EPA-540/1-86-027
Agency
of Emergency and
It at Response
.mgton DC 20460
Off'ce of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
Superfund
oEPA
HEALTH EFFECTS ASSESSMENT
FOR 1,1-DICHLOROETHANE
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EPA/540/1-86-027
September 1984
HEALTH EFFECTS ASSESSMENT
FOR 1.1-DICHLOROETHANE
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 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 It 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-
chloroethane. 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 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) sources have
been extensively utilized:
U.S. EPA. 1980b. Ambient Water Quality Criteria for Chlorinated
Ethanes. Environmental Criteria and Assessment Office, Cincinnati,
OH. EPA 440/5-80-029. NTIS PB 81-117624. (Cited 1n U.S. EPA,
1983b)
U.S. EPA. 1983b. Drinking Water Criteria Document for 1.1-D1-
chloroethane. Prepared by the Environmental Criteria and Assess-
ment Office, Cincinnati, OH, OHEA for the Office of Drinking Water,
Washington, DC. Final draft.
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 1n
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, 1s 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 Hfespan [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 1n U.S. EPA (1983a).
For compounds for which there is sufficient evidence of cardnogenicHy,
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-|*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 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 Inter-
pretation and use of the quantitative estimates.
Tox1colog1cal data are limited to subchronlc Inhalation studies. The
U.S. EPA (1983b) has employed these data to estimate an acceptable oral
exposure level of 8.1 mg/day which 1s adopted here as the oral AIC. An
Inhalation AIC of 9.7 mg/day has been estimated based on subchronlc Inhala-
tion data. A CS of 9.8 was calculated based on kidney damage 1n cats
exposed for 26 weeks to a TWA level of 750 ppm.
Limited data Indicate that 1 ,l-d1chloroethane may have the potential for
carcinogenic activity 1n experimental animals.. Data were Inadequate for
quantitative risk assessment. Additional experimental data are needed in
order to adequately address the Issue of potential cardnogenicHy.
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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 In 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
3
. . . 3
, , 3
4
4
. . . 4
4
5
. . . 5
. . . 7
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS.
3.4.
3.5.
3.3.2. Inhalation
TOXICANT INTERACTIONS
HEALTH EFFECTS IN HUMANS
4. CARCINOGENICITY
7
7
7
7
4.1.
4.2.
4.3.
4.4.
REGUL
HUMAN DATA
BIOASSAYS
OTHER RELEVANT DATA
4.3.1. Mutagenldty Tests
WEIGHT OF EVIDENCE
I\TORY STANDARDS AND CRITERIA
9
9
11
11
12
13
V11
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TABLE OF CONTENTS (cont.)
Page
6. RISK ASSESSMENT 15
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) 15
6.1.1. Oral 15
6.1.2. Inhalation 15
6.2. ACCEPTABLE INTAKE CHRONIC (AIC) 18
6.2.1. Oral 18
6.2.2. Inhalation 18
6.3. CARCINOGENIC POTENCY (q-|*) 19
6.3.1. Oral 19
6.3.2. Inhalation 19
7. REFERENCES 20
APPENDIX: Summary Table for 1 ,l-D1chloroethane 25
V111
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LIST OF TABLES
No. Title
4-1 Summary of Incidence of Statistically Significant Primary
Tumors 1n Osborne-Mendel Rats and B6C3F-| Mice 10
5-1 Regulatory Standards and Criteria 14
6-1 Calculated Animal Dose 1n mg/kg/day 17
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
CNS Central nervous system
CS Composite score
Kow Octanol/water partition coefficient
LOAEL Lowest-observed-adverse-effect level
MED Minimum effective dose
NOEL No-observed-effect level
ppm Parts per million
RV,j Dose-rating value
RVe Effect-rating value
SGOT Serum glutamate oxaloacetate transamlnase
SGPT Serum glutamate pyruvate transamlnase
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-d1chloroethane (CAS Registry No. 75-34-3), also known as ethylldene
chloride or ethylldene dlchloMde, are given below.
Chemical class:
Molecular weight:
Vapor pressure:
Water solubility:
Kow:
Soil mobility:
(predicted as retardation
factor for a soil depth of
140 cm and organic carbon
content of 0.087%)
BCF:
Half-life 1n air:
Half-life 1n water:
halogenated aliphatic hydrocarbon
98.96
182 mm Hg at 20°C (Archer, 1979)
5500 mg/S. at 20°C (Archer, 1979)
61.6 (Valvan! et al., 1981)
1.2 (estimated)
6.6 (estimated)
'l.5 months (Callahan et al., 1979)
1-5 days (estimated)
A soil retardation factor of 1.2 has been estimated for 1,1 dlchloro-
ethane using the soil adsorption coefficient and K (Schwarzenbach and
Westall, 1981). The KQW value for 1,1-dlchloroethane (61.6) 1s Inter-
mediate between the K values for chloroform (93) and 1,2-d1chloroethane
ow
(30). The soil retardation factor for a soil depth of 140 cm and organic
carbon content of 0.087% 1s 1.2 for both 1,2-d1chloroethane and chloroform
(Wilson et al., 1981). Therefore, the retardation factor for 1,1-dlchloro-
ethane has been estimated to be 1.2.
