540186051
United Slates
Environmental Protection
Agency
Office of Emergency and
Remedial Response
Washington DC 20460
Office of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
Superfund
£EPA
HEALTH EFFECTS ASSESSMENT
FOR 1,1-DICHLOROETHYLENE
5 Library Collection
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EPA/540/1-86-051
September 1984
HEALTH EFFECTS ASSESSMENT
FOR 1,1-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
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DISCLAIMER
This report has been funded wholly or In 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 I,l-d1-
chloroethylene. 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-Hne 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 In 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) sources have
been extensively utilized:
U.S. EPA. 1980b. Ambient Water Quality Criteria for Olchloro-
ethylenes. Environmental Criteria and Assessment Office, Cincin-
nati, OH. EPA 440/5-80-041. NTIS PB 81-117525.
U.S. EPA. 1983b. Health Assessment Document for Vlnylldene
Chloride. Environmental Criteria and Assessment Office, Research
Triangle Park, NC. EPA 600/8-83-031A. NTIS PB 84-126762.
The Intent In 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 1s
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.
111
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The AIC, acceptable Intake chronic, Is similar In 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 lifespan [see U.S. EPA (1980a) for a discussion
of this concept]. The AIC is route specific and estimates acceptable
exposure for a given route with the implicit assumption that exposure by
other routes 1s insignificant.
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 in U.S. EPA (1983a).
For compounds for which there Is sufficient evidence of cardnogenicity,
AIS and AIC values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980a). Since cancer is 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-j*s have been computed based on oral
and inhalation data if available.
1v
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ABSTRACT
In order to place the risk assessment 1n proper context, the reader Is
referred to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate use
and Interpretation of the quantitative estimates.
Evidence for the cardnogenlcHy of 1 ,l-d1chloroethylene In animals 1s
limited. There are essentially no useful human data. A number of oral
exposure experiments have yielded negative results, as have Inhalation
studies. One Inhalation study showed a significant Increase 1n the Inci-
dence of kidney adenocarclnomas 1n mice exposed to 1 ,l-d1chloroethylene
vapors. Mutagenlclty evaluations 1n numerous in vitro systems have yielded
positive results.
The U.S. EPA (1983b) has used the kidney adenocardnoma data 1n male
mice for the computation of a human q-|* for Inhalation exposure to
1 ,l-d1chloroethylene and derived a q-|* of 1.47X10"1 (mg/kg bw/day)"1.
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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. Dr. 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.
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.
SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
CHRONIC
3.2.1. Oral
3.2.2. Inhalation
Page
1
2
. . . 2
, , 2
3
, . 3
. . . 3
, , , 3
6
. . . 6
. . . 8
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS.
3.3.1. Oral 8
3.3.2. Inhalation 8
3.4. TOXICANT INTERACTIONS 9
4. CARCI^OGENICITY 10
4.1. HUMAN DATA , 10
4.1.1. Oral 10
4.1.2. Inhalation 10
4.2. BIOASSAYS 10
4.2.1. Oral 10
4.2.2. Inhalation 10
4.3. OTHER RELEVANT DATA 13
4.4. WEIGHT OF EVIDENCE 17
5. REGULATORY STANDARDS AND CRITERIA 18
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TABLE OF CONTENTS (cont.)
Page
6. RISK ASSESSMENT 19
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) 19
6.2. ACCEPTABLE INTAKE CHRONIC (AIC) 19
6.3. CARCINOGENIC POTENCY (q-j*) 19
6.3.1. Oral 19
6.3.2. Inhalation 19
7. REFERENCES 20
APPENDIX A: Summary Table for 1,l-01chloroethylene 31
APPENDIX Bl: Cancer Data Sheet for Derivation of q-|* 32
APPENDIX B2: Calculation of q-|* 33
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LIST OF TABLES
No. Title
3-1 Effect on Experimental Animals of Long Term Inhalation of
1 ,l-D1chloroethylene
3-2 Pathologic Effects of Long-Term Ingestlon of 1,l-D1chloro-
ethylene Incorporated 1n the Drinking Water of
Sprague-Dawley Rats 7
4-1 Results of Oral Carclnogenlclty Bloassays of 1,l-01chloro-
ethylene 11
4-2 Results of Inhalation Carclnogenlclty Bloassay of
l,l-D1chloroethylene 12
4-3 Distribution of the Different Types of Mammary Tumors
After Exposure by Inhalation to 1 ,l-D1chloroethylene
1n A1r After 137 Weeks 14
4-4 Distribution of the Different Types of Tumors After
Exposure by Inhalation to 1,l-D1chloroethyulene In
A1r After 121 Weeks 15
1x
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LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
AIC Acceptable Intake chronic
AIS Acceptable Intake subchronlc
BCF B1oconcentrat1on factor
bw Body weight
CAS Chemical Abstract Service
CS Composite score
LOEL Lowest-observed-effect level
ppm Parts per million
STEL Short-term exposure limit
TLV Threshold limit value
TWA Time-weighted average
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1. ENVIRONMENTAL CHEMISTRY AND FATE
The relevant physical and chemical properties and environmental fate of
I,l-d1chloroethylene (CAS No. 75-35-4), commonly known as vlnylldene
chloride, are as follows:
Chemical class: halogenated aliphatic
hydrocarbon
Molecular weight: 96.94 (Mabey et al., 1981)
Vapor pressure: 600 mm Hg at 25°C (U.S. EPA, 1983b)
Water solubility: 2250 mg/l at 25°C (U.S. EPA, 1983b)
Octanol/water partition
coefficient: 69 (estimated) (Mabey et al., 1981)
BCF: 7 (estimated from the equation of
Velth et al., 1979)
Half-lives 1n
A1r: 2 days (CupHt, 1980)
Water: 1-6 days (estimated)
The half-life of 1 ,l-d1chloroethylene In aquatic media has been esti-
mated from the reaeratlon rate ratio of 0.601 and the oxygen reaeratlon rate
constant of 0.19-0.96 day'1 as given by Mabey et al. (1981).
