 mg/m3; 8-h
TWA exposure; 13.9-yr
mean duration; mostly
females), 30 unexposed
workers (mostly females),
and 81 unexposed workers
(mostly males), a 50%
increase in creatinine-
adjusted geometric
mean concentration of
urinary (32 glucuronidase
and a 100% increase in
geometric mean urinary
lysozyme were observed in
dry cleaners compared
with either control group.
(human)
In a 30-d study, male
mice
(10-20/sex/dose;
NMRI) exposed to
vapor
(0-1,612 mg/m3;
24 h/d, continuous)
exhibited increased
kidney weight (by
39%) at >403 mg/m3
(in female mice, the
effect occurred at
1,612 mg/m3).
(mouse, inhalation,
short-term)
t Urinary glucose
and proteins, serum
gamma-glutamyl
transpeptidase; and
blood urea nitrogen,
and kidney
histopathology were
observed at higher
exposure levels.
In a 12-mo study, male
rats (75/dose; Wistar)
exposed to vapor
(0-7,668 mg/m3; 6 h/d,
6 d/wk) exhibited
increased kidney
weights at >256 mg/m3.
(rat, inhalation,
chronic)
No histopathology at
highest exposure levels.
46
cis-1,2-Dichloroethylene
-------
EPA/690/R-22/001F
Table A-6. Comparison of Effects on Target Organs/Systems Following Short-term, Subchronic, and Chronic
Exposure to cis- 1,2-DCE (Oral) and Candidate Analogues (Inhalation)a'b
Target Organ/
System
civ-1,2-DC Ec
?/y/m.v-1,2-DCE
1,1-DCE
Perc
TCEd
Vinyl Chlorided
Effect®'''8 (species)
Kidney,
continued
In the 90-d study,
increases in relative
and absolute kidney
weights (3-23%) did
not reach statistical
significance in
females; however, in
males, increases in
relative (but not
absolute) kidney
weight (14%) were
statistically significant
at >32 mg/kg-d. Refer
to Table 3 in the main
document for more
details.
(rat, oral, short-term
and subchronic)j
In a 103-wk study, mice
(49-50/sex/dose; B6C3F1)
exposed to vapor
(0-1,356 mg/m3; 6 h/d,
5 d/wk) exhibited
nephrosis at >678 mg/m3.
(mouse, inhalation,
chronic)
t Kidney weight and
histopathology were
observed at higher
exposure levels.
Respiratory
In a 14-d study, rats
(5/sex/group; strain not
specified) exposed to
vapor (to
0-91,900 mg/m3 for
4 h) exhibited irregular
respiration at
>53,400 mg/m3
immediately following
exposure.
(rat, inhalation, acute)
In 1-, 2-, 8- and 16-wk
studies in rats
(6 females/dose; SPR
Wistar) exposed to vapor
(793 mg/m3; 8 h/d,
5 d/wk), slight pulmonary
capillary hyperemia and
alveolar septum
distension were observed
in all six rats in all four
exposure duration groups.
(rat, inhalation, acute
and subchronic)
In a 14-wk study, rats
(10/sex/dose; F344/N)
exposed to vapor
(0-396 mg/m3; 6 h/d,
5 d/wk) exhibited
olfactory epithelium
mineralization at
25 mg/m3; olfactory
epithelium atrophy was
also observed in males
at >25 mg/m3.
(rat, inhalation,
subchronic)k
In a 103-wk study, mice
(49-50/sex/dose; B6C3F1)
exposed to vapor
(0-1,356 mg/m3; 6 h/d,
5 d/wk) exhibited acute
passive congestion of the
lungs at >678 mg/m3.
(mouse, inhalation,
chronic)
In 28- and 90-d
studies, rats (Wistar)
exposed to vapor
(0-2,021 mg/m3;
4 h/d, 5 d/wk)
exhibited lung
lesions (bronchiolitis
and alveolitis) at
2,021 mg/m3.
(rat, inhalation,
short-term and
subchronic)
In a 5- to 6-mo study,
male mice (3-13/dose;
CD-I) exposed to
vapor
(0-15,337 mg/m3;
5 h/d, 5 d/wk) exhibited
proliferation and
hypertrophy of
bronchial epithelium,
hypersecretion of
mucin, and hyperplasia
of alveolar epithelium
at >6,390 mg/m3.
(mouse, inhalation,
chronic)
47
cis-1,2-Dichloroethylene
-------
EPA/690/R-22/001F
Table A-6. Comparison of Effects on Target Organs/Systems Following Short-term, Subchronic, and Chronic
Exposure to cis- 1,2-DCE (Oral) and Candidate Analogues (Inhalation)a'b
Target Organ/
System
civ-1,2-DC Ec
?/y/«.s-1,2-DCE
1,1-DCE
Perc
TCEd
Vinyl Chlorided
Effect®'''8 (species)
Respiratory,
continued
In a 90-d study, rats
(15/sex/group; Crl:CD
[SD] BR) exposed to
vapor (0-16,000 mg/m3;
6 h/d, 5 d/wk) exhibited
no upper or lower
respiratory lesions.
(rat, inhalation,
subchronic)
In a 105-wk study,
mice (50/sex/dose;
B6C3F1/N) exposed to
vapor (0-100 mg/m3;
6 h/d, 5 d/wk) exhibited
nasal turbinate
atrophy, hyperostosis,
and metaplasia of the
respiratory olfactory
epithelium at
>25 mg/m3.
{mouse, inhalation,
chronic)k
In a 14-wk study, female
mice (10/sex/dose;
B6C3F1/N) exposed to
vapor (0-396 mg/m3;
6 h/d, 5 d/wk) exhibited
increased relative lung
weights (by 12-16%) at
>50 mg/m3.
(mouse, inhalation,
chronic)
Hyperostosis, turbinate
atrophy, chronic lung
inflammation,
respiratory epithelium
hyperplasia, metaplasia,
and necrosis and
laryngeal lesions were
noted at higher levels.
Erosion of the nasal
mucosa, thrombosis, and
squamous metaplasia in
the nasal cavity were
observed at higher levels.
No noncancer lung
effects were
observed in chronic
studies at higher
levels.
48
cis-1,2-Dichloroethylene
-------
EPA/690/R-22/001F
Table A-6. Comparison of Effects on Target Organs/Systems Following Short-term, Subchronic, and Chronic
Exposure to cis- 1,2-DCE (Oral) and Candidate Analogues (Inhalation)a'b
Target Organ/
System
civ-1,2-DC Ec
?/y/«.s-1,2-DCE
1,1-DCE
Perc
TCEd
Vinyl Chlorided
Effect®'''8 (species)
Neurological
ND
ND
ND
In 65 households in
buildings collocated with
dry cleaners
(65 children; geometric
mean exposure
0.34 mg/m3; 10-yr mean
duration of residence)
and 61 households in
residential buildings
without dry cleaners
(71 children), decreased
visual contrast sensitivity
and color vision
impairment was
observed for exposed
subjects compared to
controls.
(human)1
In a 90-d study, gerbils
(4/sex/dose; Mongolian)
exposed to vapor
(0-407 mg/m3; 24 h/d,
continuous) exhibited
decreased DNA content in
the frontal cortex at
>407 mg/m3.
(gerbil, inhalation,
subchronic)
In a 13-wk study,
male rats (5/dose;
JCL-Wistar) exposed
to vapor
(0-1,612 mg/m3;
8 h/d, 5 d/wk)
exhibited decreased
wakefulness during
exposure and a
decreased
postexposure
sleeping heart rate
at >269 mg/m3.
(rat, inhalation,
chronic)
I Swimming speed,
t auditory threshold,
depressed amplitude
of auditory-evoked
potentials, latency in
visual discrimination
response, j shock
avoidance and startle
response, behavioral
changes, and
astroglial
hypertrophy were
observed at higher
exposure levels.
In a 20-wk study, rats
(90/sex/dose; F344)
exposed to vapor
(0-128 mg/m3; 1 h/d,
5 d/wk) exhibited no
neurological effects.