The BCF value of 6.6 given above has been estimated from the following
equation: log BCF = 0.85 log KQW - 0.70 (Velth et al., 1979).
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The ratio of the reaeratlon rate constants for 1 ,l-d1chloroethane has
been experimentally determined to be 0.71 (Smith et al., 1980). The half-
life value has been estimated from this reaeratlon rate ratio and the oxygen
reaeratlon rates 1n representative water bodies (0.19-0.96 day"1), with
the assumption that the volatilization 1s a first order process (Mabey et
al., 1981).
The half-life value for 1,l-d1chloroethane 1n soil could not be located
1n the available literature; however, evaporation 1s expected to be the pre-
dominant loss mechanism from the soil surface. The half-life for soil
evaporation should be longer than Us evaporation half-life from water. In
subsurface soil, the loss of 1 ,l-d1chloroethane through blodegradatlon 1s
expected to be Insignificant (Wilson et al., 1983). Therefore, I,l-d1-
chloroethane may persist 1n soil and 1s expected to be removed primarily
through leaching Into groundwater.
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
No studies have been conducted regarding gastrointestinal absorption of
1,l-d1cnloroethane. Based on similarities of molecular size and UpophlUc-
1ty as evidenced by olive oil/water partition coefficients (69.2 for I,l-d1-
chloroethane and 39.8 for 1,2-d1chloroethane) (Sato and Nakajlma, 1979), It
was suggested that gastrointestinal absorption of 1 ,l-d1chloroethane may
proceed somewhat faster than absorption of 1,2-d1chloroethane. Spreaflco et
al. (1980) reported rapid absorption of 1,2-d1chloroethane 1n rats after
single oral doses of 25 mg/kg bw or 150 mg/kg bw 1n corn oil.
2.2. INHALATION
No studies regarding the extent or rate of absorption from Inhalation of
1 ,l-d1chloroethane have been located. Goldstein et al. (1974) suggested
that with gases having a blood/air partition coefficient of >1.2, respira-
tion Is the limiting factor In reaching equilibrium. Sato and Nakajlma
(1979) reported blood/air coefficients of 4.7 and 19.5 for 1,1- and l,2-d1-
chloroethane, respectively. Therefore, 1t might be expected that I,l-d1-
chloroethane would be absorbed moderately from Inhalation exposure, but
absorbed less and eliminated more rapidly than 1,2-d1chloroethane, which
helps explain the observation that the Inhalation toxldty of 1 ,l-d1chloro-
ethane 1s less than the toxldty of 1,2-d1chloroethane (Lazarew, 1929).
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Few studies of the effects of subchronlc oral administra-
tion of 1 ,l-d1chloroethane on animals have been located. In a very limited
study, Larson et al. {1955} Intubated three mongrel dogs with 200 mg/kg bw
1 ,l-d1chloroethane 6 days/week for 8 weeks to study the effects on the
adrenal gland. All three test animals survived the treatment and none had
significant hlstologlcal changes 1n the adrenals. Other parameters of
toxldty were not reported.
Preliminary to conducting a long-term cardnogenesls bloassay In rats
and mice, NCI (1978) conducted a subchronlc range-finding study by adminis-
tering 1 ,l-d1chloroethane 1n corn oil by gavage. Groups of five male and
five female Osborne-Mendel rats were given 562, 1000, 1780, 3160 or 5620
mg/kg bw/day 5 days/week for 6 weeks. Male rats 1n the 1000 and 1780 dose
groups and females 1n the 1780 and 3160 mg/kg/day groups exhibited body
weight depression. Mortality occurred In two female rats 1n the 3160 mg/kg/
day group. Groups of five male and five female B6C3F, mice were treated
with 1000, 1780, 3160, 5620 or 10,000 mg/kg/day 5 days/week for 6 weeks. No
body weight depression occurred 1n mice, but mortality occurred 1n two male
and three female mice 1n the 5620 mg/kg/day dose group. These studies were
too limited 1n their assessment of criteria of toxlclty to be useful 1n risk
assessment.
3.1.2. Inhalation. In a subchronlc Inhalation study, Hofmann et al.
(1971) exposed groups of 10 rats, 4 cats, 4 rabbits and 10 guinea pigs to
500 ppm (-2025 mg/m3} 1 ,l-d1chloroethane 6 hours/day, 5 days/week for 13
weeks. No effects were reported 1n any of the animals tested. Exposure to
1000 ppm (~4050 mg/m3) 6 hours/day, 5 days/week using the same test
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animals continued for another 13 weeks. The most sensitive animal tested
appeared to be the cat, the only animal 1n which adverse effects were noted.
Blood urea nitrogen levels were Immediately elevated and rose steadily to
week 24, at which time they peaked at ~3 times the control levels. Blood
creatlnlne levels showed a parallel but less dramatic Increase. No Increase
of SGOT or SGPT was noted. Hlstopathologlcal examination of the cats
revealed renal tubular dilatation and degeneration. Indicating renal damage.
