INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
ENVIRONMENTAL HEALTH CRITERIA 176
1,2-DICHLOROETHANE
(SECOND EDITION)
This report contains the collective views of an international group of
experts and does not necessarily represent the decisions or the stated
policy of the United Nations Environment Programme, the International
Labour Organisation, or the World Health Organization.
First draft prepared by Ms K. Hughes, Environmental Health
Directorate, Health Canada
Published under the joint sponsorship of the United Nations
Environment Programme, the International Labour Organisation, and the
World Health Organization
World Health Organization
Geneva, 1995
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WHO Library Cataloguing in Publication Data
1,2-Dichloroethane - 2nd ed.
(Environmental health criteria ; 176)
1.Ethylene dichlorides - toxicity I.Series
ISBN 92 4 157176 4 (NLM Classification: QV 633)
ISSN 0250-863X
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CONTENTS
ENVIRONMENTAL HEALTH CRITERIA FOR 1,2-DICHLOROETHANE
Preamble
1. SUMMARY
1.1. Identity, physical and chemical properties,
and analytical methods
1.2. Sources of human and environmental exposure
1.3. Environmental transport, distribution and
transformation
1.4. Environmental levels and human exposure
1.5. Kinetics and metabolism in laboratory animals
1.6. Effects on laboratory mammals and in vitro
test systems
1.7. Effects on humans
1.8. Effects on non-target organisms in the
laboratory and field
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND
ANALYTICAL METHODS
2.1. Identity
2.2. Physical and chemical properties
2.3. Conversion factors
2.4. Analytical methods
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1. Natural occurrence
3.2. Anthropogenic sources
3.2.1. Production levels and processes
3.2.2. Uses
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND
TRANSFORMATION
4.1. Transport and fate in the environment
5. ENVIRONMENTAL LEVELS AND POPULATION EXPOSURE
5.1. Environmental levels
5.1.1. Ambient air
5.1.2. Indoor air
5.1.3. Drinking-water
5.1.4. Surface water
5.1.5. Food
5.1.6. Soils and sediments
5.1.7. Consumer products
5.2. General population exposure
5.2.1. Ambient air
5.2.2. Indoor air
5.2.3. Drinking-water
5.2.4. Food
5.2.5. Other media
5.3. Occupational exposure during manufacture,
formulation or use
6. KINETICS AND METABOLISM IN LABORATORY ANIMALS
AND HUMANS
6.1. Absorption
6.2. Distribution
6.3. Metabolic transformation
6.4. Elimination and excretion
6.5. Retention and bioaccumulation
7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO
TEST SYSTEMS
7.1. Single exposure
7.2. Skin and eye irritation
7.3. Short-term exposure
7.4. Subchronic exposure
7.4.1. Inhalation
7.4.2. Ingestion
7.5. Chronic exposure and carcinogenicity
7.5.1. Inhalation
7.5.2. Ingestion
7.5.3. Other routes of administration
7.5.4. Initiation/promotion bioassays
7.6. Mutagenicity and related end-points
7.7. Reproductive toxicity, embryotoxicity and
teratogenicity
7.8. Immunological effects
7.9. Toxicological interactions with other agents
8. EFFECTS ON HUMANS
8.1. Case reports
8.2. Epidemiological studies
9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY
AND FIELD
9.1. Aquatic organisms
9.1.1. Microorganisms
9.1.2. Invertebrates
9.1.3. Vertebrates
9.2. Terrestrial organisms
9.2.1. Invertebrates
9.2.2. Vertebrates
9.2.3. Plants
10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON
THE ENVIRONMENT
10.1. Evaluation of human health risks
10.2. Environmental assessment
11. CONCLUSIONS AND RECOMMENDATIONS FOR PROTECTION OF
HUMAN HEALTH AND THE ENVIRONMENT
12. FURTHER RESEARCH
13. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES
REFERENCES
RESUME
RESUMEN
NOTE TO READERS OF THE CRITERIA MONOGRAPHS
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* * *
A detailed data profile and a legal file can be obtained from the
International Register of Potentially Toxic Chemicals, Case postale
356, 1219 Châtelaine, Geneva, Switzerland (Telephone No. 9799111).
* * *
This publication was made possible by grant number 5 U01
ES02617-15 from the National Institute of Environmental Health
Sciences, National Institutes of Health, USA, and by financial support
from the European Commission.
