EPA/690/R-20/006F | September 2020 | FINAL
United States
Environmental Protection
Agency
Provisional Peer-Reviewed Toxicity Values for
trans-l,2-Dichloroethylene
(CASRN 156-60-5)
xvEPA
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JBI 1#%, United Slates
Environmental Protection
ImI M * Agency
EPA/690/R-20/006F
September 2020
https://www.epa.gov/pprtv
Provisional Peer-Reviewed Toxicity Values for
trans-1,2-Dichloroethylene
(CASRN 156-60-5)
[Noncancer Inhalation Values]
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
Lucina E. Lizarraga, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
CONTRIBUTOR
Q. Jay Zhao, MPH, PhD, DABT
Center for Public Health and Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
Allen Davis, MSPH
Center for Public Health and Environmental Assessment, Washington, DC
Paul G. Reinhart, PhD, DABT
Center for Public Health and Environmental Assessment, Research Triangle Park, NC
This document was externally peer reviewed under contract to:
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the content of this PPRTV assessment should be directed to the U.S. EPA
Office of Research and Development (ORD) CPHEA website at
https://www.epa.gov/pprtv/forms/contact-us-about-pprtvs.
in
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS v
BACKGROUND 1
QUALITY ASSURANCE 1
DISCLAIMERS 2
QUESTIONS REGARDING PPRTVs 2
INTRODUCTION 3
REVIEW OF POTENTIALLY RELEVANT DATA FOR DERIVATION OF NONCANCER
INHALATION REFERENCE VALUES 8
HUMAN STUDIES 12
Inhalation Exposures 12
ANIMAL STUDIES 12
Inhalation Exposures 12
OTHER DAT A 17
Inhalation Toxicity Studies 26
Oral Toxicity Studies 26
Other Route Toxicity Studies 27
Absorption, Distribution, Metabolism, and Excretion Studies 28
Physiologically Based Pharmacokinetic Models 29
Mode-of-Action/Mechanistic Studies 29
DERIVATION 01 PROVISIONAL VALUES 31
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 31
Derivation of a Subchronic and Chronic Provisional Reference Concentration 32
APPENDIX A. SCREENING PROVISIONAL VALUES 36
APPENDIX B. DATA TABLES 39
APPENDIX C. BENCHMARK CONCENTRATION MODELING RESULTS 50
APPENDIX D. REFERENCES 62
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COMMONLY USED ABBREVIATIONS AND ACRONYMS
a2u-g
alpha 2u-globulin
LC50
median lethal concentration
ACGIH
American Conference of Governmental
LD50
median lethal dose
Industrial Hygienists
LOAEL
lowest-observed-adverse-effect level
AIC
Akaike's information criterion
MN
micronuclei
ALD
approximate lethal dosage
MNPCE
micronucleated polychromatic
ALT
alanine aminotransferase
erythrocyte
AR
androgen receptor
MOA
mode of action
AST
aspartate aminotransferase
MTD
maximum tolerated dose
atm
atmosphere
NAG
7V-acetyl-P-D-glucosaminidase
ATSDR
Agency for Toxic Substances and
NCI
National Cancer Institute
Disease Registry
NOAEL
no-observed-adverse-effect level
BMC
benchmark concentration
NTP
National Toxicology Program
BMCL
benchmark concentration lower
NZW
New Zealand White (rabbit breed)
confidence limit
OCT
ornithine carbamoyl transferase
BMD
benchmark dose
ORD
Office of Research and Development
BMDL
benchmark dose lower confidence limit
PBPK
physiologically based pharmacokinetic
BMDS
Benchmark Dose Software
PCNA
proliferating cell nuclear antigen
BMR
benchmark response
PND
postnatal day
BUN
blood urea nitrogen
POD
point of departure
BW
body weight
PODadj
duration-adjusted POD
CA
chromosomal aberration
QSAR
quantitative structure-activity
CAS
Chemical Abstracts Service
relationship
CASRN
Chemical Abstracts Service registry
RBC
red blood cell
number
RDS
replicative DNA synthesis
CBI
covalent binding index
RfC
inhalation reference concentration
CHO
Chinese hamster ovary (cell line cells)
RfD
oral reference dose
CL
confidence limit
RGDR
regional gas dose ratio
CNS
central nervous system
RNA
ribonucleic acid
CPHEA
Center for Public Health and
SAR
structure activity relationship
Environmental Assessment
SCE
sister chromatid exchange
CPN
chronic progressive nephropathy
SD
standard deviation
CYP450
cytochrome P450
SDH
sorbitol dehydrogenase
DAF
dosimetric adjustment factor
SE
standard error
DEN
diethylnitrosamine
SGOT
serum glutamic oxaloacetic
DMSO
dimethylsulfoxide
transaminase, also known as AST
DNA
deoxyribonucleic acid
SGPT
serum glutamic pyruvic transaminase,
EPA
Environmental Protection Agency
also known as ALT
ER
estrogen receptor
SSD
systemic scleroderma
FDA
Food and Drug Administration
TCA
trichloroacetic acid
FEVi
forced expiratory volume of 1 second
TCE
trichloroethylene
GD
gestation day
TWA
time-weighted average
GDH
glutamate dehydrogenase
UF
uncertainty factor
GGT
y-glutamyl transferase
UFa
interspecies uncertainty factor
GSH
glutathione
UFC
composite uncertainty factor
GST
glutathione-S-transferase
UFd
database uncertainty factor
Hb/g-A
animal blood-gas partition coefficient
UFh
intraspecies uncertainty factor
Hb/g-H
human blood-gas partition coefficient
UFl
LOAEL-to-NOAEL uncertainty factor
HEC
human equivalent concentration
UFS
subchronic-to-chronic uncertainty factor
HED
human equivalent dose
U.S.
United States of America
i.p.
intraperitoneal
WBC
white blood cell
IRIS
Integrated Risk Information System
IVF
in vitro fertilization
Abbreviations and acronyms not listed on this page are defined upon first use in the
PPRTV document.
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
TRANS-l ,2 -DICHLOROETHYLENE (CASRN 156-60-5)
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 Agency 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. Environmental
Protection Agency's (EPA's) PPRTV website at https://www.epa.gov/pprtv. PPRTV
assessments are eligible to be updated on a 5-year cycle and revised as appropriate to incorporate
new data or methodologies that might impact the toxicity values or affect the characterization of
the chemical's potential for causing adverse human-health effects. Questions regarding
nomination of chemicals for update can be sent to the appropriate U.S. EPA Superfund and
Technology Liaison (https://www.epa.gov/research/fact-sheets-regional-science).
QUALITY ASSURANCE
This work was conducted under the U.S. EPA Quality Assurance (QA) program to ensure
data are of known and acceptable quality to support their intended use. Surveillance of the work
by the assessment managers and programmatic scientific leads ensured adherence to QA
processes and criteria, as well as quick and effective resolution of any problems. The QA
manager, assessment managers, and programmatic scientific leads have determined under the
QA program that this work meets all U.S. EPA quality requirements. This PPRTV was written
with guidance from the CPHEA Program Quality Assurance Project Plan (PQAPP), the QAPP
titled Program Quality Assurance Project Plan (PQAPP) for the Provisional Peer-Reviewed
Toxicity Values (PPRTVs) and Related Assessments/Documents (L-CPAD-0032718-QP), and the
PPRTV development contractor QAPP titled Quality Assurance Project Plan—Preparation of
Provisional Toxicity Value (PTV) Documents (L-CPAD-0031971-QP). As part of the QA
system, a quality product review is done prior to management clearance. A Technical Systems
Audit may be performed at the discretion of the QA staff.
All PPRTV assessments receive internal peer review by at least two Center for Public
Health and Environmental Assessment (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 Office of Research and Development (ORD) CPHEA website at
https://www.epa.gov/pprtv/forms/contact-us-about-pprtvs.
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INTRODUCTION
trans-1,2-Dichloroethylene {trans- 1,2-DCE), CASRN 156-60-5, belongs to the
chloroethylene class of compounds (Dreher et al.. 2014). trans- 1,2-DCE is an isomer of
dichloroethylene. The cis- isomer (CASRN 156-59-2) and the trans- isomer of
1,2-dichloroethylene have different physical, chemical, and biological properties.
trans- 1,2-DCE, the focus of this report, is used as a solvent for waxes, resins, lacquers, and
thermoplastics; for the extraction of rubber; as a refrigerant, an extractant of oil and fats from
fish and meat, a degreasing agent, a surface cleaning agent, and a foam blowing additive; and in
pharmaceutical manufacturing and silicone etching as a source of HC1 (Dreher et al.. 2014).
trans- 1,2-DCE is listed on the U.S. EPA's Toxic Substances Control Act (TSCA) public
inventory (U.S. EPA. 2017a). is registered with Europe's Registration, Evaluation, Authorisation
and Restriction of Chemicals (REACH) program (ECHA. 2018). and was assessed by the
U.S. EPA in a High Production Volume (HPV) Hazard Characterization report (U.S. EPA.
2015).
trans- 1,2-DCE is a byproduct of vinyl chloride, trichloroethylene (TCE), and
tetrachloroethylene production. It can be withdrawn and purified from the waste streams of
these processes (Dreher et al.. 2014). trans-1,2-DCE can also be synthesized by thermal
cracking of 1,1,2-trichloroethane or by chlorination of acetylene.
The empirical formula for trans- 1,2-DCE is C2H2CI2 and its structure is shown in
Figure 1. A table of physicochemical properties for trans-l,2-DCE is provided below
(see Table 1). trans- 1,2-DCE is a liquid with high vapor pressure and water solubility.
Volatilization of trans- 1,2-DCE from water and dry surfaces is expected based on the measured
Henry's law constant of 9.38 x 10 3 atm-m3/mol and vapor pressure of 331 mm Hg. In the air,
trans- 1,2-DCE will exist in the vapor phase, trans- 1,2-DCE will degrade in the atmosphere by
reacting with photochemically produced hydroxyl radicals, nitrate radicals, and ozone; estimated
half-lives based on these reactions are 6.6, 3 10, and 5.7 days, respectively (HSDB. 2013). High
mobility is expected in soil based on a measured Koc of 59. In an Organisation for Economic
Co-operation and Development (OECD) 301D test and other closed bottle biodegradation
studies, trans- 1,2-DCE was not readily biodegradable; however, multiple studies indicate that
trans- 1,2-DCE may be degraded under anaerobic conditions. For example, 73% of the initial
trans- 1,2-DCE was removed when incubated for 6 months under anaerobic conditions with
organic sediment obtained from the Florida Everglades; vinyl chloride was generated as a
degradation product (HSDB. 2013). Furthermore, the blood-air partition coefficients determined
for trans-1,2-DCE in humans and rats are 6.04 (± 0.38) and 9.58 (± 0.94) (Gargas et al.. 1989).
respectively, which are important for understanding regional deposition/absorption of this
chemical and for dosimetry conversions (see section on "Animal Studies" for more details).
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CI
CI
Figure 1. trans- 1,2-DCE (CASRN 156-60-5) Chemical Structure
Table 1. Physicochemical Properties of trans- 1,2-DCE (CASRN 156-60-5)a
Property (unit)
Value
Physical state
Liquid
Boiling point (°C)
48.7
Melting point (°C)
-49.8
Density (g/cm3 at 20°C)
1.2565
Vapor pressure (mm Hg at 25°C)
331
pH (unitless)
NA
pKa (unitless)
NA
Solubility in water (mg/L at 25 °C)
4,520
Octanol-water partition constant (log Kow)
2.06
Henry's law constant (atm-m3/mol at 24°C)
9.38 x 10-3
Soil adsorption coefficient (Koc)
59
Atmospheric OH rate constant (cm3/molecule-sec at 25°C)
2.34 x 10-12
Atmospheric half-life (d)
6.6 (calculated based on the compound's measured
OH rate constant)
Relative vapor density (air = 1)
3.67
Molecular weight (g/mol)
96.94
Flash point (closed cup in °C)
6
Blood-air partition coefficient (human)b
6.04 ±0.38
Blood-air partition coefficient (rat)b
9.58 ±0.94
'HSDE5 (2013); all values are measured unless otherwise noted.
bGargas et al. (1989).
NA = not applicable; trans- 1,2-DCE = trans-1.2-dichlorocthvlcnc.
A summary of available toxicity values for trans- l ,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 trans- 1,2-DCE (CASRN 156-60-5)
Source
(parameter)3'b
Value
(applicability)
Notes
Reference0
Noncancer
IRIS (RfC)
NV
Information reviewed but value not
derived
U.S. EPA (2010)
IRIS (RfD)
0.02 mg/kg-d
Based on decrease in number of
antibody-forming cells against sRBCs
in male mice
DWSHA (RfD)
0.02 mg/kg-d
NA
U.S. EPA (2012a)
HEAST (subchronic RfD)
0.2 mg/kg-d
Based on increased serum ALP in a
90-d drinking water study in mice
U.S. EPA (2011)
ATSDR (MRL, inhalation
acute)
0.2 ppm
Based on fatty degeneration of the
liver in rats exposed for 8 hr
ATSDR (1996)
ATSDR (MRL, inhalation
intermediate)
0.2 ppm
Based on fatty degeneration of the
liver in rats exposed for 8 or 16 wk
ATSDR (MRL, oral
intermediate)
0.2 mg/kg-d
Based on increased serum ALP in male
mice exposed for 90 d
Ca.1F,PA (ADD)
0.0048 mg/kg-d
Based on decreased antibody response
to sRBCs
CalEPA (2018b)
IPCS
NV
NA
IPCS (2018)
AEGL (AEGL-1)
10 min: 280 ppm
30 min: 280 ppm
60 min: 280 ppm
4 hr: 280 ppm
8 hr: 280 ppm
Based on ocular irritation in humans
U.S. EPA (2017b);
U.S. EPA (2008)
AEGL (AEGL-2)
10 min: 1,000 ppm
30 min: 1,000 ppm
60 min: 1,000 ppm
4 hr: 690 ppm
8 hr: 450 ppm
Based on narcosis in rats
(4 and 8 hr) or anesthetic effects in
humans (10, 30, and 60 min)
AEGL (AEGL-3)
10 min: 1,700 ppm
30 min: 1,700 ppm
60 min: 1,700 ppm
4 hr: 1,200 ppm
8 hr: 620 ppm
Based on a no-effect level for death in
rats (4 and 8 hr) or dizziness,
intracranial pressure, and nausea in
humans (10, 30, and 60 min)
ACGIH (TLV-TWA)
200 ppm
Based on CNS impairment and eye
irritation
ACGIH (2018)
OSHA (PEL)
200 ppm (790 mg/m3)
8-hr TWA for general industry,
construction, and shipyard
employment
OSHA (2017a):
OSHA (2020):
OSHA (2017b)
NIOSH (REL)
200 ppm (790 mg/m3)
TWA for up to a 10-hr workday during
a 40-hr workweek
NIOSH (2016)
NIOSH (IDLH)
1,000 ppm
Based on acute inhalation toxicity data
in humans
NIOSH (2016):
NIOSH (2014)
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Table 2. Summary of Available Toxicity Values for trans- 1,2-DCE (CASRN 156-60-5)
Source
(parameter)3'b
Value
(applicability)
Notes
Reference0
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 (2012a)
HEAST
NV
NA
U.S. EPA (2011)
NTP
NV
NA
NTP (2016)
IARC
NV
NA
IARC (2017)
CalFPA
NV
NA
CalEPA (2011);
CalEPA (2017);
CalEPA (2018a)
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; IPCS = International Programme on Chemical Safety;
IRIS = Integrated Risk Information System; NIOSH = National Institute for Occupational Safety and Health;
NTP = National Toxicology Program; OSHA = Occupational Safety and Health Administration.
Parameters: ADD = acceptable daily dose; AEGL = acute exposure guideline levels; IDLH = immediately
dangerous to life or health concentrations; MRL = minimum risk level; PEL = permissible exposure limit;
REL = recommended exposure limit; RfC = reference concentration; RfD = reference dose; TLV = threshold limit
value; TWA = time-weighted average; WOE = weight of evidence.
°Reference date is the publication date for the database and not the date the source was accessed.
ALP = alkaline phosphatase; CNS = central nervous system; NA = not applicable; NV = not available;
sRBC = sheep red blood cell; trans-1,2-DCE = trans-1.2-dichlorocthvlcnc.
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Non-date-limited literature searches were conducted in October 2017 and updated in
April 2020 for studies relevant to the derivation of noncancer inhalation provisional toxicity
values for trans- 1,2-DCE (CASRN 156-60-5). The database searches for PubMed, TOXLINE
(including TSCATS1), and Web of Science were conducted by an information specialist and
records stored in the U.S. EPA's Health and Environmental Research Online (HERO) database.
The following additional databases were searched for health-related data: 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 Health Effects Assessment Summary Tables
(HEAST), U.S. EPA Integrated Risk Information System (IRIS), U.S. EPA Office of Water
(OW), U.S. EPA TSCATS2, International Agency for Research on Cancer (IARC), Japan
Existing Chemical Data Base (JECDB), National Institute for Occupational Safety and Health
(NIOSH), National Toxicology Program (NTP), OECD Existing Chemicals Database, OECD
Screening Information Data Set (SIDS) High Production Volume Chemicals via IPCS INCHEM,
Occupational Safety and Health Administration (OSHA), and World Health Organization
(WHO).
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REVIEW OF POTENTIALLY RELEVANT DATA FOR DERIVATION OF
NONCANCER INHALATION REFERENCE VALUES
The primary focus of this PPRTV assessment is to evaluate the feasibility of deriving
provisional inhalation reference values. As such, Table 3 provides an overview of the noncancer
inhalation database for trans- 1,2-DCE, and includes all potentially relevant acute, short-term,
subchronic, and chronic studies, as well as reproductive and developmental toxicity studies. An
oral reference dose (RfD) of 0.02 mg/kg-day and a weight-of-evidence (WOE) descriptor of
"Inadequate Information to Assess Carcinogenic Potential" is available for trans- 1,2-DCE from
the U.S. EPA's IRIS (U.S. EPA. 2010). Toxicity data for other routes (including oral exposure)
are briefly summarized as supplemental information for hazard identification (see "Other Data"
section for more details). Principal studies are identified in bold. The phrase "statistical
significance" or the term "significant," used throughout the document, indicates ap-value of
< 0.05 unless otherwise specified.
