United States
Environmental Protection
1=1 m m Agency
EPA/690/R-11/020F
Final
2-03-2011
Provisional Peer-Reviewed Toxicity Values for
cis-1,2-Dichloroethylene
(CASRN 156-59-2)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Jon Reid, PhD, DABT
National Center for Environmental Assessment, Cincinnati, OH
Note: Because the subchronic p-RfD presented in this document is based solely on the 2010
IRIS information, no external review was performed. All of the information provided in this
PPRTV document was available to peer reviewers during the standard IRIS peer review process.

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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS	iv
BACKGROUND	1
HISTORY	1
DISCLAIMERS	1
QUESTIONS REGARDING PPRTVS	2
INTRODUCTION	2
HUMAN AND ANIMAL STUDIES	2
DERIVATION 01 PROVISIONAL VALUES	3
DERIVATION OF PROVISIONAL ORAL REFERENCE DOSES	3
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS	6
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR	6
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES	6
APPENDIX A. REFERENCES	7
in
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COMMONLY USED ABBREVIATIONS
BMC
benchmark concentration
BMD
benchmark dose
BMCL
benchmark concentration lower bound 95% confidence interval
BMDL
benchmark dose lower bound 95% confidence interval
HEC
human equivalent concentration
HED
human equivalent dose
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELhec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional reference concentration (inhalation)
p-RfD
provisional reference dose (oral)
POD
point of departure
RfC
reference concentration (inhalation)
RfD
reference dose (oral)
UF
uncertainty factor
UFa
animal-to-human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete-to-complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL-to-NOAEL uncertainty factor
UFS
subchronic-to-chronic uncertainty factor
WOE
weight of evidence
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
CIS-1,2-DICHLOROETHYLENE (CASRN 156-59-2)
BACKGROUND
HISTORY
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1)	EPA's Integrated Risk Information System (IRIS)
2)	Provisional Peer-Reviewed Toxicity Values (PPRTVs) used in EPA's Superfund
Program
3)	Other (peer-reviewed) toxicity values, including
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR);
~	California Environmental Protection Agency (CalEPA) values; and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's IRIS. PPRTVs are developed according to a Standard
Operating Procedure (SOP) and are derived after a review of the relevant scientific literature
using the same methods, sources of data, and Agency guidance for value derivation generally
used by the EPA IRIS Program. All of the information provided in this PPRTV document was
available to peer reviewers during the standard IRIS peer review process. PPRTVs differ from
IRIS values in that PPRTVs do not receive the multiprogram consensus review provided for IRIS
values. This is because IRIS values are generally intended to be used in all EPA programs, while
PPRTVs are developed specifically for the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a 5-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV documents conclude that
a PPRTV cannot be derived based on inadequate data.
DISCLAIMERS
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and Resource Conservation and Recovery Act (RCRA) program offices are advised to
carefully review the information provided in this document to ensure that the PPRTVs used are
appropriate for the types of exposures and circumstances at the Superfund site or RCRA facility
in question. PPRTVs are periodically updated; therefore, users should ensure that the values
contained in the PPRTV are current at the time of use.
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It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV document and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
QUESTIONS REGARDING PPRTVS
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
On September 30, 2010, IRIS (U.S. EPA, 2010) posted a chronic RfD of
0.002 mg/kg-day for cis-1,2-dichloroethylene based on a sub chronic-duration oral rat study
(90 days) by McCauley et al. (1995, 1990), using a point of departure (POD) from a benchmark
dose level (BMDLio) of 5.1 mg/kg-day and a combined UF of 3000 (UFh = 10; UFa = 10;
UFl = 1; UFS = 10; and UFD = 3). Development of the subchronic p-RfD in this PPRTV
document has been accomplished using only information provided in the IRIS toxicological
review of cis-1,2-dichloroethylene (CASRN 156-59-2) (U.S. EPA, 2010). All of the information
provided in this PPRTV document was available to peer reviewers during the standard IRIS peer
review process.
IRIS does not generally post subchronic-duration values. However, because the IRIS
chronic value was developed from a subchronic-duration study by utilizing the UFS of 10, a
subchronic p-RfD is presented in this PPRTV document based on this same study. The PPRTV
duplicates only the key information necessary to succinctly support the derivation of a
subchronic p-RfD. Full details are available on the IRIS database (see the References
section—U.S. EPA [2010]), but omits much of the detailed information and the reader is directed
to the IRIS online document for details.