Environmental Health Criteria
PREAMBLE
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The original impetus for the Programme came from World
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Sources of exposure
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Environmental levels and human exposure
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* Effects on laboratory mammals and in vitro test systems
* Effects on humans
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WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR 1,2-DICHLOROETHANE
Members
Dr T. Bailey, US Environmental Protection Agency, Washington DC, USA
Dr A.L. Black, Department of Human Services and Health, Canberra,
Australia
Mr D.J. Clegg, Carp, Ontario, Canada
Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood, Abbots
Ripton, Huntingdon, Cambridgeshire, United Kingdom
(Vice-Chairman)
Dr P.E.T. Douben, Her Majesty's Inspectorate of Pollution, London,
United Kingdom (EHC Joint Rapporteur)
Dr P. Fenner-Crisp, US Environmental Protection Agency,
Washington DC, USA
Dr R. Hailey, National Institute of Environmental Health Sciences,
National Institutes of Health, Research Triangle Park, USA
Ms K. Hughes, Environmental Health Directorate, Health Canada, Ottawa,
Ontario, Canada (EHC Joint Rapporteur)
Dr D. Kanungo, Central Insecticides Laboratory, Government of India,
Ministry of Agriculture & Cooperation, Directorate of Plant
Protection, Quarantine & Storage, Faridabad, Haryana, India
Dr L. Landner, MFG, European Environmental Research Group Ltd,
Stockholm, Sweden
Dr M.H. Litchfield, Melrose Consultancy, Denmans Lane, Fontwell,
Arundel, West Sussex, United Kingdom (CAG Joint Rapporteur)
Professor M. Lotti, Institute of Occupational Medicine, University of
Padua, Padua, Italy (Chairman)
Professor D.R. Mattison, University of Pittsburgh, Graduate School of
Public Health, Pittsburgh, Pennsylvania, USA
Dr J. Sekizawa, National Institute of Health Sciences, Tokyo, Japan
Dr P. Sinhaseni, Chulalongkorn University, Bangkok, Thailand
Dr S.A. Soliman, King Saud University, Bureidah, Saudi Arabia
Dr M. Tasheva, National Centre of Hygiene, Medical Ecology and
Nutrition, Sofia, Bulgaria (CAG Joint Rapporteur)
Mr J.R. Taylor, Pesticides Safety Directorate, Ministry of
Agriculture Fisheries and Food, York, United Kingdom
Dr H.M. Temmink, Wageningen Agricultural University, Wageningen, The
Netherlands
Dr M.I. Willems, TNO Nutrition and Food Research Institute, Zeist, The
Netherlands
Secretariat
Ms A. Sundén Byléhn, International Register of Potentially Toxic
Chemicals, United Nations Environment Programme, Châtelaine,
Switzerland
Dr P. Chamberlain, International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland
Dr J. Herrman, International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland
Dr K. Jager, International Programme on Chemical Safety, World Health
Organization, Geneva, Switzerland
Dr P. Jenkins, International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland
Dr W. Kreisel, World Health Organization, Geneva, Switzerland
Dr M. Mercier, International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland
Dr M.I. Mikheev, Occupational Health, World Health Organization,
Geneva, Switzerland
Dr G. Moy, Food Safety, World Health Organization, Geneva, Switzerland
Mr I. Obadia, International Labour Organisation, Geneva, Switzerland
Dr R. Plestina, International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland
Dr E. Smith, International Programme on Chemical Safety, World Health
Organization, Geneva, Switzerland (EHC Secretary)
Mr J. Wilbourn, International Agency for Research on Cancer, Lyon,
France
ENVIRONMENTAL HEALTH CRITERIA FOR 1,2-DICHLOROETHANE
The Core Assessment Group (CAG) of the Joint Meeting on
Pesticides (JMP) met in Geneva from 25 October to 3 November 1994.
Dr W. Kreisel, Executive Director, welcomed the participants on behalf
of WHO, and Dr M. Mercier, Director, IPCS, on behalf of the IPCS and
its cooperating organizations (UNEP/ILO/WHO). The Core Assessment
Group reviewed and revised the draft monograph and made an evaluation
of the risks for human health and the environment from exposure to
1,2-dichloroethane (ethylene dichloride).
The first draft of the monograph was prepared by Ms K. Hughes,
Environmental Health Directorate, Health Canada. The second draft,
revised in the light of international comment, was also prepared by
Ms K. Hughes. Dr E. Smith and Dr P.G. Jenkins, both members of the IPCS
Central Unit, were responsible for the scientific content and
technical editing respectively.
The efforts of all who helped in the preparation and finalization
of the monograph are gratefully acknowledged.
* * *
1,2-Dichloroethane was previously evaluated by a WHO Task Group
in 1986 and published by WHO in 1987 as Environmental Health Criteria
62.
ABBREVIATIONS
BCF bioconcentration factor
BUN blood urea nitrogen
ECD electron capture detector
FID flame ionization detector
GC gas chromatography
GSH glutathione
gamma-GT gamma-glutamyltranspeptidase
HECD Hall electron capture detector
LOEL lowest-observed-effect level
MS mass spectrometry
NOEL no-observed-effect level
PIB piperonyl butoxide
SGOT serum glutamic-oxalic transaminase
SGPT serum glutamic-pyruvic transaminase
TEAM total exposure assessment methodology
TWA time-weighted average
1. Summary
1.1 Identity, physical and chemical properties, and analytical
methods
1,2-Dichloroethane (ethylene dichloride) is a synthetic chemical
which is a colourless liquid at room temperature. It is also highly
volatile, with a vapour pressure of 8.5 kPa (at 20°C), and is soluble
in water, with a solubility of 8690 mg/litre (at 20°C). The log
octanol/water partition coefficient is 1.76.
Analysis for 1,2-dichloroethane in environmental media is usually
by gas chromatography, in combination with electron capture or flame
ionization detection or mass spectrometry. Detection limits range
from 0.016 to > 4 µg/m3 in air, 0.001 to 4.7 µg/litre in water, and
from 6 to 10 µg/kg in various foodstuffs.
1.2 Sources of human and environmental exposure
The principal use of 1,2-dichloroethane is in the synthesis of
vinyl chloride monomer, and to a lesser extent in the manufacture of
various chlorinated solvents. It is also incorporated into anti-knock
gasoline additives (although this use is declining with the phase-out
of leaded gasoline in some countries), and has been used as a
fumigant. Total annual production of 1,2-dichloroethane in Canada in
1990 and the USA in 1991 was 922 and 6318 kilotonnes, respectively.
1.3 Environmental transport, distribution and transformation
The majority of 1,2-dichloroethane released to the environment is
in emissions to air. It is moderately persistent in air; the
estimated atmospheric lifetime is between 43 and 111 days.
