EPA-540/1-86-002
&EPA
Environmental protection
Agency
; 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
HEALTH EFFECTS ASSESSMENT
FOR 1,2-DICHLOROETHANE
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EPA/540/1-86-002
September 1984
HEALTH EFFECTS ASSESSMENT
FOR 1.2-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 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 1t 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 1,2-
dlchloroethane. 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. 1980a. Ambient Water Quality Criteria for Chlorinated
Ethanes. Environmental Criteria and Assessment Office, Cincinnati,
OH. EPA 440/5-80-029. NTIS PB 81-117400.
U.S. EPA. 1983a. Reportable Quantity for 1,2-D1chloroethane.
Prepared by the Environmental Criteria and Assessment Office,
Cincinnati, OH, OHEA for the Office of Solid Waste and Emergency
Response, Washington, DC.
U.S. EPA. 1984. Health Assessment Document for Ethylene
D1chlor1de. External Review draft. Environmental Criteria and
Assessment Office, . Research Triangle Park, NC, OHEA-.
EPA-600/8-84-006A. NTIS PB84-209865.
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 JUC, acceptable Intake chronic, 1s similar 1n concept to the ADI
(acceptable dally Intake). It Is 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 expo-
sure 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 (1983b).
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 (1983b). Since cancer 1s a
process that 1s 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 1n proper context, the reader 1s
referred 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.
1,2-D1chloroethane has been shown to be carcinogenic 1n mice and rats
following oral exposure. Existing data have not demonstrated an association
between Inhalation exposure and cancer 1n experimental animals. Human data
are lacking.
U.S. EPA (1984) has computed a q-|* of 6.9xlO~2 (mg/kg/day)-1 for
1,2-d1chloroethane using data on the Incidence of hemanglosarcomas 1n male
rats.
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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. ENVIRONMENTAL CHEMISTRY AND FATE
2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1.
2.2.
ORAL
INHALATION
3. 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
4. CARCINOGENICITY
4.1.
4.2.
4.3.
4.4.
HUMAN DATA
BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
OTHER RELEVANT DATA
WEIGHT OF EVIDENCE
5. REGULATORY STANDARDS AND CRITERIA
Page
1
3
. . . 3
, , , 5
5
5
. . . 5
6
8
. . . 8
9
13
. . . 13
13
15
, , , 16
. . . 16
16
. . . 16
28
. . . 29
31
. . . 33
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* TABLE OF CONTENTS
Page
6. RISK ASSESSMENT 34
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) 34
6.2. ACCEPTABLE INTAKE CHRONIC (AIC) 34
6.3. CARCINOGENIC POTENCY (q-|*) 34
6.3.1. Oral 10
6.3.2. Inhalation 10
7. REFERENCES 35
APPENDIX: Summary Table for 1,2-D1chloroethane 44
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UST OF TABLES
No.
4-1
4-2
4-3
4-4
4-5
4-6
4-7
4-8
4-9
5-1
Title
Design Summary for 1 ,2-D1chloroethane Gavage Experiment In
Osborne-Mendel Rats
Design Summary for 1 ,2-D1chloroethane Gavage Experiment In
B6C3F-] Mice
Terminal Survival of Osborne-Mendel Rats Treated With 1,2-
Dlchloroethane (EDC)
Tumor Incidence and Statistical Significance 1n Male
Osborne-Mendel Rats
Tumor Incidence and Statistical Significance 1n Female
Osborne-Mendel Rats
Terminal Survival of B6C3F] Mice Treated With 1,2-
Dlchloroethane
Tumor Incidence and Statistical Significance In Male
B6C3F-] Mice
Tumor Incidence and Statistical Significance 1n Female
B6C3F] Mice
Mutagenldty of 1 ,2-D1chloroethane 1n Salmonella typhlmuMum
Assay
Current Reaulatorv Standards and Criteria
Page
17
19
21
22
23
24
26
27
29
33
1x
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LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
AIC Acceptable Intake chronic
AIS Acceptable Intake subchronlc
CS Composite score
PEL Frank-effect level
GI Gastrointestinal
GLC Gas-I1qu1d chromatography
1.p. IntraperHoneal
LOAEL Lowest-observed-adverse-effect level
MED Minimum effective dose
NADPH N1cot1nam1de adenlne dlnucleotlde phosphate (reduced
form)
NOEL No-observed-effect level
PCB • PolychloMnated blphenyl.
RVd Dose-rating value
RVe Effect-rating value
SRBC Sheep red blood cells
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
l,2-d1chloroethane (CAS No. 107-06-2) are summarized below.
Chemical class
Molecular weight
Vapor pressure
Water solubility
Octanol/water partition
coefficient
Soil mobility
(predicted as retardation factor
for soil depth of 140 cm and
organic carbon content of 0.087%)
B1oconcentrat1on factor
(1n blueglll, Lepomls macrochlrus)
Half-lives 1n:
Air
Water
halogenated aliphatic
hydrocarbon (purgeable
halocarbons)
98.98
64 mm Hg at 20°C (U.S.
EPA, 1984)
8524 mg/8. at 20°C
(Horvath, 1982)
30.2 (Hansch and Leo,
1979)
1.2 (Wilson et al.. 1981)
2 (U.S. EPA, 1980a)
36-127 days (U.S. EPA,
1984)
4 hours (U.S. EPA, 1984)
The half-life of 4 hours for 1,2-d1chloroethane In water 1s an estimated
value under a wind speed of 3 m/sec, a water current of 1 m/sec and a water
depth of 1 m. This half-life value Is probably a lower limit for evapora-
tion In water, since partlculate material 1n natural water will retard the
evaporation process.
A half-life of 1,2-d1chloroethane 1n soil could not be located 1n the
available literature; however, evaporation 1s expected to be the predominant
loss mechanism from the soil surface. The half-life for soil evaporation
should be longer than Its evaporation half-life from water (Wilson et al.,
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1981). In subsurface soil, blodegradatlon and other chemical degradation of
1,2-d1chloroethane 1s likely to be slow (U.S. EPA, 1984; WHson et al.,
1981). Therefore, 1,2-dlchloroethane 1s expected to transport downward
through soils, especially through soils with low organic matter content.
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL MAMMALS
2.1. ORAL
Pertinent data regarding oral absorption of 1,2-d1chloroethane 1n humans
could not be located 1n the available literature, but numerous reports of
accidental or suicidal 1ngest1on of the chemical Indicate very high absorp-
tion (NIOSH, 1976).
Very high absorption of 1,2-d1chloroethane has been demonstrated clearly
1n laboratory animals. Reltz et al. (1982) administered 150 mg 14C-1,2-
d1chloroethane/kg bw 1n corn oil to rats. Recovery of radioactivity 1n
exhaled air, urine and carcass at the end of 48 hours was virtually com-
plete. Spreaflco et al. (1978, 1979, 1980) administered 25, 50 or 150 mg
1,2-d1chloroethane/kg bw 1n corn oil by gavage to rats. Absorption was
rapid, with peak blood levels occurring within 20 minutes. Peak blood
levels appeared to be linearly related to dose level, although tissue levels
did not, which the authors Interpreted to suggest passive transport across
the GI tract.
