EPA-540/1-86-015
Environmental Protection
Agency
Office of Emergency and
Remedial Response
Washington DC 20460
Superfund
&EPA
Off'ce of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
HEALTH EFFECTS ASSESSMENT
FOR cis-1,2-DICHLOROETHYLENE
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EPA/540/1-86-015
September 1984
HEALTH EFFECTS ASSESSMENT
FOR CIS-1,2-DICHLOROETHYLENE
U.S. Environmental Protection Agency
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Cincinnati, OH 45268
U.S. Environmental Protection Agency
Office of Emergency and Remedial Response
Office of Solid Waste and Emergency Response
Washington, DC 20460
U.S. Environment! Protection Agency
Region V, Li'-'.-r -
230 So' 0 ••''"•*-. -.-t
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DISCLAIMER
This report has been funded wholly or 1n part by the United States
Environmental Protection Agency under Contract No. 68-03-3112 to Syracuse
Research Corporation. It has been subject to the Agency's peer and adminis-
trative review, and H has been approved for publication as an EPA document.
Mention of trade names or commercial products does not constitute endorse-
ment or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with cls-1,2-
dlchloroethylene. All estimates of acceptable Intakes and carcinogenic
potency presented 1n this document should be considered as preliminary and
reflect limited resources allocated to this project. Pertinent toxlcologlc
and environmental data were located through on-line literature searches of
the Chemical Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data
bases. The basic literature searched supporting this document 1s current up
to September, 1984. Secondary sources of Information have also been relied
upon 1n the preparation of this report and represent large-scale health
assessment efforts that entail extensive peer and Agency review. The
following Office of Health and Environmental Assessment (OHEA) source has
been extensively utilized:
U.S. EPA. 1980a. Ambient Water Quality Criteria for Dlchloro-
ethylenes. Environmental Criteria and Assessment Office, Cincin-
nati, OH. EPA 440/5-80-041. NTIS PB 81-117525.
The Intent 1n these assessments 1s to suggest acceptable exposure levels
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited In
scope tending to generate conservative (I.e., protective) estimates. Never-
theless, the Interim values presented reflect the relative degree of hazard
associated with exposure or risk to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for sys-
temic toxicants (toxicants for which cancer 1s not the endpolnt of concern).
The first, the AIS or acceptable Intake subchronlc, 1s an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval (I.e., for an Interval that
does not constitute a significant portion of the Hfespan). This type of
exposure estimate has not been extensively used or rigorously defined, as
previous risk assessment efforts have been primarily directed towards
exposures from toxicants 1n ambient air or water where lifetime exposure Is
assumed. Animal data used for AIS estimates generally Include exposures
with durations of 30-90 days. Subchronlc human data are rarely available.
Reported exposures are usually from chronic occupational exposure situations
or from reports of acute accidental exposure.
The AIC, acceptable Intake chronic, 1s similar 1n concept to the ADI
(acceptable dally Intake). It 1s an estimate of an exposure level that
would not be expected to cause adverse effects when exposure occurs for a
significant portion of the Hfespan [see U.S. EPA (1980b) for a discussion
of this concept]. The AIC 1s route specific and estimates acceptable
exposure for a given route with the Implicit assumption that exposure by
other routes 1s Insignificant.
111
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Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for ranking reportable quanti-
ties; the methodology for their development -1s explained 1n U.S. EPA (1983).
For compounds for which there 1s sufficient evidence of cardnogenldty,
AIS and AIC values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980b). Since cancer 1s a
process that Is not characterized by a threshold, any exposure contributes
an Increment of risk. Consequently, derivation of AIS and AIC values would
be Inappropriate. For carcinogens, q-|*s have been computed based on oral
and Inhalation data 1f available.
1v
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ABSTRACT
In order to place the risk assessment evaluation 1n proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate
Interpretation and use of the quantitative estimates presented.
Data were Inadequate to estimate AIS or AIC values for either oral or
Inhalation routes. Data were also Inadequate to assess the carcinogenic
potency of this chemical.
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Or. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and Helen Ball was^the Project
Officer. The final documents 1n this series were prepared for the Office of
Emergency and Remedial Response, Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of A1r Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by:
Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1.
2.2.