1,2-Dichloroethane is transported to the stratosphere, where
photolysis may produce chlorine radicals which may in turn react with
ozone. Some 1,2-dichloroethane may be released in industrial
effluents to the aquatic environment, from which it is removed rapidly
by volatilization. 1,2-Dichloroethane may also leach to groundwater
near industrial waste sites. It is not expected to bioconcentrate in
aquatic or terrestrial species.
1.4 Environmental levels and human exposure
Mean concentrations of 1,2-dichloroethane in recent surveys of
ambient air in non-source-dominated areas of cities range from 0.07 to
0.28 µg/m3, while mean levels in residential indoor air are reported
to range from < 0.1 to 3.4 µg/m3. In drinking-water, mean
concentrations are generally less than 0.5 µg/litre.
1,2-Dichloroethane has only rarely been detected in foodstuffs in
recent surveys and, since it has low potential for bioaccumulation,
food is unlikely to be a major source of exposure.
Based on estimates of mean exposure from various media, the
predominant source of exposure to 1,2-dichloroethane by the general
population is indoor and outdoor air, only minor amounts being
contributed by drinking-water. Intake of 1,2-dichloroethane from food
is probably negligible. The amount inhaled in ambient air may be
greater in the vicinity of industrial sources.
1.5 Kinetics and metabolism in laboratory animals
1,2-Dichloroethane is readily absorbed following inhalation,
ingestion or dermal exposure and is rapidly and widely distributed
throughout the body. It is rapidly and extensively metabolized in
rats and mice, with principally sulfur-containing metabolites being
eliminated in the urine in a dose-dependent manner. Metabolism
appears to be saturated or limited in rats at levels of exposure
resulting in blood concentrations of 5 to 10 µg/ml. Levels of DNA
alkylation were higher following exposure to a bolus dose by gavage
than in the case of inhalation over a 6-h period.
1,2-Dichloroethane appears to be metabolized via two principal
pathways; the first involves a saturable microsomal oxidation mediated
by cytochrome P-450 to 2-chloroacetaldehyde and 2-chloroethanol
followed by conjugation with glutathione. The second pathway entails
direct conjugation with glutathione to form S-(2-chloroethyl)-
glutathione, which may be non-enzymatically converted to a glutathione
episulfonium ion; this ion can form adducts with DNA. Although DNA
damage has been induced by the P-450 pathway in vitro, several lines
of evidence indicate that the glutathione conjugation pathway is
probably of greater significance than the P-450 pathway as the major
route for DNA damage.
1.6 Effects on laboratory mammals and in vitro test systems
The acute toxicity of 1,2-dichloroethane is low in experimental
animals. For example, inhalation LC50s for rats exposed for 6 or
7.25 h ranged from 4000 mg/m3 to 6600 mg/m3, while oral LD50s
for rats, mice, dogs and rabbits ranged from 413 to 2500 mg/kg body
weight.
The results of short-term and subchronic studies in several
species of experimental animals indicate that the liver and kidneys
are the target organs; reliable NOELs or LOELs were not attained in
general due to inadequate documentation and the limited range of
end-points examined in small groups of animals. In a series of early
limited studies, morphological changes in the liver were observed in
several species following subchronic exposure to airborne
concentrations as low as 800 mg/m3. Increases in the relative liver
weight have been observed in rats following subchronic oral
administration of doses of 49 to 82 mg/kg body weight per day or more
for 13 weeks. Little information was presented on non-neoplastic
effects in available chronic studies. Changes in serum parameters
indicative of liver and kidney toxicity were observed in rats exposed
to airborne concentrations as low as 202 mg/m3 for 12 months,
although histopathological examinations were not conducted in this
study.
The carcinogenicity of 1,2-dichloroethane has been investigated
in a few limited bioassays on experimental animals (limitations
include short duration of exposure and high mortality). Significant
increases were not reported in the incidence of any type of tumour in
Sprague-Dawley rats or Swiss mice exposed to up to 607 mg/m3 for 78
weeks and observed until spontaneous death. Mortality was high in
rats in this study, although it was not related to concentration, and
the incidence rates were not adjusted for differential mortality among
groups. There was a nonsignificant increase in the incidence of
mammary gland adenomas and fibroadenomas in female Sprague-Dawley rats
exposed to 200 mg/m3 for 2 years in an assay in which no other
compound-related toxicity was observed.
In contrast, there was convincing evidence of increases in tumour
incidence in two species following ingestion. Significant increases
in the incidence of tumours at several sites (including squamous cell
carcinomas of the stomach (males), haemangiosarcomas (males and
females), fibromas of the subcutaneous tissue (males), adenocarcinomas
and fibroadenomas of the mammary gland (females)) were observed in
Osborne-Mendel rats administered TWA daily doses of 47 or 95 mg/kg
body weight per day by gavage for 78 weeks. Similar increases in the
incidences of tumours at multiple sites (including
alveolar/bronchiolar adenomas (males and females), mammary gland
adenocarcinomas (females) and endometrial stromal polyp or endometrial
stromal sarcoma combined (females) and hepatocellular carcinomas
(males)) occurred in B6C3F1 mice administered TWA daily doses of 97 or
195 mg/kg body weight per day (males) or 149 or 299 mg/kg body weight
per day (females) by gavage for 78 weeks.
The incidence of lung tumours (benign papillomas) was
significantly increased in female mice following repeated dermal
application of 1,2-dichloroethane for 440 to 594 days. Repeated
intraperitoneal injections of 1,2-dichloroethane resulted in
dose-related increases in the number of pulmonary adenomas per mouse
in a susceptible strain, although none of these increases was
significant. Concomitant exposure to inhaled 1,2-dichloroethane and
disulfiram in the diet resulted in an increased incidence of
intrahepatic bile duct cholangiomas and cysts, subcutaneous fibromas,
hepatic neoplastic nodules, interstitial cell tumours in the testes
and mammary adenocarcinomas in rats, compared to rats administered
either compound alone or untreated controls. No potential to initiate
or promote tumour development was evident in three bioassays, although
the extent of histopathological examination was limited in these
studies.