Torkelson and Rowe (1981) summarized an unpublished subchronlc Inhala-
tion study by Dow Chemical Company 1n which unspecified numbers of rats,
guinea pigs, rabbits and dogs were exposed to 500 or 1000 ppm (2025 or 4050
mg/m3, respectively) 1 ,l-d1chloroethane for 7 hours/day, 5 days/week for 6
months. Blood chemistries, necropsy and hlstologlcal examinations revealed
no changes attributed to the exposure. Based on the studies by Torkelson
and Rowe (1981) and Hoffman et al. (1971), a NOEL of 500 ppm (2025 mg/m3)
can be suggested for subchronlc Inhalation exposure to 1 ,l-d1chloroethane 1n
rats, cats, rabbits, guinea pigs and dogs.
3.2. CHRONIC
3.2.1. Oral. The only study of chronic oral toxldty to 1,l-d1chloro-
ethane was reported In the NCI cardnogenldty assay (NCI, 1978). Groups of
50 male and 50 female Osborne-Mendel rats and B6C3F, mice were Intubated
with I,l-d1chloroethane 1n corn oil. Control and vehicle control groups
consisted of 20 male and 20 female animals of each species. Treatments were
administered 5 days/week for 3 weeks, followed by 1 dose-free week and 3
additional treatment weeks over the 78-week treatment period. The following
time weighted dosages for treatment days were obtained: male rats, high-
dose group 764 mg/kg bw/day, low-dose group 382 mg/kg bw/day; female rats,
high-dose group 950 mg/kg bw/day, low-dose group 475 mg/kg bw/day. Mice
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were treated 5 days/week for 78 weeks with the dosage Increased after 6
weeks and again after 9 weeks. The TWA doses for treatment days for male
mice were 2885 and 1442 mg/kg bw/day for low- and high-dose groups, respec-
tively; for female mice, these doses were 3331 and 1665 mg/kg bw/day,
respectively. Rats were observed for an additional 33 weeks and mice for an
additional 13 weeks, after which survivors were killed. All animals that
died or were killed when moribund or at the conclusion of the observation
period were subjected to necropsy.
For both male and female rats, body weight curves for treatment and
vehicle control groups were similar and somewhat below untreated controls.
All groups of rats exhibited a hunched appearance, abdominal urine stains,
labored breathing, wheezing and nasal discharge. By the conclusion of the
trial, all surviving rats exhibited these signs, though the incidence early
In the study appeared to be slightly higher 1n the treatment groups.
Mortality was high in both male and female groups of rats and appeared to be
slightly higher 1n 1,l-d1chloroethane-exposed groups, though no signifi-
cantly greater mortality was observed 1n the high-dose groups. Chronic
murlne pneumonia and kidney inflammation accounted for the vast majority of
mortality among both control and treatment groups.
Body weight curves for male and female mice seemed unaffected by treat-
ment or vehicle; there appeared to be no definitive signs of 1,1-dichloro-
ethane toxlcity in physical appearance or behavior throughout the study.
Examination of statistically predicted survival curves Indicated that sur-
vival of both male and female mice had been adversely affected by the high
dose of I,l-d1chloroethane, although no specific pathological lesions were
observed at significantly higher incidences 1n treated groups. Because of
the Increased mortality associated with treatment, no NOEL or LOAEL was
defined by this study for mice.
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3.2.2. Inhalation. No pertinent data concerning chronic Inhalation expo-
sure to 1 ,l-d1chloroethane could not be located 1n the available literature.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Pertinent data regarding teratogenldty or reproductive
dysfunction 1n humans or animals associated with 1ngest1on of 1 ,l-d1chloro-
ethane could not be located 1n the available literature.
3.3.2. Inhalation. Pertinent data regarding teratogenldty or reproduc-
tive dysfunction 1n humans related to Inhalation exposure to 1,l-d1chloro-
ethane could not be located 1n the available literature. Schwetz et al.
(1974) exposed rats to 0, 3800 or 6000 ppm 1,1-dlchloroethane for 7 hours/
day on days 5-15 of gestation. A significantly Increased Incidence of
delayed ossification of sternebrae resulted from exposure to 6000 ppm
1 ,l-d1chloroethane. Assuming a body weight of 0.35 kg and an Inhalation
rate of 0.26 mVday for rats, exposure to 3800 ppm for 7 hours/day, corre-
sponding to an Intake of -3333 mg/kg/day, was found to be a NOEL 1n this
study. Because this Intake (-3333 mg/kg/day) 1s greater than the Intake
(269 mg/kg/day) calculated for rats 1n the study by Hofmann et al. (1971),
the Schwetz et al. (1974) study will not Impact risk assessment.
3.4. TOXICANT INTERACTIONS
Pertinent data on the toxic Interactions of 1,l-d1chloroethane with
other xenoblotlcs could not be located 1n the available literature; however,
1t can be anticipated that exposure to other agents which deplete glutathlon
would enhance Us toxldty.
3.5. HEALTH EFFECTS IN HUMANS
Limited Information 1s available concerning the effects of 1,1-dlchloro-
ethane on humans. At one time the compound was used as an anesthetic, with
an anesthetic pressure of 0.026 atmospheres, -105,000 mg/m3 (Miller et
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al., 1965). The ability of the compound to Induce cardiac arrhythmias
caused discontinuation of Us use as an anesthetic (Browning, 1965). It 1s
probable that human exposure to sufficiently high levels would cause CNS
depression and respiratory tract and skin Irritation, since many other
chlorinated aHphatlcs do (Parker et al., 1979). No dose-response data
concerning these phenomena are available.