(rat, inhalation,
chronic)
49
cis-1,2-Dichloroethylene
-------
EPA/690/R-22/001F
Table A-6. Comparison of Effects on Target Organs/Systems Following Short-term, Subchronic, and Chronic
Exposure to cis- 1,2-DCE (Oral) and Candidate Analogues (Inhalation)a'b
Target Organ/
System
civ-1,2-DC Ec
?/y/m.v-1,2-DCE
1,1-DCE
Perc
TCEd
Vinyl Chlorided
Effectefg (species)
Neurological,
continued
Changes in fatty acid
composition in the brain,
i brain weight, j activity,
changes in auditory
response, and t amplitude
of flash evoked potential
peak N3 were observed at
higher exposure levels.
Hematological
(red cell)
In 14- and 90-d studies
in rats (10/sex/dose;
Sprague Dawley)
exposed orally (gavage;
0-1,940 mg/kg-d; 97%
purity), small decreases
in RBC, hematocrit and
hemoglobin—not
deemed to be
biologically
significant—were
observed. In the 14-d
study, no significant
changes in hemoglobin
or RBC counts were
observed at any dose
level
(97-1,940 mg/kg-d),
but significant
decreases (11%) in
hematocrit were
observed in females at
291 mg/kg-d.
In a 90-d study, rats
(15/sex/dose; Crl:CD BR)
exposed to vapor
(0-15,860 mg/m3; 6 h/d,
5 d/wk; >99.4% purity)
showed decreased mean
hemoglobin (in males) at
>3,965 mg/m3 after 45 d.
In females, mean
monocyte count was
decreased at
15,860 mg/m3 after 45 d;
these changes were not
considered
toxicologically important
and did not occur at the
90-d sampling time.
(rat, inhalation,
subchronic)
In 6-, 12-, and 18-mo
studies in rats (86/group;
Sprague Dawley)
exposed to vapor
(40 and 160 mg/m3 for
the first 5 wk, then
100 and 300 mg/m3 for
the remainder; 6 h/d,
5 d/wk), no
hematological effects
were observed.
(rat, inhalation, chronic)
In a population of dry
cleaners (135 mg/m3, 8-h
TWA geometric mean
exposure; 1-to 12-mo
duration; 29 men and
27 women), and
unexposed workers
(30 men and 35 women),
no hematological effects
were observed.
(human)
In a 104-wk study in rats
(50/sex/dose; F344)
exposed to vapor
(0-4,070 mg/m3; 6 h/d,
5 d/wk), the only
hematology change noted
was an increase in mean
corpuscular hemoglobin in
female rats exposed to
4,070 mg/m3.
(rat, inhalation, chronic)
In a 4-wk study,
female rats (8/dose;
Sprague Dawley)
exposed to vapor
(0-5,374 mg/m3;
6 h/d, 4 d/wk;
99.99% purity)
showed no
hematological effects
at 5,374 mg/m3.
(rat, inhalation,
short-term)
In an 8-wk study, male
mice (4/dose; CD-I)
exposed to vapor
(0-2,600 mg/m3; 6 h/d,
5 d/wk) showed no
hematological effects at
2,600 mg/m3.
(mouse, inhalation,
subchronic)
50
cis-1,2-Dichloroethylene
-------
EPA/690/R-22/001F
Table A-6. Comparison of Effects on Target Organs/Systems Following Short-term, Subchronic, and Chronic
Exposure to cis- 1,2-DCE (Oral) and Candidate Analogues (Inhalation)a'b
Target Organ/
System
civ-1,2-DC Ec
?/y/m.v-1,2-DCE
1,1-DCE
Perc
TCEd
Vinyl Chlorided
Effectefg (species)
Hematological
(red cell),
continued
In the 90-d study,
decreases in
hemoglobin and RBC
counts (6-8%) were
significant at
291 mg/kg-d in
females; decreases in
hematocrit in females
(10%) and hemoglobin
in males (6%) were
significant at
>291 mg/kg-d. Refer to
Table 3 in the main
document for more
details.
(rat, oral, short-term
and subchronic)
Immunological
ND
In 8- and 16-wk studies in
rats (6 females/dose; SPR
Wistar) exposed to vapor
(793 mg/m3; 8 h/d,
5 d/wk), severe
pneumonic infiltration
(not further characterized)
was observed in the lungs
of 3/6 exposed rats at
both exposure durations
but not in controls.
(rat, inhalation,
subchronic and chronic)
ND
In a 4-wk study in female
rats (8/dose;
Sprague Dawley) exposed
to vapor (0-6,793 mg/m3;
6 h/d, 5 d/wk; 99.98%
purity), no immunological
effects were observed.
(rat, inhalation, short-
term)
In a 30-d study, mice
(10-20/sex/dose;
NMRI) exposed to
vapor
(0-1,612 mg/m3;
24 h/d, continuous)
exhibited decreased
spleen weights (by
24-41%) at
>1,612 mg/m3.
(mouse, inhalation,
short-term)
i Splenic anti-sRBC
IgM response and
i serum IgG were
observed at higher
exposure levels.
In an 8-wk study, male
mice (4/dose; CD-I)
exposed to vapor
(0-2,600 mg/m3; 6 h/d,
5 d/wk) exhibited an
increase in spontaneous
lymphocyte
proliferation at
>26 mg/m3.
(mouse, inhalation,
subchronic)
t Spleen weight and
i WBC counts were
observed at higher
exposure levels.
51
cis-1,2-Dichloroethylene
-------
EPA/690/R-22/001F
Table A-6. Comparison of Effects on Target Organs/Systems Following Short-term, Subchronic, and Chronic
Exposure to cis- 1,2-DCE (Oral) and Candidate Analogues (Inhalation)a'b
Target Organ/
System
civ-1,2-DC Ec
?/y/«.s-1,2-DCE
1,1-DCE
Perc
TCEd
Vinyl Chlorided
Effect®'''8 (species)
Immunological,
continued
In a 90-d study in rats
(15/sex/dose; Crl:CD
BR) exposed to vapor
(0-15,860 mg/m3; 6 h/d,
5 d/wk; >99.4% purity),
decreased WBC and
lymphocyte counts
(18-25%) were
observed in exposed
animals, reaching
statistical significance in
males at 15,860 mg/m3
after 45 d (WBC and
lymphocyte counts) and
90 d (lymphocyte counts
only).
(rat, inhalation,
subchronic)m
52
cis-1,2-Dichloroethylene
-------
EPA/690/R-22/001F
Table A-6. Comparison of Effects on Target Organs/Systems Following Short-term, Subchronic, and Chronic
Exposure to cis- 1,2-DCE (Oral) and Candidate Analogues (Inhalation)a'b
Target Organ/
System
civ-1,2-DC Ec
?/y/«.s-1,2-DCE
1,1-DCE
Perc
TCEd
Vinyl Chlorided
Effectefg (species)
Developmental
ND
In a developmental study
in rats (24 dams/dose;
Crl:CD BR) exposed to
vapor (0-47,580 mg/m3;
6 h/d, GDs 7-16),
decreased fetal weight
(by 4-6%) and a
nonsignificant increase in
hydrocephalus were
observed at
47,580 mg/m3.
(rat, inhalation,
developmental)
In a developmental
study in mice
(15-65 dams/dose;
CD-I) exposed to vapor
(0-1,189 mg/m3;
22-23 h/d, GDs 6-16),
incidence of fetuses with
unossified incus and
incompletely ossified
sternebrae was increased
at >59 mg/m3.
(mouse, inhalation,
developmental)
In developmental studies
in rats (17-30 dams/dose;
Sprague Dawley) and mice
(17-30 dams/dose; Swiss-
Webster) exposed to vapor
(0-2,035 mg/m3; 7 h/d,
GDs 6-15), increased fetal
resorptions in rats and
decreased fetal weight and
delayed ossification in
mice were observed at
2,035 mg/m3.
(rat and mouse, inhalation,
developmental)
In a developmental
study in rats
(30 dams/dose;
Long-Evans)
exposed to vapor
(0-9,673 mg/m3;
6 h/d, 7 d/wk;
GDs 0-20),
decreased fetal
weight and
incomplete skeletal
ossification were
observed at
9,673 mg/m3.