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Table 3. Summary of Potentially Relevant Noncancer Data for fra«s-l,2-DCE (CASRN 156-60-5)
Category3
Number of Male/Female,
Strain, Species, Study
Type, Reported
Concentrations, Study
Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes'
Human
1. Inhalation (mg/m3)
Acute
2 M, 5-30 min
Reported concentrations:
275, 825, 950, 1,000,
1,200, 1,700, or
2,200 ppm
1,090, 3,270,
3,770, 3,960,
4,758, 6,740,
8,723
Dizziness (self-report) at 3,270 mg/m3 after 5 min.
At higher exposure concentrations, slight burning
of eyes, drowsiness, "intracranial pressure," and
nausea that persisted for 0.5 hr after exposure. No
self-reported effects at 1,090 mg/m3.
1,090
3,270
Lehmann
and Schmidt-
Kehl (1936)
as cited in
U.S. EPA
(2008)
SS
Animal
1. Inhalation (mg/m3)
Short term
6 F, Wistar, rat, 8 hr/d,
5 d/wk, 1 or 2 wk
Reported concentrations:
0 or 200 ppm
HECer = 0,
189°
HECpu = 0,
2,500d
Significant increase in capillary hyperemia and
alveolar septum distension in the lung at 1 wk;
incidence was elevated, but not significant, at 2 wk
because the effect was also observed in
2/6 controls at that time.
At 1 and 2 wk, incidences of fat accumulation in
the liver lobule and in Kupffer cells were higher
than controls but were not statistically significant.
NDr
189®
Freundt et al.
PR
(1977)
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Table 3. Summary of Potentially Relevant Noncancer Data for fra«s-l,2-DCE (CASRN 156-60-5)
Category3
Number of Male/Female,
Strain, Species, Study
Type, Reported
Concentrations, Study
Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes'
Subchronic
6 F, Wistar, rat, 8 hr/d,
5 d/wk, 8 or 16 wk
Reported concentrations:
0 or 200 ppm
HECer = 0,
189°
HECpu = 0,
2,500d
Significant increase in capillary hyperemia and
alveolar septum distension in the lung at 8 and
16 wk.
At 8 and 16 wk, incidences of fat accumulation in
the liver lobule and in Kupffer cells were higher
than controls but were not statistically significant.
NDr
189
Freundt et al.
(1977)
PR
Subchronic
15 M/15 F Crl:CD (SD)
BR, rat, 6 hr/d, 5 d/wk
for 90 d
Reported
concentrations: 0,200,
1,000, or 4,000 ppm
HECer = 0,
140, 710,
2,800c
Concentration-related decreases in WBC and
lymphocyte counts in rats with statistically
significant changes in males after 45-d (WBC
and lymphocyte counts) and 90-d (WBC counts)
sampling time points.
710
2,800
Kellv (1998)
PS,
NPR
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Table 3. Summary of Potentially Relevant Noncancer Data for fra«s-l,2-DCE (CASRN 156-60-5)
Category3
Number of Male/Female,
Strain, Species, Study
Type, Reported
Concentrations, Study
Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes'
Reproductive/
Developmental
24 F, Crl:CD BR, rat,
6 hr/d, GDs 7-16
Reported concentrations:
0, 2,000, 6,000, or
12,000 ppm
HECer = 0,
I,980, 5,950,
II,890°
Maternal: ocular irritation (i.e., increased
lacrimation). At higher concentrations (>5,950),
periocular stain (brown), lethargy, salivation, wet
perinasal hair, and mild effects on maternal body
weights were also reported.
Fetal: Decreased fetal body weights (4-6%) and
nonsignificant increase in the incidence of
hydrocephalus.
Maternal: NDr
Fetal: 5,950
Maternal: 1,980
Fetal: 11,890
Hunt et al.
(1993);
Haskell
Laboratories
(1988)
PR
aDuration 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% lifespan for humans (>30 days up to approximately 90 days in typically used laboratory animal species); and chronic = repeated exposure
for >10% lifespan for humans (>~90 days to 2 years in typically used laboratory animal species) (U.S. EPA. 2002).
bDosimetry: The units for inhalation concentrations are expressed as mg/m3. Concentration is calculated as concentration in ppm x molecular weight of trans- 1,2-DCE
(96.9438 g/mol) ^ 24.45 L/mol. Concentrations from animal studies are presented as HECs (in mg/m3) for PU and ER using the equations recommended by the U.S.
EPA (1994) (see Footnotes C and D).
°HECer = concentration (mg/m3) x (hours/day exposed ^ 24 hours) x (days/week exposed ^ 7 days) x ratio of blood-gas partition coefficient (animal: human), using a
default coefficient of 1 because the rat blood-air partition coefficient of 9.58 is greater than the human blood-air partition coefficient of 6.04 as indicated by Gargas et at
(1989).
dHECpu = concentration (mg/m3) x (hours/day exposed ^ 24) x (days/week exposed ^ 7) x RGDRPU. RGDRPU is the pulmonary regional gas dose ratio (animal:human);
see Equations 4-28 in U.S. EPA (1994) for calculation of RGDRPU and default values for variables.
"Although the study authors considered the lung lesions systemic in nature based on similar observations after i.p. and oral exposure routes, the potential contribution of
airway exposure cannot be ruled out [see study summary for Freundt et at (1977) in the " Animal Studies" section for more details]; therefore, the vapor concentration of
793 mg/m3 was converted to HECs for both extrarespiratory (HECEr) and airway exposure pulmonary effects (HECpu). The estimated HECEr of 182 mg/m3 was
ultimately selected for all lesions because it is more health-protective.
fNotes: NPR = not peer reviewed; PR = peer reviewed; PS = principal study; SS = data from secondary source.
ER = extrarespiratory effects; F = female(s); GD = gestation day; HEC = human equivalent concentration; i.p. = intraperitoneal;
LOAEL = lowest-observed-adverse-effect level; M = male(s); NDr = not determined; NOAEL = no-observed-adverse-effect level; RGDR = regional gas dose ratio;
PU = pulmonary effects; trans- 1,2-DCE = /rcw?.v-1.2-dich 1 orocthv 1 cnc: WBC = white blood cell.
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HUMAN STUDIES
Inhalation Exposures
Acute Studies
Lehmann and Schmidt-Kehl (1936) as cited in U.S. EPA (2008)
In an acute exposure study, two male graduate students were exposed themselves to
concentrations of trans-l,2-DCE vapors of 275, 825, 950, 1,000, 1,200, 1,700, or 2,200 ppm
(1,090, 3,270, 3,770, 3,960, 4,758, 6,740, or 8,723 mg/m3)1 in a closed-room environment for
5-30 minutes. The concentrations of trans- 1,2-DCE within the chamber were determined
analytically, and the effects of exposure were self-reported. No effects were reported following
5 minutes of exposure to 1,090 mg/m3 (see Table B-l). At higher concentrations, dizziness,
burning of eyes, and drowsiness were reported. At 6,740 and 8,723 mg/m3, symptoms included
"intracranial pressure" and nausea that persisted for approximately 30 minutes after the exposure
period. A no-observed-adverse-effect level (NOAEL) of 1,090 mg/m3 and a
lowest-observed-adverse-effect level (LOAEL) of 3,270 mg/m3 are identified for clinical
symptoms after acute exposure to trans- 1,2-DCE in humans.
Short-Term, Subchronic, and Chronic Studies
No repeated inhalation exposure studies on trans- 1,2-DCE in humans have been
identified.
ANIMAL STUDIES
Inhalation Exposures
Short-Term and Subchronic Studies
Freundt el al. (1977)
In a published, peer-reviewed study, Freundt et al. (1977) evaluated toxicity in rats
following short-term and subchronic-duration exposures to trans- 1,2-DCE vapors (purity not
reported). Groups of mature female SPF Wistar rats weighing 180-200 g at the start of the study
were exposed to trans- 1,2-DCE at nominal concentrations of 0 or 200 ppm (0 or 793 mg/m3)1
8 hours/day, 5 days/week for 1, 2, 8, or 16 weeks (six rats/group). Exposure concentrations were
monitored via gas chromatography. Monitoring of clinical signs and measurements of body
weights, feed consumption, serum chemistry, and organ weights were either not reported or were
not included in the study design. At the appropriate times of sacrifice, gross necropsies were
performed. Lung, liver, kidney, spleen, brain, muscle (quadriceps), and sciatic nerve tissues
from six rats and their concurrent controls were fixed and stained with scarlet red (a lipid stain)
or hematoxylin and eosin (H & E) for histological examination. No statistical analyses on
histopathology incidences were reported.
Histopathological findings included capillary hyperemia2 and distension of the alveolar
septum in the lungs of all the rats exposed to 793 mg/m3 trans- 1,2-DCE at each exposure
duration (increases in the incidence of lung lesions were statistically significant at 1, 8, and
16 weeks) (see Table B-2). There were no lung lesions in the concurrent controls at 8 and
16 weeks; however, capillary hyperemia and distension of the alveolar septum were observed in
1/6 and 2/6 controls at 1 and 2 weeks, respectively. The lung lesions were graded as "slight
Concentration in mg/m3 is calculated as concentration in ppm x molecular weight of trans- 1,2-DCE
(96.9438 g/mol) - 24.45 L/mol.
2Capillary hyperemia refers to the enlargement of blood vessels due to an increase in the arterial blood supply to a
tissue (active hyperemia) or a decrease in blood flow out of the tissue (congestion) (Mosier. 2017).
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changes" for all exposure groups. Severe pneumonic infiltration (not further characterized) was
observed in the lungs of 3/6 exposed rats at both 8 and 16 weeks, but not in the controls.
These same researchers also observed pulmonary capillary hyperemia and alveolar
septum distension significantly increased in rats exposed to trans- 1,2-DCE by acute inhalation
exposure and at low incidence in rats acutely administered trans- 1,2-DCE via intraperitoneal
(i.p.) injection or gavage (see Table 4 in the "Other Studies" section below).
Fatty accumulation in the liver lobules and Kupffer cells was seen at all exposure
durations at higher incidence than in the corresponding control, but differences from controls
were not statistically significant at any duration, either because incidence in the treated group
was low or because the lesions were also seen in the matched control group (see Table B-2). In
addition, the study had low power to detect statistically significant differences because of the
small group sizes. Lesions were graded as either "slight" or "severe," with no middle category.
At 1- and 2-week exposure durations, all liver lesions were graded as "slight changes." "Severe"
lesions were only seen in Kupffer cells at 8 weeks (in both treated and control animals) and in
the liver lobule in three of the five treated rats showing lesions at 16 weeks (total number of rats
examined per group was six).
Low incidences of fat accumulation in the liver lobules and Kupffer cells were also
observed following acute inhalation and oral exposures, and no liver lesions were seen after i.p.
injection (see Table 4).
Short-term and subchronic LOAELs of 793 mg/m3 (the only concentration evaluated)
were identified based on significantly increased incidence of pulmonary capillary hyperemia and
distension of the alveolar septum in female Wistar rats exposed to trans- 1,2-DCE vapors for
8 hours/day, 5 days/week, for 1, 2, 8, or 16 weeks. Although the study authors considered the
lung lesions to be systemic because similar observations were made after i.p. and oral exposure
routes, a blood-air partition coefficient of 9.58 in rats suggests that inhaled trans- 1,2-DCE is
likely to penetrate the alveolar region. Therefore, the potential contribution of airway exposure
cannot be ruled out, and the vapor concentration of 793 mg/m3 (8 hours/day, 5 days/week) was
converted to human equivalent concentrations for both extrarespiratory (HECer of 189 mg/m3)3
and airway exposure pulmonary effects (HECpu of 2,500 mg/m3).4
Kelly a998)
The toxicity of trans- 1,2-DCE (99.86% purity) was evaluated in groups of Crl:CD (SD)
BR rats (15 males and 15 females/group) in an unpublished study following OECD Guideline
No. 413 (Kellv, 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 [SE], reported by the study author to two significant
3HEC for extrarespiratory effects was calculated by treating trans- 1,2-DCE as a Category 3 gas and using the
following equation from U.S. EPA (1994) methodology: HECer = concentration (mg/m3) x (hours/day
exposed 24 hours) x (days/week exposed 7 days) x ratio of blood-gas partition coefficient (animal:human),
using a default coefficient of 1 because the rat blood-air coefficient of 9.58 is greater than the human blood-air
coefficient of 6.04, as indicated by Gargas et at (1989).
4HEC for airway exposure pulmonary effects was calculated using the following equation from U.S. EPA (1994)
methodology: HECpu = concentration (mg/m3) x (hours/day exposed ^ 24) x (days/week exposed ^ 7) x RGDRPU.
RGDRpu is the pulmonary regional gas dose ratio (RGDR) (animal:human); see Equations 4-28 in U.S. EPA (1994)
for calculation of RGDRPU and default values for variables.
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figures) of 0, 200 ± 0.48, 1,000 ± 1.3, or 4,000 ± 4.7 ppm of trans-l,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).1 Ten rats/sex/group were designated for toxicological
evaluations and the remaining five rats/sex/group were designated for 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 and food consumption
were measured in all animals weekly.
In the toxicology evaluation group, blood samples were collected for 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 implanted subcutaneously in designated rats. At sacrifice, the liver and duodenum were
collected and processed for 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 of Bartlett's test were
significant, Kruskal-Wallis and Mann-Whitney U tests. One-way ANOVA tests for linear trend
were conducted for the purposes of this 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 4,000-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
16,000-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
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groups 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.
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 NOAEL of 4,000 mg/m3 (HEC: 710 mg/m3) and a LOAEL of 16,000 mg/m3
(HEC: 2,800 mg/m3) were identified from this study based on statistically significant decreases
in WBC and lymphocyte counts in male rats exposed to trans- 1,2-DCE vapor for up to 90 days
under the study conditions described. Although statistically significant changes were not
observed at specific exposure levels, concentration-related decreases in WBC at 45 days and
lymphocytes at 90 days also occurred in females according to trend test results. The reported
concentrations of 0, 790, 4,000, and 16,000 mg/m3 correspond to HECer values of 0, 140, 710,
and 2,800 mg/m3, respectively (maintaining the stated two significant figures).3
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Reproductive/Developmental Studies
Hurtt et ill. (1993); Haskell Laboratories (1988)
Mated and presumed pregnant female Crl:CD BR rats (24/group) were exposed by
inhalation to nominal trans- 1,2-DCE vapor (99.64% purity) concentrations of 0, 2,000, 6,000, or
12,000 ppm (equivalent to 0, 7,930, 23,800, or 47,580 mg/m3)1 for 6 hours daily on Gestation
Days (GDs) 7-16. Measured exposure concentrations were within 5% of nominal values
throughout the study. Animals were monitored twice daily (pre-and postexposure) for clinical
signs. Observations were also recorded during exposure to assess the overall state of the
animals, including response to a sound stimulus, but were limited to those visible in the front half
of the exposure chamber. Body weights were recorded on GDs 1, 7-17, and 22. Feed
consumption was measured on alternating days from GDs 1-19 and on GD 22. At sacrifice
(GD 22), dams were examined for gross pathologic changes. Liver and gravid and empty uterus
weights were measured, and the numbers of live, dead, or resorbed fetuses and corpora lutea
were determined. Fetal parameters recorded included fetal weights, sex, external alterations, and
mean litter weights, which were calculated after omitting any fetuses considered stunted
(i.e., fetuses weighing the same or less than the maximum stunted weight). Half of the fetuses in
each litter, and all those appearing malformed or stunted, were examined for visceral alterations.
The remaining fetuses were examined for skeletal alterations. Statistical analysis was performed
by the study authors. ANOVA, Jonckheere's, or Cochran-Armitage tests were used to test for
linear trends. Where appropriate, Fisher's exact, Dunnett's, or Mann-Whitney U tests were used
for pairwise comparisons. For fetal effects, the litter (i.e., the proportion of affected fetuses per
litter or the litter mean) was used as the unit of comparison.
No dams died prior to the scheduled sacrifice. Observations during exposure (6 hours
daily) showed that trans- 1,2-DCE had a narcotizing effect on dams at >23,800 mg/m3 (incidence
data were not provided). Outside of the daily exposure period, there were significant,
dose-related increases in incidences of dams showing clinical signs (see Table B-6). Increased
lacrimation indicative of ocular irritation was observed at all exposure levels (>7,930 mg/m3)
with incidence rates of 54-100%. Other clinical signs included brown periocular staining and
alopecia at >23,800 mg/m3, and lethargy, salivation, and wet perinasal hair at 47,580 mg/m3.
Maternal body-weight gain was significantly reduced by 33% during the exposure period
in the 47,580-mg/m3 group, relative to controls, with the biggest difference occurring on the first
days of exposure (GDs 7-9; see Table B-7). Maternal body-weight gain was also significantly
reduced during GDs 11-13 of the exposure period in the 23,800-mg/m3 group. Conversely,
mean maternal body weights were reduced relative to controls at the highest concentration
(47,580 mg/m3) throughout the exposure periods, but the reductions were small (4—6%) and not
statistically significant. Food consumption was significantly reduced in both the 47,580- and
23,800-mg/m3 groups during the total exposure period, and also at the 7,390-mg/m3 group during
GDs 13-15 (see Table B-8); however, decreases in food intake at the lowest exposure
concentration were not accompanied by any changes in maternal weights. Further, the biological
significance of the reductions in body-weight gain was unclear, given that mean body weights
were mostly unchanged in the dams. Postmortem examinations found no significant effect on
absolute or relative maternal liver weights in any group.