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4. CARCINOGENICITY
4.1. HUMAN DATA
Pertinent data concerning the cardnogenldty of 1,1-dlchloroethane 1n
humans could not be located 1n the available literature.
4.2. BIOASSAYS
The only cardnogenldty bloassay concerning 1 ,l-d1chloroethane located
1n the available literature was conducted by NCI (1978). The protocol and
noncardnogenlc data generated by this study were discussed In Section 3.2.
Under the conditions of this study, male rats showed no significant change
1n the Incidence of neoplasla which were compound related. Female rats
(Table 4-1) showed a significant dose-response relationship 1n the Incidence
of hemanglosarcoma when measured by the Cochran-ArmHage test for linear
trend 1n proportions comparing the two dose groups with either the matched
vehicle control (p=0.041) or the pooled vehicle control groups (p=0.021).
By the Cochran-ArmHage test, a significant (p=0.043) dose-related Incidence
of mammary adenocardnomas was also observed. Results of the Fisher Exact
test showed no significant Incidence of either of these tumors. Because of
high mortality early 1n the study, statistical analysis of data only from
survivors of >1 year of exposure was also performed. Using the Cochran-
ArmHage test, statistical significance (p=0.034) was demonstrated only for
mammary adenocardnoma 1n female rats. Results using the Fisher Exact test
were statistically negative.
In male mice surviving >1 year, the Cochran-ArmHage test demonstrated a
significant (p=0.016) dose-related Incidence of hepatocellular carcinoma
compared with pooled vehicle controls. Using the Fisher Exact test, a
probability level of p=0.027 was calculated by comparing high dose and
pooled vehicle control groups. Applying the Bonferronl criterion, which
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TABLE 4-1
Summary of Incidence of Statistically Significant Primary Tumors In Osborne-Hendel Rats and B6C3F) N1cea>b
Species Tumor Type
Female rats mammary adenocarclnoma
p values0
Female rats hemanglosarcoma
p values0
Female rats mammary adenocarclnomas
surviving
>52 weeks
p values0
Female mice endometrlal stromal polyp
p values0
Hale mice hepatocellular carcinoma
surviving
>52 weeks
p values0
Pooled Vehicle
Control
1/39 (0.03)
NS
0/39 (0.00)
p=0.021
NR
0/79 (0.00)
p=0.005
6/72 (0.08)
p=0.016
Hatched Vehicle
Control
0/19 (0.00)
p=0.043
0/19 (0.00)
p=0.041
0/16 (0.00)
p=0.034
0/20 (0.00)
p=0.036
1/19 (0.05)
NS
Low Dose
1/50 (0.02)
NS
0/50 (0.00)
NS
1/28 (0.04)
NS
0/47 (0.00)
NS
8/48 (0.17)
NS
High Dose
5/50 (0.10)
NS
4/50 (0.08)
NS
5/31 (0.16)
NS
4/46 (0.09)
p=0.017*
8/32 (0.25)
p=0.027*«d
aSource: NCI. 1978
bExper1mental design summarized In text
cThe probability level for the Cochran-Armltage test Is given beneath the Incidence of tumors In the corresponding control group when
p<0.05; otherwise, not significant (NS) Is Indicated. The probability level for the Fisher Exact test for the comparison of a treated group
with a control group Is given beneath the Incidence of tumors In that treated group when p<0.05; the asterisk (*) Indicates comparison of the
treated group with the pooled vehicle control group.
dThe Fisher Exact test probability level of p=0.027 was marginal and not considered significant under the Bonferronl criterion.
NR » Not reported; NS = Not significant
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requires that the normally accepted level of statistical significance
(p<0.05) be divided by the number of dose levels (2), resulted 1n an accept-
able p value of <0.025 for statistical significance. By this criterion, the
Incidence of hepatocellular carcinoma 1n the high dose group was considered
to be marginal and not statistically different from the Incidence 1n the
pooled vehicle control group.
In female mice, the Cochran-Armitage test showed a significantly posi-
tive dose-response relationship 1n the Incidence of benign endometMal stro-
mal polyps when compared with the matched vehicle control (p=0.036) or
pooled vehicle control (p=0.005) groups. By the Fisher Exact test, the In-
cidence of endometrlal stromal polyps 1n the high groups was significantly
(p=0.017) higher than In pooled vehicle controls.
Based on the results of statistical analysis and the low survival of all
groups, the NCI (1978) concluded that "these findings are Indicative of the
possible carcinogenic potential of the test compound. However, ... there
was no conclusive evidence for the carclnogenldty of 1 ,l-d1chloroethane 1n
Osborne-Mendel rats or B6C3F, mice."
4.3. OTHER RELEVANT INFORMATION
4.3.1. Mutagen1c1ty Tests. Simmon et al. (1977) tested the mutagenlc ac-
tivity of several chemicals Identified 1n drinking water 1n the Ames
Salmonella typh1mur1um/m1crosomal activation assay. Doses of the chemicals
ranged up to 5 mg/plate. Negative results were reported for 1 ,l-d1chloro-
ethane 1n S. typhlmurlum strains TA1535, TA1537, TA1538, TA98 and TA100,
although the specific dose of 1,l-d1chloroethane used and corresponding
plate counts were not specified.