(rat, inhalation,
developmental)
In developmental
studies in mice
(30-40 dams/dose;
CF-1) exposed to vapor
(0-1,278 mg/m3; 7 h/d,
10 d; GDs 6-15) and in
rabbits
(15-20 dams/dose;
New Zealand) exposed
to vapor
(0-1,278 mg/m3; 7 h/d,
13 d; GDs 6-18),
delayed ossification
was observed at
1,278 mg/m3.
(mouse and rabbit,
inhalation,
developmental)
53
cis-1,2-Dichloroethylene
-------
EPA 690 R-22 00IF
Table A-6. Comparison of Effects on Target Organs/Systems Following Short-term, Subchronic, and Chronic
Exposure to cis-l,2-DCE (Oral) and Candidate Analogues (Inhalation)a'b
Target Organ/
System
cis-l,2-DCEe
trans-i ,2-DCE
1,1-DCE
Perc
TCEd
Vinyl Chlorided
Effectefg (species)
References
DuPont Haskell Lab
Kellv (1998): Hurtt et al.
NTP (2015): Ouast et al.
Boverhof et al. (2013):
Boverhof et al.
Thornton et al. (2002):
(1999); McCaulev et al.
(1993): DuPont (1988):
(1986): Henck et al.
Mcdennott et al. (2005):
(2013): Kumar et al.
Bi et al. (1985): Helm-
(1995); McCaulev et al.
Haskell Laboratories
(1979): RaniDv et al.
Brodkin et al. (1995): JISA
(2002): Arito et al.
et al. (1981): Johnet al.
(1990)
(1988): Freundt et al.
("19771: Short etal.
(1993): Caietal. (1991):
(1994): Kiellstrand et
(1981): Suzuki (1981):
(1977)
(1977c): Short et al.
Karlsson et al. (1987):
al. (1983):
Slianna and Gehrine
(1977b): Short etal.
Mennear et al. (1986):
Dorfmueller et al.
(1979): Suzuki (1978):
(1977a)
NTP (1986): Kiellstrand et
(1979)
John et al. (1977)
al. (1984): Franchini et al.
(1983): Schwetz et al.
(1975): Storm et al. (2011)
aWhen possible, exposure concentrations are reported in units of mg/m3 to enable interstudy comparisons. Concentrations reported in parts per million were converted to
mg/m3 using: concentration in ppm x molecular weight (g/mol)] ^ 24.45 (L/mol).
bDuration categories are defined as follows: acute = exposure for <24 hours; short term = repeated exposure for 24 hours to <30 days; long-term (subchronic) = repeated
exposure for >30 days to <10% life span for humans (>30 days up to approximately 90 days in typically used laboratory animal species); and chronic = repeated exposure
for >10% life span for humans (>~90 days to 2 years in typically used laboratory animal species) (U.S. EPA. 2002a).
°No subchronic- or chronic inhalation data available; effects listed are following acute inhalation or oral exposure as noted.
dThe subchronic and chronic inhalation toxicity values for TCE and the chronic toxicity value for vinyl chloride were derived following route-to-route extrapolations from
oral studies (see Table A-5). Effects from oral studies on candidate analogues are not included here.
eThe lowest LOAELs or highest NOAELs for effects on the target organ/system are shown; > indicates that other effects were reported at concentrations greater than or
equal to the lowest LOAEL. Selected effects observed at higher exposure concentrations are listed.
fSpecies where effects in the target organ/system were observed are shown in parentheses.
gEffects used for derivation of toxicity values shown in Table A-5 are in bold.
hMidzonal fatty changes, listed as an observed effect at higher exposure levels, formed the basis for the inhalation chronic RfC (U.S. EPA. 2002b). see Table A-5. The
lowest LOAEL value shown is from new data reported in ATSDR (2019a).
'Basis for the inhalation intermediate MRL (ATSDR. 2006).
Basis for chronic RfD derived by IRIS (U.S. EPA. 2010) and subchronic provisional p-RfD derived in a previous PPRTV assessment for cis-1,2-DCE (U.S. EPA. 2011c).
kBasis for the inhalation intermediate and chronic MRLs (ATSDR. 2019a). See Table A-5 footnote b regarding the chronic toxicity value for 1,1-DCE.
'Basis for the inhalation intermediate MRL and the chronic MRL and RfC (ATSDR. 2019b: U.S. EPA. 2012).
mBasis for the inhalation screening subchronic and chronic RfCs (U.S. EPA. 2020).
t = increased; j = decreased; 1,1-DCE = 1,1-dichloroethylene; BuChE = plasma butyrylcholinesterase; c/.v-1.2-DCE = cis-1.2-dichlorocthvlcnc: DNA = deoxyribonucleic
acid; GD = gestation day; IRIS = Integrated Risk Information System; LOAEL = lowest-observed-adverse-effect level; MRL = minimal risk level; ND = not determined;
NOAEL = no-observed-adverse-effect level; Perc = tetrachloroethylene; PPRTV = Provisional Peer-Reviewed Toxicity Value; RBC = red blood cell; RfC = reference
concentration; RfD = reference dose; sRBC = sheep red blood cell; TCE = trichloroethylene; irans-\ ,2-DCE = /rcw/.v-1.2-dich 1 orocthv 1 cnc: WBC = white blood cell.
54
cis-1,2-Dichloroethylene
-------
EPA/690/R-22/001F
Acute Effects
The lowest observed inhalation median lethal concentration (LC50) values for
cz's-l,2-DCE are 54,320 and 65,500 mg/m3, in rats exposed for 4 hours and mice exposed for
2 hours, respectively (Kelly et al.. 2000; Lehmann and Schmidt-Kehl. 1936). Inhalation LC50
values for candidate analogues ranged from 25,178 mg/m3 (1,1-DCE) to 460,113 mg/m3 (vinyl
chloride) in rats and 200 mg/m3 (1,1-DCE) to 294,000 mg/m3 (vinyl chloride) in mice
(see Table A-5). Although limited conclusions can be drawn from acute data, it is clear that the
acute potency of c/s-1,2-DCE is greater than that of vinyl chloride for exposure via inhalation.
The LC 50 value for trans-\ ,2-DCE (95,556 mg/m3) is within twofold of the LC50 value for
cis-1,2-DCE (54,320 mg/m3) in rats exposed for 4 hours (Kelly et al.. 2000).
Liver Effects
No inhalation studies evaluating the potential for cis- 1,2-DCE to promote liver effects are
available. Oral exposure to cis- 1,2-DCE produced dose-related increases in absolute and/or
relative liver weights in rats treated for 14 or 90 days, albeit without accompanying changes in
serum chemistry or histopathology, even at the highest doses tested. Findings after oral exposure
to 1,2-DCE were similar to those for the cis isomer, primarily involving increases in
absolute and relative liver weight with limited clinical chemistry changes and no accompanying
histopathology. Hepatic effects, including increases in absolute and relative liver weight, fatty
changes, necrosis, and altered hepatocyte morphology, were also observed for the other
candidate analogues by the oral route.
Liver effects have also been observed following inhalation exposure to each candidate
analogue. Fatty degeneration in the liver lobule was observed in rats following repeated
inhalation exposure to trans- 1,2-DCE vapors. A supporting in vitro study on liver perfusates
supplemented with either cis- or trans- 1,2-DCE in the gas phase showed increasing levels of
lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alanine aminotransferase
(ALT) in the perfusate with time, indicative of liver damage (Bonse et al.. 1975). The enzyme
levels were higher in the c/.s- l ,2-DCE-exposed perfusate compared with the trans- 1,2-DCE-
exposed perfusate. Acute oral and injection studies that tested liver and plasma enzyme levels in
rats exposed to the cis- and trans- 1,2-DCE isomers also showed somewhat greater effects from
the cis isomer (Mcmittan. 1986; Jenkins et al.. 1972).