Significant increases in the mean number of early resorptions per litter were observed in
dams in the 23,800- and 47,580-mg/m3 exposure groups (see Table B-9). The study authors
reported that the resorption rate in the control animals was unusually low and that the observed
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responses, even in the high-exposure group, fell within the range of historical control data
collected from the same laboratory during the previous 2 years (historical mean resorptions per
litter were 1.0, 0.8, 1.5, 0.6, and 0.9; no further details were provided). These uncertainties
combined with the lack of changes in other reproductive parameters (i.e., pregnancy rate, corpora
lutea, number of fetuses per litter) evaluated in the study question the biological significance of
the increased resorptions.
A statistically significant decrease in litter-adjusted mean fetal weight was seen in the
47,580-mg/m3 group, primarily in the female fetuses (see Table B-9). Fetal weights were
reduced by 6% in female fetuses and by 4% in all fetuses, compared with controls. Incidences of
malformations (external, head, visceral, skeletal) in treated groups did not differ significantly
from controls. A nonsignificant increase was found for incidence of hydrocephalus
(accumulation of fluid within the brain), which was seen in five fetuses from four litters in the
47,580-mg/m3 group and one fetus in the control group.
Data on variations in the published version of the study (Hum et al.. 1993) only partially
match the data from the unpublished report (Haskell Laboratories. 1988). According to the
unpublished report, the incidence of fetal variations (mean percent of fetuses affected per litter)
was significantly increased in all treated groups relative to controls, due to significant increases
in visceral variations (primarily distended ureter and small renal papilla) in the low- and
mid-exposure groups (but not in the high-exposure group) and skeletal variations (primarily
rudimentary lumbar ribs) in the high-exposure group. In contrast, the published report omits the
data for distended ureter and rudimentary lumbar ribs (data for "rudimentary ribs" in this report
correspond to data for rudimentary cervical ribs in the unpublished report) and finds no effect on
variations per litter based on a combined analysis of variations and retardations (analyzed
separately in the unpublished report) using different incidence values than the unpublished
report. No discussion of these data or explanation for the discrepancy is provided in the
published report, so it is unclear how to interpret these results.
A maternal LOAEL of 7,930 mg/m3 (the lowest concentrated tested) was determined for
trans- 1,2-DCE in this study based on a significant increase in ocular irritation (i.e., lacrimation)
in the dams. A NOAEL could not be determined. At higher exposure concentrations
(>23,800 mg/m3), brown periocular staining, alopecia, lethargy, salivation, wet perinasal hair,
and mild effects on maternal body weight (significant reductions in body-weight gain and food
consumption but not mean body weight) were reported. A fetal NOAEL of 23,800 mg/m3 and
LOAEL of 47,580 mg/m3 were determined based on significantly reduced fetal weight. A
nonsignificant increase in hydrocephalus at the 47,580-mg/m3 concentration was also suggestive
of a chemical-related effect. The nominal exposure concentrations of 7,930, 23,800, and
47,580 mg/m3 correspond to HECer values of 0, 1,980, 5,950, and 11,890 mg/m3, respectively.3
OTHER DATA
Other relevant data for trans- 1,2-DCE include acute inhalation studies, oral studies, and
studies by other routes. The findings from these studies are briefly summarized below as
supplemental information for hazard identification. More detailed descriptions of the individual
studies are provided in Table 4.
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Table 4. Other Studies on fra«s-l,2-DCE Toxicity
Test3
Materials and Methods
Results
Conclusions
References
Effects in animals following acute inhalation exposure
Acute
OF1SPF mice (number and sex unknown)
were exposed to trans- 1,2-DCE vapors for
6 hr.
Mortality. Causes of death not reported.
Mouse LC50 (6 hr) = 86,131 mg/m3
Gradiski et al.
(1978) as cited in
U.S. EPA (2008)
Acute
Crl:CD (SD) BR rats (5 M and 5 F) were
exposed to trans- 1,2-DCE vapors for 4 hr at
concentrations ranging from 12,300 to
34,100 ppm (48,770-135,200 mg/m3).
Observed effects during exposure
included prostration, decreased
responsiveness, and death. Effects in
survivors after exposure included
lethargy, irregular respiration,
weakness, and transitory weight loss.
Rat LC50 (4 hr) = 95,556 mg/m3
Kelly (1999) as
cited in U.S. EPA
(2008)
Acute
Three mice (sex and strain unknown) were
exposed to trans- 1,2-DCE vapors for
30-155 min at 45,000-129,000 mg/m3.
Disequilibrium and lethargy were
observed at all tested concentrations.
100% mortality at >75,000 mg/m3.
The low concentration of
45,000 mg/m3 is associated with
neurological effects (CNS
depression).
Lehmann and
Schmidt-Kehl
(1936) as cited in
U.S. EPA (2008)
Acute
2-3 M or F cats were exposed to
trans- 1,2-DCE vapors for 22-348 min at
72,000-189,200 mg/m3 or for 10-390 min at
43,000-191,000 mg/m3.
Disequilibrium and lethargy were
observed at all tested concentrations;
the time to effect decreased with
increasing exposure concentrations.
Narcosis was observed at
>72,000 mg/m3.
The low concentration of
43,000 mg/m3 is associated with
neurological effects (CNS
depression).
Lehmann and
Schmidt-Kehl
(1936) as cited in
U.S. EPA (2008)
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Table 4. Other Studies on fra«s-l,2-DCE Toxicity
Test3
Materials and Methods
Results
Conclusions
References
Acute
Female Wistar rats (6/group) were exposed to
trans- 1,2-DCE vapors for 8 hr at
concentrations of 793, 3,960, or
11,900 mg/m3, each with a matched
air-exposed control group.
Significant increases were seen in
incidence of capillary hyperemia and
alveolar septum distension in the lung in
all treated groups relative to their
matched controls. Severity of the lesion
was graded as "slight" in most affected
rats, but "severe" in two rats each at
3,960 and 11,900 mg/m3 (no middle
grade was used). Low incidences of fat
accumulation in the liver lobule and
Kupffer cells were reported in all
treated groups (1 or 2/6), but also one of
the matched control groups. Fibrous
swelling and hyperemia of the cardiac
muscle (graded as "severe") was seen in
2/6 rats at 11,900 mg/m3. No signs of
CNS depression were observed in any
group.
The low concentration of
793 mg/m3 is associated with
histopathological changes in the
lung.
Freundt et al.
(1977)
Effects in humans following oral exposure
Case-control study at
the Marine Corps base
at Camp Lejeune;
children from mothers
who resided at Camp
Lejeune at any time
during pregnancy
between 1968-1985
Cases: neural tube
defects (n = 15); oral
clefts (n = 24);
childhood cancer
(n = 13)
Controls: 526 children
Estimated monthly exposure levels of
trans- 1,2-DCE from contaminated drinking
water at Camp Lejeune were based on water
modeling, residential history, and family
housing records.
Unexposed: no residential exposure
Low: >0 to <5 ppb
High: >5 ppb
Exposed: had residential exposure
Other contaminants in drinking water included
perchloroethylene, trichloroethylene, vinyl
chloride, and benzene.
ORs (95% CI)
Exposed
Neural
tube defects: 1.1 (0. ¦4-3.1)
Oral clefts: 0.5(0.2-1.3)
Childhood
cancers: 1.5 (0.5-4.7)
Similar results were observed with
adjustments for other potential risk
factors or when comparisons were made
between high and unexposed categories.
No associations were found
between trans- 1,2-DCE exposure
in utero or during early childhood
and cases of neural tube defects,
oral clefts, or childhood cancers.
Ruckart et al.
(2013)
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Table 4. Other Studies on fra«s-l,2-DCE Toxicity
Test3
Materials and Methods
Results
Conclusions
References
Case-control study at
the Marine Corps base
at Camp Lejeune;
males born prior to
1969 and diagnosed
with cancer between
1995-2013
Male breast cancer
cases at VA hospital:
n = l\
Facility controls
(patients with cancer
not known to be
associated with solvent
exposure): n = 373
Estimated cumulative and monthly exposure
levels to trans-\ ,2-DCE from contaminated
drinking water at Camp Lejeune:
Cumulative low: >0 to <472 ppb
Cumulative high: >472 ppb
Monthly low: >0 to <94 ppb
Monthly high: >94 ppb
Other contaminants in drinking water included
perchloroethylene, trichloroethylene, vinyl
chloride, and benzene.
Adjusted ORs (95% CI) for association
between trans- 1,2-DCE and breast
cancer.
Cumulative
Low: 0.56 (0.02-3.83)
High: 1.50 (0.30-6.11)
Adjusted hazard ratio (95% CI) for age
at onset of breast cancer by exposure
level.
Cumulative
Low: 0.64 (0.06-7.01)
High: 2.72 (0.52-14.18)
Suggestive evidence of a possible
association between exposure to
trans- 1,2-DCE and early age at
onset of male breast cancer.
Study was limited to a small
number of participants in the
cumulative high-exposure group
(n = 3), which resulted in a large
CI.
Similar results for
perchloroethylene and vinyl
chloride.
Ruckart et al.
(2015)
Effects in animals following oral exposure
Acute
Female Wistar rats (10/dose) were treated by
gavage with single doses of 0.5, 0.75, 0.9, 1.0,
1.1, or 1.25 mL/kg irons-1,2-DCE in olive oil.
Deaths recorded at >0.75 mL/kg.
Clinical symptoms were not reported.
Two rats in each of the 0.9, 1.0, and
1.1 mL/kg groups showed capillary
hyperemia and alveolar septal
distension in the lung and fibrous
swelling and hyperemia in cardiac
muscle (all changes graded as "severe").
Two rats in the 0.9 mL/kg group
showed "severe" fatty infiltration of the
liver lobules and Kupffer cells.
RatLDso: 1.0 (0.9-1.1) mL/kg
[equivalent to 1,256 mg/kg]b
Freundt et al.
(1977)
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Table 4. Other Studies on fra«s-l,2-DCE Toxicity
Test3
Materials and Methods
Results
Conclusions
References
Acute
Male and female S-D CD rats (10/sex/group)
received single oral doses of trans- 1,2-DCE
by gavage in corn oil.
Deaths occurred within 30 hr after
dosing. CNS depression, ataxia, and
depressed respiration were observed at
all doses; the severity was dose
dependent. No compound-related gross
pathological findings were observed.
Rat male
LD50: 7,902 (6,805-9,175) mg/kg
Rat female
LD50: 9,939 (6,494-15,213) mg/kg
Haves et al.
(1987)
Acute
Male and female CD-I mice received single
oral doses of trans- 1,2-DCE by gavage in
emulphor.
Deaths occurred over a 10-d period
following administration. Dead animals
had hyperemia of mucosal surfaces of
the stomach and small intestines.
Decreased activity, ruffled fur, ataxia,
loss of righting reflex, hunchbacked
appearance, and death were noted at
>1,600 mg/kg; the severity was dose
dependent.
Mouse male LD50: 2,122
(1,874-2,382) mg/kg
Mouse female
LD50: 2,391 (2,055-2,788) mg/kg
Barnes et al.
(1985)
Short term
Male mice (9-10/group) were dosed daily
with 0, 21, or 210 mg/kg trans- 1,2-DCE for
14 d by gavage in emulphor.
Endpoints evaluated included body weights,
select organ weights, hematology and serum
chemistry analysis, and functional
immunological assessments (e.g., immune
responses to sRBCs, and delayed
hypersensitivity responses).
No notable exposure-related changes in
any of the endpoints evaluated.
No evidence of systemic or
immune effects at doses up to
210 mg/kg-d.
Barnes et al.
(1985); ShoDD et
al. (1985):
Munson et al.
(1982)
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Table 4. Other Studies on fra«s-l,2-DCE Toxicity
Test3
Materials and Methods
Results
Conclusions
References
Subchronic
Groups of S-D CD rats (20/sex/dose) were
administered trans- 1,2-DCE in 1% emulphor
in drinking water at 0, 402, 1,314, or
3,114 mg/kg-d (males) orO, 353, 1,257, or
2,809 mg/kg-d (females) for 90 d.
Endpoints evaluated included body weights,
hematology and serum chemistry analysis,
urinalysis, select organ weights, and
histopathology.
Statistically significant increases in
absolute kidney weight (13-15%) and
kidney :brain weight ratio (11%), and
nonsignificant increase in kidney :body
weight ratio (10-11%), in females at
1,257 and 2,809 mg/kg-d. No
significant effect on kidney weight in
males, and no corresponding
pathological or clinical chemistry
changes. No notable exposure-related
changes in any of the other endpoints
evaluated.
Limited evidence for an effect on
kidneys in females at
>1,257 mg/kg-d.
Haves et al.
(1987)
Subchronic
Groups of CD-I mice (15-23/sex/dose) were
administered trans- 1,2-DCE in 1% emulphor
in drinking water for 90 d at doses of 0, 17,
175, or 387 mg/kg-d (males) or 0, 23, 224, or
452 mg/kg-d (females).
Endpoints evaluated included body weights,
gross pathology, organ weights, hematology,
serum and liver chemistry, histopathology, and
functional immunological assessments
(e.g., immune responses to sRBCs, and
delayed hypersensitivity responses).
Absolute and/or relative thymus weights
significantly decreased in females at
>224 mg/kg-d. No significant effect on
thymus weight in males, and no
corresponding pathological or clinical
chemistry changes. Significant
decrease in sRBC-responsive cells in
males at >175 mg/kg-d. No
corresponding effect in females. No
notable exposure-related changes in any
of the other endpoints evaluated.
Limited evidence for an effect on
the thymus in females at
>224 mg/kg-d and humoral
immune response in males at
>175 mg/kg-d.
Barnes et al.
(1985); ShoDD et
al. (1985)
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Table 4. Other Studies on fra«s-l,2-DCE Toxicity
Test3
Materials and Methods
Results
Conclusions
References
Subchronic
Groups of F344/N rats (10/sex/dose) were
administered trans- 1,2-DCEby microcapsule
in feed at average daily doses of 0, 190, 380,
770, 1,540, or 3,210 mg/kg-d (males) or 0,
190, 395, 780, 1,580, or 3,245 mg/kg-d
(females) for 14 wk.
Endpoints evaluated included: clinical signs,
FOB neurological tests (on Wk 4 and 13),
body weights, hematology and biochemistry
parameters, organ weights, and gross and
microscopic examinations.
Absolute and relative liver weights
significantly increased in females at
>395 mg/kg-d, although magnitude did
not increase with dose. No effect on
liver weight in males, and no
corresponding pathological or clinical
chemistry changes. No notable
exposure-related changes in any of the
other endpoints evaluated.
Limited evidence for an effect on
the liver in females at
>395 mg/kg-d.
NTP (2002)
Subchronic
Groups of B6C3F1 (10/sex/dose) mice were
administered trans- 1,2-DCEby microcapsule
in feed at average daily doses of 0, 480, 920,
1,900, 3,850, or 8,065 mg/kg-d (males) or 0,
450, 915, 1,830, 3,760, or 7,925 mg/kg-d
(females) for 14 wk.
Endpoints evaluated included: clinical signs,
FOB neurological tests (on Wk 4 and 13),
body weights, hematology and biochemistry
parameters, organ weights, and gross and
microscopic examinations.
Relative liver weight significantly
increased in males at >1,900 mg/kg-d
and in females at >3,760 mg/kg-d,
although the magnitude did not
necessarily increase with dose. No
effect on absolute liver weights, and no
corresponding pathological or clinical
chemistry changes. No notable
exposure-related changes in any of the
other endpoints evaluated.
Limited evidence for an effect on
liver in males at >1,900 mg/kg-d
and females at >3,760 mg/kg-d.
NTP (2002)
Effects in animals following i.p. exposure
Acute
Female Wistar rats (10/dose) were
administered trans- 1,2-DCE i.p. at doses
ranging from 4.0-10.0 mL/kg.
Deaths occurred at all doses. Clinical
symptoms were not reported. One rat in
the 6.0 mL/kg group and two rats in the
10.0 mL/kg group showed capillary
hyperemia and alveolar septal
distension in the lung and fibrous
swelling and hyperemia in cardiac
muscle (all changes graded as "severe").
Rat i.p. LD50: 6.0 (5.1-7.1) mL/kg
[equivalent to 7,680 mg/kg]
Freundt et al.
(1977)
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Table 4. Other Studies on fra«s-l,2-DCE Toxicity
Test3
Materials and Methods
Results
Conclusions
References
Acute
Female NMRI mice (10/dose) were
administered trans- 1,2-DCE i.p. at doses
ranging from 2.0-8.0 mL/kg.
Deaths occurred at all doses.
Symptoms following injection included
motor excitement, convulsions,
narcosis, compulsory walking during
narcosis, and increased respiratory rate.
Gross pathology observations included
hyperemia of the liver, kidneys, urinary
bladder, and intestines; intestinal
hemorrhage; and hematuria.
Mouse i.p. LD5o: 3.2
(2.8-3.7) mL/kg
[equivalent to 4,096 mg/kg]
Freundt et al.
(1977)
Effects in animals following dermal/ocular exposure
Acute (dermal lethality
study)
NZW rabbits (2 M and 3 F) received a single
dose of 13 mL (5,000 mg/kg) trans- 1,2-DCE
applied neat to clipped, intact skin for 24 hr
under occlusion and were observed for 14 d.
No rabbits died during the study. Three
of the rabbits lost weight after dosing.
The only clinical signs were skin
reactions at the application site. Dermal
irritation progressed from mild
erythema and edema at 24 hr to severe
erythema and edema with necrosis and
Assuring of the skin at 7 d.
Rabbit dermal LD5o: >5,000 mg/kg
DuPont (1988a)
Acute (dermal irritation
study)
NZW rabbits (5 M and 1 F) received a single
dose of 0.5 mL trans-1,2-DCE applied neat to
clipped, intact skin for 24 hr under occlusion
and were observed for 72 hr.