Nesnow (1982) reported a positive response of 1,1-dlchloroethane In an
enhanced viral transformation assay 1n Syrian hamster embryo cells, using
the methods of Hatch et al. (1982). Details of protocol were not reported.
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4.4. WEIGHT OF EVIDENCE
The only bloassay of the cardnogenldty of 1,1-d1chloroethane located
was the NCI (1978) bloassay described previously. High mortality among all
groups probably precluded significant occurrence of tumors related to
long-term exposure. Welsburger (1977) reviewed NCI bloassays of several
halogenated allphatlcs and noted striking similarities In the types of
tumors produced. An example was the formation of hepatocellular carcinoma
Induced 1n mice by 1 ,l-d1chloroethane and tetrachloroethylene. Although the
Incidence of hepatocellular carcinoma 1n mice exposed to 1 ,l-d1chloroethane
was not significant (see Section 4.2.), the similarity 1n lesions produced
by other halogenated allphatlcs raises a concern that the marginal results
obtained with 1 ,l-d1chloroethane are biologically, 1f not statistically,
significant. Nevertheless, neither IARC nor the Carcinogen Assessment Group
of the U.S. EPA has officially classified 1 ,l-d1chloroethane as to cardno-
genlcHy, based presumably on a lack of evidence for human cardnogenlcHy
and the marginal slgnflcance of the NCI bloassay which 1s considered to be
limited evidence for animal cardnogenlcHy. Applying the criteria for
evaluating weight of evidence proposed by the Carcinogen Assessment Group
(Federal Register, 1984), 1 ,l-d1chloroethane 1s most appropriately classi-
fied a Group D-Not Classified chemical.
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5. REGULATORY STANDARDS AND CRITERIA
Table 5-1 lists the various regulatory standards and criteria for
1,1-dlchloroethane.
The AC6IH (1980) recommended a TWA-TLV of 200 ppm (-810 mg/m3) for
occupational exposure to 1 ,l-d1chloroethane, with a STEL of 250 ppm (-101
mg/m3). This recommendation 1s based In part on the data of Hofmann et
al. (1971) and the unpublished data of the Dow Chemical Company cited In
Torkelson and Rowe (1981) (see Chapter 3). The current OSHA standard for
occupational exposure to 1 ,l-d1chloroethane Is 100 ppm (-405 mg/m3), but
no NIOSH criterion for occupational exposure exists (Parker et al., 1979).
In discussing the derivation of ambient water quality criteria for
chlorinated ethanes, the U.S. EPA (1980b) concluded that "Insufficiency In
the available data" precluded establishment of a satisfactory criterion for
1 ,l-d1chloroethane. The nature of the deficiencies 1n the data was not
discussed. In a subsequent review (U.S. EPA, 1983b), 'an ADI of 8.1 mg/day
for a 70 kg man was proposed. This estimate was based on the NOEL of 2025
mg/m3 defined 1n Hofmann et al. (1971) and employed a rat 24-hour breath-
Ing volume of 0.22 mVday, an absorption coefficient of 0.5 and an uncer-
tainty factor of 1000.
No currently available Information described human populations that may
be particularly sensitive to 1,l-d1chloroethane. The U.S. EPA (1980b,
1983b) stated that no Information was available on unusual sensitivity of
any groups to any of the chlorinated ethanes. The U.S. EPA (1980b) sug-
gested, however, that Individuals with Hver Insufficiency or exposure to
other hepatotoxlns may be at Increased risk. Presumably, Individuals with
Impaired renal function may also be unusually sensitive to exposure to
I,l-d1chloroethane.
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TABLE 5-1
Regulatory Standards and Criteria
Criterion Standard Reference
TLV 200 ppm AC6IH, 1980
(-810 mg/m3)
STEL 250 ppm ACGIH, 1980
(-1010 mg/m3)
OSHA 100 ppm Parker et al., 1979
(-405 mg/m3)
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6. RISK ASSESSMENT
Risk assessment data for 1,l-d1chloroethane are presented in the
Appendix to this report.
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
6.1.1. Oral. Only two reports were located regarding subchronic oral
exposure in animals. These reports and their limitations were discussed in
Section 3.1. Because of the limited scope of these studies, it was not
possible to derive a maximum tolerable daily dose for subchronic oral
exposure. However, U.S. EPA (1983b) has used the subchronic Inhalation data
of Hofmann et al. (1971) to estimate acceptable oral exposure. Using their
approach, this study defines a NOEL for rats in units of mg/kg/day as
follows:
(2025 mq/m3) (0.22 mVday) (0.5) (6 hr/24 hr) (5 days/7 days)
0.35 kg
=115 mg/kg/day
The value of 0.22 mVday represents the default 24-hour rat breathing
volume employed, 0.5 represents the assumed absorption coefficient and 0.35
kg the default rat body weight. Multiplying by 70 kg and dividing by an
uncertainty factor of 100 (10 for interspecies variability and 10 for inter-
Individual variability) results in an estimated AIS of 81 mg/day.