ORAL
INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1.
3.2.
3.3.
3.4.
SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
CHRONIC
3.2.1. Oral
3.2.2. Inhalation
TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.3.1. Oral
3.3.2. Inhalation
TOXICANT INTERACTIONS
CARCINOGENICITY
4.1.
4.2.
4.3.
4.4.
HUMAN DATA
4.1.1. Oral
4.1.2. Inhalation
BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
OTHER RELEVANT DATA
WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
Page
1
3
. . . 3
3
4
4
. . . 4
4
, , 5
. . . 5
5
5
. . . 5
, , , 5
5
, . . 6
6
. . . 6
6
, , 6
. . . 6
6
. . . 6
7
. . . 8
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TABLE OF CONTENTS (cent.)
RISK
6.1.
6.2.
6.3.
ASSESSMENT
ACCEPTABLE INTAKE SUBCHRONIC (AIS)
6.1.1. Oral
6.1.2. Inhalation
ACCEPTABLE INTAKE CHRONIC (AIC)
6.2.1. Oral
6.2.2. Inhalation
CARCINOGENIC POTENCY (q-|*)
6.3.1. Oral
6.3.2. Inhalation
REFERENCES
Page
9
9
9
9
9
9
9
9
9
9
10
APPENDIX: Summary Table for ds-l,2-01chloroethylene 14
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LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
AIC Acceptable Intake chronic
AIS Acceptable Intake subchronlc
BCF Bloconcentratlon factor
CS Composite score
MFO Mixed function oxldase
ppm Parts per million
STEL Short-term exposure limit
TLV Threshold limit value
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
The relevant physical and chemical properties and environmental fate of
ds-l,2-d1chloroethylene (CAS No. 156-59-2) are given below.
Chemical class: halogenated aliphatic hydrocarbon
Molecular weight: 96.95
Vapor pressure at 25°C: 208 mm Hg (Torkelson and Rowe, 1981)
Water solubility at 20°C: 3500 mg/a. (Torkelson and Rowe, 1981)
Octanol/water partition
coefficient: 5 (estimated)
BCF: 0.8 (estimated)
Half-lives 1n
Air: 1.3 days (Hendry and Kenly, 1979)
Water:
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Pertinent data regarding the fate of c1s-l ,2-d1ch1oroethy"lene in soil
could not be located in the available literature. Based on the behavior of
the compound in aquatic media, evaporation of cis-1,2-dichloroethylene from
the soil surface is expected to be the predominant loss mechanism. In sub-
surface soil, biodegradation of this compound is likely to be a slow process
(Tabak et al., 1981). Therefore, the compound is expected to have the
potential to leach from subsurface soil into groundwater. Page (1981)
reported cis-1,2-dichloroethylene in groundwaters from New Jersey at a
frequency of 44%.
-2-
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL MAMMALS
2.1. ORAL EXPOSURE
Pertinent data regarding the oral absorption of c1s-l ,2-d1chloroethylene
could not be located 1n the available literature. The U.S. EPA (1980a)
estimates that "virtually 100 percent of Ingested DCE may be absorbed
systemically," based on the studies of Daniel (1963) and Monster et al.
(1976) using trlchloroethylene.
2.2. INHALATION
Pertinent data regarding the absorption of ds-1,2-d1chloroethylene from
the respiratory tract could not be located In the available literature. The
U.S. EPA (1980a) estimates that "35 to 50 percent of Inhaled DCE...may be
absorbed systemlcally," based on the studies of Daniel (1963) and Monster et
al. (1976) using trlchloroethylene.
-3-
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Springer (1965) administered a mixture of ds- and trans-
l,2-d1chloroethylene to rats for 7 weeks (0.05, 0.25, 0.5 or 1.0 g/kg). It
was not clear from the review 1f these were dally, weekly or total doses.
No adverse effects were reported at any dose level. Pertinent data regard-
Ing the subchronlc oral toxlclty of pure ds-1,2-d1chloroethylene could not
be located In the available literature.
ds-1,2-D1chloroethylene administered to rats as a single dose of either
400 or 1500 mg/kg by gavage 1n corn oil resulted 1n Increases 1n a series of
hepatic enzymes which are Indicators of hepatotoxldty. The authors suggest
that ds-1,2-d1chloroethylene Is a less potent hepatotoxln than I,l-d1-
chloroethylene. In addition, the ds Isomer of 1,2-d1chloroethylene appears
to be slightly more hepatotoxlc than the trans Isomer with respect to these
endpolnts (Jenkins et a!., 1972).