No to moderate erythema was observed
24, 48, and 72 hr after application. No
edema was observed throughout the
study.
trans-1,2-DCE was a moderate skin
irritant under the conditions of this
study.
DuPont (1988c)
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Table 4. Other Studies on fra«s-l,2-DCE Toxicity
Test3
Materials and Methods
Results
Conclusions
References
Acute (ocular irritation
study)
NZW rabbits (2 F) received a single dose of
0.01 mL trans-1,2-DCE applied neat to the
right eye (left eyes acted as controls). The
eyes of one rabbit were washed with water
20 sec after application; the other rabbit's eyes
remained unwashed. The rabbits were
observed for 3 d.
Both treated eyes exhibited moderate
iritis, conjunctival redness, copious
blood-tinged discharge, and chemosis.
The effects were more severe in the
washed eye, which also showed severe
corneal opacity and moderate to severe
microscopic corneal injury. Recovery
in both eyes occurred within 3 d.
trans- 1,2-DCE was a severe eye
irritant under the conditions of this
study.
DuPont (1988b)
aDuration 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% lifespan for humans (>30 days up to approximately 90 days in typically used laboratory animal species); and chronic = repeated exposure
for >10% lifespan for humans (>~90 days to 2 years in typically used laboratory animal species) (U.S. EPA. 2002).
bDose in mg/kg is calculated as dose in mL/kg x density of trans- 1,2-DCE (1,256 mg/mL).
CI = confidence interval; CNS = central nervous system; F = female(s); FOB = functional observation battery; i.p. = intraperitoneal; LC50 = median lethal concentration;
LD50 = median lethal dose; LOAEL = lowest-observed-adverse-effect level; M = male(s); NZW = New Zealand White; OR = odds ratio; S-D = Sprague-Dawley;
sRBC = sheep red blood cell; trans-1,2-DCE = trans-1.2-dichloroethy lene: VA = Veterans Affairs.
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Inhalation Toxicity Studies
A cute Animal Studies
Acute lethality studies reported median lethal concentration (LCso) values of
95,556 mg/m3 in rats after 4 hours of exposure and 86,131 mg/m3 in mice after 6 hours of
exposure to trans-1,2-DCE vapor [Kelly (1999) and Gradiski et al. (1978) as cited in U.S. EPA
(2008)1. Effects indicative of central nervous system (CNS) depression were reported in the rat
study, including prostration and decreased responsiveness during exposure and lethargy,
irregular respiration, and weakness in survivors after exposure [Kelly (1999) as cited in U.S.
EPA (2008)1. Disequilibrium and lethargy were observed in mice and cats at trans-1,2-DCE
vapor concentrations around 43,000 mg/m3, with narcosis and death first occurring at around
72,000 mg/m3 [Lehmann and Schmidt-Kehl (1936) as cited in U.S. EPA (2008)1.
No signs of CNS depression were seen in rats exposed to trans- 1,2-DCE vapor
concentrations up to 1 1,900 mg/m3 for 8 hours (Freundt et al.. 1977). Histological findings in
this study were similar to those observed by the same researchers in short- and long-term
experiments described above: significantly increased capillary hyperemia and alveolar septum
distension in the lung at >793 mg/m3 (graded as "slight" in most animals, but "severe" in two
rats, each at 3,960 and 11,900 mg/m3) and low incidence of fat accumulation in the liver lobule
and Kupffer cells in all treated groups (but also one of the matched air-exposed control groups).
An additional finding in the acute study was fibrous swelling and hyperemia of cardiac muscle in
2/6 rats at 11,900 mg/m3. All of these lesions were also seen at low incidence in acute oral and
i.p. injection studies by these same researchers, described in more detail below and in Table 4.
Oral Toxicity Studies
Human Studies
Residents living at specific sites within the Marine Corp base at Camp Lejeune from the
1968 through 1985 were exposed to contaminated drinking water containing TCE (1,400 ppb
highest level detected) and the TCE degradation products, vinyl chloride and trans- 1,2-DCE
(407 ppb highest level tested) (Ruckart et al.. 2013; Sonnenfeid. 1998). Ruckart et al. (2013)
found no associations between residents with high monthly exposures to trans- 1,2-DCE (>5 ppb)
in utero and early childhood and developmental effects, including oral clefts and neural tube
defects, or with presence of childhood cancers. A follow-up study (Ruckart et al .. 2015) found
suggestive evidence of a potential association between early age onset of male breast cancer and
estimated high cumulative (>472 ppb) exposure to trans- 1,2-DCE. The study reported similar
results for other contaminants (i.e., perchloroethylene and vinyl chloride), but the study was
limited by the small number of participants in the high-exposure group (n = 3).
Animal Studies
Due to the limited data available on trans- 1,2-DCE inhalation toxicity, evidence from
oral animal studies was considered as supplementary data for the inhalation assessment. Oral
exposure studies include acute oral lethality studies in rats and mice (Haves et al.. 1987; Barnes
et al.. 1985; Freundt et al. 1977). a short-term range-finding study in mice (Barnes et al.. 1985;
Shopp et al.. 1985; \ tun son et al.. 1982). and four subchronic toxicity studies (two each in rats
and mice) (NTP. 2002; Haves et al.. 1987; Barnes et al.. 1985; Shopp et al.. 1985) (see Table 4).
Short-Term Studies
A 14-day range-finding study in mice found no notable exposure-related systemic or
immune effects at doses up to 210 mg/kg-day (Barnes et al.. 1985; Shopp et al.. 1985; \ tun son et
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al.. 1982). In addition to a standard array of systemic endpoints, the study included investigation
of functional immune humoral and cell-mediated responses.
Subchronic Studies
Subchronic studies performed by the administration of trans- 1,2-DCE in 1% emulphor in
drinking water for 90 days found evidence of potential treatment-related effects, including
significantly increased kidney weight in rats and decreased thymus weight in mice (both changes
in females only, with no corroborating changes in pathology or clinical chemistry endpoints)
(Haves et al.. 1987; Barnes et al.. 1985; Shopp et al.. 1985). The mouse study also included an
assessment of immune function and showed a statistically significant decrease (26%) in the
number of Immunoglobulin M (IgM) antibody-forming cells (AFC) in the spleen after challenge
with sheep red blood cells (sRBC) in males at > 175 mg/kg day (Shopp et al.. 1985). Subchronic
studies featuring exposure to trans- 1,2-DCE by microcapsules in the feed for 14 weeks in mice
and rats showed significant increases in liver weight (female rats at >395 mg/kg-day and in male
and female mice at >1,900 mg/kg-day), but these increases were not accompanied by related
pathological or clinical chemistry changes (N I P. 2002). The IRIS assessment on trans-1,2-DCE
considered the decreased AFCs in male mice as biologically significant and indicative of a
functional suppression of the humoral immune system, establishing an RfD based on this effect
(U.S. EPA. 2010).
Acute Studies
Acute oral LDso values for trans- 1,2-DCE were 1,256 mg/kg in female Wistar rats treated
by gavage in olive oil (Freundt et al.. 1977). 7,902 and 9,939 mg/kg, respectively, in male and
female Sprague-Dawley (S-D) rats treated by gavage in corn oil (Haves et al.. 1987). and 2,122
and 2,391 mg/kg, respectively, in male and female CD-I mice treated by gavage in emulphor
(Barnes et al.. 1985). Signs of CNS depression were associated with animal deaths, including
decreased activity, ataxia, depressed respiration, and loss of righting reflex (Haves et al.. 1987;
Barnes et al.. 1985). In female Wistar rats, Freundt et al. (1977) reported low incidences in
treated groups of capillary hyperemia and alveolar septal distension in the lung, fatty infiltration
of the liver lobules and Kupffer cells, and fibrous swelling and hyperemia in cardiac muscle, the
same lesions seen in inhalation studies by these researchers.
Other Route Toxicity Studies
Intraperitoneal Injection
LDso values from injection studies were 7,680 mg/kg in rats and 4,096 mg/kg in mice
(Freundt et al.. 1977). After injection, the mice exhibited clinical signs indicative of neurological
effects, including motor excitement, convulsions, narcosis, and increased respiratory rate.
Clinical signs were not reported for rats. As in the oral lethality study, treated rats showed low
incidence of capillary hyperemia and alveolar septal distension in the lung and fibrous swelling
and hyperemia in cardiac muscle, lesions also seen in inhalation studies performed by these
researchers. Mice showed a different set of lesions, including hyperemia in the liver, kidney,
urinary bladder, and intestine, as well as intestinal hemorrhage and hematuria.
Dermal Exposure
trans- 1,2-DCE was only moderately irritating to the skin in a dermal irritation study in
rabbits conducted using an undiluted dose of 0.5 mL (DuPont, 1988c). but produced severe
erythema and edema with necrosis and fissuring of the skin after 7 days in a dermal toxicity
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study conducted using a much larger undiluted dose of 13 mL (5,000 mg/kg) (DuPont. 1988a).
Still, no animals died in this study, indicating that the dermal LDso was >5,000 mg/kg.
Ocular Exposure
trans-1,2-DCE was found to be a severe eye irritant in an ocular irritation study in rabbits
conducted using an undiluted dose of 0.01 mL (DuPont 1988b). Effects included corneal injury.
Absorption, Distribution, Metabolism, and Excretion Studies
Absorption
Experimental data show inhaled trans- 1,2-DCE to be well absorbed through the lungs, a
result that is consistent with the blood-air partition coefficients estimated in humans and rats for
this chemical [6.08 and 9.58, respectively; Gargas et al. (1989)1. Approximately 72-75% of
inhaled trans- 1,2-DCE is estimated to be absorbed into the lungs in humans [Lehmann and
Schmidt-Kehl (1936) as cited in AT SDR (1996)1. Closed-chamber gas uptake studies in rats
have shown rapid absorption of trans- 1,2-DCE over the first 1.5-2 hours of exposure, followed
by leveling off as a steady state is approached, with approximately 50% of the gas remaining in
the chamber at the end of the first phase of absorption (Andersen et al .. 1980; Filser and Bolt
1979). A second phase of absorption followed, showing proportional first-order decline in
chamber levels of trans- 1,2-DCE at low concentrations (20-30 ppm) and slower, constant
(zero-order) decline at higher concentrations (1,000-10,000 ppm), suggesting saturation of
trans- 1,2-DCE metabolism at the higher concentrations. No studies quantifying the rate or
extent of trans- 1,2-DCE uptake following oral or dermal exposure were located.
Distribution
No studies have been identified that investigated the tissue distribution of trans- 1,2-DCE
in the body. Tissue-air partition coefficients determined for rats in vitro were 8.96 for liver, 3.52
for muscle, and 148 for fat (Gargas et al.. 1988). suggesting that trans- 1,2-DCE in the blood will
be distributed to the liver and will accumulate preferentially in fat.
Metabolism
Studies both in vitro and in vivo indicate that metabolism of trans- 1,2-DCE is initiated
upon the binding of trans- 1,2-DCE to the active site of hepatic microsomal cytochrome P450s
(CYP450s) (Costa and Ivanetich. 1982). Upon activation, presumably by CYP2E1 (in hepatic
tissue), trans- 1,2-DCE is metabolized to an unstable epoxide intermediate that rearranges to form
2,2-dichloracetaldehyde, which is enzymatically converted to dichloroacetic acid (DCA) and
2,2-dichloroethanol acid by alcohol dehydrogenase (Nakaiima. 1997; Costa and Ivanetich. 1984;
Bonse et al.. 1975). DCA appears to be the primary metabolite, with only trace amounts of
2,2-dichloroethanol and 2,2-dichloracetaldehyde formed (Costa and Ivanetich. 1984). The rate
and total amount of trans- 1,2-DCE metabolites produced appear to be slower and less than the
cis- isomer. Although CYP2E1 is likely the primary CYP450 responsible for trans- 1,2-DCE
metabolism, other CYP450s may also be involved. In vitro inhibition studies by Costa and
Ivanetich (1982) indicated that metyrapone, a specific inhibitor of CYP3A4, was able to suppress
trans- 1,2-DCE metabolism, while phenobarbital, an inducer of CYPs, including CYP34A,
increased trans- 1,2-DCE metabolism. Studies indicate that both cis- and trans-1,2-DCE (or their
metabolites) are capable of suicide inhibition, with trans- 1,2-DCE being the more potent
inhibitor (U.S. EPA. 2008; Nakahama et al.. 2000; Hanioka et al.. 1998; Lilly et al.. 1998;
Mathews et al.. 1998; Barton et al.. 1995; Ctewetl and Andersen. 1994; Freundt and Macholz.
1978. 1972). The turnover velocity (Vmax) of trans-1,2-DCE was determined to be
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2.4 mg/hour-kg by Filser and Bolt (19791 3.4 mg/hour-kg by Andersen et al. (1980). and
3 mg/hour-kg by Gargas et al. (1988). In a later study, Gargas et al. (1990) compensated for
enzyme inhibition and resynthesis and determined the Vmax value to be 2.49 mg/hour-kg.
Excretion
Data on excretion of trans- 1,2-DCE are limited. The metabolite DCA is ultimately
broken down into carbon dioxide or further metabolized by oxidative dichlorination to produce
glyoxylate (Costa and Ivanctich. 1984. 1982). Glyoxylate can further undergo oxidation to
oxylate, which is either excreted in urine or reduced to glycolic acid, followed by transamination
to glycine with subsequent formyl group transfer to form serine [see the IRIS Toxicological
Review for Dichloroacetic Acid (U.S. EPA. 2003)1. Trace amounts of dichloroethanol are
expected to be ultimately exhaled.
Physiologically Based Pharmacokinetic Models
Pharmacokinetic modeling of trans- 1,2-DCE has been performed in several studies (I,illy
et al.. 1998; Barton et al.. 1995; Gargas et al.. 1990; Andersen et al.. 1980; Filser and Bolt,
1979). A four-compartment physiologically based pharmacokinetic (PBPK) model (fat, slowly
and rapidly perfused tissues, and liver) linked by the arterial blood supply with the chemical
entering the pulmonary circulation via the lungs, developed by I .illy et al. (1998). was the first
model to quantitatively describe the mechanisms of both suicide inhibition of CYP2E1 along
with its resynthesis. The model, based on a model for styrene (Ramsey and Andersen. 1984).
was created using kinetic constants from Gargas et al. (1988) and partition coefficients from
Gargas et al. (1989). This model approximates experimentally obtained animal data, but because
of the lack of human data on CYP2E1 inhibition and/or resynthesis, neither validation nor
calibration of the model for allometric scaling to humans is possible without introducing
considerable uncertainty (Lilly et al.. 1998). More recently, Pevret and Krishnan (2012)
attempted to develop quantitative property-property relationship (QPPR) models from available
animal data to estimate intrinsic clearance of 26 different volatile organic compounds (VOCs),
including trans-l,2-DCE, for future incorporation into human PBPK models and simulation of
blood concentration profiles associated with inhalation exposures. The results of their
experiments indicate medium confidence in using the trans- 1,2-DCE QPPR in a human
inhalation PBPK model to evaluate areas under the curve (AlJCs) (Pevret and Krishnan. 2012).
Mode-of-Action/Mechanistic Studies
Studies in vivo and in vitro indicate that trans- 1,2-DCE suppresses select liver and lung
CYP450s by binding to the heme moiety of CYP450. This leads to both suicide inhibition of
trans- 1,2-DCE metabolism and the metabolic inhibition of xenobiotics and other mixed function
oxidase substrates (U.S. EPA. 2008; Nakahama et al.. 2000; Hanioka et al.. 1998; Mathews et al..
1998; Barton et al.. 1995; Freundt and Macholz. 1978. 1972). The development of this
hypothesis followed observations of significant increases in hexobarbital sleeping time and
zoxazolamine paralysis times in rats exposed to trans- 1,2-DCE vapors, in which trans- 1,2-DCE
was thought to be interfering with the oxidative metabolism of hexobarbital and zoxazolamine
(Freundt and Macholz, 1978). Further experimentation led the study authors to conclude that
trans-1,2-DCE was competing for the Type 1 binding site of CYP450. In a later study. Barton et
al. (1995) showed that pre-exposure of rats to 40 ppm trans-1,2-DCE for 1.5 hours resulted in
marked inhibition of TCE and vinyl chloride metabolism by competitive inhibition.
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Numerous studies have been done to identify the specific CYP450s inhibited by
trans- 1,2-DCE, based on altered protein levels or activity. It seems that the effects on CYP450s
are likely dependent upon exposure route and may also be strain specific and tissue dependent.
For example, in hepatic microsomes extracted from Wistar rats injected with 500 mg/kg of
trans-1,2-DCE, CYP3A was suppressed but not CYP2E1 (Nakahama et al.. 2000). A similar
study in Wistar rats also found no differences in CYP2E1 protein levels in liver microsomes after
injection of-727 mg/kg for 4 consecutive days (Hanioka et al.. 1998). In male F344 rats,
however, injection of 100 mg/kg of trans- 1,2-DCE resulted in marked inhibition of hepatic
CYP2E1, with no effect on CYP3A (Mathews et al.. 1998). At least three other studies indicate
hepatic CYP2E1 as a major target of trans-\,2-DCE inhibition in F344 and S-D rats following in
vivo exposures to trans-1,2-DCE vapors (I.illy et al.. 1998; Barton et al.. 1995).
Organ specificities have also been observed. When comparing the effects on CYP450s
from liver and lung microsomes from rats injected i.p. with 500 mg/kg trans- 1,2-DCE, CYP2B
and CYP2E1 were suppressed in the lung, but not in the liver (Nakahama et al.. 2000). In the
same study, ethoxyresorufin O-deethylase (EROD) and erythromycin A'-demethylase
significantly decreased in liver microsomes; in lung, specific decreases in pentoxyresorufin
O-dealkylase (PROD) were observed (Nakahama et al.. 2000). In mice, however, PROD
significantly increased in liver microsomes at i.p. doses >213 mg/kg, indicating CYP2B1
induction (Paolini et al.. 1994; Paolini et al.. 1992).