6.1.2. Inhalation. Reports of two subchronic inhalation studies of
1 ,l-d1chloroethane 1n animals were discussed in Section 3.1. The study by
Hofmann et al. (1971) demonstrated a NOEL of 500 ppm (-2025 mg/m3) in
rats, cats, rabbits and guinea pigs when exposed for 6 hours/day, 5 days/
week for 13 weeks. After this exposure schedule, the 1,1-dichloroethane
concentration was increased to 1000 ppm (4050 mg/m3) for an additional 13
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weeks. The 1000 ppm level also represented a NOEL for all test animals
except cats In which elevated blood urea nitrogen was detected and adverse
hlstologlc changes 1n the kidney observed. For the cat, 1000 ppm represents
a LOAEL. An unpublished subchronlc Inhalation study conducted by Dow Chemi-
cal Company and summarized by Torkelson and Rowe (1981) supports the NOEL
suggested by the earlier study.
Estimated Inhaled doses may be calculated for each exposed species and
will vary 1n accordance with the ratio of ventilation volume/time to body
weight. Estimates of ventilation volume are rough estimates since these
values are particularly sensitive to experimental conditions and manipula-
tions. The estimated animal doses are presented 1n Table 6-1. Since the
cat data provide the most protective dose estimate (138 mg/kg/day), this
dose 1s chosen as a starting point for the AIS estimate. Assuming a human
body weight of 70 kg and applying an uncertainty factor of 100 results 1n an
AIS of 96.6 mg/day.
A CS for 1,l-d1chloroethane was calculated based on the kidney damage
observed by Hofmann et al. (1971) 1n cats exposed to 500 ppm for 13 weeks
and 1000 ppm for an additional 13 weeks. An RV of 7 was chosen for the
effects on the kidneys because there was hlstologlc evidence of kidney
damage with demonstrable decrement 1n organ functions (I.e., elevated blood
urea nitrogen). A human MED was calculated by expanding the TWA exposure,
750 ppm, from 6-24 hours/day and from 5-7 days/week. It was also assumed
that humans Inhale 20 m3 of a1r/24 hours and that 1,l-d1chloroethane
absorption Is 50%. An uncertainty factor of 10 was applied to convert from
subchronlc to chronic data resulting 1n a human MED of 542 mg/day, which
corresponds to an RV, of 1.4. A CS of 9.8, the product of RV. and
RVg, 1s calculated.
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TABLE 6-1
Calculated Animal Dose 1n mg/kg/daya
Dose 1n mq/kq bw/day
Species
Rats
Cats
Rabbits
Guinea pigs
Inhalation Rate
(mVday)b
0.22
1.26
1.6
0.23
Body Weight
(kg)b
0.35
3.3
1.13
0.43
2025 mg/m3
227
138
512
193
4050 mg/m3
455
276
1024
387
aSource: Hofmann et a!., 1971
bEst1mated Inhalation rates and body weights
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6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
6.2.1. Oral. The only report of chronic oral exposure to 1,1-dichloro-
ethane was the NCI (1978) bloassay discussed In Section 3.2. As noted
before, animals In both dosage levels and control groups experienced pro-
nounced early mortality. Although not statistically significant, some
potentlatlon of mortality In rats appeared to be related to treatment. U.S.
EPA (1983b) has used the subchronlc Inhalation data for the rat from Hofmann
et al. (1971) to develop an ADI. It 1s suggested that their estimate be
used for the AIC. The basis for the proposed AIC of 8.1 mg/day 1s explained
1n Section 6.1.1. with the addition of an uncertainty factor of 10 (combined
uncertainty factor of 1000) to extrapolate from subchronlc to chronic
exposure.
6.2.2. Inhalation. No reports of chronic Inhalation exposure of humans
or animals to 1,l-d1chloroethane could not be located 1n the available
literature. The AC6IH (1980) recommended a TLV of 200 ppm, based on the
studies by Hofmann et al. (1971) and Dow Chemical Company (n.d.), while the
OSHA standard for occupational exposure to 1,1-dichloroethane is a TLV of
100 ppm. The TLV of 100 ppm could be used to estimate acceptable exposure,
using an uncertainty factor of 10. The uncertainty factor of 10 1s used to
protect especially sensitive members of populations.
Calculation of the dose is as follows: The TLV (405 mg/m3) x 10 m3
Inhaled/workday x (5 workdays * 7 days/week) * 10 (UF) = 289 mg/day.
The AIC derived from the TLV is ~3-fold higher than the Interim AIS derived
for subchronlc exposure. The discrepancy may reflect differences and
uncertainties in the methodologies for obtaining TLVs and calculating
acceptable Intakes from animal data, or species differences 1n sensitivity
between cats and humans to the toxicity of 1,l-d1chloroethane. It Is
proposed that the more protective approach to AIC development be employed.
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Starting with the AIS of 96.6 mg/day and applying an additional uncertainty
factor of 10 to extrapolate from subchronlc to chronic exposure results 1n
an AIC of 9.7 mg/day. This value should be reevaluated when additional data
are available.