3.1.2. Inhalation. Exposure of rats for 8 hours to trans-1,2-d1chloro-
ethylene at a concentration of 200 ppm Induced fatty degeneration of the
hepatocytes and Kupffer cells (Freundt et a!., 1977). In an additional
study, exposure of rats for 8 hours to a concentration of 200 ppm ds-1,2-
dlchloroethylene resulted In Inhibition of the MFO system as measured by
hexobarbltal sleeping time, zoxazolamlne paralysis time and formation of
4-am1no-ant1pyrene from amlnopyrene. The c1s Isomer was a more potent
Inhibitor than the trans Isomer (Freundt and Macholz, 1978). Subsequent
work suggests that these effects are mediated by a P-450 generated reactive
metabolite which Interacts with the heme moiety at the active site of P-450
(Costa and Ivanetlch, 1982). Also, It Is probably nephrotoxlc by analogy to
1,1-dtehloroethylene (U.S. EPA, 1980a).
-4-
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3.2. CHRONIC
3.2.1. Oral. Pertinent data regarding the chronic oral toxldty of
c1s-l,2-dlchloroethylene could not be located In the available literature.
3.2.2. Inhalation. Pertinent data regarding the chronic Inhalation
toxldty of ds-l,2,-d1chloroethylene could not be located 1n the available
literature. In an unpublished study, Torkelsen (1965) reported no effects
on growth, mortality, organ and body weights, hematology, clinical chem-
istry, gross pathology or hlstopathology 1n rats, rabbits, guinea pigs or
dogs exposed to 500 or 1000 ppm 1,2-d1chloroethylene (mixed Isomers) 7
hours/day, 5 days/week for 6 months.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Pertinent data regarding the teratogenldty or other repro-
ductive effects of orally administered ds-1,2-d1chloroethylene could not be
located 1n the available literature.
3.3.2. Inhalation. Pertinent data regarding the teratogenldty or other
reproductive effects of inhaled c1s-l,2-d1chloroethylene could not be
located 1n the available literature.
3.4. TOXICANT INTERACTIONS
Pertinent data regarding the Interactions of ds-1,2-d1chloroethylene
with other toxicants could not be located 1n the available literature. Due
to the effects of ds-1,2-d1chloroethylene on cytochrome P-450, however, 1t
would be expected that this compound could affect the toxldty of other
compounds that are metabolized by the MFO system.
-5-
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4. CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral. Pertinent data regarding the cardnogenldty of orally
administered cls-1,2-d1chloroethy1ene 1n humans could not be located In the
available literature.
4.1.2. Inhalation. Pertinent data regarding the cardnogenldty of
Inhaled ds-1,2-d1chloroethylene In humans could not be located 1n the
available literature.
4.2. BIOASSAYS
4.2.1. Oral. Pertinent data regarding the cardnogenldty of orally
administered ds-1,2-dlchloroethylene 1n experimental animals could not be
located 1n the available literature.
4.2.2. Inhalation. Pertinent data regarding the cardnogenldty of
Inhaled ds-1,2-d1chloroethylene 1n experimental animals could not be
located 1n the available literature.
4.3. OTHER RELEVANT DATA
Grelm et al. (1975) reported negative results for ds-1,2-dlchloro-
ethylene using EscheMchla coll K12 as the Indicator organism. Cerna and
Kypenova (1977) found that ds-1,2-d1chloroethylene was not mutagenlc 1n
Salmonella tester strains using the spot test without metabolic activation.
ds-1,2-D1chloroethylene was found to produce a dose-dependent Increase 1n
mutations using the host-media bloassay, however, and also to Induce chromo-
somal aberrations as Indicated by cytogenlc analysis of bone marrow cells
Isolated from mice given repeated 1ntraper1toneal Injections (Cerna and
Kypenova, 1977).
ds-1,2-D1chloroethylene did not Increase the recombination rate,
frequency of point mutations or gene conversion 1n Saccharomyces cereveslae
(GalU et al., 1982).