For 1,1-DCE, prolonged inhalation exposure has been shown to produce liver lesions
ranging from fatty change to necrosis in rats and mice, and hepatotoxicity was identified as the
critical effect for derivation of the 1,1-DCE chronic reference concentration (RfC). Increased
liver weight also was noted. Hepatotoxicity of 1,1-DCE has been attributed to metabolites that do
not undergo GSH conjugation in the liver and covalently bind with tissue macromolecules. The
1.1-DCE metabolites 1,1-dichloroethene epoxide, 2-chloroacetyl chloride, and
2.2-dichloroacetaldehyde, when unconjugated, are presumed hepatic toxicants (ATSDR. 2019a).
The 1,1-DCE oxidation product 2,2-dichloroacetaldehyde is shared with cis- 1,2-DCE. Toxicity
of 1,1-DCE is correlated with CYP2E1 concentrations and increases under conditions of GSH
depletion; however, fatty change, primarily in the centrilobular region, was observed in the
absence of GSH depletion.
Hepatic lesions, such as centrilobular hypertrophy, and increased relative liver weight
have also been reported for subchronic inhalation exposure to vinyl chloride, and this is the basis
for the ATSDR intermediate minimal risk level (MRL). The chronic RfC is also based on hepatic
55
cis-1,2-Dichloroethylene
-------
EPA/690/R-22/001F
effects, although by route-to-route extrapolation from chronic oral data. Vinyl chloride liver
toxicity is thought to be related to the production of the reactive intermediate metabolites,
2-chloroethylene oxide and 2-chloroacetaldehyde, which are known to bind to liver proteins and
macromolecules in liver tissue (ATSDR. 2006; U.S. EPA. 2000). Reactive intermediates from
metabolism of cis- and trans- 1,2-DCE are known to bind to the heme moiety of CYP450
molecules, and other data also show protein and lipid binding by metabolites of 1,2-DCE (isomer
not stated) in liver microsomes (U.S. EPA. 2020). Both 1,2-DCE isomers and vinyl chloride
have structural alerts for protein binding (see Figure A-l).
Both TCE and Perc have also been found to produce liver effects. Perc inhalation
exposure resulted in parenchymal changes in humans and liver enlargement and vacuolization of
hepatocytes in laboratory animals, while inhalation exposure to TCE caused increased liver
weights, serum chemistry changes, and enlarged vacuolated hepatocytes. The Perc and TCE
metabolite, DC A, which is also a metabolite of cis- 1,2-DCE, has been linked to liver toxicity
(ATSDR. 2019b). but Perc and TCE also generate other reactive metabolites that likely
contribute to hepatotoxicity. Perc hepatotoxicity occurs even when CYP450 pathways are
perturbed, suggesting that the alternative GSH conjugation pathway (and subsequent formation
of reactive metabolites) likely contributes to this toxicity (ATSDR, 2019b). Much like Perc,
reactive metabolites from the oxidation-independent GSH conjugation pathway also likely
contribute to TCE hepatotoxicity (ATSDR. 2019c). Direct GSH conjugation of parent
compound, as occurs for Perc and TCE, is not known to occur for cis- 1,2-DCE.
Kidney Effects
No data are available on the potential for cis- 1,2-DCE to cause kidney effects following
inhalation exposure. In orally exposed rats, cis- 1,2-DCE produced an increase in relative kidney
weights in males not accompanied by supporting effects (e.g., histopathology or clinical
chemistry changes), even at the highest dose. The increase in kidney weight is the basis for both
the subchronic provisional reference dose (p-RfD) derived in a previous PPRTV assessment and
the chronic reference dose (RfD) derived by IRIS for c/.s- l ,2-DCE, Results similar to
cis-1,2-DCE (increases in kidney weights without supporting changes in serum chemistry or
histopathology) were observed following oral exposure to trans- 1,2-DCE. Renal effects,
including increases in kidney weight, increased blood urea nitrogen (BUN), cytomegaly, and
toxic nephropathy were observed for the other candidate analogues by the oral route.
Increased kidney weights following inhalation exposure were observed for all candidate
analogues except trans- 1,2-DCE. Kidney weight increases were accompanied by additional
evidence of renal toxicity, such as histological, serum chemistry, and/or urinalysis changes for
1,1-DCE, Perc, and TCE. 1,1-DCE kidney toxicity is thought to be associated with P-lyase
bioactivation of hepatic GSH conjugates and/or their derivatives to reactive species (ATSDR.
2019a). For Perc and TCE, the toxic renal effects are thought to be due to the formation of
reactive GSH-dependent metabolites following nonoxidative GSH conjugation with the parent
compounds. Data suggest that GSH conjugation and the formation of GSH-dependent
metabolites such as »Y-(1,2-dichlorovinyl)cysteine (1,2-DCVC) play a significant role in both
Perc and TCE-induced renal toxicity (ATSDR. 2019b. c). GSH conjugation of the parent
compound and formation of reactive GSH-dependent metabolites are not observed for
cis- 1,2-DCE.
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Respiratory Effects
No subchronic- or chronic inhalation studies evaluating the potential for c/s-1,2-DCE to
cause respiratory effects are available, although irregular respiration was reported immediately
after acute inhalation exposure to lethal levels of cis-1,2-DCE in rats (DuPont Haskell Lab.
1999). Following oral exposure, no clinical signs of respiratory distress or histopathology in the
lung were observed; lungs were not weighed in the available study (McCaulev et al.. 1995;
McCaulev et al.. 1990). Limited information is available about respiratory effects of candidate
analogues following oral exposure, although gavage administration of TCE has been reported to
cause dyspnea and pulmonary vasculitis.
Lung effects, including capillary hyperemia (vinyl chloride and trans- 1,2-DCE) alveolar
septum distention (TCE, vinyl chloride, and trans- 1,2-DCE) congestion (vinyl chloride)
bronchiolitis and alveolitis (Perc, TCE, vinyl chloride, and 1,1-DCE) and hyperplasia (Perc,
TCE, and vinyl chloride) were observed in inhalation studies of all candidate analogues but only
sporadically. 1,1-DCE and Perc were the only candidate analogues reported to produce upper
respiratory effects following inhalation exposure, primarily lesions such as hyperplasia,
metaplasia, and erosion of the nasal mucosa. Mineralization and atrophy of the olfactory
epithelium in rodents was the basis for the intermediate and chronic inhalation MRL values for
1,1-DCE. Nasal lesions were not observed in rats exposed to trans- 1,2-DCE at concentrations up
to 15,860 mg/m3 for 90 days in a study that included histopathological examination of upper and
lower respiratory tract tissues at all exposure levels (U.S. HP A. 2020).
Neurological Effects
No subchronic or chronic inhalation studies evaluating the potential for cis- 1,2-DCE to
cause neurological effects are available. Animals acutely exposed to lethal concentrations of
cis-1,2-DCE vapors showed signs of CNS depression (DuPont Haskell Lab. 1999). No
behavioral clinical signs or changes in brain weight or histopathology were observed in animals
treated for 90 days with doses up to 872 mg/kg-day of cis-1,2-DCE by gavage (McCaulev et al ..
1995; McCaulev et al.. 1990).
Among candidate analogues, no data are available on neurological effects for
trans- 1,2-DCE or 1,1-DCE following repeated inhalation exposure, and negative results were
observed in neurotoxicity testing on vinyl chloride. In contrast, neurotoxicity is a sensitive
endpoint for Perc and has been demonstrated in humans. The intermediate inhalation MRL for
Perc is based on color vision changes, while both the chronic inhalation MRL and the chronic
RfC are based on cognitive and reaction time changes and color vision changes in humans. In
animals, Perc induced various neurotoxic effects, including electrophysiological changes,
auditory changes, and effects on the brain (ATSDR. 2019b). In general, the neurotoxic effects of
Perc are thought to be due to the parent compound rather than metabolites (ATSDR. 2019b).
TCE has also been shown to induce neurological effects, such as decreased wakefulness and
sleeping heart rate, auditory changes, behavioral changes, visual changes, and astroglial
hypertrophy in animal studies. The TCE metabolite, chloral hydrate, has been shown to act as a
CNS depressant through inhibition of neuronal receptors (ATSDR. 2019c).