HUMAN AND ANIMAL STUDIES
Refer to the IRIS toxicological review of cis-1,2-dichloroethylene (U.S. EPA, 2010) for
summaries of human and animal studies.
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DERIVATION OF PROVISIONAL VALUES
DERIVATION OF PROVISIONAL ORAL REFERENCE DOSES
On September 30, 2010, IRIS (U.S. EPA, 2010) posted an RfD of 0.002 mg/kg-day based
on a subchronic-duration oral rat study (90 days) by McCauley et al. (1995, 1990), using a POD
from a BMDLio of 5.1 mg/kg-day and a combined UF of 3000 (UFh = 10; UFa = 10; UFl = 1;
UFS = 10; and UFD = 3).
Background on the principal study provided in the IRIS file (i.e., EPA [2010],
Section I. A.2) is indicated below:
McCauley et al. (1995, 1990) administered 0, 32, 97, 291, or 872 mg/kg-day
cis-l,2-DCE by corn oil gavage to male andfemale Spr ague-Daw ley rats
(10 rats/sex/group) for 90 days. At the end of the 90-day exposure period,
animals were sacrificed and the brain, gonads, heart, kidneys, adrenals, liver,
spleen, and thymus were weighed and examined for gross pathology. Blood
samples were collectedfor hematological and clinical chemistry examinations.
Tissues from controls and the high-dose group animals were examinedfor
histopathologic changes.
Clinical observations during the study were reported by the authors as minimal
and not compound-related. Gavage deaths were present in both the treated and
control groups (1/10 female rats at 32 mg/kg-day; 1/10 female rats at
97 mg/kg-day; 1/10 male controls; 3/10 male rats at 291 mg/kg-day; 4/10 male
rats at 872 mg/kg-day). Terminal body weights in male rats at the two highest
dose groups were lower than controls by 10-11%, but were not considered by the
author as statistically significant; no treatment-related effects on body weight
were reported in female rats.
Absolute liver weights were statistically significantly increased by 10, 15[] and
24% in female rats at doses of97, 291, and 872 mg/kg-day, respectively. The
increases in absolute liver weight of 6, 13, 5[] and 15% in male rats of the 32[-],
97[~], 291[-] and 872[-]mg/kg-day dose groups, respectively, were not
statistically significant nor dose related. Relative liver weights were statistically
significantly increased in a dose-related manner in males andfemales. The
increases were 15, 17, and 32% for males and 14, 19, and 30% for females at 97,
291, and 872 mg/kg-day, respectively. Histopathological evaluation revealed no
specific hepatic injury. The authors concluded that there was a consistent,
dose-related increase in relative liver weight in both sexes and that this effect, in
light of the negative histopathology findings, may reflect hypertrophy and
hyperplasia.
Absolute kidney weights in female rats were increased by 3, 16, 17, and 17%
compared to the control at doses of32, 97, 291, and 872 mg/kg-day, respectively,
but were not statistically significant. In male rats increases in absolute kidney
weight of 9, 17, 7, and 14% for the 32, 97, 291, and872 mg/kg-day dose groups,
respectively, were not statistically significantly elevated compared to the control
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nor dose related. Statistically significant increases in relative kidney weights
were recorded in male rats in all dose groups (14, 19, 19, and 27% at 32, 97, 291,
and 872 mg/kg-day, respectively). Female rats exhibited increased (although not
statistically significant) relative kidney weights in the three highest doses (19, 23,
and 23% at 97, 291, and 872 mg/kg-day, respectively). Relatively large variances
in the female dose groups may explain why relative kidney weight increases in
females were not statistically significant. Histopathological findings for kidney
effects were negative, leading the authors to hypothesize that the increases in
relative kidney weight may be due at least in part to decreased body weight gain.
Sporadic changes (although noted as statistically significant) in some clinical
chemistry parameters were observed. Blood urea nitrogen (BUN) levels were
significantly decreased (40%) at the highest dose in males but not in females.