The half-life of 1,l-d1chloroethylene 1n soil could not be located 1n
the literature available; however, evaporation 1s expected to be the pre-
dominant loss mechanism from the soil surface. Based on the octanol/water
partition coefficient and aqueous solubility 1t can be speculated that
leaching may play a significant role 1n determining the fate of this chemi-
cal 1n soils. In fact, the detection of this compound In several ground-
waters (U.S. EPA, 1983b) Is Indicative of the Teachability of this compound
from soils.
-1-
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL MAMMALS
2.1. ORAL
A number of Investigators have reported the rapid appearance of labeled
1,1,-dlchloroethylene In the urine and expired air of rats given an Intra-
gastrlc dose of [14C] 1 ,l-d1chloroethylene (position of label unspecified)
(McKenna et al., 1978; Relchert et al., 1979; Jones and Hathway, 1978).
These Investigators concluded that the systemic absorption of 1 ,l-d1chloro-
ethylene following IntragastMc administration 1s rapid and fairly complete.
2.2. INHALATION
Andersen et al. (1979) exposed fasted male rats to atmospheres contain-
ing various concentrations of 1 ,l-d1chloroethylene 1n a closed chamber.
They observed an Initial rapid phase followed by a slow phase of uptake.
The rapid phase was believed to represent whole body equilibrium and was
first-order with a rate constant of 2.2 hour'1 (t,.-=0.315 hour). The
slow phase was believed to represent metabolism.
-2-
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Rampy et al. (1977) administered 50, 100 or 200 mg
I,l-d1chloroethylene/a. drinking water to groups of 10 male and 10 female
Sprague-Dawley rats for 90 days. There was an Increased Incidence of cyto-
plasmlc vacuollzatlon of hepatocytes 1n the high dose groups.
Quast et al. (1983) administered capsules containing 1 ,l-d1chloroethyl-
ene 1n peanut oil (0, 6.25, 12.5 or 25 mg/kg bw/day) to groups of four male
and four female beagle dogs for 97 days. No effects were observed on
general appearance or demeanor, body weight, food consumption, hematology,
clinical chemistry, urlnalysls, organ weights, gross pathology or hlsto-
pathology.
3.1.2. Inhalation. Subchronlc exposure to 1 ,l-d1chloroethylene results
predominantly In damage to the liver and kidneys (Irish, 1962; Prendergast
et al., 1967; Gage, 1970; Rampy et al., 1977). The most thorough of these
studies was the study by Prendergast et al. (1967) 1n which rats, guinea
pigs, rabbits, dogs and monkeys were exposed to atmospheric concentrations
ranging from 20-395 mg/m3 1 ,l-d1chloroethylene for up to 90 days (Table
3-1). Intermittent exposure (8 hours/day, 5 days/week, for 6 weeks) to 395
mg/m3 produced no deaths, visible signs of toxldty or hlstopathologlcal
changes 1n any species. At each dose level, the Inhalation chamber typi-
cally contained 50 rats (Long-Evans or Sprague-Dawley), 15 Hartley guinea
pigs, 3 squirrel monkeys, 3 New Zealand rabbits and 2 beagle dogs. The
controls consisted of 304 rats, 314 guinea pigs, 57 monkeys, 48 rabbits and
34 dogs. Continuous exposure to concentrations up to 189 mg/m3 produced
dose-related mortality in guinea pigs and monkeys. For guinea pigs, mortal-
ity was significantly Increased over controls in the three highest dose
-3-
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TABLE 3-1
Effect on Experimental Animals of Long Term Inhalation of l,l-D1chloroethylene*
Concentration
100 ppm
(395±32 mg/m3)
48 ppm
(189+6.2 mg/m3)
Schedule
30 exposures,
8 hours/day,
5 days/week
90 days,
24 hours/day
Species
rat
guinea pig
rabbit
dog
monkey
rat
guinea pig
Mortality
0/15
0/15
0/3
0/2
0/3
0/15
7/15
Significant Findings
None
None
Weight loss In treated animals
None
Weight loss 1n treated animals
Animals gained less weight than controls.