Hematological Effects (Red Blood Cell [RBC] Parameters)
No inhalation studies on cis- 1,2-DCE evaluating hematological effects were identified. In
oral studies, decreases in RBC, hemoglobin, and/or hematocrit were reported, but these changes
were small in magnitude, not clearly related to dose, within the normal range of variation (U.S.
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EPA. 2010). and possibly reflective of increased water intake observed in the treated rats. They
were not considered biologically significant or indicative of an effect of cz's-1,2-DCE exposure
(U.S. EPA, 2010). Similar to cis-1,2-DCE, slight decreases of uncertain biological significance
were observed in RBC parameters in one study of rats orally exposed to trans- 1,2-DCE (out of
several available) and in an oral study of a 50:50 mixture of the 1,2-DCE isomers. Hematological
effects, including decreases in RBC, hemoglobin, and clotting time of blood were observed for
the TCE and vinyl chloride by the oral route.
No changes in RBC parameters were observed for any candidate analogue by inhalation
exposure.
Immunological Effects (Including White Blood Cell [WBC] Parameters)
No inhalation studies evaluating the potential for cis- 1,2-DCE to cause immunological
effects are available. In an oral study in which female rats were administered cz's-1,2-DCE for
90 days, no significant changes in WBC parameters were observed; however, significantly
increased absolute and relative thymus weights (by 13 and 17%, respectively) were observed in
females at the highest dose (872 mg/kg-day). Decreases in thymus weights were observed in
female animals orally dosed with the trans isomer at concentrations >224 mg/kg-day (U.S. EPA.
2020). The chronic RfD for trans-1,2-DCE is immune-related, based on suppression of spleen
cell antibody production against sheep red blood cells (sRBCs) in mice (U.S. EPA. 2010).
Evidence of immunosuppression and immunotoxicity, including decreases in humoral immunity,
increased T-cell hyperactivity, and decreased spleen cellularity is observed following oral
exposure to TCE. Limited information is available about immunological effects of other
candidate analogues following oral exposure.
No studies are available that evaluate immune functional changes in response to
cw-1,2-DCE by any route of exposure. The trans- 1,2-DCE screening subchronic and chronic
p-RfCs are based on decreased WBC and lymphocyte counts in rats. These changes were not
associated with histopathology in immune system organs (thymus, spleen, and bone marrow); the
weights of these organs were not measured. Although reductions in lymphocyte counts following
exposure to trans- 1,2-DCE have been hypothesized to reflect a stress-related increase in
glucocorticoid levels, no direct evidence supporting this hypothesis is available. Upon further
evaluation, the U.S. EPA concluded that the effect on WBC and lymphocyte counts were related
to exposure to trans-1,2-DCE (U.S. EPA. 2020). Pneumonic infiltration and severe fatty
degeneration in Kupffer cells following inhalation exposure to trans-1,2-DCE could also be
considered immune-related—Kupffer cells are highly phagocytic macrophages known to protect
systemic circulation from gastrointestinal bacteria (ATSDR. 1996). In inhalation studies of TCE,
mice exhibited significant reductions in spleen weight and serum immunoglobulin G (IgG)
levels. Exposed rats had a reduced splenic anti-sRBC- IgM response (ATSDR. 2019c). In
addition to fetal heart malformations, the intermediate and chronic inhalation MRLs and the
chronic RfC value for TCE are based on decreased thymus weights in mice exposed to TCE in
drinking water (route-to-route extrapolation). Inhalation exposure to vinyl chloride resulted in
increases in spleen weights in multiple species and in spontaneous proliferation/transformation
of lymphocytes isolated from the spleens of exposed mice. A decrease in WBC counts was
observed at higher exposure levels (ATSDR. 2006). No immune-related effects have been
observed for Perc following inhalation exposure, and no long-term inhalation studies on
1,1-DCE evaluating immunotoxicity endpoints were identified.
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Developmental Effects
No inhalation or oral studies on c/s-1,2-DCE that evaluated the potential for
developmental effects were identified. Developmental effects, including decreased litter sizes,
anophthalmia, and increased collagen content of the skin, were observed following oral exposure
to Perc, TCE, and vinyl chloride. Limited information is available about developmental effects
following oral exposure to trans- 1,2-DCE or 1,1-DCE.
Developmental effects indicative of developmental delay (reduced fetal weights and
incomplete or delayed ossification) were reported for every candidate analogue following
inhalation exposure, in most cases at exposure levels also causing maternal toxicity. The
intermediate and chronic inhalation MRLs and the chronic RfC for TCE were based, in part, on
fetal heart malformations in mice exposed to TCE in drinking water (route-to-route
extrapolation). Studies in humans offer some support for a potential association between
projected TCE exposure via vapor intrusion and cardiac birth defects (ATSDR. 2019c). No
laboratory inhalation studies on any candidate analogue, including TCE, reported fetal heart
effects.
Summary
In summary, limited data (no subchronic- or chronic inhalation studies, and only a single
subchronic oral study) are available on cis- 1,2-DCE for inhalation toxicity comparisons with the
candidate analogues. The sensitive effects of subchronic oral exposure to cis- 1,2-DCE were mild
increases in liver and kidney weights, with limited accompanying serum chemistry or
histopathology changes up to the highest doses tested. The liver and kidney were identified as
target organs for the other candidate analogues following inhalation exposure, generally showing
a variety of lesions and related changes in addition to increases in organ weights. Other
potentially relevant endpoints identified for candidate analogues following inhalation exposure
include upper respiratory lesions (1,1-DCE, Perc), neurological effects (Perc, TCE),
immunological effects (trans- 1,2-DCE, TCE), and developmental effects (all candidates).
Weight-of-Evidence Approach
A tiered weight-of-evidence (WOE) approach as described in Wang et al. (2012) was
used to select the overall best analogue chemical. The approach focuses on identifying a
preferred candidate for three types of analogues: structural analogues, toxicokinetic or metabolic
analogues, and toxicity-like analogues. Selection of the overall best analogue chemical is then
based on all of the information from the three analogue types, and the following considerations
used in a WOE approach: (1) lines of evidence from U.S. EPA assessments are preferred;
(2) biological and toxicokinetic data are preferred over the structural similarity comparisons;
(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 conservative/health-protective 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 most structural similarity may be preferred.
Fifteen unique analogues were identified as part of this assessment: six structural
analogues, eight metabolism-related analogues, and one compound identified on the basis of both
structural and metabolic similarities (trans- 1,2-DCE). Of the candidate analogues,
trans- 1,2-DCE is the most appropriate structural and metabolic analogue for c/.s- l ,2-DCE, with
the same shared structural features (i.e., an alkene and two vinylic chlorine atoms), shared
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structural alerts, similar physicochemical properties, and common metabolic pathways
(i.e., CYP450-mediated metabolism resulting in an unstable epoxide intermediate that rearranges
to form 2,2-dichloroacetaldehyde, which is then enzymatically converted to 2,2-dichloroethanol
and DCA with little downstream GSH conjugation). That quantitative differences exist between
the 1,2-DCE isomers in uptake, overall rate of metabolism, and relative amounts of unique
metabolites produced is acknowledged, although data were not located to inform the impact of
these toxicokinetic differences on toxicological potency or effect. Major toxicokinetic
differences, including longer clearance times, GSH conjugation pathways that yield reactive
metabolites, and primary elimination route of exhalation, suggest that Perc and TCE are less
suitable analogues for cis- 1,2-DCE.
Limitations in the toxicity data available for cis- 1,2-DCE, including lack of inhalation
data, pose challenges for evaluating analogues on the basis of toxicodynamic comparisons.
Target organs/systems identified from oral studies with c/.s- l ,2-DCE are the liver and kidney
(organ weight increases with limited serum chemistry or histopathological changes), and the
derivation of the chronic and subchronic RfD values was based on kidney effects. Although the
relevance of directly comparing oral and inhalation data is uncertain, the liver and/or kidney
were also identified as relevant target organs for all of the analogues following inhalation
exposure. Other relevant toxicity targets of inhalation exposure shared among the analogues
include upper respiratory lesions (1,1-DCE, Perc), neurological effects (Perc, TCE),
immunological effects (trans- 1,2-DCE, TCE), and developmental effects (all candidates).