Serum calcium levels were significantly elevated by 8 and 10% in males at the 32
and 97 mg/kg-day doses, respectively, and serum phosphorus was significantly
decreased by 14% in males exposed to 32 mg/kg-day. In females, serum
phosphorus was significantly increased by 34 and 25% in the groups dosed with
97 and 291 mg/kg-day, respectively. No significant changes were reported in AST
activity. Hemoglobin and hematocrit level, and red blood cell (RBC) count were
significantly decreased in female rats dosed at 291 mg/kg-day, while only
hematocrit was significantly decreased in females dosed with 872 mg/kg-day. In
males, similar decreases (ranging from 6 to 10% compared with the control)
occurred in hemoglobin in the 291[-] and 872[-]mg/kg-day groups and in
hematocrit in the 97[~], 291[-] and 872[-]mg/kg-day groups. Overall, the
changes in clinical chemistry and hematology parameters were considered by the
authors to be marginal and of questionable biological significance. No
noteworthy compound-related histopathological changes were observed in any
dose group.
IRIS utilized a BMD approach to develop the POD as indicated below:
Increased relative kidney weight in male andfemale rats (McCauley et al. (1995,
1990) was identified as the critical effect. Benchmark dose (BMD) modeling
methodology (U.S. EPA, 2000) was used to determine the point of departure
(POD) by estimating the effective dose at a specified level of response (BMDx)
and its 95% lower confidence limit (BMDLx). A 10% change in relative kidney
weight compared with the control was selected as the benchmark response (BMR)
level. A BMR of 10% change in relative kidney weight was selected by analogy to
body weight, for which a 10% change is generally recognized as a minimally
biologically significant change (U.S. EPA, 2000).
All of the models for continuous data (i.e., linear, polynomial, power, and Hill
models) in U.S. EPA's BMDS (version 2.1) were fit to relative kidney weight data.
For the male rat, BMDS modeling of relative kidney weight data showed that only
the Hill model adequately fit the data (test 4 y p> 0.1). The other continuous
models fit to these data, the polynomial (linear and degree>2) and power models,
exhibited significant lack of fit. The Hill model predicted a BMDio and BMDLio
of 19.8 and 5.1 mg/kg-day, respectively. For the female rat, the Hill model
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provided the best fit of the relative kidney weight data (based on the model with
the lowest Akaike Information Criteria (AIC) value and adequate visual fit of the
data). The Hill model predicted a BMD w and BMDL w of 55.2 and
10.4 mg/kg-day, respectively. The POD for the RfD for cis-l,2-DCE was selected
as 5.1 mg/kg-day based on male rat relative kidney weight, the lower of the male
andfemale BMDLw values for this endpoint.
A subchronic p-RfD is developed from IRIS's (2010) reporting of McAuley et al. (1995,
1990) (omitting the extrapolation to chronic duration, i.e., UFS of 10).
Subchronic p-RfD = BMDLio UFc
= 5.1 mg/kg-day ^ 300
= 0.017 or 2 x 10"2 mg/kg-day
The discussion of the uncertainty factors utilized by IRIS is shown below:
An intraspecies UF (UFh) of 10 was applied to account for potentially sensitive
human subpopulations in the absence of quantitative information on the
variability of response to cis-l,2-DCE in the human population. Factors that
could contribute to a range of human response to cis-l,2-DCE were discussed in
Section 4.8 of the Toxicological Review of cis-1,2-Dichloroethylene and
trans-1,2-Dichloroethylene (U.S. EPA, 2010). Intrahuman variability in CYP450
levels that are responsible for metabolism of cis-1,2-DCE to reactive metabolites
has been documented. This variation in CYP450 could alter susceptibility to
cis-1,2-DCE toxicity. Individual variability in nutritional status, alcohol
consumption, or the presence of underlying disease could also alter metabolism of
cis-1,2-DCE. To account for these uncertainties, a factor of 10 was includedfor
individual variability.
An interspecies UF (UFa) of 10 was applied to account for the variability in
extrapolating from laboratory animals to humans. No information was available
to characterize the toxicokinetic or toxicodynamic differences between
experimental animals and humans for cis-1,2-DCE.
An UF of 1 was used for extrapolation from a LOAEL to a NOAEL (UFjJ because
the current approach is to address this factor as one of the considerations in
selecting a BMR for BMD modeling. In this case, a BMR of a 10% change in
relative kidney weight compared with the control was selected under an
assumption that it represents a minimally biologically significant change.
An UF of 3 was used to account for database deficiencies (UFu). The study used
in this RfD derivation, McCauley et al. (1995, 1990), is the only study of
repeat-dose toxicity available for cis-1,2-DCE. The database for this isomer is
missing studies of reproductive toxicity, including a two-generation reproductive
toxicity study, and developmental toxicity; however, the developmental toxicity
potential for cis-1,2-DCE is informed by a series of range-finding studies of the
developmental toxicity of a mixture of cis-1,2-DCE isomers (composition of
isomers unknown) (NTP, 1991a, b, c). No evidence of developmental toxicity was
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observed in mice or rats based on the parameters evaluated in these
range-finding studies (gravid uterus weight, fetal body weight, number of fetuses
[live/dead], implantation sites, and resorptions).