In in vitro assays, 1,2-dichloroethane has been consistently
positive in mutagenicity bioassays in Salmonella typhimurium.
Responses have been greater in the presence of an exogenous activation
system (possibly due to activation by the cytochrome system) than in
its absence, and mutagenicity was more than doubled in S. typhimurium
expressing the human GSTA1-1 gene. In cultured mammalian cells,
1,2-dichloroethane forms adducts with DNA. It also induces
unscheduled DNA synthesis in primary cultures of rodent and human
cells and gene mutation in several cell lines. Mutation frequency in
human cell lines has been correlated with differences in
glutathione- S-transferase activity. In in vivo studies,
1,2-dichloroethane induced somatic cell and sex-linked recessive
lethal mutations in Drosophila melanogaster and the compound bound
to DNA in all reported studies in rats and mice. Although primary DNA
damage in liver and sister chromatid exchange has been observed in
studies in mice, there has been no evidence for micronucleus
induction.
Based on the results of a limited number of studies, there is no
evidence that 1,2-dichloroethane is teratogenic in experimental
animals. There is also little convincing evidence that it induces
reproductive or developmental effects at doses below those which cause
other systemic effects. Available data on the immunotoxicity of
1,2-dichloroethane are limited.
1.7 Effects on humans
Acute incidental exposure to 1,2-dichloroethane by inhalation or
ingestion has resulted in a variety of effects in humans, including
effects on the central nervous system, liver, kidney, lung and
cardiovascular system.
The potential carcinogenicity of 1,2-dichloroethane in exposed
human populations has not been extensively investigated. Mortality
due to pancreatic cancer was significantly increased in a group of
workers at a chemical production plant who had been exposed
principally to 1,2-dichloroethane (in combination with other
chemicals). Mortality due to pancreatic cancer increased with
duration of exposure. In addition, although the number of cases was
small, and the association with duration of exposure was less
consistent, mortality due to leukaemia was also increased in these
workers. No association between occupational exposure to
1,2-dichloroethane and brain cancer was noted in a small case-control
study. Although the incidence of colon and rectal cancer increased
with the concentration of 1,2-dichloroethane in drinking-water in an
inherently limited ecological study, concomitant exposure to other
substances may have contributed to the observed effects.
1.8 Effects on non-target organisms in the laboratory and field
The effects of exposure to 1,2-dichloroethane on a number of
other organisms in the laboratory and field have been investigated.
For aquatic microorganisms, IC50s or EC50s for various end-points
have been reported to range from 25 to 770 mg/litre. The lowest
reported LC50 value for Daphnia was 220 mg/litre, while effects on
reproductive success and growth were observed at 20.7 and
71.7 mg/litre, respectively. Based on available data, the most
sensitive freshwater vertebrate species appears to be the northwestern
salamander (Ambystoma gracile), in which 9-day larval survival (4
days post-hatch) was reduced at 2.54 mg/litre. Only limited data are
available on the toxicity of 1,2-dichloroethane to terrestrial
organisms.
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL METHODS
2.1 Identity
The empirical formula for 1,2-dichloroethane (ethylene
dichloride) is C2H4Cl2 and the molecular structure is as
follows:
H H
' '
Cl - C - C - Cl
' '
H H
Synonyms include EDC, 1,2-DCE, 1,2-bichloroethane, 1,2-ethylene
dichloride, acethylenchlorid, alpha, beta-dichloroethane, bichlorure
d'ethelene, ethyleen dichloride, ethylene chloride, glycol dichloride,
and sym-dichlorothane. Trade names include: Borer sol, Brocide,
Destruxo,l Di-chlor-mulson, Dichlor-mulsion, Dutch liquid, Dutch oil,
ENT 1656, Freon 150, Gaze Olefiant and Granosan (which also contains
carbon tetrachloride).
The Chemical Abstract Service (CAS) registry number for
1,2-dichloroethane is 107-06-2.
2.2 Physical and chemical properties
1,2-Dichloroethane is a clear, colourless liquid at room
temperature. It is a highly volatile and flammable synthetic chemical
which absorbs infrared light at several wavelengths (7, 12 and 13 µm).
Other properties of 1,2-dichloroethane are presented in Table 1.
2.3 Conversion factors
1 ppm = 4 mg/m3
1 mg/m3 = 0.25 ppm (at 25°C and 760 mmHg)
Table 1. Physical properties of 1,2-dichloroethanea
Physical state liquid
Colour colourless
Odour sweet, chloroform-like
Relative molecular mass 98.96
Density d20 1.253
Refractive index r20 1.4449
D
Boiling point 83°C
Melting point -35°C
Water solubility 8690 mg/litre (20°C)
Vapour pressure 8.5 kPa (20°C)
Saturation concentration in air 350 g/m3 (20°C)
537 g/m3 (30°C)
log Kow 1.76
log Koc 1.28
Henry's law constant 111.5 Pa.m3/mol (25°C)
Flash point 12-15°C
Limits of flammability in air 275-700 mg/litre
a From: Archer (1979); Chiou et al. (1979); Konemann (1981);
Warner et al. (1987); Worthing & Hance (1991)
2.4 Analytical methods
Methods of analysis of 1,2-dichloroethane in various
environmental media are described in Table 2. Gas chromatography,
coupled with electron capture or flame ionization detection or mass
spectrometry, is commonly used for analysis of 1,2-dichloroethane in
most media.