Hani oka et al. (1998) evaluated CYP450 protein content as well as CYP450-dependent
monooxygenase activities in liver microsomes from both male and female Wistar rats injected
with -727 mg/kg trans- 1,2-DCE consecutively for 4 days, identifying possible sex differences.
In males, the protein content of the male-specific CYP2C11/6 was significantly reduced.
Decreases in testosterone 2a-hydroxylase (T2AH) activity (37% decreased) and increases in
EROD and 7-methoxyresorufin O-demethylase (MROD) activities were also observed in males
only.
Other in vivo studies in rats have evaluated the effects of trans- 1,2-DCE on liver or lung
enzyme activities. Treatment with trans- 1,2-DCE had no significant effects on the activities of
liver alcohol dehydrogenase or mitochondrial or microsomal aldehyde dehydrogenases 5 hours
following dosing with trans-1,2-DCE (100 mg/kg i.p.) (Mathews et al.. 1998); no significant
effects on liver glucose-6-phosphatase, ALP, or tyrosine transaminase in Holtzman rats
following gavage administration of 400 or 1,500 mg/kg trans-1,2-DCE (Jenkins et al.. 1972);
and no significant increases in hepatic lipid hydroperoxides in male F344 rats after an i.p. dose of
100 mg/kg (Mathews et al.. 1997). In mice, /Miitrophenol hydroxylase activities increased after
injection of 1,089 mg/kg trans-1,2-DCE (Paolini et al.. 1992). and in a 90-day oral toxicity
study, alanine hydroxylase activity was decreased in female mice at all doses tested (23, 224, and
452 mg/kg-day) (Barnes et al.. 1985).
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DERIVATION OF PROVISIONAL VALUES
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
The database of potentially relevant studies for deriving provisional reference values for
trans- 1,2-DCE is limited. No repeated-exposure inhalation studies on trans- 1,2-DCE in humans
have been identified. Available animal inhalation studies include a subchronic study in rats
exposed for up to 16 weeks (Freundt et al.. 1977). an unpublished non-peer-reviewed 90-day
study conducted by DuPont (Kelly. 1998). and a published peer-reviewed developmental toxicity
study in rats (Hurtt et al.. 1993; Haskell Laboratories, 1988). No chronic inhalation studies have
been identified.
Freundt et al. (1977) observed increased incidences of lung and liver lesions (pulmonary
capillary hyperemia and distension of the alveolar septum and fatty accumulation in liver lobules
and Kupffer cells) at 793 mg/m3 in rats exposed for up to 16 weeks. The lung lesions were
similarly observed after i.p. and oral exposures, suggesting that the effects may be systemic.
However, the precise mechanism of trans-1,2-DCE-induced lung lesions is unknown and a
potential effect due to airway exposure could not be ruled out. Therefore, FLECs were estimated
for both extrarespiratory and airway exposure pulmonary effects (FLECer of 189 mg/m3 and
FLECpu of 2,500 mg/m3, respectively). The estimated FLECer of 189 mg/m3 was ultimately
selected for all lesions because it is more sensitive. Furthermore, Freundt et al. (1977) had
several important limitations. These included the use of a single exposure concentration, which
precludes evaluation of exposure concentration-response relationships, small sample sizes
(six rats/group) that provide low statistical power to detect effects, testing of a single sex, and a
study design that did not include evaluating other relevant endpoints (e.g., organ-weight data or
clinical chemistry evaluations). Additionally, there is uncertainty in the lung and liver lesions
reported by Freundt et al. (1977) given that no histopathological changes in the lung or the liver
or any other supportive evidence of liver or respiratory toxicity were observed in rats from the
90-day inhalation study by Kelly (1998) at higher exposure concentrations (790-16,000 mg/m3).
Note that the Freundt et al. (1977) and the Kelly (1998) studies used different staining
methodologies for histopathology. Thus, it is not possible to determine whether such differences
could have contributed to the discrepancies in the histopathological findings, particularly with
respect to the liver lesions r Freundt. et al. (1977) used both H & E and a lipid stain (scarlet red)
and observed fat accumulation in the liver, while Kelly (1998) used only H & E staining and
reported no effects]. Overall, the Freundt et al. (1977) study was considered to be inadequate for
deriving a provisional reference concentration (p-RfC) because of the outstanding deficiencies in
study design and methodology outlined previously.
Decreases in WBC and lymphocyte counts were reported in rats with statistically
significant changes occurring only in males (decreased WBC and lymphocytes at 45 days and
decreased WBC at 90 days) at the highest exposure concentration (16,000 mg/m3 or an FLECer of
2,800 mg/m3) (Kelly. 1998). Furthermore, trend test results were generally statistically
significant supporting concentration-related decreases in WBC and lymphocyte counts in both
males and females (see Table B-3). When considering that alterations in circulating WBC and
lymphocytes showed consistency in the directionality and magnitude of effects across sexes and
sampling time points, the results suggest potential treatment-related effects on the immune
system. Histopathological evaluations of immune system organs (thymus, bone marrow, and
spleen) did not provide corroborative evidence of immunotoxicity, but more direct measures of
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immune function were not included in the study (Kelly. 1998). The immune system is a
sensitive target for trans- 1,2-DCE via the oral route, and suppression of humoral immunity in
mice (i.e., decreased AFC in response to sRBC challenge; see summary of Oral Toxicity Studies
for further details) was used to derive an oral RfD for this chemical (U.S. HP A. 2010). The
supportive evidence of humoral immunosuppression in mice after oral administration increases
confidence in the observed immune-related hematological response from the Kellv (1998) study.
The developmental study (Hurtt et al.. 1993; Haskell Laboratories. 1988) reported
increased ocular irritation (i.e., lacrimation) in dams at >7,930 mg/m3 (HECer: 1,980 mg/m3) and
other clinical signs (brown periocular staining, lethargy, and salivation) and mild effects on
maternal body weights (significant reductions in body-weight gain and food consumption but not
mean body weights) occurred at >23,800 mg/m3 (HECer: >5,950 mg/m3). Fetal effects,
including significant reductions in body weight and nonsignificant increases in the incidence of
hydrocephalus, were observed at the highest concentration (47,580 mg/m3 [HECer:
11,890 mg/m3]). However, confounding effects with overt maternal toxicity and the lack of
significant findings for other developmental endpoints evaluated in the study by Hurtt et al.
(1993) and Haskell Laboratories (1988) (i.e., external, visceral, and skeletal malformations)
suggest that trans- 1,2-DCE is not a potent developmental toxicant. Similarly, evidence from
reproductive/developmental studies in mice and rats exposed to a mixture of cis- and
trans- 1,2-DCE following oral administration demonstrated a lack of developmental toxicity, with
maternal toxicity occurring only at high doses (>5,778 mg/kg-day) (NTP. 1991 a. b).
In summary, the inhalation toxicity database for trans- 1,2-DCE in experimental animals
showed alterations in WBC and lymphocyte counts in rats after a 90-day exposure reflective of
potential immune-related effects (Kelly. 1998) and clinical signs of maternal toxicity related to
the irritant effects of this compound from a developmental rat study with gestational exposure
(GDs 7-16) (Hurtt et al.. 1993; Haskell Laboratories. 1988). The studies by Kelly (1998) and
Hurtt et al. (1993)/Haskett Laboratories (1988) were adequate for dose-response analysis because
they included multiple concentrations, evaluated relevant endpoints, and identified sensitive
effects at similar concentrations (HECer of 2,800 mg/m3 for Kelly (1998) and HECer:
1,980 mg/m3 for Hurtt et al. (1993) and Haskell Laboratories (1988); therefore, these studies
were considered further for benchmark concentration (BMC) modeling for potential derivation
of p-RfC values.
Derivation of a Subchronic and Chronic Provisional Reference Concentration
To provide a basis for comparing potential points of departure (PODs) and critical effects
for deriving p-RfCs for trans- 1,2-DCE, data sets for the most sensitive endpoints from the
subchronic rat study by Kelly (1998) and the developmental rat study by Hurtt et al. (1993) and
Haskell Laboratories (1988) were evaluated via Benchmark Dose Software (BMDS,
Version 3.1). Based on consistencies in the directionality and magnitude of the responses, the
decreases in WBC and lymphocytes in both males and females from the Kelly (1998) study were
modeled via BMDS and results from the longer sampling time point were preferred (90 days).
The increased lacrimation in dams from the Hurtt et al. (1993) and Haskell Laboratories (1988)
study was significant at all exposure levels but responses were high even at the lowest exposure
group (54% at HECer: 1,980 mg/m3). Based on the limited information in this data set to inform
the model fit at the low-dose region, BMDS modeling was not attempted and the corresponding
LOAEL of 1,980 mg/m3 was selected as a candidate POD for this endpoint. Increased brown
periocular staining and alopecia in dams showed a concentration-response gradient and,
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therefore, were considered amenable for BMDS modeling (Hurtt ct al.. 1993; Haskell
Laboratories. 1988). Other clinical signs in maternal animals (lethargy, salivation, and wet
perinasal hair) occurred mostly in the high-dose group and were not modeled via BMDS. The
developmental effects (reduced fetal body weight and hydrocephalus) in the Hurtt ct al. (1993)
and Haskell Laboratories (1988) study were excluded from potential POD derivation because
they were only observed at the highest concentration tested (HECer: 11,890 mg/m3) and the
interpretation of the results is confounded by the overt maternal toxicity reported at lower
exposure concentrations (HECer > 1,980 mg/m3) and the lack of additional supportive evidence
of developmental toxicity.
All available continuous and dichotomous-variable models in the BMDS were fit to the
data sets (see Table C-l) from the studies by Kelly (1998). Hurtt et al. (1993) and Haskell
Laboratories (1988). Appendix C contains details of the modeling results for these data sets.
The HEC, in mg/m3, was used as the dose metric. The benchmark response (BMR) for the
alterations in WBC and lymphocyte counts was 1 standard deviation (SD) change from control
means because no information is available regarding the change in response that would be
considered biologically significant. Incidence data for periocular staining and alopecia were
modeled using a standard BMR of 10% extra risk for dichotomous data. One or more of the
models provided adequate fit for each data set except decreased WBC and lymphocytes in
female rats. Candidate PODs, including the benchmark concentration lower confidence limits
(BMCLs) from the selected models, are presented in Table 5. Candidate PODs that were not
successfully evaluated via BMDS analysis, are presented as NOAELs and LOAELs.
The benchmark concentration lower confidence limit 1 SD (BMCLisd) (HEC) of
109 mg/m3 for decreased lymphocyte counts in males at Day 90 from the subchronic-duration rat
study (Kelly. 1998) is the lowest candidate POD in the available inhalation toxicity database for
*ra«s-l,2-DCE. Additionally, the lowest dose tested (LOAEL [HEC] of 1,980 mg/m3) in the
Hurtt et al. (1993) and Haskell Laboratories (1988) study was identified as the candidate POD
for increased lacrimation in dams after gestational exposure (GDs 7-16). The study by Kellv
(1998) is considered more appropriate for deriving subchronic and chronic p-RfCs than the Hurtt
et al. (1993) and Haskell Laboratories (1988) study because of its longer exposure duration
(90 days vs. 10 days). Also, the estimated BMCLisd for immune-related effects from the Kellv
(1998) study is at least an order of magnitude lower than the LOAEL for increased lacrimation in
Hurtt et al. (1993) and Haskell Laboratories (1988), and no evidence of ocular irritation or other
clinical signs were found in the 90-day study at lower exposure concentrations (HEC:
>140 mg/m3) (Kellv. 1998). Furthermore, the observed maternal effects in the developmental
study are related to irritant effects and other clinical signs of systemic toxicity and not associated
with reproductive/developmental function [fetal effects were only observed at the highest
concentration (HECer: 1 1,890 mg/m3) in the presence of overt maternal toxicity (Hurtt et al ..
1993; Haskell Laboratories. 1988)1. In summary, Kellv (1998) is selected as the principal study
because it identified the most sensitive POD and was adequate in experimental design and
protocol. However, because the study is not peer reviewed, screening-level p-RfC values are
derived for trans- 1,2-DCE in Appendix A, in lieu of p-RfC values.
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Table 5. Candidate PODs in Rats Exposed to trans- 1,2-DCE (CASRN 156-60-5) for
Deriving p-RfCsa
Endpoint
NOAEL (HEC)
(mg/m3)
LOAEL (HEC)
(mg/m3)
BMCL (HEC)
(mg/m3)
POD (HEC)
(mg/m3)
Kellv (1998). 90-d study
WBC counts in males
(D 90)b
710
2,800
133
133
(BMCLisd)
WBC counts in females
(D 90)b
710
2,800
DUB
(No models provided
adequate fit to data)
710
(NOAEL)
Lymphocyte counts in
males (D 90)b'c
710
2,800
109
109
(BMCLisd)
Lymphocyte counts in
females (D 90)b
710°
2,800
DUB
(No models provided
adequate fit to data)
710
(NOAEL)
Hurtt et al.
(1993); Haskell Laboratories (1988). developmental studv from GDs 7-16
Lacrimation
NDr
1,980
DUB (Limited
information in data set
to inform model fit at
the low-dose region)
1,980
(LOAEL)
Periocular stain (brown)
1,980
5,950
1,110
1,110
(BMCLio)
Alopecia
1,980
5,950
2,190
2,190
(BMCLio)
aModeling results are described in more detail in Appendix C.
bNOAEL/LOAEL determinations are based on consistent evidence (both in directionality and magnitude) of WBC
and lymphocyte changes observed across sexes and exposure durations at the highest concentration, which was
associated with statistically significant changes in males (decreased WBC and lymphocyte counts at 45 days and
decreased WBC counts at 90 days). Furthermore, trend test results were generally statistically significant
supporting concentration-related decreases in WBC and lymphocyte counts in both males and females
(see Table B-3).
°Chosen as the critical effect for deriving p-RfCs.
BMCL = benchmark concentration lower confidence limit; BMDS = Benchmark Dose Software; DUB = data
unamenable to BMDS; GD = gestation day; HEC = human equivalent concentration;
LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; NDr = not
determined; POD = point of departure; p-RfC = provisional reference concentration; SD = standard deviation;
trans-1,2-DCE = trans-1.2-dichlorocthvlcne: WBC = white blood cell.
Screening p-RfCs are summarized in Table 6 and described in Appendix A.
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Table 6. Summary of Noncancer Inhalation Reference Values for
trans- 1,2-DCE (CASRN 156-60-5)
Toxicity Type
(unit)
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
300
Kellv (1998)
Screening chronic
p-RfC (mg/m3)
Rat/M
Decreased
lymphocyte counts
4 x lQ-2
BMCLisd
109
3,000
Kellv (1998)
BMCL = benchmark concentration lower confidence limit; HEC = human equivalent concentration; M = male;
POD = point of departure; p-RfC = provisional reference concentration; SD = standard deviation;
trans-1,2-DCE = trans-1.2-dichlorocthvlcnc: UFc = composite uncertainty factor.
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APPENDIX A. SCREENING PROVISIONAL VALUES
For reasons noted in the main Provisional Peer-Reviewed Toxicity Value (PPRTV)
document, it is inappropriate to derive provisional reference concentrations (p-RfCs) for
trans-1,2-dichloroethylene {trans- 1,2-DCE). However, 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.
DERIVATION OF SCREENING PROVISIONAL INHALATION REFERENCE
CONCENTRATIONS
As discussed in the main body of the report, Kelly (1998) was an adequately designed
subchronic study that evaluated a number of endpoints following exposure to three
concentrations of trans- 1,2-DCE. This study was chosen as the principle study and the
corresponding benchmark concentration lower confidence limit 1 standard deviation (BMCLisd)
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. The observed leukopenia in rats (decreased white blood cell [WBC] and
lymphocyte counts) was determined to be treatment related and suggests potential effects on the
immune system. The critical effects for deriving a chronic oral reference dose (RfD) were based
on altered immune function in mice (U.S. HP A. 2010). which provide additional evidence to
suggest that trans-1,2-DCE targets the immune system. The Kelly (1998) study used
whole-body inhalation exposure for compound administration; therefore, additional exposure
through the gastrointestinal tract due to grooming is possible. This potential source of
uncertainty cannot be quantified based on the available information. As a conservative estimate,
the identified critical effects are assumed to be mostly due to inhalation exposure.
Derivation of Screening Subchronic Provisional Reference Concentration
The screening subchronic p-RfC is derived 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.
Screening Subchronic p-RfC = POD (HEC) ^ UFc
= 109 mg/m3 300
= 4 x 10 ' mg/m3
Table A-l summarizes the uncertainty factors for the screening subchronic p-RfC for
trans-1,2-DCE.
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Table A-l. Uncertainty Factors for the Screening Subchronic p-RfC for
trans- 1,2-DCE (CASRN 156-60-5)
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
Cateeorv 3 eas. as specified in U.S. EPA (1994) guidelines for deriving p-RfCs.
UFd
10
A UFd of 10 is applied to account for deficiencies and uncertainties in the database. The inhalation
database consists of a subchronic study that tested only a single exposure level and limited endpoints
(Freundt et al.. 19771 a comprehensive, but non-peer-reviewed subchronic studv (Kellv. 19981 and a
developmental toxicity studv (Hunt et al.. 1993; Haskell Laboratories. 19881 all in rats. However,
none of the inhalation exposure studies included immune function assays, which are considered to be
most sensitive for evaluating immunotoxicitv (Luster et al.. 19921 The lack of these assavs in the
database represents a major source of uncertainty. Indeed, the selected critical effect (decreased
lymphocyte counts) provides suggestive evidence of immunotoxicity and the oral RfD for
trans-1,2-DCE was based on suppression of humoral immunity in mice (U.S. EPA. 2010).
Additionally, there are no multigenerational reproductive toxicity studies for this chemical.
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.