6.3. CARCINOGENIC POTENCY (q.,*)
6.3.1. Oral. Results of the NCI (1978) bloassay of 1 ,l-d1chloroethane
suggested that this compound may have carcinogenic properties. The signifi-
cant positive treatment-response associations elucidated by the Cochran-
Armltage test for hemanglosarcoma and mammary adenoma 1n female rats are not
necessarily Invalidated by the negative results of the Fisher exact test.
Heavy mortality among the control groups as well as the treatment groups and
application of the Bonferronl criterion undoubtedly contributed to the lack
of statistical significance of the Fisher exact test. The heavy mortality
among treatment groups probably resulted 1n underestimating the true
carcinogenic potential of 1 ,l-d1chloroethane, especially In light of the
positive treatment-response association manifest by the Cochran-Armltage
test. Furthermore, as pointed out by Welsburger (1977) (see Section 4.4.),
striking similarities 1n the types of tumors produced by other chlorinated
allphatlcs are suggestive of a carcinogenic role for 1,1-dlchloroethane.
Nonetheless, as Indicated by the review panel for the NCI (1978) bio-
assay on 1,1-dlchloroethane, the compound should be retested to resolve the
Issue of cardnogenlclty. Heavy mortality among both treatment and control
groups precluded using the data from this study to generate unit carcino-
genic risk estimates. Also, the physical condition of the animals was
markedly stressed and did not appoxlmate a normal human population.
6.3.2. Inhalation. Pertinent data regarding the cardnogenlclty of
1,1-dlchloroethane could not be located 1n the available literature.
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7. REFERENCES
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Cincinnati, OH. p. 130. (Cited In U.S. EPA, 1983b)
Archer, W.L. 1979. Other chloroethanes. In.: K1rk-0thmer Encyclopedia of
Chemical Technology, 3rd ed., Vol. 5, M. Grayson and D. Eckroth, Ed. John
Wiley and Sons, Inc., NY. p. 722-742.
Browning, E. 1965. Toxldty and Metabolism of Industrial Solvents.
Elsevler Publishing Co., Amsterdam. (Cited 1n U.S. EPA, 1983b)
Callahan, M.A., M.W. Sllmak, N.W. Gabel., et al. 1979. Water-Related
Environmental Fate of 129 Priority Pollutants, Vol. II. Office of Water
Planning and Standards, Office of Water and Waste Management, U.S. EPA,
Washington, DC. EPA 440/4-79-029b.
Dow Chemical Company, n.d. Unpublished data. (Cited 1n U.S. EPA, 1983b)
Federal Register. 1984. Environmental Protection Agency. Proposed
guidelines for carcinogenic risk assessment. 49 FR 46294-46299.
Goldstein, A., L. Arnonow and S.M. Kalman. 1974. Principals of Drug
Action: The Basis of Pharmacology, 2nd ed. John Wiley and Sons, Inc., NY.
p. 338-347. (Cited In U.S. EPA, 1983b)
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-------
Hatch, G.G., P.D. Mamaz, M.L. Ayer, B.C. Casto and S. Nesnow. 1982.
Methods for detecting gaseous and volatile carcinogens using cell transfor-
mation assays. In: Genotoxlc Effects of Airborne Agents, R.R. Tice, D.L.
Costa and K.M Scharch, Ed. Plenum Publishing Corp., NY. p. 75-90. (Cited
1n U.S. EPA, 1983b)
Hofmann, H.T., H. B1rnst1el and P. Jobst. 1971. The Inhalation toxldty of
1,1- and l,2-d1chloroethane. Arch. Toxlkol. 27: 248-265. (Cited In U.S.
EPA, 1983b)
Larson, P.S., G.R. Hennlgar, J.K. Flnnegan, R.B. Smith, Jr. and H.B. Haag.
1955. Relation of chemical structure to production of adrenal cortical
atrophy or hypertrophy 1n the dog by derivatives of 2,2-b1s(p-chlorophenyl)-
I,l-d1chloroethane (ODD, IDE). J. Pharmacol. Exptl. Therap. 115: 408-412.
(Cited 1n U.S. EPA, 1983b).
Lazarew, N.W. 1929. Concerning the strength of the narcotic effect of the
vapors of the chlorine derlvatles of methanes, ethanes, and ethylenes.
Arch. Exp. Pathol. Pharmakol. 141: 19-24. (Cited In U.S. EPA, 1983b)
Mabey, W.R., J.H. Smith, R.T. Podell, et al. 1981. Aquatic Fate Process
Data for Organic Priority Pollutants. Monitoring and Data Support D1v,
Office of Water Regulations and Standards, Washington, DC. EPA 440/4-81-014.
Miller, K.W., W.D.M. Paton and E.B. Smith. 1965. Site of action of general
anesthetics. Nature. 206: 574-577. (Cited 1n U.S. EPA, 1983b)
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NCI (National Cancer Institute). 1978. Bloassay of 1 ,l-d1chloroethane for
possible cardnogenlclty. CAS No. 75-34-3. Gov. Rep. Announce. Index
(U.S.) 78(22): 113. (Cited 1n U.S. EPA, 1983b)
Nesnow, S. 1982. Summary of Results of Bloassays of Volatile Carcinogens
and Mutagens 1n Enhancement of SA7 Virus Transformation 1n SNE Cells.