Hepatic lesions. Renal lesions.
Mortality occurred between day 4 and
26 ppm
(10H4.4 mg/m3)
90 days,
24 hours/day
dog
monkey
rat
guinea pig
rabbit
dog
monkey
0/2
3/9
0/15
3/15
0/3
0/2
2/3
day 9 of exposure. Slight elevation
of liver alkaline phosphatase activity
and serum glutamlc-pyruvlc transamlnase
activity.
Animals lost weight. Hepatic lesions.
One dog developed an adrenal cortical
adenoma.
Mortality occurred on days 26, 60 and
64. Animals lost weight. Hepatic
lesions.
None
Mortality occurred between day 3 and
day 5 of exposure.
Animals lost weight.
Animals lost weight.
Mortality occurred between day 3 and
day 6 of exposure.
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TABLE 3-1 (cont.)
I
en
I
Concentration
16 ppm
(6H5.7 mg/m3)
5 ppm
(20*2.1 mg/m3)
Control
Schedule
90 days,
24 hours/day
90 days,
24 hours/day
NR
Species
rat
guinea pig
dog
monkey
rat
guinea pig
dog
monkey
rat
guinea pig
rabbit
dog
monkey
Mortality
0/15
3/15
0/2
0/9
2/45
2/45
0/6
1/21
7/304
2/314
2/48
0/34
1/57
Animals
Mortal!
None
Animals
Animals
None
Animals
None
None
Significant Findings
gained less weight than controls.
ty occurred on day 3 and day 4.
lost weight.
gained less weight than controls.
lost weight.
*Source: Prendergast et al., 1967
NR = Not reported
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groups (61, 101 and 189 mg/m3) and was of borderline significance at the
20 mg/m3 exposure level (p=0.078, l-ta1led Fisher exact test). Growth
depression was noted in all species at the high dose level. Renal lesions
were observed 1n rats and hepatic lesions and/or enzyme changes were
observed 1n all species at the high dose level; however, no hlstologlcal
lesions w"ere found at concentrations of <101 mg/m3. Depressed weight gain
and Increased mortality were observed 1n some species at all exposure levels.
3.2. CHRONIC
3.2.1. Oral. 1 ,l-D1chloroethylene was administered 1n the drinking water
{50, 100 or 200 mg/a.) to groups of 48 male and 48 female Sprague-Oawley
rats for 2 years (Quast et al., 1983; Humlston et al., 1978; Rampy et al.,
1977). These water concentrations provided doses of 5-12, 8-20 and 16-40
mg/kg bw/day, respectively. The control groups consisted of 80 males and 80
females. 1 ,l-D1chloroethylene had no significant effect on general appear-
ance, body weight, food consumption, water consumption, hematology, urlnaly-
s1s, clinical chemistry or organ weights. Gross and hlstopathologlcal exam-
ination revealed a number of statistically significant lesions (Table 3-2),
the most Important of which were hepatocellular fatty changes and peMportal
hepatoceljular hypertrophy.
The chronic toxldty of 1 ,l-d1chloroethylene has also been determined 1n
F344/N rats and B6C3F1/N mice. Fifty animals/sex/dose were given 0, 1 or 5
mg/kg bw/day (rats) or 0, 2 or 10 mg/kg bw/day (mice) by gavage, 5 days/week
for 2 years (NTP, 1982). Mortality and growth rates were not affected at
either dose level 1n either species. Increased Incidences of chronic renal
Inflammation were observed 1n the high dose rats (males, 43/48 vs. 26/50
controls; females, 9/44 vs. 3/49 controls) and liver necrosis in high dose
male mice (7/49 vs. 1/46 controls).
-6-
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TABLE 3-2
Pathologic Effects of Long-Term Ingestlon of 1 ,l-D1chloroethylene
Incorporated 1n the Drinking Water of Sprague-Oawley Rats*
Effect
Dose Level
100 ppm 200 ppm
M F M F
Increased Incidence of Intra-abdomlnal
fluid or blood 1n abdominal cavity
Increased Incidence 1n the total number of
rats with hepatocellular fatty change or
fatty degeneration
Increased Incidence of hepatocellular
fatty change with location 1n lobule not
specified
Increased Incidence 1n perlportal
hepatocellular fatty change
Increased Incidence of perlportal
hepatocellular hypertrophy
Increased Incidence of hepatic
centrllobular atrophy
Increased Incidence of mammary gland
f1broadenomas/adenof1bromas
*Source: U.S. EPA, 1983b; Humlston et al., 1978
M = male; F = female
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3.2.2. Inhalation. Rampy et al. (.1977) and McKenna et -al. (1982)
reported the results of a Dow Chemical Company 2-year Inhalation study 1n
which groups of 104 male and 104 female Sprague-Dawley rats were exposed to
0, 10 or 40 ppm (0, 39.7 or 158.6 mg/m3) 1 ,l-d1chloroethylene 6 hours/day,
5 days/week, for 5 weeks, after which the exposures were Increased to 0, 25
or 75 ppm (0, 99.1 or 297.4 mg/m3) for the remainder of the 18-month
exposure period (-73 weeks). No dose-related changes were observed 1n
mortality* body weight, hematology or clinical chemistry. Hepatocellular
fatty changes were observed 1n both sexes at both dose levels. This effect
was reversible after treatment was discontinued. Similar hepatic changes
have been reported In mice and rats exposed to 55 ppm (218.1 mg/m3) 6
hours/day, 5 days/week for 6-12 months (TWA=38.9 mg/m3) (Lee et al., 1977;
Hong et al., 1981).