Table 2. Analytical methods for 1,2-dichloroethane in environmental mediaa
Sample matrix Preparation method Analytical method Sample detection Percentage Reference
limit recovery
Air collect sample on Tenax(R)-GC absorbent GC/MS 100 ng/m3 not available Wallace et al.
(1984)
not available GC/MS < 20 ng/m3 ± 5% precision Grimsrud &
(< 5 ppt) Rasmussen (1975)
collect in 6-litres canisters; direct GC/ECD-MS > 4 µg/m3 not available Pleil et al.
injection (> 1 ppb) (1988)
collect air sample in tubes filled with GC/MS 30 pg/sample 98-108% Jonsson & Berg
solid absorbent; heat sample tubes; (1980)
monitor for 1,2-dichloroethane using
selected ion monitoring
collect sample on Tenax(R) TA; thermal GC/ECD 16 ng/m3 not available Class &
desorption (4 ppt) Ballschmiter (1986)
charcoal-tube sampler; desorption with GC/FID 10 µg/sample not available NIOSH (1984)
CS2 solvent
continuous monitoring and breath infra-red not available not available Baretta et al.
analysis spectroscopy (1969)
sampling on charcoal or Chromosorb GC/FID 1.2 µg/m3 not available Parkes et al.
(1976)
Table 2. cont'd.
Sample matrix Preparation method Analytical method Sample detection Percentage Reference
limit recovery
collect sample on Tenax(R) polymeric GC/MS 32 ng/m3 not available Krost et al. (1982)
beads
Water purge-and-trap GC/MS 5 ng/litre not available Wallace et al.
(1984)
purge-and-trap GC/FID 0.1 µg/litre 99% Warner & Beasley
(0.1 ppb) (1984)
headspace/cryogenic trapping HR capillary 80 ng/litre 75% Comba & Kaiser
GC/ECD (1983)
Water and purge-and-trap GC 30 ng/litre 1.04-1.06C US EPA (1982b)
wastewater 97.8% (method 601)
grab sample GC/MS 4.7 µg/litre 1.02 + 0.45C US EPA (1982b)
99% (method 624)
modified purge-and-trap GD/HECD and FID FID 0.1 µg/litre; FID 78%; Otson & Williams
simultaneous HECD < HECD 79% (1982)
0.1 µg/litre
stripping by helium adsorption on GC/FID or MS 1 ng/litre not available Sauer (1981)
Tenax(R)
stripping by helium or nitrogen, GC with 0.1-0.4 µg/litre not available Symons et al.
sorption on Tenax(R) or chromosorb microcoulometric (1975)
detection
not available GC/MS 0.5 µg/litre not available Fujii (1977)
Table 2. cont'd.
Sample matrix Preparation method Analytical method Sample detection Percentage Reference
limit recovery
Grains, legumes, acidified acetone-water extraction; GC/ECD not available 14-75% Daft (1987, 1988,
spices, citrus isooctane back extraction; for liquids, 1989, 1991, 1993)
fruits, isooctane extraction
beverages,
dairy
products, meat
Table-ready stirred with water; purge-and-trap GC/ECD 6 µg/kg 85-104% Heikes (1987b);
foods on Tenax(R) GC; hexane desorption (6 ppb) Heikes & Hopper
(1986)
Fish add fish tissue to reagent grade water; GC/MS 10 µg/kg 85 ± 11% Easley et al.
disrupt cells ultrasonically; analyse (1981)
sample by purge-and-trap method
spiked samples of ground fish tissue; GC/MS not available 92 ± 5%c Hiatt (1981)
vaporize VOCs from fish sample under
vacuum and condense in purge-and-trap
homogenize fish sample; remove residual GC/MS-fused not available not available Hiatt (1983)
moisture by vacuum distillation silica capillary column
Sediment spiked samples; vaporize VOCs under GC/MS not available 96 ± 17%c Hiatt (1981)
vacuum and condense in purge-and-trap
a Modified from: ATSDR (1994); CS2 = carbon disulfide; ECD = electron capture detector; FID = flame ionization detector; GC = gas
chromatography; HECD = Hall electron capture detector; MS = mass spectrometry;
b VOCs = volatile organic carbon compounds
c Reported as percentage spike recoveries for 25 µg/kg (ppb) spikes
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1 Natural occurrence
1,2-Dichloroethane is a synthetic chemical which has no known
natural sources.
3.2 Anthropogenic sources
3.2.1 Production levels and processes
1,2-Dichloroethane, first produced in 1795, was the first
chlorinated hydrocarbon to be synthesized (IARC, 1979). It is
manufactured by either the catalytic vapour-phase or liquid-phase
chlorination of ethylene or by oxychlorination of ethylene
(Archer, 1979). Most commercial grade 1,2-dichloroethane is 97-99%
pure (Drury & Hammons, 1979).
The total annual production of 1,2-dichloroethane in Canada in
1990 was estimated to be 922 000 tonnes (CPI, 1991), while the total
production in the USA in 1991 was 6 318 000 tonnes (Chemical Marketing
Reporter, 1992), increasing from a production value of 5 038 000
tonnes in 1980 (Kirschmer & Ballschmiter, 1983). More than 1 million
tonnes of 1,2-dichloroethane was produced in the United Kingdom in
1991 (UK HSE, 1992). 1,2-Dichloroethane is released to the
environment principally through emissions to ambient air during its
production and that of vinyl chloride monomer. 1,2-Dichloroethane is
recovered from waste streams of manufacturing facilities in a
two-stage distillation operation. This waste stream is then
incinerated (McPherson et al., 1979), the estimated destruction
efficiency being 99.99% (US EPA, 1986).