Personal communication presented at Peer Review Meeting for Chloroform held
at ECAO/RTP on December 7, 1982. (Cited 1n U.S. EPA, 1983b)
Parker, J.C., G.E. Casey and L.J. Bahlnon. 1979. NIOSH current Intelli-
gence bulletin No. 27. Chloroethanes: Review of toxldty. Am. Ind. Hyg.
Assoc. J. 40(3): A46-A60. (Cited 1n U.S. EPA, 1983b)
Sato, A. and T. Nakajlma. 1979. A structure-activity relationship of some
chlorinated hydrocarbons. Arch. Environ. Health. 34: 69-75. (Cited 1n
U.S. EPA, 1983b)
Schwarzenbach, R.P. and J. Westall. 1981. Transport of nonpolar organic
compounds from surface water to groundwater. Laboratory sorptlon studies.
Environ. Sc1. Technol. 15: 1360-1367.
Schwetz, B.A., B.K.J. Leong and P.O. Gehrlng. 1974. Embryo- and fetotoxlc-
Ity of Inhaled carbon tetrachloMde, 1,1-dlchloroethane and methyl ethyl
ketone 1n rats. Toxlcol. Appl. Pharmacol. 28: 452-464. (Cited 1n U.S.
EPA, 1980)
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Simmon, V.F., K. Kaufanen and R.G. Tardlff. 1977. Mutagenlc activity of
chemicals Identified 1n drinking water. Dev. Toxlcol. Environ. Sc1. 2:
249-258. (Cited In U.S. EPA, 1983b)
Smith, J.H., D.C. Bomberger, Jr. and D.L. Haynes. 1980. Prediction of the
volatilization rates of high volatility chemicals from natural water bodies.
Environ. Sd. Techno!. 14: 1332-1337.
Spreaflco, F., E. Zuccato and F. Murcurcl. 1980. Pharmocoklnetlcs of
ethylene dlchlorlde In rats treated by different routes and Its long-term
Inhalatory toxldty. in: Banbury Report No. 5, Ethylene Dlchlorlde: A
Potential Health Risk, B. Ames, P. Infante and R. Rertz, Ed. Cold Springs
Harbor Laboratory, Cold Springs Harbor, NY. p. 107-148. (Cited 1n U.S.
EPA, 1983b)
Torkelson, T.R. and V.K. Rowe. 1981. IrK Patty's Industrial Hygiene and
Toxicology, Vol. 2b, 3rd ed., G.D. Clayton and E.E. Clayton, Ed. John Wiley
and Sons, Inc., NY. p. 3488-3490. (Cited In U.S. EPA, 1983b)
U.S. EPA. 1980a. Guidelines and Methodology Used 1n the Preparation of
Health Effects Assessment Chapters of the Consent Decree Water Quality
Criteria. 45 FR 79347-79357.
U.S. EPA. 1980b. Ambient Water Quality Criteria for Chlorinated Ethanes.
Environmental Criteria Assessment Office, Cincinnati, OH. EPA-440/5-80-029.
NTIS PB81-117624. (Cited 1n U.S. EPA, 1983b)
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U.S. EPA. 1983a. 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
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U.S. EPA. 1983b. Drinking Water Criteria Document for 1 ,l-D1chloroethane.
Prepared by the Environmental Criteria and Assessment Office, Cincinnati,
OH, OHEA for the Office of Drinking Water, Washington, DC. Final draft.
Valvanl, S.C., S.H. Yalkowsky and T.J. Roseman. 1981. Solubility and
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Veith, G.D., D.L. Defoe and B.V. Bergstedt. 1979. Measuring and estimating
the bioconcentratlon factor of chemicals 1n fish. J. Fish. Res. Board Can.
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Weisburger, E.K. 1977. Carcinogeniclty studies on halogenated hydro-
carbons. Environ. Health Perspect. 21: 7-16. (Cited in U.S. EPA, 1983b)
Wilson, J.T., C.G. Enfleld, W.J. Dunlap, R.L. Cosby, D.A. Foster and L.B.
Baskln. 1981. Transport and fate of selected organic pollutants 1n a sandy
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24: 225-?:^.
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APPENDIX
Summary Table for 1,l-D1chloroethane
en
i
Inhalation
AIS
AIC
Maximum
composite
score
Oral
AIS
AIC
Species Experimental Effect Acceptable Intake
Dose/Exposure (AIS or AIC)
cat 500 ppm none 96.6 mg/day
(2025 mg/m3)
cat 500 ppm none 9.7 mg/day
(2025 mg/ma)
cat TWA 750 ppm kidney damage, 9.8
6 hours/day, elevated blood urea
5 days/week nitrogen (RVe = 7)
for 26 weeks
(RVd = 1.4)
rat 500 ppm none 81 mg/day
(2025 mg/ma)
rat 500 ppm* none 8.1 mg/day
(2025 mg/ma)
Reference
Hofmann et al
1971
Hofmann et al
1971
Hofmann et al
1971
Hofmann et al
1971
* *
* t
* »
* »
Hofmann et al.,
1971;
U.S. EPA, 1983b
'Based on Inhalation data as proposed by U.S. EPA (1983b)
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