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. NHschke et al. (1980, 1983) administered 1 ,l-d1chloro-
ethylene 1n the drinking water (50, 100 or 200 mg/i) to Sprague-Dawley
rats for 3 generations. Each parental generation consisted of 10 males and
20 females. There were a number of statistically significant effects on
reproduction; however, these effects were not dose-related and occurred
sporadically throughout the 3 generations. These effects were, therefore,
probably not related to exposure to 1 ,l-d1chloroethylene. At doses of 100
and 200 mg/S., statistically significant Increases 1n hepatocellular fatty
changes were observed In the F, males and females and the F_ females.
3.3.2. Inhalation. The teratogenldty of Inhaled 1 ,l-d1chloroethylene
has been tested 1n rats, rabbits and mice (Short et al., 1977a; Murray et
al., 1979). Signs of fetal toxldty, minor skeletal alterations and soft-
tissue alterations were observed at doses that produced maternal toxldty
-8-
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and were considered to be feto- and embryotoxlc manifestations of maternal
toxicity.^ Maternal tox1c1ty In rats was observed by Short et al. (1977a) at
exposure levels as low as 15 ppm.
3.4. TOXICANT INTERACTIONS
The metabolism of dichloroethylenes Involves the production of reactive
epoxlde Intermediates that bind covalently to cellular macromolecules (Bonse
et al., 1975; Hathway, 1977; McKenna et al., 1978). Compounds such as
dlsulflram decrease the covalent binding of 1 ,l-d1chloroethylene and protect
against lethality and hepatotoxldty (Short et al., 1977b). Pretreatment
with Inducers of mlcrosomal enzyme systems also decreased the hepatotoxldty
of 1,1-dlchloroethylene (Reynolds et al., 1975; Jenkins et al., 1972), but
Increased mortality (Carlson and Fuller, 1972). Compounds that deplete
cellular glutathlone Increase the hepatotoxldty of 1 ,l-d1chloroethylene
(Jaeger et al., 1973a,b, 1974, 1977).
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4. CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral. Pertinent data regarding the oral cardnogenlcHy of
1,1-dichloroethylene 1n humans could not be located 1n the available
literature.
4.1.2. Inhalation. Ott et al. (1976) Investigated the effects of occupa-
tional exposure to 1 ,l-d1chloroethylene (<0.2% vinyl chloride) among 138 Dow
Chemical Company workers. TWA concentrations were estimated based on job
descriptions and Industrial hygiene surveys; the subjects were divided Into
groups exposed to <10 ppm (assumed 5 ppm average), 10-24 ppm (assumed 17 ppm
average) and >25 ppm (assumed 43 ppm average). There were no statistically
significant differences between the exposed groups and controls matched for
age and smoking habits; however, the population examined In the study may
not be adequate for the detection of cancer.
4.2. BIOASSAYS
4.2.1. Oral. The available data regarding the oral carcinogeniclty of
1,l-d1chloroethylene In experimental animals are summarized in Table 4-1.
These studies have failed to demonstrate a carcinogenic potential for
1,1-dichloroethylene 1n either rats or mice following oral exposure.
4.2.2. Inhalation. The available data on the inhalation carcinogenicity
of 1,1-dichloroethylene in experimental animals are summarized in Table 4-2.
The only studies in which 1,1-dichloroethylene has produced positive results
are those of Maltoni et al. (1977, 1980) 1n which Sprague-Oawley rats and
Swiss mice were used. There were at least 30 animals/sex/dose at the begin-
ning of the exposure period, with 90-100 animals/sex in the controls. Rats
were exposed to atmospheres containing 0, 10, 25, 50, 100 or 150 ppm (0,
39.7, 99.1, 198.3, 396.5 or 594.8 mg/m3) 1,1-dichloroethylene, 4 hours/
day, 4-5 days/week, for 12 months.