Spreaflco et al. (1978, 1979, 1980) also derived rate constants for
absorption by rats at each dose level. They observed a markedly lower rate
constant for the highest (150 mg/kg) dose. At the lowest dose given (25
rag/kg), one-half the dose was absorbed from the GI tract by 3.3 minutes, and
at the highest dose (150 mg/kg), one-half the dose was absorbed by 6.4
minutes. When the rate of absorption of 25 and 50 mg 1,2-d1chloroethane/kg
was determined with water vehicle, 1t was found that absorption was more
rapid than with corn oil vehicle (k 1n water = 0.299, k 1n oil = 0.209
a a
for 25 mg/kg dose). Wlthey et al. (1982) further Investigated the effect
of vehicle on absorption rate of 1,2-d1chloroethane by administering 100
mg/kg bw in water or corn oil to fasted rats. The post absorptive peak
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blood concentration was ~5-fold higher with water vehicle (84.6
compared with corn oil vehicle (15.9 yg/mi). Furthermore, peak blood
concentrations were reached 3 times more quickly with water vehicle (3.2
minutes) compared with corn oil vehicle (10.6 minutes).
2.2. INHALATION
Absorption of Inhaled 1,2-d1chloroethane 1n man has not been quantl-
tated, but the fact that the chemical has a moderately high (80 mm Hg at
25°C) vapor pressure and a high blood/air partition coefficient (19.5) (Sato
and Nakajlma, 1979) suggests rapid and complete pulmonary absorption.
Urusova (1953) reported that women exposed to -15.5 ppm 1,2-d1chloro-
ethane 1n air during a normal workday accumulated the chemical 1n breast
milk. Initial concentrations In exhaled air following exposure were 14.5
ppm, Indicative that the women absorbed 1,2-d1chloroethane through their
lungs and reached blood and total body equilibrium with Inspired air within
the dally work period.
ReHz et al. (1980, 1982) exposed four Osborne-Mendel rats to 150 ppm
1,2-d1chloroethane for 6 hours. Equilibrium In blood was reached 1n =1
hour and was maintained at ~9 yg/mi. Upon termination of exposure,
blood levels fell rapidly, approaching 0 1n about 1.5 hours. Spreaflco et
al. (1980) exposed rats to atmospheric concentrations of 50 or 250 ppm
1,2-d1chloroethane for 6 hours. Blood equilibria were reached at ~2 and ~3
hours, respectively, for low- and high-dose groups. Blood levels attained
by high-dose group rats (-29.36 yg/ma.) were considerably higher than
those attained by low-dose group rats (1.34
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Reports of subchronlc oral exposure of humans to
1,2-d1chloroethane could not be located In the available literature. Only
one bloassay Involving subchronlc animal oral exposure to 1,2-d1chloroethane
was located. Munson et al. (1982) exposed male CD-I mice to three concen-
trations of 1,2-d1chloroethane 1n drinking water. The calculated TWA doses
consumed based on measured water consumption were 3, 24 and 189 mg/kg bw/day
for a 90-day exposure period. Concurrent with this study, mice were exposed
to 4.9 or 49 mg/kg bw/day by gavage for 14 days. Total numbers of mice 1n
each group were not specified. Exposure to 1,2-d1chloroethane 1n the 14-day
study did not affect body weight; 90-day exposure 1n drinking water elicited
a dose-dependent decrease 1n growth rate and water consumption. Body
weights were recorded for 32 mice In each group In the 90-day trial, but an
unspecified number were weighed 1n the 14-day trial. At the termination of
either study, organ weights (liver, spleen, lung, thymus, kidney, brain)
were not affected by treatment. Hematologlc parameters were evaluated 1n
10-12 and 16 mice/dose group 1n the 14- and 90-day studies, respectively.
Hematologlc parameters were unaltered by treatment, with the exception that
exposure to 49 mg/kg/day 1,2-d1chloroethane by gavage for 14 days depressed
leukocyte counts -30%. Leukocyte counts remained normal In drinking
water-exposed rats at the end of 90 days.
The status of the humoral Immune system was evaluated by measuring the
number of antibody-forming cells to SRBC after 14 and 90 days, the serum
antibody level to SRBC after 90 days and the lymphocyte response to Upo-
polysacchaMde from Salmonella typhosa 0901 after 90 days (Munson et al.,
1982). Evaluation of 10-12 mice/group 1n the 14-day study showed that
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1,2-dichloroethane reduced (p<0.05) the number of antibody-forming cells In
both low- and high-dose groups. Mice 1n the 90-day study showed no signi-
ficant reduction 1n antibody-forming cells, nor did they show a significant
response in hemagglutination titer or spleen cell response to Upopoly-
sacchaMde. Cell-mediated Immunity, evaluated by measuring the delayed
hypersensitivlty reaction to sheep erythrocytes and the response to the
T-lymphocyte mitogen, concanavalin A, revealed a significant (p<0.05) inhi-
bition 1n both 14-day groups but no inhibition 1n the 90-day groups. These
investigators observed immunosuppresslon In the 14-day gavage-exposed mice
but no significant Immunosuppresslon In the 90-day drinking water-exposed
mice. They suggested that bolus administration of 1,2-d1chloroethane may
have resulted 1n a higher effective dose at the 1mmunorespons1ve site than
did administration through the drinking water. A second explanation offered
was that over a period of time l,2-d1chloroethane may induce Us own metab-
olism, reducing Us concentration at the effective site.
3.1.2. Inhalation. Reports of repeated exposure of humans to
1,2-dichloroethane are 1n Section 3.2.2., regarding chronic inhalation
exposure.
Several investigators have subjected numerous species of animals to
inhalation exposure of 1,2-dichloroethane for various lengths of time.
Spencer et al. (1951) exposed monkeys, rats, guinea pigs and rabbits to 100
ppm (405 mg/m3) or 400 ppm (1620 mg/m3) 1,2-dichloroethane for periods
ranging from -24-36 weeks. Exposure was 7 hours/day, 5 days/week. Addi-
tionally, rats and guinea pigs were exposed to 200 ppm (810 mg/m3) for -30
and 36 weeks, respectively. Concentrations of 400 ppm 1,2-dichloroethane in
air resulted 1n mortality 1n monkeys (2/2), guinea pigs (16/16) and rats
(30/30) within 2-40 exposures. A group of three rabbits exposed to
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400 ppm for 165 exposures (33 weeks) evidenced no effect on general appear-
ance, body weight, histology of selected organs, hematologlc parameters or
blood chemistries; rabbits were clearly the most resistant species tested.
Administration of 200 ppm 1,2-dlchloroethane for 151 exposures was asso-
ciated with no adverse effects on general appearance, behavior, growth,
final body or organ weights or gross or hlstologlc pathology 1n 30 rats.