-6-
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4.4. WEIGHT OF EVIDENCE
Pertinent data regarding the carclnogenlcity of ds-1,2-d1chloroethylene
In humans or animals could not be located 1n the available literature.
Using the criteria for evaluating the overall weight of evidence for
carclnogenlcity to humans proposed by the Carcinogen Assessment Group of the
U.S. EPA (Federal Register, 1984), cls-1,2-d1chloroethylene Is most appro-
priately designated a Group D-Not Classified chemical.
-7-
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5. REGULATORY STANDARDS AND CRITERIA
The ACGIH (1980, T983) has establshed a TLV of 200 ppm (-790 mg/m3)
and a STEL of 250 ppm (-1000 mg/m3) based on an unpublished study by
Torkelsen (1965) (see Section 3.2.2.). This standard does not distinguish
between the els and trans Isomers.
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6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
6.1.1. Oral. The available data were Inadequate for the derivation of an
oral AIS for ds-1,2-d1chloroethylene.
6.1.2. Inhalation. The available data were Inadequate for the derivation
of an Inhalation AIS for cls-1,2-d1chloroethylene.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
6.2.1. Oral. The available data were Inadequate for the derivation of an
oral AIC. for ds-l,2-d1chloroethylene.
6.2.2. Inhalation. The available data were Inadequate for the derivation
of an Inhalation AIC for c1s-l,2-d1chloroethylene. The data regarding the
toxldty of ds-1,2 and trans-1,2-d1chloroethylene were Investigated to
determine the suitability for derivation of CS values based on chronic
toxldty. Data were Insufficient for derivation of a CS for c1s-l,2-d1-
chloroethylene.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. Pertinent data regarding the carclnogenldty of c1s-l,2-d1-
chloroethylene following oral exposure could not be located 1n the available
literature. Therefore, no q * could be derived.
6.3.2. Inhalation. Pertinent data regarding the Inhalation carclno-
genldty of c1s-l,2-d1chloroethylene could not be located 1n the available
literature. Therefore, no q,* could be derived.
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7. REFERENCES
AC6IH (American Conference of Governmental Industrial Hyg1en1sts). 1980.
Documentation of the Threshold Limit Values, 4th ed. (Includes supplemental
documentation, 1981). Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1983.
TLVs. Threshold Limit Values for Chemical Substances and Physical Agents 1n
the Work Environment with Intended Changes for 1983-1984. Cincinnati, OH.
Cerna, M. and H. Kypenova. 1977. Mutagenlc activity of chloroethylenes
analyzed by screening system tests. Mutat. Res. 46: 214-215. (Cited In
U.S. EPA, 1980a)
Costa, A.K. and K.M. Ivanetlch. 1982. The 1,2-d1chloroethylenes: Their
metabolism by hepatic cytochrome P-450 in vitro. Blochem. Pharmacol. 31:
2093-2102.
Daniel, J.W. 1963. The metabolism of 36C1-labeled tMchloroethylene and
tetrachloroethylene 1n the rat. Blochem. Pharmacol. 12: 795-802. (Cited
In U.S. EPA, 1980a)
Federal Register. 1984. Environmental Protection Agency. Proposed guide-
lines for carcinogenic risk assessment. Federal Register. 49: 46294-46299.
Freundt, K.J. and J. Macholz. 1978. Inhibition of mixed function oxldases
1n rat liver by trans- and ds-1,2-d1chloroethylene. Toxicology. 10:
131-139.
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Freundt, K.J., 6.P. Llebaldt and E. Liberwirth. 1977. Toxldty studies on
trans-1,2-d1chloroethylene. Toxicology. 7: 141-153.
GalU, A., et al. 1982. Genetic effects of 1,2-d1chloroethylene. 1. In
vitro study. Boll. Soc. Ital. B1ol. Sper. 58: 860.
Grelm, H., G. Bonse, Z. Radwan, D. Relchert and D. Henschler. 1975.