UFl
1
A UFl of 1 is applied because the POD is a BMCL.
UFS
1
A UFS of 1 is applied because the POD for the subchronic p-RfC was derived from subchronic data.
UFC
300
Composite UF = UFA x UFD x UFH x UFL x UFS.
BMCL = benchmark concentration lower confidence limit; HEC = human equivalent concentration;
LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; POD = point of
departure; p-RfC = provisional reference concentration; RfD = oral reference dose;
trans- 1,2-DCE = trans-1.2-dichlorocthvlene: 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 Screening Chronic Provisional Reference Concentration
In the absence of available chronic inhalation studies on trans- 1,2-DCE, the POD from
the subchronic study by Kelly (1998) was used to derive a screening chronic p-RfC. The
screening chronic p-RfC is derived by applying a UFc of 3,000 (reflecting a UFa of 3, a UFh of
10, a UFd of 10, and a sub chronic-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.
Screening Chronic p-RfC = POD (HEC) UFc
= 109 mg/m3 3,000
= 4 x 1 () 2 mg/m3
Table A-2 summarizes the uncertainty factors for the screening chronic p-RfC for
trans-1,2-DCE.
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Table A-2. Uncertainty Factors for the Screening Chronic p-RfC for
trans- 1,2-DCE (CASRN 156-60-5)
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
Cateeorv 3 eas. as specified in U.S. EPA (1994) guidelines for deriving p-RfCs.
UFd
10
A UFd of 10 is applied to account for deficiencies and uncertainties in the database. The inhalation
database consists of a subchronic studv that tested onlv a sinsle exposure level (Freundt et al.. 19771
a comprehensive, but non-peer-reviewed subchronic studv (Kellv. 19981 and a developmental
toxicity studv (Hunt et al.. 1993; Haskell Laboratories. 19881 all in rats. However, none of the
inhalation exposure studies included immune function assays, which are considered to be most
sensitive for evaluating immunotoxicitv (Luster et al.. 19921 The lack of these assavs in the database
represents a major source of uncertainty. Indeed, the selected critical effect (decreased lymphocyte
counts) provides suggestive evidence of immunotoxicity and the oral RfD for trans- 1,2-DCE was
based on suppression of humoral immunitv in mice (U.S. EPA. 2010). Additionally. there are no
multigenerational reproductive toxicity studies for this chemical.
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.
UFl
1
A UFl of 1 is applied because the POD is a BMCL.
UFS
10
A UFS of 10 is applied because the POD for the chronic p-RfC was derived from subchronic data.
UFC
3,000
Composite UF = UFA x UFD x UFH x UFL x UFS.
BMCL = benchmark concentration lower confidence limit; HEC = human equivalent concentration;
LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; POD = point of
departure; p-RfC = provisional reference concentration; RfD = oral reference dose;
trans- 1,2-DCE = trans-1.2-dichlorocthvlene: 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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APPENDIX B. DATA TABLES
Table B-l. Human Exposure to trans- 1,2-DCE (CASRN 156-60-5) Vapors3
Concentration (mg/m3)
Exposure Time (min)
Effectb
1,090
5
No effect
3,270
10
Slight dizziness after 5 min
3,770
5
Slight burning of eyes
3,960
30
Dizziness after 10 min; slight burning of eyes
4,758
10
Dizziness after 5 min; drowsiness; slight burning of eyes
6,740
5
Dizziness after 3 min; slight burning of eyes; "intracranial
pressure"; nausea that persisted for a half an hour after exposure
8,723
5
Severe dizziness after 5 min; "intracranial pressure"; nausea that
persisted for half an hour after exposure
"Lchmann and Schmidt-Kehl as cited in U.S. EPA (2008).
bEffects were self-reported.
trans-1,2-DCE = trans-1.2-dichlorocthvlcne.
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Table B-2. Incidence of Lesions in Female Wistar Rats Exposed to
trans- 1,2-DCE (CASRN 156-60-5) Vapors3
Exposure Duration and
Concentration [HECer]1"
in mg/m3
Fat Accumulation in
Liver Lobule
Fat Accumulation in
Kupffer Cells
Capillary Hyperemia and
Alveolar Septum
Distension in the Lung
1 wk
0
793 [189]
0/6 (0%) [NA]°
2/6 (33%) [+]
0/6 (0%) [NA]
2/6 (33%) [+]
1/6 (17%) [+]
6/6* (100%) [+]
2 wk
0
793 [189]
0/6 (0%) [NA]
4/6 (67%) [+]
0/6 (0%) [NA]
4/6 (67%) [+]
2/6 (33%) [+]
6/6 (100%) [+]
8 wk
0
793 [189]
0/6 (0%) [NA]
3/6 (50%) [+]
1/6 (17%) [++]
3/6 (50%) [++]
0/6 (0%) [NA]
6/6* (100%) [+]d
16 wk
0
793 [189]
2/6 (33%) [+]
5/6 (83%) [+(2), ++(3)]
2/6 (33%) [+]
5/6 (83%) [+]
0/6 (0%) [NA]
6/6* (100%) [+]d
aFreimdt et at (1977).
bAlthough the study authors considered the lung lesions systemic in nature based on similar observations after i.p.
and oral exposure routes, the potential contribution of airway exposure cannot be ruled out [see study summary for
Kelly (1998) in the "Animal Studies" section for more details]. Therefore, the vapor concentration of 793 mg/m3
was converted to HECs for both extrarespiratory (HECer of 189 mg/m3) and airway exposure pulmonary effects
(HECpu of 2,500 mg/m3). The HECer was ultimately selected for all lesions because it is more sensitive.
°Values denote number of animals showing changes total number of animals examined (% incidence) [severity,
graded as + = slight change or ++ = severe change].
dThree rats exhibited severe pneumonic infiltration.
* Significantly different from control by two-tailed Fisher's exact test (p < 0.05), as conducted for this review.
ER = extrarespiratory; HEC = human equivalent concentration; NA = not applicable; PU = pulmonary effects;
trans-1,2-DCE = trans-1.2-dichlorocthvlene.
40
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Table B-3. Select Hematological Results in Male and Female Crl:CD (SD) BR Rats
Exposed to trans- 1,2-DCE (CASRN 156-60-5) Vapors for 6 Hours/Day, 5 Days/Week
for 90 Days3
Endpoint
Exposure Concentration [HECer] in mg/m3
0
790 [140]
4,000 [710]
16,000 [2,800]
Male
Hemoglobin (g/dL)
D 45
16.1 ±0.7b-c
15.6 ± 0.5 (-3%)
15.3 ± 0.4* (-5%)
15.4 ± 0.7* (-4%)
D 90
15.8 ±0.6
15.4 ± 0.5 (-3%)
15.9 ± 0.6 (+1%)
15.8 ± 0.4 (0%)
Hematocrit (%)
D 45
47 ±3
45 ± 2 (-4%)
44 ± 2* (-6%)
44 ± 2* (-6%)
D 90
47 ±2
45 ± 2 (-4%)
46 ± 2 (-2%)
47 ± 2 (0%)
WBC (x 103/fiL)
D 45
17.2 ± 2.3#
15.0 ± 2.3 (-13%)
16.5 ±4.1 (-4%)
13.9 ± 1.6* (-19%)
D 90
15.7 ± 2.0#
13.6 ±2.5 (-13%)
13.6 ±3.4 (-13%)
12.6 ± 1.8 (-20%)
Lymphocytes (/(iL)
D 45
13,953 ± 2,321#
12,187 ±2,293 (-13%)
13,766 ± 3,455 (-1%)
10,451 ± 900* (-25%)
D 90
12,901 ± 1,961#
10,670 ±2,189 (-17%)
10,706 ± 2,766 (-17%)
9,597 ± 1,230* (-26%)
Monocytes (/jliL)
D 45
1,689 ±585
1,221 ± 570 (-28%)
1,367 ± 754 (-19%)
2,020 ± 913 (+19%)
D 90
1,449 ± 443
1,455 ±515 (+0.4%)
1,269 ± 494 (-12%)
1,441 ±620 (-0.6%)
Female
Hemoglobin (g/dL)
D 45
15.2 ± 1.0
15.0 ± 0.2 (-1%)
15.0 ± 0.7 (-1%)
14.8 ± 0.6 (-3%)
D 90
15.3 ±0.8
15.0 ± 0.6 (-2%)
15.1 ± 0.9 (-1%)
15.3 ± 0.5 (0%)
Hematocrit (%)
D 45
44 ±3
44 ± 1 (0%)
44 ± 2 (0%)
43 ± 2 (-2%)
D 90
46 ±2
46 ± 2 (0%)
46 ± 2 (0%)
46 ± 2 (0%)
WBC (x 103/fiL)
D 45
15.5 ± 4.9#
13.5 ±2.7 (-13%)
13.2 ±3.3 (-15%)
12.1 ± 2.2 (-22%)
D 90
11.7 ± 4.5
10.1 ±0.9 (-14%)
9.0 ± 2.3 (-23%)
9.6 ±2.1 (-18%)
41
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Table B-3. Select Hematological Results in Male and Female Crl:CD (SD) BR Rats
Exposed to trans- 1,2-DCE (CASRN 156-60-5) Vapors for 6 Hours/Day, 5 Days/Week
for 90 Days3
Endpoint
Exposure Concentration [HECer] in mg/m3
0
790 [140]
4,000 [710]
16,000 [2,800]
Lymphocytes (/(iL)
D 45
13,295 ±4,389
11,508 ±2,792 (-13%)
11,244 ±2,880 (-15%)
10,516 ± 1,989 (-21%)
D 90
10,239 ± 4,147#
8,337 ± 892 (-19%)
7,705 ± 2,147 (-25%)
7,948 ± 1,943 (-22%)
Monocytes (/jliL)
D 45
1,204 ±534
801 ±299 (-33%)
927 ± 622 (-23%)
606 ± 273*(-50%)
D 90
627 ± 372
792 ± 378 (+26%)
519 ±341 (-17%)
700 ± 475 (+12%)
aKellv (1998).
bData are mean ± SD for 10 rats/group.
°Value in parentheses is % change relative to control = [(treatment mean - control mean) + control mean] x 100.
* Significantly different from control by Dunnett's multiple comparison test (p < 0.05), as reported by the study
author.
"Statistically significant trend according to ordinary one-way ANOVA test for linear trend performed for the
purposes of this assessment using GraphPad Prism software (Version 8.4.2) to evaluate potential treatment-related
hematological changes (i.e., WBC and lymphocyte counts) (GraphPad. 2018).
ANOVA = analysis of variance; ER = extrarespiratory; HEC = human equivalent concentration; SD = standard
deviation; /ra«s-l,2-DCE = trans-1.2-dichlorocthvlcnc: WBC = white blood cell.
42
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Table B-4. Select Serum Biochemistry Results in Male and Female Crl:CD (SD) BR Rats
Exposed to trans- 1,2-DCE (CASRN 156-60-5) Vapors for 6 Hours/Day, 5 Days/Week
for 90 Days3
Endpoint
Exposure Concentration [HECer] in mg/m3
0
790 [140]
4,000 [710]
16,000 [2,800]
Male
ALP (U/L)
D 45
124 ± 27b-c
103 ± 20 (-17%)
122 ± 17 (-2%)
106 ± 20 (-15%)
D 90
90 ±22
76 ± 10 (-16%)
89 ± 10 (-1%)
81 ± 17 (-10%)
ALT (U/L)
D 45
43 ±6
39 ± 7 (-9%)
38 ± 5 (-12%)
38 ± 7 (-12%)
D 90
44 ± 12
38 ± 7 (-14%)
71 ± 108 (+61%)
40 ± 6 (-9%)
AST (U/L)
D 45
106 ± 29
83 ± 10 (-22%)
88 ± 13 (-17%)
97 ± 26 (-8)
D 90
103 ±25
85 ± 20} (-17)
124 ± 98 (+20%)
96 ± 18 (-7%)
SDH (U/L)
D 45
20.6 ±4.4
16.6 ± 4.5 (-19%)
13.6 ±3.6* (-34%)
15.4 ± 4.4* (-25%)
D 90
18.7 ±4.3
14.1 ±4.6} (-25%)
22.5 ± 25.5 (+20%)
14.9 ± 2.9 (-20%)
Albumin (g/dL)
D 45
4.7 ±0.1
4.5 ± 0.2* (-4%)
4.5 ± 0.2* (-4%)
4.4 ± 0.2* (-6%)
D 90
4.7 ±0.2
4.6 ± 0.2 (-2%)
4.8 ± 0.3 (+2%)
4.8 ± 0.2 (+2%)
Glucose (mg/dL)
D 45
90 ±7
96 ± 5 (+7%)
97 ± 8 (+8%)
106 ± 14* (+18%)
D 90
98 ±8
107 ± 12 (+9%)
112 ± 17 (+14%)
117 ± 12* (+19%)
Female
ALP (U/L)
D 45
58 ±9
74 ± 12} (+28%)
70 ± 24 (+21%)
60 ± 9 (+3%)
D 90
38 ± 12
47 ± 8 (+24%)
46 ± 16 (+21%)
46 ± 8 (+21%)
ALT (U/L)
D 45
39 ± 12
32 ± 5 (-18%)
37 ± 8 (-5%)
34 ± 3 (-13%)
D 90
35 ±7
31 ±5 (-11%)
37 ± 8 (+6%)
41 ±23 (+17%)
AST (U/L)
D 45
88 ± 17
86 ± 13 (-2%)
83 ± 10 (-6%)
78 ±9 (-11%)
D 90
86 ± 19
78 ± 5 (-9%)
79 ± 16 (-8%)
88 ± 34 (+2%)
SDH (U/L)
D 45
19.0 ±4.0
15.3 ± 1.9* (-19%)
15.7 ±2.3* (-17%)
13.0 ± 1.9* (-32%)
D 90
15.1 ± 3.5
14.1 ±2.4 (-7%)
13.7 ±3.4 (-9%)
15.1 ± 10.2 (0%)
43
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Table B-4. Select Serum Biochemistry Results in Male and Female Crl:CD (SD) BR Rats
Exposed to trans- 1,2-DCE (CASRN 156-60-5) Vapors for 6 Hours/Day, 5 Days/Week
for 90 Days3
Endpoint
Exposure Concentration [HECer] in mg/m3
0
790 [140]
4,000 [710]
16,000 [2,800]
Albumin (g/dL)
D 45
5.6 ±0.4
5.1 ±0.2* (-9%)
5.7 ± 0.6 (+2%)
5.6 ± 0.4 (0%)
D 90
5.8 ±0.5
5.5 ± 0.5 (-5%)
5.8 ± 0.6 (0%)
5.8 ± 0.3 (0%)
Glucose (mg/dL)
D 45
97 ±9
100 ±11 (+3%)
102 ± 10 (+5%)
108 ±8 (+11%)
D 90
103 ±9
108 ± 8 (+5%)
114 ± 15 (+11%)
121 ±15* (+17)
aKellv (1998).
bData are mean ± SD for 10 rats/group.
0Value in parentheses is % change relative to control = [(treatment mean - control mean) + control mean] x 100.
* Significantly different from control by Dunnett's multiple comparison test (p < 0.05), as reported by the study
author.
{Significantly different from control by Mann-Whitney U test (p < 0.05), as reported by the study author.
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; ER = extrarespiratory;
HEC = human equivalent concentration; SD = standard deviation; SDH = sorbitol dehydrogenase;
trans-1,2-DCE = trans-1.2-dichlorocthvlcne.
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Table B-5. Select Organ Weights of Male and Female Crl:CD (SD) BR Rats Exposed to
trans- 1,2-DCE (CASRN 156-60-5) Vapors for 6 Hours/Day, 5 Days/Week for 90 Days3
Endpoint
Exposure Concentration [HECer] in mg/m3
0
790 [140]
4,000 [710]
16,000 [2,800]
Male
Final body weight (g)
477.6 ±50.2b-c
475.6 ± 40.3 (-0.4%)
454.8 ± 32.7 (-5%)
485.1 ± 52.2 (+2%)
Liver, absolute (g)
12.886 ± 1.857
13.451 ± 1.607 (+4%)
13.267 ± 1.516 (+3%)
13.652 ±2.003 (+6%)
Liver, relative (% BW)
2.693 ±0.187
2.824 ±0.179 (+5%)
2.914 ±0.201 (+8%)
2.808 ±0.191 (+4%)
Kidney, absolute (g)
3.463 ±0.325
3.618 ±0.391 (+4%)
3.518 ±0.239 (+2%)
3.626 ±0.256 (+5%)
Kidney, relative (% BW)
0.728 ±0.071
0.761 ± 0.06 (+5%)
0.775 ± 0.048 (+6)
0.752 ± 0.059 (+3%)
Adrenals, absolute (g)
0.059 ±0.007
0.063 ± 0.008 (+7%)
0.052 ± 0.007 (-12%)
0.056 ± 0.01 (-5%)
Adrenals, relative (% BW)
0.012 ±0.002
0.013 ± 0.002 (+8%)
0.012 ±0.001 (0%)
0.011 ±0.002 (-8%)
Female
Final body weight (g)
267.8 ±28.9
271.2 ±21.1 (+1%)
272.6 ± 23 (+2%)
274.2 ±21.1 (+2%)
Liver, absolute (g)
7.677 ± 0.0985
7.925 ± 1.158 (+3%)
8.195 ±0.771 (+7%)
8.312 ±0.825 (+8%)
Liver, relative (% BW)
2.877 ±0.342
2.918 ± 0.297 (+1%)
3.014 ±0.275 (+5%)
3.043 ±0.324 (+6%)
Kidney, absolute (g)
1.976 ±0.296
1.963 ±0.216 (-0.7%)
2.109 ±0.203 (+7%)
2.077 ±0.159 (+5%)
Kidney, relative (% BW)
0.737 ±0.057
0.724 ±0.051 (-2%)
0.775 ± 0.067 (+5%)
0.76 ± 0.067 (+3%)
Adrenals, absolute (g)
0.065 ± 0.009
0.066 ± 0.009 (+2%)
0.07 ± 0.007 (+8%)
0.065 ± 0.016 (0%)
Adrenals, relative (% BW)
0.024 ± 0.003
0.024 ± 0.003 (0%)
0.026 ± 0.004 (+8%)
0.024 ± 0.005 (0%)
aKellv (1998).
bData are mean ± SD for 10 rats/group.