Although toxicity comparisons revealed commonality among oral exposure to cis- 1,2-DCE and
inhalation exposure to candidate analogues, several notable differences were also apparent. Both
Perc and TCE have an oxidation-independent GSH conjugation pathway, not observed in
cz'5-1,2-DCE metabolism, that produces reactive metabolites thought to contribute to liver and
kidney toxicity. In addition, the neurotoxic effects of Perc are thought to be due to the parent
compound rather than to any metabolites shared with cis- 1,2-DCE. Similarly, the TCE
neurotoxic effects are thought to be mediated partially by the nonshared metabolite, chloral
hydrate. Based on major differences in both toxicodynamics and toxicokinetics, Perc and TCE
are not suitable analogues for cis- 1,2-DCE and were not considered further.
From the remaining candidates (trans- 1,2-DCE, 1,1-DCE, and vinyl chloride),
trans- 1,2-DCE is selected as the source analogue for the derivation of inhalation toxicity values
primarily on the basis of structural and metabolic considerations, with some support from limited
oral toxicity data comparisons. Table A-7 presents oral toxicity values and data for cis- and
trans- 1,2-DCE. cis-1,2-DCE and trans- 1,2-DCE elicited similar, mild effects on the liver and
kidney after subchronic oral exposure (organ weight increases with limited serum chemistry and
histopathological changes). Differences in RfD values point to potential differences in potency,
which could be related to the differences in uptake and metabolism described above. Still, the
subchronic point of departure (POD) for trans- 1,2-DCE is only -threefold higher than the
subchronic POD for cis- 1,2-DCE, and critical effects (mild liver and kidney effects) were similar
across isomers. Subchronic human equivalent dose (HED) PODs for the two isomers are within
twofold of each other. For chronic PODs, the potency difference is more pronounced (the POD is
~13-fold higher and HED POD is ~7-fold higher for trans-1,2-DCE compared with c/.s- l ,2-DCE)
and the critical effects are different (immunotoxicity for trans- 1,2-DCE and increased kidney
weight for cis- 1,2-DCE).
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Table A-7. Comparison of Subchronic and Chronic Oral Toxicity Values and Effects on Target Organs/Systems
Following Oral Exposure to cis- 1,2-DCE and trans-l,2-DCEa
Chemical
ei.v-l,2-DCE
?/y/m.v-1,2-DCE
Repeat-dose toxicity—subchronic
POD (mg/kg-d); [HED POD
(mg/kg-d)]b
5.1; (1.3)
17; (2.4)
POD type
BMDLio
NOAEL
Intermediate UFC
300 (UFa = 10; UFh = 10; UFD = 3)
100 (UFa = 10; UFH = 10)
Subchronic RfD/p-RfDs or intermediate
MRL (mg/kg-d)
2 x 10-2
2 x 10-1
Critical effects
Increased relative kidney weight
Increased serum ALP
Species
Rat
Mouse
Duration
90 d
90 d
Route (method)
Oral (gavage)
Oral (drinking water)
Source
U.S. EPA (2011c)
ATSDR (1996)
Repeat-dose toxicity—chronic
POD (mg/kg-d)
5.1; (1.3)
65; (9.1)
POD type
BMDLio
BMDLisd
Chronic UFC
3,000 (UFa = 10; UFH = 10; UFD = 3; UFS = 10)
3,000 (UFa = 10; UFH = 10; UFD = 3; UFS = 10)
Chronic RfD/p-RfD (mg/kg-d)
2 x 10-3
2 x 10-2
Critical effects
Increased relative kidney weight
Suppression of the humoral immune system (decreased spleen
antibody production against sRBCs)
Species
Rat
Mouse
Duration
90 d
90 d
Route (method)
Oral (gavage)
Oral (drinking water)
Source
U.S. EPA (2010)
U.S. EPA (2010)
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Table A-7. Comparison of Subchronic and Chronic Oral Toxicity Values and Effects on Target Organs/Systems
Following Oral Exposure to cis- 1,2-DCE and trans-l,2-DCEa
Chemical
ei.v-l,2-DCE
trans- 1,2-DCE
Effects on target organs/systems in subchronic and chronic studies
Target organ/system
Effect (species)b c d
Liver
>97 mg/kg-d
t relative liver weight, t absolute liver weight;
90 d (rat)
>175 mg/kg-d
t serum ALP; f relative liver weight;
90 d (mouse, rat)
Doses up to 872 mg/kg-d tested:
no changes in AST or histopathology
Observations at higher doses:
t absolute and relative liver weight
No clinical chemistry changes in other studies up to
3,760 mg/kg-d. No histopathology.
Kidney
>32 mg/kg-d
t relative kidney weight;
90 d (rat)
Doses up to 872 mg/kg-d tested:
No adverse clinical chemistry changes or histopathology.
>1,257 mg/kg-d
t absolute kidney weight and kidney:brain weight ratio,
nonsignificant increase in kidney :body weight ratio;
90 d (rat, mouse)
No clinical chemistry or histopathology at higher doses.
Respiratory
No clinical signs or lung histopathology up to 872 mg/kg-d
(lung weight not measured);
90 d (rat)
452 mg/kg-d
| lung weight;
90 d (mouse)
No histopathology at higher doses.
Neurological
No clinical signs or changes in brain weight or histopathology
up to 872 mg/kg-d;
90 d (rat)
No clinical signs, changes in brain weight or histopathology up
to 3,245 mg/kg-d (rat) or 8,065 mg/kg-d (mousey,
14 wk
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Table A-7. Comparison of Subchronic and Chronic Oral Toxicity Values and Effects on Target Organs/Systems
Following Oral Exposure to cis- 1,2-DCE and trans-l,2-DCEa
Chemical
ei.v-l,2-DCE
?/y/m.v-1,2-DCE
Hematological (red cell)
>97 mg/kg-d
i hematocrit;
90 d (rat)
Doses up to 872 mg/kg-d tested:
I hemoglobin and RBC count
Observed changes were small and not biologically significant.
>380 mg/kg-d
I RBC counts;
90 d (rat, mouse)
Immunological
872 mg/kg-d (highest dose)
t relative thymus weight in females;
90 d (rat)
>175 mg/kg-d
Significant decrease in sRBC-responsive cells;
90 d (mouse)
No changes in relative spleen weight. No histopathology in
spleen or thymus.
Observations at higher doses:
i absolute and relative thymus weight
No histopathology at highest dose.
Developmental
ND
ND
aU.S. EPA-derived toxicity values are reported. In instances where no U.S. EPA toxicity value is available, ATSDR MRL values are shown.
'HED PODs were calculated using: HED POD = POD x (BWa/BWh)1'4. Reference body weights were taken from U.S. EPA (1988). Because data for CD-I mice were
not available, a reference body weight for the average (based on BAF1 and B6C3F1) mouse was used in the HED POD calculations for trans- 1,2-DCE.
°The lowest LOAELs or highest NOAELs for effects on the target organ/system are shown; > indicates that other effects were reported at doses greater than or equal to
the lowest LOAEL. Selected effects observed at higher doses are listed.
dSpecies for which effects in the target organ/system were observed are shown in parentheses. The lowest LOAEL was observed in the first species listed.
t = increased; [ = decreased; ALP = alkaline phosphatase; AST = aspartate aminotransferase; ATSDR = Agency for Toxic Substances and Disease Registry;
BMDL = benchmark dose lower confidence limit; BMDLio = 10% benchmark dose lower confidence limit; BWa = animal body weight; BWh = human body weight;
cis- 1,2-DCE = 6/.V-1.2-dichlorocthylcnc: HED = human equivalent dose; LOAEL = lowest-observed-adverse-effect level; MRL = minimal risk level; ND = not
determined; NOAEL = no-observed-adverse-effect level; p-RfD = provisional reference dose; POD = point of departure; RBC = red blood cell; RfD = reference dose;
SD = standard deviation; sRBC = sheep red blood cell; trans- 1,2-DCE = trans- 1,2-dichloroethylene; UFa = interspecies uncertainty factor; UFC = composite uncertainty
factor; UFd = database uncertainty factor; UFH = intraspecies uncertainty factor; UFS = subchronic-to-chronic uncertainty factor; U.S. EPA = U.S. Environmental
Protection Agency.