Guinea pigs (16) exposed to 200 ppm for 180 exposures evidenced reduced
growth, reduced final body weights, and hepatomegaly (males only) and
hepatic degeneration 1n both sexes. Guinea pigs appeared to be more sen-
sitive to 1,2-d1chloroethane than did rats In this study. Exposure of rats,
guinea pigs, rabbits and monkeys to 100 ppm 1,2-d1chloroethane for 121-178
exposures resulted 1n no adverse effects on general behavior, appearance,
growth, mortality, final body or organ weights, gross or microscopic path-
ology, selected hematologlc parameters or blood chemistries. In this study,
100 ppm l,2-d1chloroethane defined a NOEL 1n all four species tested.
Heppel et al. (1946) demonstrated heavy mortality 1n rabbits (5/5),
guinea pigs (14/20) and rats (16/16) exposed to 400 ppm 1,2-d1chloroethane
after 4 (rats), 45 (guinea pigs) or 97 (rabbits) exposures of 7 hours/day, 5
days/week. Male puppies (3) or adult female dogs (6) experienced no mor-
tality and only slight fatty degeneration of the liver when exposed to 400
ppm 1,2-d1chloroethane for 167-177 exposures. Spencer et al. (1951) demon-
strated no mortality 1n rats or guinea pigs exposed to 200 ppm 1,2-dlchloro-
ethane for >151 exposures; however, Heppel et al. (1946) noted heavy mor-
tality In rats (7/12), guinea pigs (5/14) and mice (18/20) after 44, 88 or 7
exposures, respectively, to 200 ppm 1n air. Exposure to 100 ppm 1,2-dl-
chloroethane for 4 months resulted 1n no adverse effects 1n 39 rats or 16
guinea pigs. Furthermore, 15/16 female rats became pregnant and rat pups
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were apparently unaffected by exposure. In this study, 100 ppm also ap-
peared to define a NOEL.
Hofmann et al. (1971) exposed 10 rats, 10 guinea pigs, 4 rabbits and 4
cats to 500 ppm 1,2-d1chloroethane for 6 weeks or 100 ppm 1,2-d1chloroethane
for 17 weeks at 6 hours/day, 5 days/week. Exposure to 500 ppm resulted In
mortality 1n all species except the cat, which showed cardlomegaly and ele-
vated blood urea nitrogen. Exposure to 100 ppm for 17 weeks resulted In no
clinical symptoms, no effects on selected blood chemistry parameters and no
change 1n liver, kidney or other (unspecified) organs. Cats exposed to 100
ppm, however, reportedly did not grow as well as unexposed (control) cats.
This study, therefore, appeared to define 100 ppm 1,2-d1chloroethane as a
LOAEL for subchronlc Inhalation exposure.
3.2. CHRONIC
3.2.1. Oral. Pertinent data regarding chronic oral exposure of humans to
1,2-d1chloroethane could not be located In the available literature. Only
one report of chronic oral exposure 1n laboratory animals, an NCI (1978)
car- dnogenlcHy bloassay, was located 1n the available literature.
Details of experimental protocol and results are given 1n Section 4.2.
Groups of male and female Osborne-Mendel rats were treated by gavage with
TWA doses of 95 or 47 mg/kg bw/day for 78 weeks and observed for an
additional 28 weeks. Groups of male and female B6C3F, mice were treated
by gavage with TWA doses of 195 or 97 mg/kg bw/day (male) or 299 or 149
mg/kg bw/day (female) for 78 weeks, followed by a 12-13 week observation
period.
No significant dose-related body weight depression in rats of either sex
was noted (NCI, 1978). Heavy mortality of treated rats occurred early In
the study, particularly in the high dose groups. It appeared that toxic,
rather than carcinogenic, effects of 1,2-d1chloroethane were responsible for
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the mortality. Mean body weight depression 1n high-dose female mice was
noted as early as the 15th week of treatment. No significant dose-related
mean body weight depression was observed 1n male mice or low-dose female
mice. A significant positive association between Increased dosage and ele-
vated mortality In female mice was determined. Between weeks 60 and 80,
mortality accounted for 72% (36/50) of high dose females. The finding of
one or more tumors 1n these mice suggested that these deaths may have been
tumor-related. No significant relation between dose and mortality 1n male
mice was found.
3.2.2. Inhalation. There are many reports of repeated occupational
exposure to 1,2-d1chloroethane, particularly 1n the foreign literature
{primarily Russian, Polish and German). Information on duration and
exposure levels 1s often poorly documented. Collectively, however, the
reports present a fairly clear picture of the clinical syndrome associated
with the toxldty of 1,2-dlchloroethane 1n man. These reports are discussed
thoroughly In U.S. EPA (1984); only a brief summary of the more relevant
data, taken from U.S. EPA (1983a), will be presented here.
Repeated exposure to 1,2-d1chloroethane vapor 1n the workplace has
resulted 1n anorexia, nausea, vomiting, weakness and fatigue, nervousness,
epigastric pain/discomfort, and Irritation of the respiratory tract and eyes
(McNally and Fostvedt, 1941; Slegel, 1947; Rosenbaum, 1947; Watrous, 1947;
Rejsek and Rejskova, 1947; Delplace et al., 1962; Suveev and Bablchenko,
1969). In one study (Suveev and Bablchenko, 1969), examination of 12 symp-
tomatic workers who were brought to a clinic revealed paleness and cold
sweat (12/12), bradycardla (9/12), systolic murmur (5/12), diarrhea (5/12;
3/12 with blood) and enlarged livers that were soft and tender to palpation
(9/12). Muffled heart sounds, Increased rate of respiration, rales, and
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coated and dry tongues were also observed, but Incidences were not stated.
Signs of nervous system dysfunction have also been reported In cases of
chronically exposed workers. These Include nystagmus, fine tongue tremors
and sluggish patellar reflex (McNally and Fostvedt, 1941); encephalic dis-
orders (Delplace et al., 1962); and decreased muscle tone, loss of reflexes,
a positive Romberg's sign and deafness (Suveev and Bablchenko, 1969). Com-
plaints of hand and arm eczema that appeared within the first year of expo-
sure were recorded 1n 11/16 cases by Delplace et al. (1962). Exposure
concentrations and Information on the types of exposures were not provided
1n any of the reports cited above.
Kozik (1957) reported the results of a health and morbidity survey of
Russian aircraft Industry workers. All of the workers 1n the study group
(size not stated) were employed 1n a shop where glue that contained 1,2-dl-
chloroethane as a solvent was used to bond rubber sheets to metal forms 1n a
soft tank fabrication process. Most of these workers were gluers, but a
small number worked Inside the completed tanks to disassemble the forms.
The chemical was emitted to the air during application and glue drying.