0Value in parentheses is % change relative to control = [(treatment mean - control mean) control mean] x 100.
* Significantly different from control by Dunnett's multiple comparison test (p < 0.05), as reported by the study
author.
BW = body weight; ER = extrarespiratory; HEC = human equivalent concentration; SD = standard deviation;
trans-1,2-DCE = trans-1.2-dichlorocthvlcnc.
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September 2020
Table B-6. Select Clinical Signs of Female Crl:CD (SD) BR Rats Exposed to
trans- 1,2-DCE (CASRN 156-60-5) Vapors for 6 Hours/Day during GDs 7-16a'b
Endpoint
Exposure Concentration [HECer] in mg/m3
0
7,930 [1,980]
23,800 [5,950]
47,580 [11,890]
GDs 7-16
Alopecia
1/24 (4%)°
2/24 (8%)
9/24* (38%)
19/24* (79%)
Lacrimation
0/24 (0%)
13/24* (54%)
22/24* (92%)
24/24* (100%)
Lethargy
0/24 (0%)
0/24 (0%)
0/24 (0%)
10/24* (42%)
Salivation
0/24 (0%)
0/24 (0%)
2/24 (8%)
17/24* (71%)
Periocular stain (brown)
1/24 (4%)
3/24 (13%)
18/24* (75%)
22/24* (92%)
Wet perinasal hair
0/24 (0%)
0/24 (0%)
1/24 (4%)
10/24* (42%)
GDs 17-22
Alopecia
1/24 (4%)
6/24 (25%)
7/24* (29%)
11/24* (46%)
aHurtt et at (1993): Haskell Laboratories (1988).
bObservations in home cage outside of exposure period.
°Values denote number of animals showing changes total number of animals examined (% incidence).
* Significantly different from control by Fisher's exact test (p < 0.05), conducted for this review.
ER = extrarespiratory; GD = gestation day; HEC = human equivalent concentration;
trans-1,2-DCE = trans-1.2-dichlorocthvlcnc.
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September 2020
Table B-7. Mean Body Weights and Body-Weight Change of Maternal Crl:CD (SD) BR
Rats Exposed to trans- 1,2-DCE (CASRN 156-60-5) Vapors for 6 Hours/Day
during GDs 7-16a
GDs
Exposure Concentration [HECer] in mg/m3
0
7,930 [1,980]
23,800 [5,950]
47,580 [11,890]
(n = 22)
(n = 24)
(n = 24)
(n = 23)b
Mean body weights (g)
GD 1
271.5 ± 18.4c d
270.3 ± 15.04 (-0.4%)
271.4 ± 17.22(0%)
270.2 ± 14.22 (-0.5%)
GD 7 (exposure start)
306.3 ±21.28
304.4 ± 18.64 (-0.6%)
307.1 ±18.18 (+0.3%)
302.1 ± 17.1 (-1%)
GD 9
310.6 ± 19.87
309.9 ± 19.72 (-0.2%)
309.5 ± 18.88 (-0.4%)
298.1 ± 15.75 (-4%)
GD 11
318.1 ±22.29
318.5 ± 19.6 (+0.1%)
317.1 ±20.39 (-0.3%)
304.3 ± 13.29 (-4%)
GD 13
331.2 ±23.24
329 ± 20.77 (-0.7%)
325.1 ±21.48 (-2%)
313.2 ± 14.75 (-5%)
GD 15
342.4 ±23.91
338 ± 22.65 (-1%)
334.5 ± 19.36 (-2%)
323.1 ±15.69 (-6%)
GD 17 (exposure end)
356.3 ±24.85
352.2 ± 25.2 (-1%)
350.4 ± 20.57 (-2%)
336.1 ± 18.15 (-6%)
GD 22
442.4 ±30.55
439.9 ± 26.52 (-0.6%)
442.1 ±23.69 (-0.1%)
422.4 ± 25.34 (-5%)
Mean body-weight change (g)
GDs 1-7
34.8 ±7.24
34.1 ± 7.04 (-2%)
35.8 ±6.61 (+3%)
32.4 ± 11.14 (-7%)
GDs 7-9 (exposure
start)
4.4 ± 10.13}
5.5 ± 4.75 (+25%)
2.4 ± 5.97 (-45%)
-4.9 ± 10.59* (-211%)
GDs 9-11
7.5 ±7.88
8.6 ± 5.07 (+15%)
7.6 ± 6.18 (+1%)
6.2 ±6.31 (-17%)
GDs 11-13
13.1 ±6.55}
10.6 ± 5.69 (-19%)
8 ±7.53* (-39%)
8.9 ± 4.6* (-32%)
GDs 13-15
11.2 ±2.82
9 ± 4.97 (-20%)
9.5 ± 6.66 (-15%)
9.9 ± 5.34 (-12%)
GDs 15-17 (exposure
end)
13.8 ±4.06
14.2 ± 5.82 (+3%)
15.9 ±6.11 (+15%)
13 ± 5.89 (-6%)
GDs 7-17 (total
exposure period)
50 ± 12.73}
47.8 ± 12.26 (-4%)
43.3 ± 10.91 (-13%)
33.4 ± 14.59* (-33%)
GDs 17-22
(postexposure)
86.1 ± 11.29
87.7 ± 8.37 (+2%)
91.7 ±9.94 (+7%)
86.3 ±11.42 (+0.2%)
Final BW (without
products of
conception)
345.3
341.2 (-1%)
343.5 (-1%)
333.2 (-4%)
aHurtt et at (1993): Haskell Laboratories (1988).
bWeight for one animal was not recorded on GD 7 (n = 22).
Data are mean ± SD.
dValue in parentheses is % change relative to control = [(treatment mean - control mean) + control mean] x 100.
* Significantly different from control by Dunnett's test (p < 0.05), as reported by the study authors.
{Significant trend by linear combination of dose ranks from ANOVA (p < 0.05), as reported by the study authors.
ANOVA = analysis of variance; BW = body weight; ER = extrarespiratory; GD = gestation day; HEC = human
equivalent concentration; ;ra«.v-1.2-DCE = /rcw/.v- 1.2-dichlorocthvlcnc.
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September 2020
Table B-8. Mean Feed Consumption of Maternal Crl:CD (SD) BR Rats Exposed to
trans- 1,2-DCE (CASRN 156-60-5) Vapors for 6 Hours/Day during GDs 7-16a
GDs
Exposure Concentration [HECer] in mg/m3
0
7,930 [1,980]
23,800 [5,950]
47,580 [11,890]
(n = 22)
(n = 24)
(n = 24)
(n = 23)
GDs 1-7
22.0 ± 3.04b,c
21.3 ±2.24 (-3%)
22.3 ± 2.09 (+1%)
22.6 ± 2.46 (+3%)
GDs 7-9 (exposure start)
21.7 ±5.34}
20.7 ±3.09 (-5%)
19.4 ±2.52 (-11%)
16.2 ± 3.37* (-25%)
GDs 9-11
23.2 ±3.58}
21.5 ±3.42 (-7%)
19.1 ±2.97* (-18%)
18 ±3.95* (-22%)
GDs 11-13
23.3 ±4.83}
21.9 ±3.14 (-6%)
20.7 ±3.01* (-11%)
20.2 ± 2.45* (-13%)
GDs 13-15
24.9 ±2.66}
22.3 ±3.04* (-10%)
21.2 ±2.67* (-15%)
21.7 ±2.76* (-13%)
GDs 15-17 (exposure end)
25.7 ±2.6}
24.1 ± 3.5 (-6%)
23.6 ±2.27* (-8%)
23.7 ±2.88 (-8%)
GDs 7-17 (total exposure
period)
23.7 ±2.85}
22.1 ±2.71 (-7%)
20.8 ± 1.82* (-12%)
20 ± 2.39* (-16%)
GDs 7-22 (post exposure)
28.0 ±2.44
27.5 ±2.51 (-2%)
28.6 ± 2.5 (+2%)
28.9 ±3.16 (+3%)
aHurtt et at (1993): Haskell Laboratories (1988).
bData are mean ± SD in units of g feed/day.
0Value in parentheses is % change relative to control = [(treatment mean - control mean) control mean] x 100.
* Significantly different from control by Dunnett's Test (p < 0.05), as reported by the study authors.
{Significant trend by linear combination of dose ranks from ANOVA (p < 0.05), as reported by the study authors.
ANOVA = analysis of variance; ER = extrarespiratory; GD = gestation day; HEC = human equivalent
concentration; SD = standard deviation; trans-1,2-DCE = trans-1.2-dichlorocthvlcnc.
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September 2020
Table B-9. Select Reproductive and Fetal Outcomes Following Maternal Crl:CD (SD) BR
Rat Exposure to trans- 1,2-DCE (CASRN 156-60-5) Vapors for 6 Hours/Day
during GDs 7-16a
Endpoint
Exposure Concentration [HECer] in mg/m3
0
7,930 [1,980]
23,800 [5,950]
47,580 [11,890]
Number pregnant
22
24
24
24
Number of litters
22
24
24
23b
Mean number per litter
Live fetuses (total)
15.3 ± 0.550, d
15.0 ± 0.49 (-2%)
15.3 + 0.44 (0%)
14.3 + 0.49 (-7%)
Resorptions
Total
0.3 ±0.12}
0.6 ± 0.20 (+100%)
0.8 + 0.16* (+167%)
1.1 + 0.27* (+267%)
Early
0.3 ±0.12}
0.6 ±0.19 (+100%)
0.8 + 0.16* (+167%)
1.1 + 0.27* (+267%)
Late
0.0 ±0.00
0.0 ±0.04
0.0 + 0.04
0.0 + 0.00
Mean fetal weight (g) per litter
Total
4.97 ±0.08}
5.13±0.07 (+3%)
5.01 + 0.06 (+0.8%)
4.76 + 0.09* (-4%)
Male
5.05
5.27 (+4%)
5.19 (+3%)
4.96 (-2%)
Female
4.88}
5.00 (+2%)
4.86 (-0.04%)
4.59* (-6%)
aHurtt et at (1993): Haskell Laboratories (1988).
bOne animal delivered on Study Day 18 with term fetuses and the animals were removed from the study.
Data are mean ± SE. No SE values were provided for some data sets.
dValue in parentheses is % change relative to control = [(treatment mean - control mean) + control mean] x 100.
* Significantly different from controls by Mann-Whitney U test (p < 0.05), as reported by the study authors.
{Significant trend by Jonckheere's test, as reported by the study authors.
ER = extrarespiratory; GD = gestation day; HEC = human equivalent concentration; SE = standard error;
trans-1,2-DCE = trans-1.2-dichlorocthvlcnc.
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APPENDIX C. BENCHMARK CONCENTRATION MODELING RESULTS
Benchmark concentration (BMC) modeling is conducted with U.S. EPA's Benchmark
Dose Software (BMDS, Version 3.1). All continuous models available within the software are
fit using a default benchmark response (BMR) of 1 standard deviation (SD) relative risk (RR)
unless a biologically determined BMR is available (e.g., BMR 10% relative deviation [RD] for
body weight based on a biologically significant weight loss of 10%), as outlined in the
Benchmark Dose Technical Guidance (U.S. EPA. 2012b). For the decreased white blood cell
(WBC) and lymphocyte counts, a standard BMR of 1 SD change from the control means was
attempted. All available dichotomous-variable models in the BMDS were fit to the incidence
data on brown periocular stain and alopecia using a BMR of 10% extra risk typically used for
dichotomous data sets.
An adequate fit is judged based on the x2 goodness-of-fitp-walue (p> 0.1), magnitude of
the scaled residuals in the vicinity of the BMR, and visual inspection of the model fit. In
addition to these three criteria forjudging adequacy of model fit, a determination is made as to
whether the variance across dose groups is homogeneous. If a homogeneous variance model is
deemed appropriate based on the statistical test provided by BMDS (i.e., Test 2), the final BMD
results are estimated from a homogeneous variance model. If the test for homogeneity of
variance is rejected (p-value < 0.1), the model is run again while modeling the variance as a
power function of the mean to account for this nonhomogeneous variance. If this
nonhomogeneous variance model does not adequately fit the data (i.e., Test 3; p-w alue < 0.1), the
data set is considered unsuitable for BMD modeling. Among all models providing adequate fit,
the lowest benchmark concentration lower confidence limit (BMCL) is selected if the BMCL
estimates from different models vary >threefold; otherwise, the BMCL from the model with the
lowest Akaike's information criterion (AIC) is selected as a potential point of departure (POD)
from which to derive the provisional reference concentration (p-RfC).
In addition, in the absence of a mechanistic understanding of the biological response to a
toxic agent, data from exposures much higher than the study lowest-observed-adverse-effect
level (LOAEL) do not provide reliable information regarding the shape of the response at low
doses. Such exposures, however, can have a strong effect on the shape of the fitted model in the
low-dose region of the dose-response curve. Thus, if lack of fit is due to characteristics of the
dose-response data for high doses, then the Benchmark Dose Technical Guidance (U.S. EPA.
2012b) document allows for data to be adjusted by eliminating the high-dose group. Because the
focus of BMC analysis is on the low-dose regions of the response curve, elimination of the
high-dose group is deemed reasonable.
BMC MODELING TO IDENTIFY POTENTIAL POINTS OF DEPARTURE FOR THE
DERIVATION OF PROVISIONAL REFERENCE CONCENTRATIONS
The selected data sets from the subchronic study by Kcllv (1998) and the developmental
study by Hurtt et al. (1993) and Haskell Laboratories (1988) were used to determine potential
PODs for the p-RfCs for trans- 1,2-DCE, using BMC analysis. Table C-l shows the data that
were modeled. Summaries of modeling approaches and results (see Tables C-2 to C-l and
Figures C-l to C-4) for each data set follow.
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Table C-l. Selected Data Sets in Rats Exposed to trans- 1,2-DCE (CASRN 156-60-5)
via Inhalation
Reference/Endpoint
Exposure Concentration [HECer]3 in mg/m3
Kellv (1998). Crl:CD (SD) BR Rats. 90 Db
0
790 [140]
4,000 [710]
16,000 [2,800]
Number of animals
10
10
10
10
WBC in males (D 90)
15.7 ± 2.0#
13.6 ±2.5 (-13%)
13.6 ±3.4 (-13%)
12.6 ± 1.8 (-20%)
WBC in females (D 90)
11.7 ± 4.5
10.1 ±0.9 (-14%)
9.0 ± 2.3 (-23%)
9.6 ±2.1 (-18%)
Lymphocytes in males (D 90)
12,901 ± 1,961#
10,670 ±2,189
(-17%)
10,706 ± 2,766
(-17%)
9,597 ± 1,230*
(-26%)
Lymphocytes in females (D 90)
10,239 ± 4,147#
8,337 ±892
(-19%)
7,705 ±2,147
(-25%)
7,948 ± 1,943
(-22%)
Hurtt et al. (1993): Haskell Laboratories (1988). Crl:CD (SD) BR Rats. GDs 7-16'
0
7,930 [1,980]
23,800 [5,950]
47,580 [11,890]
Periocular stain (brown)
1/24 (4%)
3/24 (13%)
18/24} (75%)
22/24} (92%)
Alopecia
1/24 (4%)
2/24 (8%)
9/24} (38%)
19/24} (79%)
'HEC calculated by treating trans- 1,2-DCE as a Category 3 gas and using the following equation from U.S. EPA
(1994) methodology: HECer = exposure concentration (mg/m3) x (hours/day exposed ^ 24 hours) x (days/week
exposed 7 days) x ratio of blood-gas partition coefficient (animal:human), using a default coefficient of 1
because the rat blood-air coefficient of 9.58 is greater than the human blood-air coefficient of 6.04 as indicated by
Gargas et al. (1989).
bWBC (x 105V|iL) and lymphocyte (/|iL) numbers are expressed as mean ± SD (% change relative to control).
°Values denote number of animals showing changes total number of animals examined (% incidence).
* Significantly different from control by Dunnett's multiple comparison test (p < 0.05), as reported by the study
authors.
{Significantly different from control by Fisher's exact test (p < 0.05), conducted for this review.
"Statistically significant trend according to ordinary one-way ANOVA test for linear trend performed for the
purposes of this assessment using GraphPad Prism software (Version 8.4.2) to evaluate potential treatment-related
hematological changes (i.e., WBC and lymphocyte counts) (GraphPad. 2018).
ANOVA = analysis of variance; ER = extrarespiratory; GD = gestation day; HEC = human equivalent
concentration; SD = standard deviation; /raws-1,2-DCE = trans-1.2-dichlorocthvlcne: WBC = white blood cell.
Model Predictions for Decreased WBC Counts in Male Rats Exposed to trans- 1,2-DCE via
Inhalation for 90 Days ("Kelly, 1998)
The procedure outlined above for continuous data was applied to the data set for
decreased WBC counts in male rats after exposure for 90 days (Kelly. 1998). Table C-2 and
Figure C-l summarize the BMC modeling results. The constant variance models provided
adequate fit to the variance data (variancep-walue > 0.1), and adequate fit to the means was
provided by several of the included models (means ^-value > 0.1). The BMCLs for models
providing an adequate fit differed by >threefold, thus the model with the lowest BMCL was
selected (Exponential 5). The BMCLisd of 133 mg/m3 from the Exponential model 5 was
selected for decreased WBC counts in males.