An UF of 1 was used since a subchronic exposure was utilized to develop a
subchronic value (UFs).
Confidence in the subchronic p-RfD value is identical to that of the chronic RfD value:
low, based on a study confidence of medium and a database confidence of low.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
There is no suitable information for developing RfC values. IRIS did not develop an RfC
value as indicated below:
The inhalation toxicity database for cis-l,2-DCE does not support derivation of
an RfC. No studies of the effects of cis-l,2-DCE by inhalation exposure in
humans were identified. In experimental animals, investigation of the inhalation
toxicity of cis-l,2-DCE is limited to an acute 4-hour inhalation LC50 study in rats
(DuPont, 1999). There are no inhalation studies of subchronic, chronic,
reproductive, or developmental toxicity of cis-1,2-DCE. Therefore, no inhalation
RfC values were derivedfor cis-1,2-DCE.
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR
The cancer WOE descriptor for c/.s- l ,2-dichloroethylene is provided in the IRIS
toxicological review of as-1,2-dichloroethylene (U.S. EPA, 2010) as "Inadequate Information to
Assess Carcinogenic Potential (both oral and inhalation)." This descriptor is based on the
absence of epidemiological studies in humans and the lack of animal studies designed to evaluate
the carcinogenic potential.
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
As indicated in the IRIS toxicological review of c/'s-1,2-dichloroethylene (U.S. EPA,
2010), the lack of data on carcinogenicity precludes the derivation of quantitative estimates for
either oral (p-OSF) or inhalation (p-IUR) exposure.
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APPENDIX A. REFERENCES
DuPont. (1999) Initial submission: letter from DuPont Haskell Laboratory to U.S. EPA re
results of 4-hour inhalation median lethality study (LC50) in rats w/cis-l,2-dichloroethylene,
dated 8/26/99. E.I. DuPont de Nemours and Company, Wilmington, DE. Submitted under
TSCA Section 8E; EPA Document No. 88990000257; NTIS No. OTS0559785.
McCauley, PT; Robinson, M; Daniel, FB; et al. (1990) The effects of subacute and subchronic
oral exposure to cis-l,2-dichloroethylene in rats. Health Effects Research Laboratory,
U.S. Environmental Protection Agency, Cincinnati, OH and Toxic Hazards Division, Air Force
Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, OH; unpublished
report.
McCauley, PT; Robinson, M; Daniel, FB; et al. (1995) The effects of subacute and subchronic
oral exposure to cis-l,2-dichloroethylene in Sprague-Dawley rats. Drug Chem Toxicol
18:171-184.
NTP (National Toxicology Program). (1991a) Range finding studies: developmental toxicity
1,2-dichloroethylene when administered via feed in Swiss CD-I mice. Public Health Service,
U.S. Department of Health and Human Services; NTP TRP 91022. Available from the National
Institute of Environmental Health Sciences, Research Triangle Park, NC.
NTP (National Toxicology Program). (1991b) Range finding studies: developmental toxicity
1,2-dichloroethylene when administered via feed in CD Sprague-Dawley rats. Public Health
Service, U.S. Department of Health and Human Services; NTP TRP 91032. Available from the
National Institute of Environmental Health Sciences, Research Triangle Park, NC.
NTP (National Toxicology Program). (1991c) Range finding studies: developmental toxicity
1,2-dichloroethylene (repeat) when administered via feed in CD Sprague-Dawley rats. Public
Health Service, U.S. Department of Health and Human Services; NTP TRP 91033. Available
from the National Institute of Environmental Health Sciences, Research Triangle Park, NC.
U.S. EPA (Environmental Protection Agency). (2000) Benchmark Dose Technical Guidance
Document. External review draft. EPA/63O/R-00/001. Available online at
http://www.epa.gov/iris/backgr-d.htm.
U.S. EPA (Environmental Protection Agency). (2010) Integrated Risk Information System
(IRIS). Office of Research and Development. National Center for Environmental Assessment,
Washington, DC. Examined Dec. 2010. Available online at http://www.epa.gov/iris/. Accessed
2010.
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