According to Kozik (1957), -500 atmospheric measurements of l,2-d1-
chloroethane were taken. Although the sampling and analytical methods were
not mentioned, NIOSH (1976) felt that the data were presented 1n sufficient
detail to permit estimations of TWA exposures. NIOSH (1976) estimated that
44-46% of the total exposure occurred during the gluing operations, when the
TWA concentrations were -28 ppm during application and -16 ppm when the glue
was drying. When other operations were performed 1n the same shop (during
the second half of the workshlft), the TWA concentration was -11 ppm. The
TWA for the total shift was estimated to be 15 ppm. Concentrations ranged
from -4-50 ppm; concentrations >20 ppm were associated only
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with the gluing and drying operations and occurred -15% of the time. NIOSH
(1976) noted, however, that the aforementioned TWA concentrations may be an
overestimate of most of the workers' exposure for several reasons. First,
the tabulation of measurements 1n the glue application category also con-
tained high values (45-52 ppm) that were experienced only by an Insignifi-
cant number of workers who disassembled the molds within the finished
tanks. Second, the measurements were apparently not breathing zone measure-
ments, and third, the ventilation system was designed with the exhaust ducts
on the floor. Considering this Information, NIOSH (1976) concluded that a
more realistic estimation of the TWA exposure of the majority of the workers
1s 10-15 ppm.
Workers (total number not stated) who were engaged 1n the production of
soft tanks during the years 1951-1955 experienced Increased morbidity and
lost workdays when compared with workers 1n the entire factory (Kozlk,
1957). Disease categories examined Included acute GI disorders, neuritis
and ret1culH1s. An 1n-depth analysis of the morbidity rate with temporary
disability for 1954-1955 showed high rates for GI diseases, Hver and gall
bladder diseases and diseases of the muscle, tendons and neuronal ganglia.
The liver and gall bladder diseases were considered by Kozlk (1957) to be
related to a specific toxic effect of 1,2-d1chloroethane (the dyspeptic
symptoms 1t causes reportedly are often diagnosed as gastritis), but the
diseases of the muscle, tendon and ganglia were associated with the numerous
repetitive motions the workers had to make when applying the glue. Further
examination of 83 of the gluers revealed diseases of the liver and bile
ducts (19/83), neurotic conditions (13/83), autonomlc dystonia (11/83),
asthenlc conditions (5/83) and goiter and hyperthyroldlsm (10/83).
-11-
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Visual-motor reactions were studied at the beginning and end of 14 work-
days 1n 17 of the gluers and 10 "control" machinists (Kozik, 1957). A
device was used to determine simple and complex reaction (color differen-
tiation) times, as well as reaction times 1n a modification of the complex
reaction task, but details of the tests were not given. A comparison of the
mean rates for all three reactions showed no significant differences 1n the
two groups either before or after work. Nervous system dysfunction was sug-
gested, however, by the results of the complicated reaction tests. "Most"
of the gluers made errors in the complex "reaction" task, while the machi-
nists made no errors. In the modified complex reaction test, errors were
committed both before and after work by 15/17 gluers; 4/10 machinists made
errors, but only at the end of the workday.
Chronic toxldty of Inhalation of 1,2-d1chloroethane In animals has been
studied by two groups of Investigators. Maltonl et al. (1980) exposed
groups of 90 male and 90 female Sprague-Dawley rats and Swiss mice to levels
of 0, 5, 10, 50 or 250 ppm 1,2-d1chloroethane 7 hours/day, 5 days/week for
78 weeks. After several days of exposure, both rats and mice 1n the high
dose (250 ppm) group evidenced "severe toxldty," and exposure was reduced
to 150 ppm for the remainder of the study. Among the groups of rats, those
exposed to 5 ppm 1,2-dichloroethane survived the longest. No dose-related
trend in mortality was noted. Female mice 1n the high (250-150 ppm) dose
groups had a lower survival rate than did mice in the other groups. No
other parameters of toxldty were mentioned 1n this study, which was de-
signed primarily as a cardnogenldty bloassay.
Spreafico et al. (1980) Investigated the effects of Inhalation of Iden-
tical concentrations (0, 5, 10, 50 or 250-150 ppm) of 1,2-dichloroethane In
air on hematologlc and clinical chemistry parameters of 3- or 12-month-old
-12-
-------
rats exposed for 3, 6, 12 or 18 months for 7 hours/day, 5 days/week. At
least eight animals from each dosage group were examined at each time In-
terval. The resul.ts suggested that 18 months of exposure to 150 ppm l,2-d1-
chloroethane resulted 1n no marked evidence of toxldty. There were no sta-
tistically significant differences between treated and control animals In
circulating levels of red blood cells, white blood cells or differential
count, platelets or total serum protein. Percentages of albumin and gamma
globulin varied during the study, but the variation was apparently not
dose-related. No significant treatment-related effects on serum levels of
liver enzymes, blUrubln, cholesterol, glucose, uric add or blood urea
nitrogen were noted In rats exposed for 18 months. Rats exposed for 12
months were 14 months old when exposure began. They showed alteration 1n
liver and kidney function, manifested by significantly altered levels of
serum hepatic enzymes and uric acid. These changes did not appear to follow
a dose-related pattern. No changes 1n hematologlc parameters or urlnalysls
were noted. H1stolog1cal examination was not a part of this study.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. No reports of teratogenlclty 1n humans or animals orally
exposed to 1,2-d1chloroethane could be located 1n the available literature.
3.3.2. Inhalation. No reports of teratogenlclty In humans associated
with Inhalation of 1,2-d1chloroethane could be located 1n the available
literature.
The ability of 1,2-d1chloroethane to cause adverse reproductive or fetal
developmental effects cannot be fully assessed, since few Investigators have
adequately studied these effects. Several Russian studies report adverse
effects such as lengthened estrus cycle, change In duration of various
phases of the estrus cycle, decreased percentage of live births, decreased
-13-
-------
fetal weight at delivery and decreased weight gain after birth. Unfortu-
nately, these reports do not present the original data; various techniques
and tests are mentioned but results are not Included, details of analytical
procedures are lacking, and Insufficient Information 1s given to support the
authors conclusions. These studies will not be reviewed here.
Rao et al. (1980) reported on a Dow Chemical Company teratogenldty
study In rats and rabbits. Groups of 16-30 rats and 19-21 rabbits were ex-
posed to 100 or 300 ppm 1,2-d1chloroethane for 7 hours/day. Rats were ex-
posed on days 6-15 of gestation, and rabbits were exposed on days 6-18 of
gestation. Rats and rabbits were sacrificed on days 21 and 29, respec-
tively, and the dams were examined for pregnancy.