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Table C-2. Modeling Results for Decreased WBC Counts in Male Rats Exposed to trans- 1,2-DCE (CASRN 156-60-5) via Inhalation
for 90 Days3
Model
Test for Significant
Difference />-Valucb
Variance
/>-Valuce
Means
/>-Valuce
Scaled Residuals
for Dose Groupd
AIC
BMCisd (mg/m3)
BMCLisd
(mg/m3)
Constant variance
Exponential (Model 2)e
0.04099776
0.174513339
0.156401211
0.212559996
192.3945021
3,275.314951
1,719.70436
Exponential (Model 3)e
0.04099776
0.174513339
0.156401221
0.212487866
192.394502
3,275.332975
1,719.682637
Exponential (Model 4)e
0.04099776
0.174513339
0.05407706
0.212621957
194.3941595
3,275.539589
0
Exponential (Model 5)e'f
0.04099776
0.174513339
0.543286877
0.802073003
189.9040762
425.1746178
133.2237321
Hill6
0.04099776
0.174513339
0.413399464
-0.169460913
191.3528436
358.1910446
0
Polynomial (2-degree)8
0.04099776
0.174513339
0.151267381
0.192437023
192.4612532
3,293.272638
1,844.258957
Polynomial (3-degree)8
0.04099776
0.174513339
0.151267382
0.192474079
192.4612532
3,293.221903
1,844.234034
Power6
0.04099776
0.174513339
0.151267382
0.192462701
192.4612532
3,293.237904
1,844.266277
Linear8
0.04099776
0.174513339
0.151267382
0.19247013
192.4612532
3,293.229914
1,844.265035
aKellv (1998).
bValues >0.05 fail to meet conventional goodness-of-fit criteria.
°Values <0.10 fail to meet conventional goodness-of-fit criteria.
dScaled residuals at dose closest to BMC.
Tower restricted to >1.
Selected model. Lowest AIC among models that provided an adequate fit.
Coefficients restricted to be negative.
AIC = Akaike's information criterion; BMC = benchmark concentration; BMCL = benchmark concentration lower confidence limit; SD = standard deviation;
trans-1,2-DCE = trans-1.2-dichlorocthvlcne.
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Frequentist Exponential Degree 5 Model with BMR of 1 Std. Dev.
for the BMD and 0.95 Lower Confidence Limit for the BMDL
£
O
Q.
LO
CD
DC
16000
14000
12000
10000
8000
6000
4000
2000
0
V.
^^Estimated Probability
^^Response at BMD
O Data
BMD
BMDL
500
1000
1500
Dose
2000
2500
Figure C-l. Exponential 5 Model for Decreased WBC Count in Male Rats Exposed to
trans- 1,2-DCE via Inhalation for 90 Days (Kelly, 1998)
Model Predictions for Decreased WBC Counts in Female Rats Exposed to trans- 1,2-DCE
via Inhalation for 90 Days (Kelly, 1998)
The procedure outlined above for continuous data was applied to the data set for
decreased WBC counts in female rats after exposure for 90 days (Kelly. 1998). Table C-3
summarizes the BMC modeling results. The constant variance model did not provide adequate
fit to the variance data (variance /;-value <0.1). The nonconstant variance provided adequate fit
to the variance data (variance /rvalue >0.1); however, none of the models provided adequate fit
to the means (means/rvalue < 0.1) and the data were deemed unsuitable for BMC modeling.
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Table C-3. Modeling Results for Decreased WBC Counts in Female Rats Exposed to trans- 1,2-DCE (CASRN 156-60-5) via
Inhalation for 90 Days3'b
Model
Test for Significant
Difference />-Valuec
Variance
/>-Valued
Means
/>-Valued
Scaled Residuals
for Dose Group®
AIC
BMCisd
(mg/m3)
BMCLisd
(mg/m3)
Nonconstant variance
Exponential (Model 2)f
0.00011423
0.131208618
0.000247266
198.0448327
9,096.561337
3,372.825057
0.364016312
Exponential (Model 3)f
0.00011423
0.131208618
0.000247266
198.0448307
9,093.465137
3,372.812265
0.36349989
Exponential (Model 4)f
0.00011423
0.131208618
0.005889908
191.1028924
-9,999
0
-9,999
Exponential (Model 5)f
0.00011423
0.131208618
0.005889908
191.1028924
-9,999
0
-9,999
Hillf
0.00011423
0.131208618
NA
190.8585656
-9,999
0
-9,999
Polynomial (2-degree)8
0.00011423
0.131208618
<0.0001
200.079418
9,717.429352
3,405.475347
0.220999848
Polynomial (3-degree)8
0.00011423
0.131208618
<0.0001
200.079418
9,717.431021
3,368.072497
0.220999463
Powerf
0.00011423
0.131208618
<0.0001
200.079418
9,717.42973
3,405.478856
0.221000229
Linear8
0.00011423
0.131208618
<0.0001
200.079418
9,717.434692
3,405.477219
0.220998999
aKellv (1998).
bNo model was selected. Neither the constant nor nonconstant variance models provide adequate fit to the variance data.
°Values >0.05 fail to meet conventional goodness-of-fit criteria.
dValues <0.10 fail to meet conventional goodness-of-fit criteria.
"Scaled residuals at dose closest to BMC.
fPower restricted to >1.
Coefficients restricted to be negative.
AIC = Akaike's information criterion; BMC = benchmark concentration.; BMCL = benchmark concentration lower confidence limit; NA = not applicable;
SD = standard deviation; trans-1,2-DCE = trans-1.2-dichlorocthvlcnc.
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Model Predictions for Decreased Lymphocyte Counts in Male Rats Exposed to
trans- 1,2-DCE via Inhalation for 90 Days ("Kelly, 1998)
The procedure outlined above for continuous data was applied to the data set for
decreased lymphocyte counts in male rats after exposure for 90 days (Kelly. 1998). Table C-4
and Figure C-2 summarize the BMC modeling results. The constant variance models provided
adequate fit to the variance data (variancep-walue > 0.1), and adequate fit to the means was only
provided by the Exponential model 5 (means /;-value > 0.1). Upon inspection of the scaled
residuals and graph of the model fit, the Exponential model 5 was determined to be adequate,
and the corresponding benchmark concentration lower confidence limit 1 standard deviation
(BMCLisd) of 109 mg/m3 was selected for decreased lymphocyte counts in males.
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Table C-4. Modeling Results for Decreased Lymphocyte Counts in Male Rats Exposed to trans- 1,2-DCE (CASRN 156-60-5) via
Inhalation for 90 Days3
Model
Test for Significant
Difference />-Valucb
Variance
/>-Valuce
Means
/>-Valuce
Scaled Residuals
for Dose Groupd
AIC
BMCisd
(mg/m3)
BMCLisd
(mg/m3)
Constant variance
Exponential (Model 2)e
<0.0001
0.107225219
0.059803913
0.257761593
733.2726356
2,578.585425
1,459.112969
Exponential (Model 3)e
<0.0001
0.107225219
0.059805795
0.258908641
733.2725726
2,574.03955
1,458.239514
Exponential (Model 4)e
<0.0001
0.107225219
0.017632017
0.259208791
735.2716134
2,573.14188
0
Exponential (Model 5)e'f
<0.0001
0.107225219
0.358034978
-0.679011939
729.6935164
217.8391027
108.924072
Hill6
<0.0001
0.107225219
0.043072427
0.240974366
733.7318245
1,361.55955
0
Polynomial (2-degree)8
<0.0001
0.107225219
0.055914165
0.226726414
733.4071423
2,660.956421
1,626.462393
Polynomial (3-degree)8
<0.0001
0.107225219
0.055914165
0.226726439
733.4071423
2,660.956401
1,957.435435
Power6
<0.0001
0.107225219
0.055914165
0.226726772
733.4071423
2,660.956125
2,237.571419
Linear8
<0.0001
0.107225219
0.055914165
0.226726165
733.4071423
2,660.956614
1,625.856447
aKellv (1998).
bValues >0.05 fail to meet conventional goodness-of-fit criteria.
°Values <0.10 fail to meet conventional goodness-of-fit criteria.
dScaled residuals at dose closest to BMC.
Tower restricted to >1.
Selected model. Lowest AIC among models that provided an adequate fit.
Coefficients restricted to be negative.
AIC = Akaike's information criterion; BMC = benchmark concentration; BMCL = benchmark concentration lower confidence limit; SD = standard deviation;
trans-1,2-DCE = trans-1.2-dichlorocthvlcne.
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Frequentist Exponential Degree 5 Model with BMR of 1 Std. Dev.
for the BMD and 0.95 Lower Confidence Limit for the BMDL
16000
14000
jj ioooo
12000
Estimated Probability
Response at BMD
O Data
£
g. 8000
cL 6000
4000
BMD
2000
BMDL
0
0
500
1000
1500
2000
2500
Dose
Figure C-2. Exponential 5 Model for Decreased Lymphocyte Count in Male Rats Exposed
to frfl«s-l,2-DCE via Inhalation for 90 Days (Kelly, 1998)
Model Predictions for Decreased Lymphocyte Counts in Female Rats Exposed to
frfl«s-l,2-DCE via Inhalation for 90 Days (Kelly, 1998)
The procedure outlined above for continuous data was applied to the data set for
decreased lymphocyte counts in female rats after exposure for 90 days (Kelly. 1998). Table C-5
summarizes the BMC modeling results. Neither the constant nor nonconstant variance models
provided adequate fit to the variance data; thus, these data were not suitable for BMC modeling.
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Table C-5. Modeling Results for Decreased Lymphocyte Counts in Female Rats Exposed to trans- 1,2-DCE (CASRN 156-60-5) via
Inhalation for 90 Days3'b
Model
Test for Significant
Difference />-Valuec
Variance
/>-Valued
Means
/>-Valued
Scaled Residuals
for Dose Group®
AIC
BMCisd
(mg/m3)
BMCLisd
(mg/m3)
Nonconstant variance
Exponential (Model 2)f
<0.0001
0.00012026
0.00065345
0.624862974
745.2710264
5,917.520848
2,873.291436
Exponential (Model 3)f
<0.0001
0.00012026
0.00066347
0.610130098
745.2389072
5,632.4976
2,885.591336
Exponential (Model 4)f
<0.0001
0.00012026
0.0460978
-9,999
736.1013398
-9,999
0
Exponential (Model 5)f
<0.0001
0.00012026
0.00018839
0.621633978
747.2594968
5,854.674263
0
Hillf
<0.0001
0.00012026
0.06328607
-9,999
735.5546089
-9,999
0
Polynomial (2-degree)8
<0.0001
0.00012026
<0.0001
0.161572813
749.8609773
5,177.931382
2,804.542348
Polynomial (3-degree)8
<0.0001
0.0001202
NA
0.170169868
751.9382154
4,891.075414
2,783.326222
Powerf
<0.0001
0.00012026
0.00023688
0.068864515
746.8014459
9,221.601015
3,150.012054
Linear8
<0.0001
0.00012026
0.00023587
0.297479128
746.810005
6,910.44751
3,146.779327
aKellv (1998).
bNo model was selected. Neither the constant nor nonconstant variance models provide adequate fit to the variance data.
°Values >0.05 fail to meet conventional goodness-of-fit criteria.
dValues <0.10 fail to meet conventional goodness-of-fit criteria.
"Scaled residuals at dose closest to BMC.
fPower restricted to >1.
Coefficients restricted to be negative.
AIC = Akaike's information criterion; BMC = benchmark concentration.; BMCL = benchmark concentration lower confidence limit; NA = not applicable;
SD = standard deviation; trans-1,2-DCE = trans-1.2-dichlorocthvlcnc.
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Model Predictions for Increased Brown Periocular Stain in Female Rats Exposed to
trans- 1,2-DCE via Inhalation during GDs 7-16 (Hurtt et at, 1993; Haskell Laboratories,
1988)
The procedure outlined above for dichotomous data was applied to the data set for
increased periocular stain in dams exposed during GDs 7-16 (Hurtt et al.. 1993; Haskell
Laboratories. 1988). Table C-6 and Figure C-3 summarize the BMC modeling results. The
Gamma, Log-Logistic, Weibull, and Log-Probit models provided adequate fit to the data
(p-value > 0.1). BMCLs for models providing adequate fit were sufficiently close (i.e., differed
by -Valueb
Scaled Residuals
for Dose Group
AIC
BMCio
(mg/m3)
BMCLio
(mg/m3)
Gamma0
0.184718398
-0.549497506
74.88282537
1,683.403683
787.047734
Log-Logisticd'e
0.494576234
-0.261788671
73.6106529
1,902.032036
1,109.478648
Multistage Degree 3f
0.071849056
-0.874916989
76.422566
1,301.926215
559.2344192
Multistage Degree 2f
0.071848167
-0.874908763
76.422566
1,301.9172
561.0782643
Multistage Degree lf
0.070439209
0.373579745
77.2565984
589.5022218
445.0414877
Weibull0
0.118212597
-0.842944016
75.66260339
1,406.540549
659.9499894
Dichotomous Hill
NA
-0.26167165
75.61065282
1,902.010142
1,109.463555
Logistic
0.070529966
-0.593068777
75.56893074
1,851.111014
1,354.408947
Log-Probit
0.408300783
-0.307020107
73.8289546
1,886.376152
1,139.58615
Probit
0.052822609
-0.687415537
76.6322265
1,756.879374
1,319.509329
aHurtt et al. (1993); Haskell Laboratories (1988).
bValues <0.1 fail to meet conventional goodness-of-fit criteria.
Tower restricted to >1.
dSlope restricted to >1.
"Selected model.
fBetas restricted to >0.
AIC = Akaike's information criterion; BMCio = benchmark concentration 10% extra risk; BMCLio = 95%
benchmark concentration lower confidence limit; NA = not applicable;
trans- 1,2-DCE = trans-1.2-dichlorocthvlcne.
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Frequentist Log-Logistic Model with BMR of 10% Extra Risk for
the BMD and 0.95 Lower Confidence Limit for the BMDL
0 2000 4000 6000 8000 10000
Dose
Figure C-3. Log-Logistic Model for Increased Brown Periocular Stain in Female Rats
Exposed to trans- 1,2-DCE via Inhalation during GDs 7-16 (Hurtt et al., 1993; Haskell
Laboratories, 1988)
Model Predictions for Increased Alopecia in Female Rats Exposed to trans- 1,2-DCE via
Inhalation during GDs 7-16 (Hurtt et al., 1993; Haskell Laboratories, 1988)
The procedure outlined above for dichotomous data was applied to the data set for
increased alopecia in dams exposed during GDs 7-16 (Hurtt et al.. 1993; Haskell Laboratories.
1988). Table C-7 and Figure C-4 summarize the BMC modeling results. All the models except
for the Dichotomous Hill model provided adequate fit to the data (p-value > 0.1). BMCLs for
models providing adequate fit were sufficiently close (i.e., differed by
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Table C-7. Modeling Results for Increased Alopecia in Female Rats Exposed to
trans- 1,2-DCE (CASRN 156-60-5) via Inhalation during GDs 7-16a
Model
/>-Valueb
Scaled
Residuals for
Dose Group
AIC
BMCio
(mg/m3)
BMCLio
(mg/m3)
Gamma0
0.921367419
0.064672437
84.41024679
3,030.480486
1,433.482044
Log-Logisticd
0.80997918
0.17231264
84.45781504
3,254.420006
1,639.029337
Multistage Degree 3e
0.845827707
-0.105411411
84.43841885
2,899.724333
1,193.819337
Multistage Degree 2e
0.84582769
-0.105410319
84.43841885
2,899.727464
1,268.742054
Multistage Degree le
0.14761207
-1.337609512
86.69714827
1,133.452408
829.2720096
Weibull0
0.893517079
-0.095298473
84.41858031
2,867.341123
1,388.839563
Dichotomous Hill
NA
0.172318998
86.45781505
3,254.436469
1,639.040203
Logistic
0.797850772
-0.284385158
82.85193042
3,125.441581
2,342.789334
Log-Probit
0.672689738
0.298111572
84.57696201
3,336.901383
1,686.21612
Probitf
0.874570178
-0.272100733
82.66926811
2,893.266258
2,193.910583
aHurtt et al. (1993): Haskell Laboratories (1988).
bValues <0.1 fail to meet conventional goodness-of-fit criteria.
Tower restricted to >1.
dSlope restricted to >1.
eBetas restricted to >0.
Selected model.
AIC = Akaike's information criterion; BMCio = benclunark concentration 10% extra risk; BMCLio = 95%
benchmark concentration lower confidence limit; NA = not applicable;
trans-1,2-DCE = trans-1.2-dichlorocthvlcnc.
Frequentist Probit Model with BMR of 10% Extra Risk for the
BMD and 0.95 Lower Confidence Limit for the BMDL
i
Estimated Probability
Response at BMD
O Data
BMD
BMDL
0 2000 4000 6000 8000 10000
Dose
Figure C-4. Probit Model for Increased Alopecia in Female Rats Exposed to trans- 1,2-DCE
via Inhalation during GDs 7-16 (Hurtt et al., 1993; Haskell Laboratories, 1988)
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APPENDIX D. REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). (2018). 2018 TLVs and
BEIs: Based on the documentation of the threshold limit values for chemical substances
and physical agents & biological exposure indices. Cincinnati, OH.
http://www.acgih.org/forms/store/ProductFormPublic/2018-tlvs-and-beis
Andersen. ME; Gargas. ML; Jones. RA; Jenkins. I J. Jr. (1980). Determination of the kinetic
constants for metabolism of inhaled toxicants in vivo using gas uptake measurements.
Toxicol Appl Pharmacol 54: 100-116. http://dx.doi.org/10.1016/0041-008XC80)9001 1 -3
AT SDR (Agency for Toxic Substances and Disease Registry). (1996). Toxicological profile for
1,2-dichloroethene [ATSDR Tox Profile], Atlanta, GA: U.S. Department of Health and
Human Services, Public Health Service, Agency for Toxic Substances and Disease
Registry. https://www.atsdr.cdc.gov/ToxProfiles/tp87.pdf
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