-10-
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TABLE 4-1
Results of Oral Carc1nogen1c1ty Bloassays of 1,l-D1chloroethylene*
Species
Sprague-
Dawley rats
Sprague-
Dawley rats
Fischer 344
rats
B6C3F1 mice
Sprague-
Dawley rats
Dose
20. 10, 5, 0.5
mg/kg for 12 months
50, 100, 200 ppm
In drinking water
5 ml/kg of a 1000
or 200 ppm solution
10 ml/kg of a 1000
or 200 ppm solution
0.5, 5, 10, 20
mg/kg/day
Route of
Administration
gavage, dally
Ingestlon
gavage,
5 days/week
gavage,
5 days/week
gavage,
5 days/week
Total Duration
of Observation
(weeks)
147
104
103
103
52-59
Findings
No statistically
significant Increase
No statistically
significant Increase
No statistically
significant Increase
No statistically
significant Increase
No brain tumors
Reference
Haltonl
et al., 1977
Quast
et al., 1983
NTP, 1982
NTP, 1982
Maltonl
et al., 1982
*Source: U.S. EPA, 1983b
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TABLE 4-2
Results of Inhalation Carclnogenlclty Bloassays of 1,1-Dlchloroethylene*
Species
Sprague-Dawley
rats
Swiss mice
Chinese hamsters
Ulster rats
i
rsj
Sprague-Dawley
rats
CD-I mice
CO rats
Sprague-Dawley
rats
CD mice
CD rats
Sprague-Dawley
rats
Dose
10. 25. SO, 100, 150
ppm, 4-5 days/week
for 12 months
10, 25 ppm. 4-5 days/
week for 12 months
25 ppm, 4-5 days/week
for 12 months
200 ppm for 6 months,
followed by 100 ppm
for 6 months, 5 days/
week
100, 75 ppm, 5 days/
week for 12 months
55 ppm. 5 days/week
55 ppm, 5 days/week
for 12 months
25, 75 ppm for
24 months
55 ppm, 5 days/week
1 , 3 or 6 months
55 ppm, 5 days/week
1. 3, 6 or 10 months
10. 25. 50. 100,
150 ppm
Route of
Administration
Inhalation,
4 hours/day
Inhalation,
4 hours/day
Inhalation,
4 hours/day
Inhalation,
4 hours/day
Inhalation,
4 hours/day
Inhalation,
6 hours/day
Inhalation,
6 hours/day
Inhalation
Inhalation.
6 hours/day
Inhalation,
6 hours/day
Inhalation,
4-5 days/week
Total Duration
of Observation
137 weeks
121 weeks
157 weeks
lifetime
lifetime
12 months
12 months
104 weeks
13. 15 or IB
months
13, 15, 18 or
22 months
52 weeks
Findings
Statistically significant
Increase In total mammary
tumors, but not carcinomas
alone, only at 10 and 100 ppm;
no dose response
Kidney carcinomas at 25 ppm
In males (none In controls)
Statistically significant
Increase In mammary carcinomas
In females; no dose response
No statistically significant
Increase
No statistically significant
Increase
No statistically significant
Increase
No statistically significant
Increase
No statistically significant
Increase
No statistically significant
Increase
No statistically significant
Increase
No statistically significant
Increase
No brain tumors
Reference
Naltonl et al.,
1977, 1980
Naltonl et al. ,
1977, 1980
Haltonl et al.,
1977, 1980
Viola and
Caputo. 1977
Viola and
Caputo, 1977
Lee et al.. 1978
Lee et al.. 1978
McKenna et al. ,
1982
Hong et al.. 1981
Hong et al., 1981
Haltonl et al..
1982
'Source: U.S. EPA. 19835
-------
The results of these studies are summarized 1n Tables 4-3 and 4-4.
There were Indications that 1 ,l-d1chloroethylene Induced mammary tumors In
both rats and mice; however, there was no clear dose-response relationship
and these tumors could not positively be attributed to exposure to 1,1-dl-
chloroethylene. The only tumors that the authors considered related to the
treatment were kidney adenocarclnomas 1n male mice.
4.3. OTHER RELEVANT DATA
1,l-D1chloroethylene has been tested for yeast and bacterial mutagenlc-
1ty In the Ames assay, the liquid suspension assay, the host-mediated assay
and exposure of bacteria to atmospheres containing 1 ,l-d1chloroethylene,
both with and without mammalian metabolic activating systems (Bartsch et
al., 1975, 1979; Malavellle et al., 1977; Simmon et al., 1977, 1979; Simmon,
1978; Baden et al., 1976, 1977, 1978; Waskell, 1978; Grelm et al., 1975;
Cerna and Kypenova, 1977; Laumbach et al., 1977; Bartsch, 1976; Barbln et
al., 1978; Bonse et al., 1975). 1 ,l-D1chloroethylene 1s mutagenlc to Esche-
rlchla coll, Salmonella typhlmurlum, BadlUs subtlUs and Saccharomyces
cerevlslae, 1n the presence, but not the absence, of a mammalian metabolic
activating system.
1,1-Dichloroethylene vapors have been demonstrated to be mutagenlc to
the plant, Tradescantla. following a 24-hour exposure to concentrations as
low as 22 ppm (87.2 mg/m3); however, a 6-hour exposure to 1288 ppm (5107
mg/m3) did not produce a mutagenlc effect (Van't Hof and Schalrer, 1982).