Signs of maternal toxldty, lethargy, ataxla, decreased body weight and
decreased food consumption were noted 1n rats exposed to 300 ppm l,2-d1-
chloroethane. Rats exposed to 100 ppm 1,2-d1chloroethane had no signs of
maternal toxldty and, 1n fact, gained statistically more weight than the
controls. No live offspring were found 1n rats exposed to 300 ppm l,2-d1-
chloroethane. No signs of fetal toxldty and no statistically significant
Increase 1n the Incidence of terata were found In fetuses of rats exposed to
100 ppm 1,2-d1chloroethane or 1n the fetuses from rabbits exposed to either
100 or 300 ppm 1,2-d1chloroethane. These authors concluded that l,2-d1-
chloroethane was not teratogenlc at the dosages tested 1n rats or rabbits,
but that fetal toxldty occurred concomltantly with maternal toxldty In
rats exposed to 300 ppm 1,2-dlchloroethane.
Because the concentration of 1,2-d1chloroethane associated In this study
with fetal toxldty (300 ppm, -1200 mg/m3) was considerably higher than
the level that Hofmann et al. (1971) found to result 1n reduced growth rate
-14-
-------
1n cats (100 ppm, -405 mg/m3), this study (Rao et al., 1980) will not
affect risk assessment.
3.4. TOXICANT INTERACTIONS
Heppel et al. (1945, 1946, 1947) produced high mortality (35%) 1n rats
given 1.3 g 1,2-d1chloroethane/kg bw orally. Pre- or postadm1n1strat1on of
methlonlne, cystelne or other sulfhydryl-contalnlng compounds markedly re-
duced mortality, presumably because these compounds enable the body to re-
store levels of glutathlone reduced by metabolism of 1,2-dlchloroethane
(Johnson, 1965, 1966, 1967).
-15-
-------
4. CARCINOGENICITY
4.1. HUMAN DATA
No case reports or ep1dem1olog1c studies of human carclnogenlcHy re-
lated to l,2-d1chloroethane were located 1n the available literature.
4.2. BIOASSAYS
4.2.1. Oral. Only one study, sponsored by the NCI (1978), examined the
cardnogenlclty of orally administered 1,2-d1chloroethane In laboratory
rodents. Osborne-Mendel rats were divided Into high- and low-dose groups
containing 50 rats of each sex. Untreated and vehicle control groups con-
tained 20 rats of each sex. In the same study, similar numbers of B6C3F.
mice were subjected to the same protocol. 1,2-01chloroethane 1n corn oil
was administered by gavage according to the schedules 1n Table 4-1 (for
rats) and Table 4-2 (for mice). Inappropriate selection of Initial doses
resulted 1n early signs of toxldty, which necessitated numerous readjust-
ments 1n dosage levels administered to both rats and mice. The final TWA
dosages for male and female rats were 95 and 47 mg/kg bw/day; for male mice,
195 and 97 mg/kg bw/day; and for female mice, 299 and 149 mg/kg bw/day for
high dose and low dose groups, respectively.
Early mortality was high 1n treated rats, particularly those In the
high-dose group. Mortality was due to a number of causes, Including
bronchopneumonla and endocardlal thrombosis. Terminal survival data 1n rats
are presented 1n Table 4-3. Tumor Incidences 1n rats and statistical signi-
ficance are summarized 1n Table 4-4 (males) and Table 4-5 (females).
Terminal survival data In mice are presented In Table 4-6. In male mice,
mortality did not appear to be dose-related because mortality was consider-
ably higher 1n the low-dose than In the high-dose group. The opposite trend
-16-
-------
TABLE 4-1
Design Summary for 1,2-D1chloroethane Gavage Experiment In Osborne-Mendel Rats3
Initial
Group Number of
Animals
HALES
Untreated control 20
Vehicle control 20
Low-dose 50
H1gh-dosee 50
FEHALES
Untreated control 20
Vehicle control 20
1,2-Dlchloroethane
Dosage**
NA
0
50
75
50
50d
0
100
150
100
100d
0
NA
0
Observation
Treated
(weeks)
NA
78
7
10
18
34
NA
7
10
18
34
NA
NA
78
Period
Untreated
(weeks)
106
32
NA
NA
NA
9
32
NA
NA
NA
9
23
106
32
TWA Dosage Over
a 78-Week Period0
NA
0
47
NA
NA
NA
NA
95
NA
NA
NA
NA
NA
0
-------
TABLE 4-1 (cont.)
CO
Group
Low-dose
H1gh-dosee
Initial
Number of 1 ,2-D1chloroethane
Animals Dosage'11
50 50
75
50
50d
0
50 100
150
100
100d
0
Observation
Treated
(weeks)
7
10
18
34
NA
7
10
18
34
NA
Period
Untreated
(weeks)
NA
NA
NA
9
32
NA
NA
NA
9
15
TWA Dosage Over
a 78-Week Period0
47
NA
NA
NA
NA
95
NA
NA
NA
NA
aSource: NCI, 1978
^Dosage, given In mg/kg bw, was administered by gavage 5 consecutive days/week.
CTWA dosage = (dosage x weeks received)
78 weeks
dThese dosages were cyclically administered with a pattern of 1 dosage-free week followed by 4 weeks (5
days/week) of dosage at the level Indicated.
eAll animals In this group died before the bloassay was terminated.
NA = Not applicable
-------
TABLE 4-2
Design Summary for 1,2-Dlchloroethane Gavage Experiment In B6C3Fi Mice3
Group
MALES
Untreated control
Vehicle control
Low-dose
High-dose
Initial
Number of
Animals
20
20
50
50
Observation Period
1,2-Dlchloroethane
Dosageb
NA
0
75
100
0
150
200
0
Treated
(weeks)
NA
78
8
70
NA
8
70
NA
Untreated
(weeks)
90
12
NA
NA
12
NA
NA
13
TWA Dosage0
NA
0
97
NA
NA
195
NA
NA
-------
TABLE 4-2 (cont.)
o
i
Group
FEMALES
Untreated control
Vehicle control
Low-dose
High-dose
aAdapted from NCI, 1978
^Dosage, given In mg/kg
CTWA dosaoe - (dosage x
Initial
Number of
Animals
20
20
50
50
1,2-Dlchloroethane
Dosage0
NA
0
125
400
150
0
250
400
300
0
Observation
Treated
(weeks)
NA
78
8
3
67
NA
8
3
67
NA
Period
Untreated
(weeks)
91
32
NA
NA
NA
13
NA
NA
NA
13
TWA Dosagec
NA •
0
149
NA
NA
NA
299
NA
NA
NA
bw, was administered by gavage 5 consecutive days/week.
weeks received)
weeks receiving chemical
NA - Not applicable
-------
TABLE 4-3
Terminal Survival of Osborne-Mendel Rats Treated With
l,2-D1chloroethane
Group
Untreated control
Vehicle control
Low-dose
High-dose
Weeks In
Study
106
110
110
101
Males
Animals Alive
at End of Study
4/20b (20%)
4/10 (20%)
1/50 (2%)
0/50C (0%)
Females
Weeks 1n
Study
106
110
101
93
Animals Alive
at End of Study
13/20b (65%)
8/20 (40%)
1/50 (2%)
0/50C (0%)
aSource: Adapted from NCI, 1978
bF1ve rats were sacrificed at 75 weeks.