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Although the liver and kidney were determined to be targets of toxicity of both cis- and
trans- 1,2-DCE, immunological effects were determined to be a more sensitive endpoint for
trans- 1,2-DCE and are used as the critical effect in deriving its screening p-RfC value. Immune-
related responses were observed for trans- 1,2-DCE by oral and inhalation exposure. Limited data
are available to evaluate potential immune-related effects caused by cis- 1,2-DCE by either oral
or inhalation exposure. However, relative thymus weights increased in female rats orally exposed
to cw-1,2-DCE for 90 days. The direction of effect was opposite in mice orally exposed to
trans- 1,2-DCE, which showed decreased absolute and relative thymus weights after 90 days. Of
note is that organ-weight changes are not the most sensitive effects for detecting immunotoxicity.
Thus, immunotoxicity cannot be ruled out for cis- 1,2-DCE as a potential target organ effect
because immune functional measures have not been evaluated via either oral or inhalation routes
of exposure for this chemical.
Differences in oral POD values for cis- and trans- 1,2-DCE described above potentially
imply that the RfC values for trans- 1,2-DCE might not be adequately protective for inhalation
exposure to cis- 1,2-DCE. However, an examination of measured rat and human blood-gas
partition coefficients for the two isomers reveals subtle differences that ultimately enhance
confidence in this case the screening p-RfC values for trans- 1,2-DCE are likely to be protective
for any effects from cis-1,2-DCE. On the basis of guidelines described in U.S. EPA (19941
human equivalent concentrations (HECs) for systemic effects from a Category 3 gas (i.e., a gas
that has its effects outside the respiratory tract, such as cis- 1,2-DCE and trans-] ,2-DCE) are
calculated by multiplying the critical concentration in the animal study by the ratio of blood-gas
partition coefficients for the chemical (animal/human), with the stipulation that a value of 1 is
used if the animal value exceeds the human value. For trans- 1,2-DCE, the rat value (9.58) is
greater than the human value (5.8-6.08), so the default coefficient of 1 was used in the
calculation, rather than the calculated value of-1.6. This means that the HEC used as the POD
for derivation of the screening p-RfCs for trans- 1,2-DCE is lower, and therefore more protective,
than it would have been based strictly on the ratio of partition coefficients (-60% of what it
would have been). For cis- 1,2-DCE, the rat and human blood-gas partition coefficients are
21.6 and 9.2-9.85, for a ratio of-2.2. Because the ratio of coefficients is larger for cis-1,2-DCE
than for trans- 1,2-DCE, use of the default ratio of 1 in the derivation of the screening RfC is
even more protective for this isomer (an HEC calculated for this isomer would be -45% of the
value it would be based strictly on the ratio of partition coefficients). Also of note is that the
screening chronic p-RfC for trans- 1,2-DCE is lower than the RfC values of all other candidate
analogues except TCE, which was determined a less appropriate analogue due to significant
toxicokinetic and toxicodynamic differences. Thus, use of the screening inhalation toxicity
values for trans- 1,2-DCE can reasonably be expected to be protective for cis-1,2-DCE toxicity
within the rough order of magnitude margin of error associated with screening toxicity values.
INHALATION NONCANCER TOXICITY VALUES
Derivation of a Screening Subchronic Provisional Reference Concentration
On the basis of the overall analogue approach presented in this PPRTV assessment,
trans- 1,2-DCE was selected as the most appropriate analogue for c/.s- l ,2-DCE for deriving
screening subchronic and chronic p-RfCs. The study used for the U.S. EPA screening subchronic
and chronic p-RfC values for cis-1,2-DCE is a 90-day inhalation study of trans- 1,2-DCE in rats
(Kelly 1998 as cited in U.S. EPA. 2020). The PPRTV assessment for trans-1,2-DCE (U.S. EPA.
2020) provided the following study summary:
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The toxicity of trans-l,2-DCE (99.86% purity) was evaluated in groups of
DCrl:CD (SD) BR rats (15 males and 15 females/group) in an unpublished study
following OECD Guideline No. 413 (Kelly, 1998) and complying with Quality
Assurance and Good Laboratory Practice (GLP) standards. Rats (approximately
7 weeks old) were exposed, whole body, to analytical concentrations
(mean ± standard error [SEJ, reported by the study author to two significant
figures) of0, 200 ± 0.48, 1,000 ± 1.3, or 4,000 ± 4.7 ppm of trans-1,2-DCE vapor
6 hours/day, 5 days/week, for 90 days (these concentrations correspond to 0, 790,
4,000, and 16,000 mg/m3, maintaining the stated significant figures). Ten
rats/sex/group were designatedfor toxicological evaluations and the remaining
five rats/sex/group were designatedfor cell proliferation evaluations. Clinical
signs were observed during exposure and immediately after the rats were
returned to their cages. Alerting response to an auditory stimulus was checked
approximately every 2 hours during each exposure and immediately after. Body
weights andfood consumption were measured in all animals weekly.
In the toxicology evaluation group, blood samples were collectedfor
hematology and serum chemistry measurements on approximate Test Days 45 and
90 from 10 male and 10 female rats from each exposure group. Urinalysis was
performed on the same rats on the same day as the blood draw. One day after the
final exposure, 10 rats per sex/exposure concentration were sacrificed for
pathological evaluations; the remaining rats (~5 rats/sex/exposure concentration)
were allowed to recover for approximately 1 month prior to sacrifice. Gross
examinations were done at necropsy; liver, kidneys, lungs, testes, ovaries, adrenal
glands, and brain were weighed, and samples from >45 tissues from 10 males
and 10 females from the control and high-exposure groups were fixed in formalin
or Bouin's solution, embedded in paraffin, stained with H & E, and examined
microscopically. For low- and mid-exposure groups, the nose, pharynx/larynx,
lungs, liver, kidneys, heart, and reproductive organs were microscopically
examined. No histopathology was done on recovery animals owing to the lack of
treatment-related lesions in the nonrecovery, high-exposure group.
Ophthalmological evaluations were done on all rats in the toxicological group at
the start of the study and at the end of the exposure period.
In the cell proliferation group, five rats/sex/exposure concentration were
sacrificed after approximately 7 and 90 days of exposure for hepatic cell
proliferation evaluations. Three days prior to each sacrifice, osmotic pumps filled
with 20 mg/mL 5-bromo-2'-deoxyuridine (BrdU) were implantedsubcutaneously
in designated rats. At sacrifice, the liver and duodenum were collected and
processedfor immunohistochemical analysis of BrdU incorporation into
deoxyribonucleic acid (DNA). Hepatic labeling indices were evaluated only for
the control and high-exposure groups.
Statistical analyses of the data performed by the study author included
analysis of variance (ANOVA), Dunnett's test for multiple pairwise comparisons,
Bartlett 's test for homogeneity, Cochran-Armitage test for trend, and when results
ofBartlett's test were significant, Kruskal-Wallis and Mann-Whitney U tests.
One-way ANOVA tests for linear trend were conductedfor the purposes of this
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assessment using GraphPad Prism software (Version 8.4.2) to evaluate potential
treatment-related hematological changes (i.e., WBC and lymphocyte counts)
(GraphPad, 2018).
One death (a female in the 4, OOO-mg/m3 cell proliferation group) was
reported; the animal was sacrificed on Test Day 85 due to an ulcer/erosion of the
skin on the tail. There were significant increases in incidences of stained or wet
perineum in female rats in the 4,000- and 16, OOO-mg/m3 toxicology evaluation
groups, but the effects were described as transient and likely related to the
stresses of exposure. No other clinical signs or significant differences in mean
body weights, body-weight gains, or food consumption between the control and
exposed were observed. Minor ophthalmologic lesions were determined to be
incidental and not compound related.