In contrast, negative results have been obtained 1n assays using cultured
mammalian cells (Drevon and Kurokl, 1979) and 1n dominant lethal assays 1n
mice (Andersen and Jenkins, 1977) and rats (Short et al., 1977c).
-13-
-------
TABLE 4-3
Distribution of the Different Types of Mammary Tumors After Exposure by Inhalation to 1.1-Dlchloroethylene In Air After 137 Weeksa>b
Hlstologlcally
Animals
(Sprague-Dawley rats.
16 Weeks Old at Start)
Group
No.
I
II
III
IV
V
VI
Concen-
trations Sex
150 ppm M
F
M/F
100 ppm H
F
M/F
50 ppm N
F
M/F
25 ppm N
F
H/F
10 ppm M
F
M/F
no treat- M
ment F
(controls) M/F
No. at
Start
60
60
120
30
30
60
30
30
60
30
30
60
30
30
60
100
100
200
Corrected*1
Number
60
60
120
30
30
60
30
30
60
28
30
58
29
30
59
87
99
186
Xe
13.3
73.3
43.3
16.7
83.3
50.0
23.3
76.7
50.0
14.3
70.0
43.1
10.3
93.3
52.5
12.6
61.6
38.7
Average
Latency
Tlmef
(weeks)
97*14
82*3
82*3
104*9
82*4
85*4
106*5
79*4
86*4
103*10
86*4
88*4
81*23
83*4
81*4
115*6
87*2
91*3
No. of
Tumors/
Tumor -
Bearing
Animals
1.0
.5
.4
.0
.7
.6
.0
.9
1.7
1.0
1.6
1.5
.1.0
1.6
1.5
1.0
1.5
1.4
X9
100.0
97.7
98.1
100.0
92.0
93.3
100.0
95.6
96.7
100.0
95.2
96.0
100.0
85.7
87.1
100.0
91.8
93.0
No.
6
38'
44
5
21'
26
7
21'
28
4
20'
24
3,
24'
27
11
44
55
Flbromas and
F Ibroadenomas
X"
75.0
88.4
86.3
100.0
91.3
92.8
100.0
95.4
96.5
100.0
100.0
100.0
100.0
100.0
100.0
100.0
78.6
82.1
Average
Latency
(weeks)
109*8
83*3
86*3
104*9
83*5
87*4
106*5
82*4
88*4
103*10
87*4
90*4
81*23
85*4
85*4
115*6
88*3
93*3
Examined
HlstotypeC
Carcinomas
No.
1
9
10
0
3
3
0
1
1
0
4
4
0
5
5
0
16
16
*h
12.5
20.9
19.6
0
13.0
10.7
0
4.5
3.4
0
20.0
16.7
0
20.8
18.5
0
28.6
23.9
Average
Latency
T1mef
(weeks)
26
78*8
73*8
0
102*10
102*10
0
68
68
0
82*10
82*10
0
90*14
90*14
0
95*5
95*5
aSource: Haltonl et al., 1980
^Exposure was for 4 hours/day, 4-5 days/week for 52 weeks
cTwo or more tumors of the same and/or different types (fIbroadenomas, carcinomas, sarcomas, carclnosarcomas) may be present In the same animals.
A carcinoma was found In one male In the 150 ppm group, and no animals were observed to have sarcomas.
('Live animals after 10 weeks, when the first tumor (a leukemia) was observed.
eThe percentages refer to the corrected numbers.
^Average age at the onset of the first mammary tumor per animal, detected at the periodic control or at autopsy.
9The percentages refer to total numbers of animals bearing mammary tumors.
"The percentages refer to total numbers of animals bearing mammary tumors, hlstologlcally examined.
^Statistically significant Increase compared to control by chl-square test (p<0.05). Comparisons are made between numbers with tumors/corrected numbers.
-------
TABLE 4-4
Distribution of the Different Types of Tumors After Exposur'e by Inhalation to 1,1-Dlchloroethylene In Air After 121 Weeks3-b
Animals with Tumors
Animals (Swiss
mice 16 weeks old
[(Groups I. II. III. IV.
V.VI) and 9 weeks
old (Groups IV bis.
Treatment VII at start]
Groups
No.
1
II
III
IV
IV bis
V
VI
Concen- Length
tratlons
200 ppm 2 days
100 ppm 2 days
50 ppm 1 week
25 ppm 52 weeks
25 ppm 52 weeks
10 ppm 52 weeks
no NA
treatment
(controls)
Sex
H
F
H/F
H
F
H/F
H
F
H/F
H
F
H/F
H
F
H/F
H
F
H/F
H
F
H/F
No. at
Start
60
60
120
30
30
60
30
30
60
30
30
60
120
120
240
30
30
60
100
100
200
Kidney Adenocarclnomas
Corrected
Number6
1
28
29
12
13
25
17
14
31
21
26
47
98
112
210
25
26
51
56
73
129
Mammary Tumors0
Average
Latency
Tlmef Corrected
No.