CA11 animals 1n this group died before the bloassay was terminated.
-21-
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TABLE 4-4
Tumor Incidence and Statistical Significance In Hale Osborne-Hendel Rats3
I
NJ
Exposure
Route
Gavage
Gavage
Gavage
Gavage
Duration Duration Purity Vehicle or
Dose or Exposure of of Study of Physical
Treatment Compound State
95 mg/kgc 78 weeks 101 weeks >99Xd corn oil
47 mg/kgc 78 weeks 110 weeks >99Xd corn oil
0 mg/kg/day 78 weeks 110 weeks NA corn oil
(matched vehicle
control)
0 mg/kg/day >52 weeks >52 weeks NA corn oil
(pooled vehicle
control )9
Target Organ
forestomach
circulatory
system
subcutaneous
tissue
forestomach
circulatory
system
subcutaneous
tissue
forestomach
circulatory
system
subcutaneous
tissue
forestomach
circulatory
system
subcutaneous
tissue
Tumor Type
squamous cell
carcinoma
hemanglosarcoma
fibroma
squamous cell
carcinoma
hemanglosarcoma
fibroma
squamous cell
carcinoma
hemanglosarcoma
fibroma
squamous cell
carcinoma
hemanglosarcoma
fibroma
Tumor
Incidence
(p value)0
9/50
(p=0.007)e
7/50
(p=0.016)e
6/50
(p=0.001)f
(p=0.039)f
3/50
("S)
9/50
(p=0.003)«
(p~0.039)f
5/50
(p=0.017)*
0/20
(p=0.010)
0/20
(NS)
0/20
(NS)
0/60
(p=0.001)
1/60
(p=0.021)
0/60
(p=0.10)
aSource: NCI, 1978
'•The probability levels for the Fischer exact test and the Cochran-ArmHage test are given beneath the Incidence of tumors In the treated
and control groups, respectively, when p<0.05; otherwise, not significant (NS) Is Indicated.
TMA dose reflecting gavage treatment 5 consecutive days/week for 78 weeks.
dPur1ty of >90X was reported by NCI (1978). Reanalysls Indicated a purity of >99X (Hooper et al., 1980).
Comparison with pooled control group
Comparison with matched control group
^Pooled control group consisted of matched controls from bioassays of 1,2-dtchloroethane. 1,1.2-trtchloroethane and trlchloroethylene.
-------
TABLE 4-5
Tumor Incidence and Statistical Significance In Female Osborne-Hendel Ratsa
INJ
CO
Exposure
Route
Gavage
Gavage
Gavage
Dose or Duration Duration
Exposure of of Study
Treatment
95 mg/kgc 78 weeks 93 weeks
47 mg/kgc 78 weeks 110 weeks
0 mg/kg >52 weeks >52 weeks
(pooled vehicle
control)?
Purity Vehicle or
of Physical
Compound State
>99Xd corn oil
>99Xd corn oil
NA corn oil
Target Organ
mammary gland
mammary gland
mammary gland
mammary gland
mammary gland
mammary gland
Tumor Type
adenocarclnoma NOS
adenocarctnoma NOS
or Hbroadenoma
adenocarclnoma NOS
adenocarclnoma NOS
or ftbroadenoma
adenocarclnoma NOS
adenocarclnoma NOS
or f Ibroadenoma
Tumor
Incidence
(p value)b
18/50
{p<0.001)e
(p«0. 002 )f
24/50
(p<0.00l)".f
1/50
(NS)
15/50
(p-0.009)*
(p-0.003)f
1/59
(p<0.001)
6/59
(p<0.001)
'Source: NCI, 1978
bThe probability levels for the Fischer exact test and the Cochran-Armltage test are given beneath the Incidence of tumors In the treated
and control groups, respectively, when p<0.05; otherwise, not significant (NS) Is Indicated.
CTUA dose reflecting gavage treatment 5 consecutive days/week for 78 weeks.
dPur1ty of >90X was reported by NCI (1978). Reanalysls Indicated a purity of >99X (Hooper et al., 1980).
'Comparison with pooled control group
fComparison with matched control group
Spooled control group consisted of matched controls from bloassays of 1,2-dlchloroethane, 1,1,2-trlchloroethane and trlchloroethylene.
NA » Not applicable; NOS < Not otherwise specified
-------
TABLE 4-6
Terminal Survival of B6C3Fi Mice Treated With 1,2-D1chloroethane*
Group
Untreated control
Vehicle control
Low-dose
High-dose
Weeks in
Study
90
90
90
91
Males
Animals Alive
at End of Study
7/20 (35%)
11/20 (55%)
11/50 (22%)
21/50 (42%)
Females
Weeks 1n
Study
90
90
91
91
Animals Alive
at End of Study
16/20 (80%)
16/20 (80%)
34/50 (68%)
1/50 (2%)
*Source: Adapted from NCI, 1978
-24-
-------
was noted for female mice. The Incidences and statistical significance of
tumor development 1n mice are summarized 1n Tables 4-7 (males) and 4-8
(females).
As detailed 1n the tables, male rats 1n the high-dose group experienced
a significant Increase 1n the Incidence of squamous cell carcinomas of the
forestomach, hemanglosarcoma and subcutaneous tissue fibroma, compared with
controls. The Incidence of all these tumors except squamous cell carcinoma
of the forestomach was also statistically significant 1n the low-dose group,
compared with controls. Mammary adenocardnoma 1n female rats occurred at a
significantly higher incidence in both treatment groups; mammary adenocar-
dnoma or fibroma occurred at significantly higher Incidence 1n the high-
dose group only when compared with controls. Both male and female mice
showed significantly Increased Incidences of pulmonary alveolar/bronchiolar
adenoma at both dosage levels. Male mice also had significantly Increased
Incidences of hepatocellular carcinoma, but this effect was noted only In
the high-dose group when compared with controls. Female mice had signifi-
cantly Increased Incidences of mammary adenocarclnomas and endometrlal
stromal polyp or sarcoma in both the high-dose and low-dose groups, compared
with controls. In this bloassay, 1,2-d1chloroethane was carcinogenic 1n
both male and female rats and mice.
4.2.2. Inhalation. Maltoni et al. (1980) exposed groups of 90 male and
90 female Sprague-Oawley rats to 0, 5, 10, 50 or 250 ppm 1,2-d1chloro-
ethane 1n inhaled air for 7 hours/day, 5 days/week for 78 weeks and observed
them until spontaneous death. After several days of exposure, the 250 ppm
group exhibited severe toxic effects, and the level of 1,2-d1chloroethane
was reduced to 150 ppm for the duration of the 78-week exposure period.
Mortality varied among groups and a dose response relationship for mortality
-25-
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TABLE 4-7
Tumor Incidence and Statistical Significance In Male B6C3F] Nice*
Exposure
Route
Gavage
Gavage
Gavage
Gavage
Duration Duration
Dose or Exposure of of Study
Treatment
195 mg/kgc 78 weeks 91 weeks
97 mg/kgc 78 weeks 90 weeks
0 mg/kg 78 weeks 90 weeks
(matched vehicle
controls)
0 mg/kg >52 weeks >52 weeks
(pooled vehicle
controls)?