Release of 1,2-dichloroethane to the atmosphere from production
facilities can occur from a number of sources. Incidental emissions
usually comprise around 50% of the total, while releases from
secondary sources, such as losses from process wastewater, valves and
vents, such as thermal oxidizer vents, handling and storage, and other
sources result in release of the balance. The US EPA estimated that
18 000 tonnes of 1,2-dichloroethane was released to the atmosphere in
the USA in 1982 from fugitive sources (e.g., valves, etc.), storage
tanks, secondary sources (e.g., emissions from wastewater treatment
processes), process vents and shipping operations (US DHHS, 1994).
1,2-Dichloroethane is also released to the atmosphere from
automobile emissions due to its incorporation into anti-knock
formulations for leaded petrol (gasoline).
1,2-Dichloroethane may enter surface waters via effluents from
industries that manufacture or use the substance. In addition, it may
enter the atmosphere or groundwater following disposal in waste sites.
3.2.2 Uses
The predominant uses of 1,2-dichloroethane is as an intermediate
in the synthesis of vinyl chloride; 99% of total demand in Canada, 90%
in Japan and 88% of total production in the USA is used for this
purpose (CPI, 1991; Chemical Marketing Reporter, 1992). It has also
been used in the production of chlorinated solvents such as
trichloroethylene, tetrachloroethylene, 1,1,1-trichloroethane,
ethyleneamines and vinylidene chloride, and in the manufacture of
anti-knock fluids containing tetraethyllead, although this latter use
has declined with the phase-out of leaded petrol. 1,2-Dichloroethane
has been used as a fumigant. However, it is no longer registered for
use on agricultural products in Canada, the USA, the United Kingdom
and Belize.
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION
4.1 Transport and fate in the environment
Due to the high vapour pressure of 1,2-dichloroethane, the
atmosphere is expected to be the predominant environmental sink for
the compound. The rate of reaction of 1,2-dichloroethane with hydroxyl
radicals has been predicted to be 3.63 × 10-13 cm3/mol-sec at
25°C (Atkinson, 1987) and 5.42 × 10-13 cm3/mol-sec at 4°C
(Nimitz & Skaggs, 1992). It was experimentally determined to be 2.09
× 10-13 cm3/mol-sec at 19°C (Qiu et al., 1992). Based on these
values, and assuming an atmospheric hydroxyl radical concentration
representative of a moderately polluted area (Finlayson-Pitts &
Pitts, 1986), the estimated atmospheric lifetime of 1,2-dichloroethane
is between 43 and 111 days. Due to the moderate persistence of
1,2-dichloroethane in the troposphere, long-range transport is
possible. Indeed, 1,2-dichloroethane has been detected in the lower
troposphere over the northern Atlantic Ocean and over the Pacific
Ocean (Singh et al., 1983; Class & Ballschmiter, 1986).
Once 1,2-dichloroethane reaches the troposphere, it undergoes
photo-oxidation to produce formyl chloride, chloroacetyl chloride,
hydrochloric acid, carbon monoxide and carbon dioxide (Spence &
Hanst, 1978). Any 1,2-dichloroethane that reaches the stratosphere
may be photolysed to produce chlorine radicals that may, in turn,
react with ozone (Spence & Hanst, 1978; Callahan et al., 1979).
However, 1,2-dichloroethane is not expected to contribute
significantly to the depletion of the stratospheric ozone layer,
since, based on either the experimental or predicted rates of reaction
between hydroxyl radicals and 1,2-dichloroethane, its ozone depletion
potential is very much less than 0.001 relative to the
chlorofluorocarbon, CFC-11. 1,2-Dichloroethane was not included as a
controlled substance in the "Montreal Protocol on Substances that
Deplete the Ozone Layer".
Volatilization is the major removal process of 1,2-dichloroethane
from the aquatic environment (Dilling et al., 1975). The half-life in
a stirred aqueous solution, at varying depths and surface areas,
ranged between 5 and 29 min (Dilling et al., 1975; Chiou et al.,
1980). Based on fate modelling (EXAMS), the predicted half-life of
1,2-dichloroethane was 9 days in a eutrophic lake and one day in a
300-km stretch of a river system (assuming a loading rate of 0.1 kg
1,2-dichloroethane in both cases) (US EPA, 1982a).
Although hydrolysis of 1,2-dichloroethane may also occur in the
aquatic environment, this is not a significant removal process, since
the half-life for hydrolysis has been estimated to be 72 years at
neutral pH and 25°C (Barbash & Reinhard, 1989). In conditions similar
to those of groundwater (i.e. in the presence of sodium sulfide, a pH
of 7, and a temperature of 15°C), the estimated half-life of
1,2-dichloroethane was 23 years (Barbash & Reinhard, 1989). The
primary products of hydrolysis are vinyl chloride and 2-chloroethanol
(Jeffers et al., 1989); vinyl chloride can be further degraded to
acetylene and acetaldehyde (Hill et al., 1976), while 2-chloroethanol
may be degraded to ethylene glycol (Ellington et al., 1988).
Microbial degradation of 1,2-dichloroethane in water has been
observed, but it is a slow process, probably due to the insufficient
time before volatilization of the substance to allow for microbial
adaptation (US EPA, 1982a). In a static flask study with initial
1,2-dichloroethane concentrations of 5 and 10 mg/litre, there was a
loss due to aerobic degradation of 20 to 63% within 7 days following
an acclimation period. However, 5 to 27% of the total loss was
attributed to volatilization (Tabak et al., 1981). The methanotrophic
bacterium Methylosinus trichosporium (Oldenhuis et al., 1989),
methylotrophic bacterium Ancylobacter aquaticus (van den Wijngaard et
al., 1992) and a nitrogen-fixing bacterium Xanthobacter autotrophicus
(Janssen et al., 1985) have been identified as microorganisms capable
of biodegrading 1,2-dichloroethane under aerobic conditions. In a
batch experiment under anaerobic conditions, Bouwer & McCarty (1983)
reported a 63% reduction in 25 days, but were unable to induce
transformation in a flow-through system when initial concentrations of
1,2-dichloroethane were 174 and 22 µg/litre, respectively.