Hematology and clinical chemistry examinations revealed statistically
significant changes in some parameters, including hemoglobin (Hb), hematocrit
(Hct), white blood cell (WBC), lymphocytes, monocytes, alkaline phosphatase
(ALP), aspartate aminotransferase (AST), sorbitol dehydrogenase (SDH),
albumin, and glucose (see Tables B-3 and B-4). The study author discounted these
changes because they either did not increase (or decrease) consistently with
increasing exposure concentration, appeared to be transient (observed at 45 days
but not 90 days) and/or were small in magnitude compared with historical
controls. However, the alterations in WBC and lymphocyte counts appeared to be
treatment related. Decreased WBC and lymphocyte counts were observed in
exposed animals, reaching statistical significance in males at the highest
exposure concentration (16,000 mg/m3) after the 45-day (WBC and lymphocyte
counts) and 90-day (lymphocyte counts only) sampling time points. The
toxicological significance of the WBC and lymphocyte responses were further
questioned by the study author, arguing that the observed changes were small
compared with historical controls but provided no further details. Kelly (1998)
also indicated that leukopenia (low WBC count and differentials) could be due to
a secondary stress response related to elevation of endogenous glucocorticoids, a
phenomenon that has been associated with exposure to irritants in inhalation
toxicity studies (Brondeau et al., 1990). However, the cause of the stress was not
identified, and there is no direct evidence to support the hypothesis of
glucocorticoid-dependent leukopenia following trans-l,2-DCE exposure. The
effects on WBC and lymphocytes were generally concentration-related and of
similar magnitude across sexes at the 16,000-mg/m3 dose group (decreases of
18-20 and 22-26% compared with controls for WBC and lymphocytes,
respectively). Statistical analysis performed by the U.S. EPA for the purposes of
this assessment provided further evidence in support of the biological significance
of the hematological findings, revealing a significant decreased trend in WBC and
lymphocyte counts in males at 45 and 90 days and in WBC counts at 45 days, and
lymphocyte counts at 90 days in females. As such, U.S. EPA considers these
effects to be related to exposure to trans-1,2-DCE. No significant urinalysis
findings were identified.
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There were no statistically significant organ-weight changes in either sex,
and absolute and relative liver and kidney weights were within 10% of control
values in all groups (see Table B-5). Incidence data reported in the study showed
no significant gross or microscopic lesions in any tissues that were attributable to
trans-1,2-DCE exposure.
In the cell proliferation group, no differences in the hepatic labeling
indices were observed between the control and 16,000-mg/m3 rats of either sex
(lower exposure groups were not evaluated).
A no-observed-adverse-effect level (NOAEL) of 4,000 mg/m3 and lowest-observed-
adverse-effect level (LOAEL) of 16,000 mg/m3 were identified from this study on the basis of
statistically significant decreases in WBCs and lymphocytes at 45 days and decreased WBC
counts at 90 days in male rats exposed to trans- 1,2-DCE vapors for up to 90 days under the study
conditions described (U.S. EPA, 2020). Also noted was that trend tests supported concentration-
related decreases in WBC and lymphocyte counts in both sexes. The reported study
concentrations of 0, 790, 4,000, and 16,000 mg/m3 were converted to corresponding HECer
(human equivalent concentration for extrarespiratory effects) values of 0, 140, 710, and
2,800 mg/m3, respectively, by U.S. EPA (2020). The 90-day WBC and lymphocyte count data
for both males and females for these endpoints were evaluated via benchmark dose (BMD)
modeling.
The benchmark concentration lower confidence limit 1 standard deviation
(BMCL isd) human equivalent concentration (HEC) of 109 mg/m3 for decreased
lymphocyte counts in male rats was identified as the most sensitive point of
departure (POD) for deriving screening-level p-RfC values for trans-1,2-DCE.
The screening subchronic p-RfC for trans- 1,2-DCE was derived from the BMCLisd of
109 mg/m3 by applying a composite uncertainty factor (UFc) of 300 (reflecting an interspecies
uncertainty factor [UFa] of 3, an intraspecies uncertainty factor [UFh] of 10, and a database
uncertainty factor [UFd] of 10) to the selected POD of 109 mg/m3 (U.S. HP A. 2020). 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.
Screening Subchronic p-RfC = Analogue POD ^ UFc
= 109 mg/m3 ^ 300
= 4 x 10"1 mg/m3
Table A-8 summarizes the UFs for the screening subchronic p-RfC for cis- 1,2-DCE.
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Table A-8. Uncertainty Factors for the Screening Subchronic p-RfC for
cis-1,2-DCE (CASRN 156-59-2)
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for uncertainty associated with extrapolating from animals
to humans, using toxicokinetic cross-species dosimetric adjustment for extrarespiratory effects from
a Category 3 gas. as specified in U.S. EPA (1994) guidelines for deriving p-RfCs.
UFh
10
A UFh of 10 is applied to account for human variability in susceptibility, in the absence of
information to assess toxicokinetic and toxicodynamic variability in humans.
UFd
10
A UFd of 10 is applied to account for deficiencies and uncertainties in the trans- 1,2-DCE analogue
database and absence of toxicity data for cis- 1,2-DCE.
UFl
1
A UFl of 1 is applied because the POD is a BMCL.
UFS
1
A UF s of 1 is applied because the POD for the subchronic p-RfC was derived from subchronic
data.
UFC
300
Composite UF = UFA x UFH x UFD x UFL x UFS.
BMCL = benchmark concentration lower confidence limit; c7.v-1.2-DCE = c /.v-l .2-dichlorocthvlcnc:
LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; POD = point of
departure; p-RfC = provisional reference concentration; trans-\ ,2-DCE = trans-1.2-dichlorocthvlcne:
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
trans- 1,2-DCE was also selected as the analogue for c/.s- l ,2-DCE for derivation of a
screening chronic p-RfC. The key study and calculation of the POD were described above for the
subchronic p-RfC. The screening chronic p-RfC for trans- 1,2-DCE was derived by applying a
UFc of 3,000 (UFa = 3, UFh = 10, UFd = 10, and a subchronic-to-chronic extrapolation
uncertainty factor [UFs] of 10 for use of a subchronic BMCL as a POD) to the selected POD of
109 mg/m3. In deriving the screening chronic p-RfC for cis- 1,2-DCE, the same uncertainty
factors were used.
Screening Chronic p-RfC = Analogue POD ^ UFc
= 109 mg/m3 ^ 3,000
= 4 x 10"2 mg/m3
Table A-9 summarizes the uncertainty factors for the screening chronic p-RfC for
cis- 1,2-DCE.
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Table A-9. Uncertainty Factors for the Screening Chronic p-RfC for
cis-1,2-DCE (CASRN 156-59-2)
UF
Value
Justification
UFa
3
A UFa of 3 (100 5) is applied to account for uncertainty associated with extrapolating from animals to
humans, using toxicokinetic cross-species dosimetric adjustment for extrarespiratory effects from a
Cateeorv 3 sas. as specified in U.S. EPA (1994) guidelines for deriving p-RfCs.
UFh
10
A UFh of 10 is applied to account for human variability in susceptibility, in the absence of
information to assess toxicokinetic and toxicodynamic variability in humans.
UFd
10
A UFd of 10 is applied to account for deficiencies and uncertainties in the trans- 1,2-DCE analogue
database and absence of toxicity data for cis- 1,2-DCE.
UFl
1
A UFl of 1 has been applied for LOAEL-to-NOAEL extrapolation because the POD is a BMCL.
UFS
10
A UF s of 10 is applied because the POD for the chronic p-RfC was derived from subchronic data.
UFC
3,000
Composite UF = UFA x UFH x UFD x UFL x UFS.
BMCL = benchmark concentration lower confidence limit; c7.v-1.2-DCE = c/.v-l .2-dichlorocthvlcne:
LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; POD = point of
departure; p-RfC = provisional reference concentration; trans-\ ,2-DCE = trans-1.2-dichlorocthvlcne:
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.
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