Purity Vehicle or
of Physical
Compound State
>99Xd corn oil
>99Xd corn oil
NA corn oil
NA corn oil
Target
Organ
lung
lung
liver
lung
liver
lung
liver
Tumor Type
alveolar/bronchlolar
adenoma
alveolar/bronchlolar
adenoma
hepatocellular
carcinoma
alveolar/bronchlolar
adenoma
hepatocellular
carcinoma
alveolar/bronchlolar
adenoma
hepatocellular
carcinoma
Tumor
Incidence
(p value)b
15/48
(p<0.001)e
(p=0.003)f
1/47
(US)
6/47
0/19
(p<0.001)
1/19
{p*0.025)
0/59
(p90X was reported by NCI (1978). Reanalysis Indicated a purity of >99* (Hooper et al., 1980).
Comparison with pooled control group
^Comparison with matched control group
QPooled control group consisted of matched controls from bloassays of 1,2-dlchloroethane, 1,1,2-trichloroethane and trlchloroethylene.
NA - Not applicable
-------
TABLE 4-8
Tumor Incidence and Statistical Significance In Female B6C3Fi Nice3
Exposure Duration Duration Purity Vehicle or
Route Dose or Exposure of of Study of Physical
Treatment Compound State
Gavage 299 mg/kgC 78 weeks 91 weeks >99Xd corn oil
Gavage 149 mg/kgc 78 weeks 91 weeks >99Xd corn oil
INJ
tM^J
Gavage 0 mg/kg 78 weeks 90 weeks NA corn oil
(matched vehicle
controls)
Gavage 0 mg/kg >52 weeks >52 weeks NA corn oil
(pooled vehicle
controls)?
Target Organ
lung
mammary gland
uterus
lung
mammary gland
uterus
lung
mammary gland
uterus
lung
mammary gland
uterus
Tumor Type •
alveolar/bronchlolar
adenoma
adenocarclnoma
endome trial stromal
polyp or sarcoma
alveolar/bronchlolar
adenoma
adenocarclnoma
endometrlal stromal
polyp or sarcoma
alveolar/bronchlolar
adenoma
adenocarclnoma
endometrlal stromal
polyp or sarcoma
alveolar/bronchlolar
adenoma
adenocarclnoma
endometrlal stromal
polyp or sarcoma
Tumor
Incidence
(p value)b
15/48
(p<0.001)«
(p=0.006)f
7/48
(p<>0.003)e
5/47
(p=0.014)e
7/50
(p=0.046)e
9/50
(p-0.001)*
(p*0.039)f
5/49
(p=0.016)
1/20
(p=0.005)
0/20
(NS)
0/20
(NS)
2/60
p<0.001)
0/60
(p.O. 007)
0/60
(P'0.017)
aSource: NCI. 1978
bThe probability levels for the Fischer exact test and the Cochran-Armltage test are given beneath the Incidence of tumors In the treated
and control groups, respectively, when p<0.05; otherwise, not significant (NS) Is Indicated.
CTUA dose reflecting gavage treatment 5 consecutive days/week for 78 weeks.
dPur1ty of >90X was reported by NCI (1978). Reanalysls Indicated a purity of >99X (Hooper et al., 1980).
Comparison with pooled control group
Comparison with matched control group
^Pooled control group consisted of matched controls from btoassays of 1,2-dlchloroethane, 1,1,2-trlchloroethane and trlchloroethylene.
NA * Not applicable
-------
was not apparent. The low-dose (5 ppm) groups had the greatest number of
survivals at the end of 52 weeks of exposure. The Incidences of tumors
found upon necropsy were low and not related to exposure to 1,2-dl-
chloroethane. Several groups of female rats showed a considerable In-
cidence of benign mammary fibromas and flbroadenomas, but the Incidence
appeared to be related to survival (age) rather than directly to treatment.
An Identical protocol was used to expose groups of 90 male and 90 female
Swiss mice to 1,2-d1chloroethane (Maltonl et al., 1980). Mice also ex-
hibited signs of severe toxldty to 250 ppm 1,2-d1chloroethane after several
days of exposure, and the concentration was reduced to 150 ppm for the dur-
ation of the 78-week treatment period. At 52 and 78 weeks, overall survival
rates were 82.4 and 45.9%, respectively. Survival of high-dose (250-150
ppm) female mice was slightly reduced. Tumor development among treatment
and control groups was low and not statistically related to treatment. .
An earlier study by Spencer et al. (1951) failed to demonstrate cardno-
genldty of 1,2-d1chloroethane 1n 15 male and 15 female Wlstar rats given
151 exposures at 200 ppm for 7 hours duration over a 212-day period.
4.3. OTHER RELEVANT DATA
Many Investigators have tested 1,2-d1chloroethane for mutagenldty 1n
microorganisms, mammalian cells jjn vitro and rodents 1_n vivo. Most of the
Investigations 1n bacteria Indicated that 1,2-d1chloroethane was weakly
mutagenic. Metabolic activation with rat hepatic S-9 fraction Increased the
strength of the response, Indicating that metabolites may be more potent
mutagens. Studies that typify this phenomenon are summarized 1n Table 4-9.
King et al. (1979) observed negative results 1n five strains of Salmonella
typhlmurlum. Excessive evaporation from the culture plates may have contri-
buted to these negative results.
-28-
-------
TABLE 4-9
Hutagenlclty of 1,2-Dlchloroethane In Salmonella typhlmurlum Assay
i
ro
Test System
Salmonella/ml c rosome
assay (vapor exposure)
SalmoneVU /m 1 c r o s ome
assay (plate test)
Salmonella/mlcrosome
assay (plate test)
Strains
TA1535
TA100
TA1538
TA98
TA153S
TA1535
TA100
Activation System
PCB-tnduced rat
liver S-9 mix
S-9 mix from
livers of un-
Induced male R
strain Mlstar
rats plus NADPH
generating system
PCB- Induced rat
liver S-9
Chemical Information
concentrations tested:
up to 231.8 i«K>l/plate
at determined by GLC
analysis of distilled
water samples.
concentration tested:
up to 45 ymol/plate
concentration tested:
36 umol/plate
Results
Negative In standard plate test.
Positive In desiccator testing
In strains TA1535 and TA100.
Positive response (2-fold
Increase without activation;
nearly 10-fold Increase with
activation). Negative controls
yielded roughly 15 revertants/
plates.