No biodegradation was observed after 35 days of incubation in an
anoxic sediment-water system in which the initial concentration of
1,2-dichloroethane was 1.0 mg/litre (pH not reported) (Jafvert &
Wolfe, 1987).
Based on its low sorption coefficient, 1,2-dichloroethane is not
expected to adsorb appreciably to soil, suspended solids or sediments.
In one study, 1,2-dichloroethane rapidly percolated through sandy soil
with a low organic matter content; no degradation was observed, and
72-74% of the initial amount was reported to have volatilized (Wilson
et al., 1981). 1,2-Dichloroethane may leach to groundwater, based on
its solubility in water, low Koc value and high mobility in soil.
Reductive dechlorination of 1,2-dichloroethane in leachates under
anaerobic conditions has been demonstrated (Lesage et al., 1993).
1,2-Dichloroethane has low potential for bioaccumulation, based
on experimental data and modelling predictions. The bioconcentration
factor (BCF) was determined to be 2, with a clearance half-life in
tissues of less than 2 days, in freshwater bluegill (Lepomis
macrochirus) exposed to 95.6 µg 1,2-dichloroethane/litre for 14 days
(Barrows et al., 1980). This is identical to the value predicted by
Isnard & Lambert (1988). Accumulation and loss of radiolabelled
1,2-dichloroethane was studied in the dab (Limanda limanda) liver
and in the oyster (Ostrea edulis). Following exposure to 3 mg/litre
for 20 days, the level in the dab liver rose rapidly to approximately
80 mg/kg and then remained stable. Following cessation of exposure,
1,2-dichloroethane levels decreased to about 12 mg/kg at 40 days. In
the oyster, the level rose to approximately 9 mg/kg in 4 days, reached
a plateau, and decreased to 3 mg/kg by 40 days after cessation of
exposure (Pearson & McConnell, 1975).
5. ENVIRONMENTAL LEVELS AND POPULATION EXPOSURE
5.1 Environmental levels
5.1.1 Ambient air
The mean concentrations of 1,2-dichloroethane in 1412 samples of
ambient air from 23 sites in 12 cities across Canada taken between
1988 to 1990 ranged from 0.07 to 0.28 µg/m3, with an overall mean of
0.13 µg/m3 and a maximum single value of 2.78 µg/m3 (Dann, 1992).
1,2-Dichloroethane was detected in 55 out of 62 samples of ambient air
from 19 out of 21 areas of Japan surveyed in 1992 at concentrations
ranging from non-detectable (i.e. < 0.004 µg/m3) to 3.8 µg/m3
(Environment Agency Japan, 1993). In the United Kingdom and the
Netherlands, average levels of 1,2-dichloroethane in rural areas were
0.08 and 0.2 µg/m3, respectively (Clark et al., 1984a,b; Guicherit &
Schulting, 1985). In both of these countries, the average
concentration in urban air was 1.2 µg/m3 (Clark et al., 1984a,b;
Guicherit & Schulting, 1985).
The US Environmental Protection Agency (US EPA, 1987) reported
levels of 1,2-dichloroethane in urban/suburban air to be generally
< 0.8 µg/m3 (< 0.2 ppb). Concentrations of 1,2-dichloroethane in
ambient air reported in several early studies conducted in 10 cities
in the USA between 1980 and 1982 were somewhat higher, mean
concentrations ranging from 0.33 µg/m3 (83 ppt) to 6.05 µg/m3
(1512 ppt) (Singh et al., 1980, 1981, 1982). Median concentrations of
1,2-dichloroethane in air of rural/remote areas, urban/suburban areas
and source-dominated areas in the USA were 0 µg/m3, 0.49 µg/m3 and
4.9 µg/m3, respectively; the maximum level was 240 µg/m3
(Brodzinsky & Singh, 1982).
Concentrations of 1,2-dichloroethane in air near areas where
chemicals are manufactured or used in the USA were found to be as high
as 736 µg/m3 (184 ppb), with an average of 110 µg/m3 (27.5 ppb)
(US EPA, 1985a). Concentrations were also high (300 µg/m3) near a
vinyl chloride manufacturing plant in the Netherlands (Kretzschmar et
al., 1976). The annual mean concentrations of 1,2-dichloroethane in
250 samples of ambient air from 12 sites in Hamburg, Germany, surveyed
in 1986-1987 ranged from 0.2 to 119 µg/m3, the highest levels being
detected in an industrial region where lubrication oil was produced
(Bruckmann et al., 1988). Levels of 1,2-dichloroethane ranged from
0.09 to 3.5 µg/m3 in heavily industrialized areas in Japan in
1980/1981 (Environment Agency, Japan, 1983). In New Jersey, USA,
where several petrochemical industries were located and there had been
substantial chemical dumping activity in the past, the mean and
maximum values for five hazardous waste sites (14 to 24 samples each)
ranged up to 1.12 µg/m3 (0.28 ppb) and 20.6 µg/m3 (5.15 ppb),
respectively (LaRegina & Bozzelli, 1986). 1,2-Dichloroethane was also
detected in air at a waste disposal site in New Jersey at levels
ranging from trace to 27 µg/m3 (6.8 ppb) (detection limit not
specified) (Pellizzari, 1982).