0
0
0
0
0
0
1
0
1
39
0
3
259
1
26
0
0
0
0
0
0
X (weeks)
0
0
0
0
0
0
5.9
0
3.2
14.3
0
6.4
25.5
0.9
12.4
0
0
0
0
0
0
0
0
0
0
0
0
64
0
64
71*5
0
71*5
75*2
77
75*2
0
_
0
0
0
0
Number6
6
53
59
21
28
49
27
28
55
29
30
59
117
118
235
30
30
60
92
97
189
No.
0
1
1
0
3
3
0
2
2
0
4"
4
1
12h
13
0
6^
6
1
2
3
Pulmonary Adenomas
Average
Latency
Time6 Corrected
X (weeks) Number6
0
1.9
1.7
0
10.7
6.1
0
7.1
3.6
0
13.3
6.8
0.8
10.2
5.5
0
20.0
10.0
1.1
2.1
1.6
0
87 .
87
0
46*3
46*5
0
39*13
39*13
0
68*11
68*11
46
69*4
67*4
0
63*5
63*5
25
49*7
41*9
5
46
53
18
26
44
26
27
53
28
29
57
113
118
231
28
30
58
80
92
172
No.
0
1
1
2
2
4
1
3
4
71
7'
14
161
111
27
111
3'
14
3
4
7
Average
Latency
T1mef
X (weeks)
0
2.2
1.9
11.1
7.7
9.1
3.8
11.1
7.5
25.0
24.1
24.6
14.2
9.3
11.7
39.3
16.0
24.1
3.7
4.3
4.1
0
57
57
62*7
53*2
58*4
62
80*8
75*7
73*6
85*6
30*4
77*3
78*6
77*3
71*5
68*4
70*4
66*7
56*7
60*4
-------
TABLE 4-4 (cont.)
Animals with Tumors
Groups
No.
VII
Treatment
Concen- Length
tratlons
no NA
treatment
(controls)
Animals (Swiss
mice 16 weeks old
[(Groups 1,11,111,1V,
V.VI) and 9 weeks
old (Groups IV bis.
VII at start]
Sex No. at
Start
N 90
F 90
H/F 180
Kidney
Adenocarclnomas
Corrected
Number6 No.
70
85
155
0
0
0
X
0
0
0
Average
Latency
Time*
(weeks)
0
0
0
Mammary
Corrected
Number* No.
80
88
168
0
0
1
Tumors0
X
0
0
0.6
Average
Latency
Time*
(weeks)
0
0
83
Pulmonary
Corrected
Number6 No.
73 3
86 2
159 5
Adenomas
Average
Latency
T1mef
X (weeks)
4.1 56*11
2.3 75*12
3.1 64 f 8
aSource: Haltonl et al., 1980
^Exposure was for 4 hours/day. 4-5 days/week for 52 weeks
CA11 mammary tumors In females were hlstologlcally diagnosed as carcinomas.
dSome pulmonary adenomas were cellular atyptas.
eA11ve animals when the first tumor was observed: kidney adenocarclnoma, 55 weeks; mammary tumor, 27 weeks; pulmonary adenoma, 36 weeks. The percentages
refer to the corrected numbers.
fAverage time from the start of the experiment to the detection (at the periodic control or at autopsy).
9p<0.01, combined 25 ppm (28/119) males vs. control males (0/196) by chl-square test. Based on corrected numbers.
np<0.01 combined control males (6/153) vs. 10 ppm males (11/28) and vs. combined 25 ppm males (29/294). Also, combined control females (6/178) vs. 10 ppm
females (3/30) and vs. combined 25 ppm females (18/147)
1p<0.01 combined control females (3/185) vs. 10 ppm females (6/30) and vs. combined 25 ppm females (16/148). Based on corrected numbers.
NA = Not applicable
-------
4.4. WEIGHT OF EVIDENCE
IARC (1982) has evaluated the evidence for cardnogenlcHy of 1,1-di-
chloroethylene and concluded that the evidence for cardnogenlcHy In humans
1s "Inadequate," the evidence for cardnogenlcHy 1n animals 1s "limited,"
and the evidence for activity In short-term tests is "sufficient." Applying
the criteria for weight of evidence proposed by the Carcinogen Assessment
Group of the U.S. EPA (Federal Register, 1984) 1 ,l-d1chloroethylene is most
appropriately classified in Group C - Possible Human Carcinogen.
-17-
-------
5. REGULATORY STANDARDS AND CRITERIA
The ACGIH (1980) has established a TLV of 5 ppm (-20 mg/m3) and a STEL
of 20 ppm (-80 mg/m3), which are believed low enough to prevent overt
toxldty in exposed workers.
The U.S. EPA (1980b) has estimated that an ambient water concentration
of 0.33 wg/8. would result In excess carcinogenic potency over a lifetime
exposure. Both NIOSH and OSHA consider 1,l-d1chloroethylene to be a
potential carcinogen and have established an exposure limit of 1.0 ppm (-4
mg/m3) as a TWA or 5 ppm (-20 mg/m3) as a !5-m1nute celling (ACGIH,
1980).