Negative
Reference
Barber et al.,
1981
Rannug and
Ramel. 1977
King et al.,
1979
TA1537
TA153B
Escherlcla coll K 12X343/113 TA98
(suspension test)
10 «H (suspension assay) Negative
2 mN/kg l.p. Injection Negative
female NMR1 mice
-------
The ability of 1,2-d1chloroethane to cause mutations 1n DrosophUa
melanogaster has also been Investigated. Sex-linked recessive lethal
mutations 1n [). melanogaster have been produced by concentrations of 50 mM
solutions of 1,2-d1chloroethane 1n 5% sucrose fed to 1- to 2-day-old males
(King et al., 1979} and by exposure of 3-day-old virgin females to 700 ppm
1n air for 4-6 hours (Shakarnls, 1969, 1970). Nylander et al. (1979)
Induced somatic cell mutations 1n D. melanogaster with 0.1% 1,2-d1chloro-
ethane 1n food given during larval development.
Tan and Hs1e (1981) showed a dose-related Increase 1n mutations 1n cul-
tured Chinese hamster ovary cells exposed to 1,2-d1chloroethane. Metabolic
activation with rat hepatic S-9 fraction Increased response about 4-fold.
Shakarnls (1969) suggested that 1,2-d1chloroethane may cause chromosomal
aberrations 1n I), melanogaster. This Investigator exposed virgin females to
700 ppm l,2-d1chloroethane for 4-6 hours and observed a significantly
(p<0.05) greater Incidence of exceptional F, offspring, Indicative of
melotlc nondlsjunctlon.
Both King et al. (1979) and Jenssen and Ramel (1980) reported negative
results 1n the mlcronucleus test 1n mouse bone marrow smears.
4.4. WEIGHT OF EVIDENCE
As discussed previously 1n Section 4.2., the NCI (1978) gavage bloassay
clearly demonstrated that 1,2-d1chloroethane was carcinogenic to both rats
and mice. Treated male rats exhibited significantly Increased Incidences of
squamous cell carcinomas of the forestomach, hemanglosarcomas and benign
subcutaneous tissue flbromas, compared with controls. Treated female rats
experienced a significantly Increased Incidence of mammary adenocardnomas,
compared with controls. Both male and female mice experienced significantly
Increased Incidences of pulmonary alveolar/bronchlolar adenomas 1n treatment
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groups, compared with controls. Treated male mice also experienced a signi-
ficantly Increased Incidence of hepatocellular carcinomas, and treated
female mice experienced Increased Incidences of mammary adenocardnomas and
endometMal tumors (both stromal polyps and sarcomas), compared with con-
trols.
Chronic (440-594 days) application of 1,2-d1chloroethane to the skin of
mice was not associated with an Increased Incidence of skin tumors, but ap-
peared to be related to an Increased Incidence of benign papHloma formation
1n the lungs (Van Duuren et al., 1979). Inhalation exposure to levels of up
to 150-250 ppm 1,2-d1chloroethane 1n rats and mice for 78 weeks failed to
result 1n significantly Increased Incidences of tumors, compared with con-
trols (Maltonl et al., 1980).
No relevant case reports or ep1demiolog1c studies of human carclno-
genldty of 1,2-dichloroethane could be located In the available literature.
Although no data exist regarding the carclnogenlclty of 1,2-d1chloro-
ethane to humans, the evidence 1s clearly sufficient that the compound 1s a
carcinogen 1n animals. Applying the criteria proposed by the Carcinogen
Assessment Group of the U.S. EPA for evaluating weight of evidence for the
carclnogenlclty of 1,2-d1chloroethane 1n humans (Federal Register, 1984),
the compound Is most appropriately classified as a Group B2 - Probable Human
Carcinogen.
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5. REGULATORY STANDARDS AND CRITERIA
Current criteria for 1,2-d1chloroethane are summarized 1n Table 5-1.
The ACGIH (1983) has recommended a TLV-TWA of 10 ppm (40 mg/m3) and a
TLV-STEL of 15 ppm (60 mg/m3) for 1,2-dlchloroethane. This TLV represents
a reduction from a previously recommended level of 50 ppm, presumably based
on the observations of numerous effects on the nervous systems and livers of
Russian workers exposed to <16 ppm 1n air (ACGIH, 1980). NIOSH (1976) cur-
rently recommends an 8-hour TWA criterion of 1 ppm with a 2 ppm celling for
short-term exposure. This represents a reduction from 5 ppm, which was
recommended in 1978.
The U.S. EPA (1980a) has recommended a criterion for 1,2-d1chloroethane
in ambient water of 9.4 vg/8., based on the NCI (1978) finding that the
chemical is a carcinogen 1n laboratory animals.
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TABLE 5-1
Current Regulatory Standards and Criteria
Location
Criterion or Standard
Reference
Workroom air:
TLV-TWA
TLV-STEL
TWA
STEL
Ambient water
10 ppm (40 mg/m3)
15 ppm (60 mg/m3)
1 ppm
2 ppm
9.4
ACSIH, 1983
NIOSH, 1976
U.S. EPA, 1980a
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6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
1,2-Dlchloroethane 1s a known animal carcinogen and data are sufficient
for computing a q ,*. Therefore, 1t 1s Inappropriate to calculate an oral
or Inhalation AIS for 1,2-d1chloroethane.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
1,2-D1chloroethane 1s a known animal carcinogen and data are sufficient
for computing a q *. Therefore, 1t 1s Inappropriate to calculate an oral
or Inhalation AIC for 1,2-d1chloroethane.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral Exposure. The U.S. EPA (1984) chose to base calculation of a
q * on the Incidence of hemanglosarcomas 1n male rats In the NCI (1978)
bloassay rather than on the Incidence of hepatic carcinomas In male mice,
because hemanglosarcomas 1n rats were considered to be more sensitive tumors
at a site further removed from direct contact with the agent. Because of
high mortality 1n the high-dose group, time-to-death data were used rather
than data based on survival >50 weeks. A q * of 6.9xlO~2 mg/kg/day for
human exposure was calculated. The Health Assessment Document on l,2-d1-
chlorothane (U.S. EPA, 1984) contains a complete discussion of the deriva-
tion of this q *.
6.3.2. Inhalation Exposure. As discussion 1n Section 4.2.2., Inhalation
exposure to 1,2-d1chloroethane failed to result 1n significant Increases 1n
tumor Incidence In Sprague-Dawley rats or Swiss mice (Maltonl et al., 1980)
or female Wlstar rats (Spencer et al., 1951). No other reports of cardno-
genlcity of 1,2-d1chloroethane by Inhalation exposure were located In the
available literature. Calculation of a q^ for 1,2-d1chloroethane by
Inhalation exposure 1s, therefore, precluded.
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Jt . • *.
WHhey, J.R., B.T. Collins .and P.6. Collins. 1982. Effect of vehicle on
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APPENDIX
Summary Table for 1,2-Dlchloroethane
Carcinogenic
Potency
Species
Experimental
Dose/Exposure
Effect
Reference
Inhalation
Oral
rat 47 mg/kg bw
hemanglosarcomas
(mg/kg/day)-1
ND
6.9xlO-2
NCI, 1978
U.S. EPA,1984
ND = Not derived
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