Mutagenlclty jm vitro and potential cardnogenldty of chlorinated ethylenes
as a function of metabolic oxlrane formation. Blochem. Pharmacol. 24:
2013-2017. (Cited in U.S. EPA, 1980a)
Hendry, O.G. and R.A. Kenley. 1979. Atmospheric reaction products of
organic compounds. Office of Toxic Substances, U.S. EPA, Washington, DC.
EPA 560/12-79-001.
Jenkins, L.J., Jr., M.J. Trabulus and S.D. Murphy. 1972. Biochemical
effects of 1 ,l-d1chloroethylene in rats: Comparisons with carbon tetrachlo-
ride and 1,2-d1chloroethylene. Toxlcol. Appl. Pharmacol. 23: 501-509.
(Cited in U.S. EPA, 1980a)
Kenaga, E.E. and C.A.I. Goring. 1980. Relationship between water solu-
bility, soil sorptlon, octanol-water partitioning and concentration of
chemicals in biota. in: Aquatic Toxicology, ASTM STP 707, J.G. Eaton, P.R.
ParMsh and A.C. HendMcks, Ed. Am. Soc. Test. Mater., Philadelphia, PA.
p. 78-115.
-11-
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Mabey, W.R., J.H. Smith, R.T. Podoll, et al. 1981. Aquatic fate process
data for organic priority pollutants. Monitoring and Data Support D1v.,
OWRS, U.S. EPA, Washington, DC. EPA 440/4-81-014.
Monster, A.C., G. Boersma and W.C. Duba. 1976. Pharmacok1net1cs of
trlchloroethylene 1n volunteers, Influence of workload and exposure con-
centration. Ind. Arch. Occup. Environ. Health. 38: 87-102. (Cited In U.S.
EPA, 1980a)
Page, 6.W. 1981. Comparison of groundwater and surface water for patterns
and levels of contamination by toxic substances. Environ. Scl. Techno!.
15: 1475-1481.
Springer, E. 1965. No titled provided. Ztschr. f.d.g. Hyg. u. 1hre
Grenzgeblete. 11: 442. (Cited 1n ACGIH, 1980)
Tabak, H.H., S.A. Quare, C.I. Mashnl and E.F. Barth. 1981. Blodegrad-
abllHy studies with organic priority pollutant compounds. J. Water Pollut.
Control Fed. 53: 1503-1518.
Torkelsen, T.R. 1965. Communication to TLV Committee, Dow Chem. Co.,
December,. (Cited In ACGIH, 1980}
Torkelson, T.R. and V.K. Rowe. 1981. Halogenated aliphatic hydrocarbons.
ITK Patty's Industrial Hygiene and Toxicology, Vol. 28, 3rd rev. ed., G.D.
Clayton and F.E. Clayton, Ed. John Wiley and Sons, NY. p. 3550.
-12-
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U.S. EPA. 1980a. Ambient Water Quality Criteria for Dlchloroethylenes.
Environmental Criteria and Assessment Office, Cincinnati, OH. EPA
440/5-80-041. NTIS PB 81-117525.
U.S. EPA. 1980b. Guidelines and Methodology Used 1n the Preparation of
Health Effects Assessment Chapters of the Consent Decree Water Quality
Criteria. Federal Register. 45:79347-79357.
U.S. EPA. 1983. Methodology and Guidelines for Reportable Quantity Deter-
minations Based on Chronic Toxldty Data. Prepared by the Environmental
Criteria and Assessment Office, Cincinnati, OH, OHEA for the Office of Solid
Waste and Emergency Response, Washington, DC.
Veith, G.D., D.L. Defoe and B.V. Bergstedt. 1979. Measuring and estimating
the bloconcentratlon factor of chemicals 1n fish. J. F1sh Res. Board Can.
36: 1040-1048.
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ro
APPENDIX
' _ o
L. =J
) s 3
: ''\ 3
. ~~ TJ
3 TJ
"i O
r-t-
CD
S a
" 9
2 Inhalation
era
S AIS
^ AIC
Oral
i AIS
1
AIC
Summary Table for c1s-l,2-D1chloroethylene
Species Experimental Effect
Dose/Exposure
ND ND ND
ND ND ND
ND ND ND
ND ND ND
Acceptable Intake Reference
(AIS or AIC)
ND ND
ND ND
ND ND
ND ND
ND - Not derived
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