-18-
-------
6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
1,1-Dlchloroethylene 1s a chemical associated with cancer In animals and
for which data are sufficient for computing a q^*. It 1s, therefore, In-
appropriate to calculate an oral or Inhalation AIS for 1,l-d1chloroethylene.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
l,l-D1chloroethylene Is a chemical associated with cancer In animals and
for which data are sufficient for computing a q^. It 1s, therefore, In-
appropriate to calculate an oral or Inhalation AIC for 1,l-d1chloroethylene.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. No data were located 1n the available literature that Indi-
cated a carcinogenic potential for orally administered 1 ,l-d1chloroethylene.
Therefore, no q * could be derived.
6.3.2. Inhalation. Only one study was located 1n the available litera-
ture that Indicated a carcinogenic response to Inhaled 1,1-dlchloroethylene
(Maltonl, et a!., 1977, 1980). In this study, groups of at least 30 Swiss
mlce/sex/dose were exposed to 0, 39.7 or 99.1 mg 1,l-d1chloroethylene/m3,
4 hours/day, 4-5 days/week, for 12 months. Kidney adenocardnomas were
observed 1n 28/119 male mice In the high dose groups as compared with 0/126
control male mice. The U.S. EPA (1983b) has analyzed these data and derived
a q * of 1.47X10"1 (mg/kg bw/day}'1. The data base from which this
q * 1s calculated 1s presented 1n Appendix B. This assessment uses the
same study as U.S. EPA (1980b); however, when the water quality document was
developed, only Interim results of this study were available, hence the
difference 1n estimates.
-19-
-------
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-24-
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-25-
-------
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McKenna, M.J., J.A. Zemple, E.O. Madrid, W.H. Braun and P.J. Gehrlng. 1978.
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following oral administration. Toxlcol. Appl. Pharmacol. 45(3): 821-835.
(Cited 1n U.S. EPA, 1983b)
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fetotoxldty of Inhaled or Ingested vinylldene chloride 1n rats and rabbits.
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NHschke, K.D., B.A. Schwetz, C.G. Humlston, et al. 1980. A Multiple
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F344/N Rats and B6C3Fl/M1ce (Gavage Study). NPT No. 80-82. NIH Publ. No.
82-1784. NTP, Research Triangle Park, NC and Bethesda, MO. U.S. DHHS, PHS,
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study of employees exposed to vinylldene chloride. J. Occup. Med. 18(11):
735-738. (Cited In U.S. EPA, 1983b)
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Effects on experimental animals of long-term Inhalation of tMchloroethy-
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Quast, J.F., C.G. Humlston, C.E. Wade, et al. 1983. A chronic toxldty and
oncogenldty study 1n rats and subchronic toxldty study 1n dogs on Ingested
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APPENDIX A
Summary Table for l,l-D1chloroethylene
Species
Experimental
Dose/Exposure
Effect
Reference
CO
Inhalation
AIS
AIC
Carcinogenic
potency
Oral
AIS
AIC
Carcinogenic
potency
mouse 39.7 or 99.1
mg/m3
kidney
adenocarclnomas
ND
ND
1.47X10"1
(mg/kg bw/day)
ND
ND
ND
Maltonl et al.,
1977, 1980;
U.S. EPA, 1983b
ND = Not derived
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APPENDIX B1
Cancer Data Sheet for Derivation of q-|*
Compound: 1 ,l-d1chloroethylene
Reference: Maltonl et al., 1980
Species, Strain, Sex: mice, Swiss, male
Body weight: 0.03 kg (assumed)
Length of exposure (le) = 52 weeks
Length of experiment (Le) = 104 weeks
Llfespan of animal (L) = 104 weeks
Tumor site and type: kidney, adenocarclnoma
Route, vehicle: Inhalation
Experimental Doses
or Exposures
(ppm)
0
10
25
Transformed Dose+
(ppm)
0
0.54
1.35
Incidence
No. Responding/No. Tested
or Examined
0/126
0/25
28/119
tTotal dose period = 1/2 total lifetime
Unadjusted q-j* from study = l.TxlO"1 (ppm)"1
Human q-j*=l .47X10"1 (mg/kg/day)'1 (see Appendix 82)
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APPENDIX B2
Calculation for
Lifetime risk of cancer associated with 1 ppm, p;
p=l-e-0'17
For I,l-d1chloroethylene: 1 pg/m3 = 0.25 ppm by the formula
C (mg/m3) = C (ppm) x MW (molecular weight
'of chemical) -f 24.45 (moles/a of air)
Lifetime risk of cancer associated with 1 mg/m3, p:
p , 1_e-(0.17)(0.25) = 4>
q * (mg/kg/day)"1 = 70 kg x 4.2 x 10"2 * 20 m3/day • 1 mg/m3 = 0.147
where:
70 = assumed body weight of humans 1n kg
20 = human Inhalation rate 1n mVday.
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