5.1.2 Indoor air
In a pilot study of samples taken for 1 year beginning in
mid-January 1991, indoor air of approximately 750 residences from 10
provinces across Canada was analysed. The mean concentration of
1,2-dichloroethane was < 0.1 µg/m3, and the maximum value
1.7 µg/m3 (detection limit not specified) (Fellin et al., 1992).
In the US EPA Total Exposure Assessment Methodology
(TEAM) study, samples of "personal" and outdoor air were taken in 600
residences of New Jersey, North Carolina, North Dakota and California.
1,2-Dichloroethane was detected only occasionally at low
concentrations, and the levels in personal air (range of mean values,
0.1 to 0.5 µg/m3) were higher than those in outdoor air (range of
mean values, 0.05 to 0.2 µg/m3) (quantifiable limit approximately
1 µg/m3) (Wallace, 1986). Based on a recent review of available
literature, mean concentrations of 1,2-dichloroethane in indoor air in
the USA ranged from 1.49 to 2.21 µg/m3 in hospitals and 4.51 µg/m3
in office buildings (US EPA, 1992).
The mean concentration of 1,2-dichloroethane in the air of 20
homes in areas in the Netherlands with "non-contaminated" soil was
3.4 µg/m3, compared to a mean outdoor level of 4.9 µg/m3. In the
crawl space or cellar of these homes, the mean concentration was
2.5 µg/m3 (Kliest et al., 1989).
1,2-Dichloroethane was also detected in the indoor air of two out
of nine residences from the Love Canal area of Niagara, New York
(0.100 µg/m3 and 0.130 µg/m3), while only trace levels were
detected in samples of outdoor air (detection limit not specified)
(Barkley et al., 1980).
5.1.3 Drinking-water
In Ontario, Canada, 1,2-dichloroethane was detected in 15 out of
> 2000 samples of drinking-water from 85 sites surveyed between 1988
and 1991; mean concentrations ranged from nondetectable (detection
limit 0.050 µg/litre) to 0.139 µg/litre, with a maximum single value
of 0.850 µg/litre, in treated water (it was not detected in untreated
water) (Ministry of Environment, 1991). 1,2-Dichloroethane was not
detected in 237 samples of drinking-water taken from 171 sites across
New Brunswick during the summer months of 1990 (detection limit
0.2 µg/litre) (Ecobichon & Allen, 1990).
In a survey of untreated and treated water from 10 potable water
treatment plants along the Great Lakes system in Ontario in 1982-1983,
1,2-dichloroethane was detected (< 0.1 µg/litre) in one sample each
for untreated and treated water in the summer, not at all in the
winter, and in two samples of each (<0.1 µg/litre) in the spring
(Otson, 1987). In an earlier survey of 30 potable water treatment
facilities serving major population centres across Canada sampled in
1979, 1,2-dichloroethane was detected frequently in both untreated and
treated water at mean concentrations of up to 2 µg/litre and
5 µg/litre, respectively (Otson et al., 1982).
Based on a summary of data on levels of 1,2-dichloroethane in
groundwater and surface water supplies from six US Federal surveys,
1,2-dichloroethane was detected in 24 out of 1973 samples of
groundwater at concentrations up to 18 µg/litre and in 12 of 589
samples of surface water at concentrations up to 19 µg/litre
(detection limits not specified) (Letkiewicz et al., 1982).
The US EPA (1987) estimated that 0.3% of groundwater and 3% of
surface water supplies contain concentrations of 1,2-dichloroethane in
the range of 0.5 to 5 µg/litre and 0.5 to 20 µg/litre, respectively
(the basis for these estimates was not specified). 1,2-Dichloroethane
was detected (detection limit not clearly specified) in 7 out of 1792
wells in Wisconsin, USA in the early 1980s; in two of the wells,
concentrations exceeded 7 µg/litre) (Krill & Sonzongni, 1986). In the
Love Canal district of Niagara, New York, 1,2-dichloroethane was
detected in the drinking-water in three out of nine residences
surveyed, at a concentration of 50 ng/litre (Barkley et al., 1980).
Concentrations of 1,2-dichloroethane in drinking-water from five
locations in Japan ranged from non-detectable (i.e. < 0.5 µg/litre)
to 0.9 µg/litre (Fujii, 1977). It was not detected in the
drinking-water samples from 100 cities in Germany (detection limit,
1.0 µg/litre) (Bauer, 1981). 1,2-Dichloroethane was not detected
(detection limit, 0.5 µg/litre) in 229 out of 232 groundwater stations
in the Netherlands surveyed from 1976 to 1978; in the other three
stations concentrations ranged from 0.8 to 1.7 µg/litre (Zoetman et
al., 1979). Concentrations of 1,2-dichloroethane ranged from 2 to
22 µg/litre in 400 samples of drinking-water from six cities in Spain
in 1987 (Freiria-Gandara et al., 1992).
5.1.4 Surface water
1,2-Dichloroethane was detected in 2% of samples in surveys in
the early 1980s of Canadian surface waters (Government of Canada,
1994), but it was not detected (detection limit of 0.08 µg/litre) in
351 samples from several lakes and rivers in Ontario (Kaiser et al.,
1983; Comba & Kaiser, 1985; Kaiser & Comba, 1986; Lum & Kaiser, 1986).
It was detected 300 m downstream of a plant manufacturing
1,2-dichloroethane in Ontario, with a maximum concentration of
16 µg/litre (Environment Canada, 1986).
1,2-Dichloroethane was detected (detection limit not specified)
in 53 of 204 sites from six river basins in the USA surveyed before
1977 at concentrations ranging from 1 to 15 µg/litre and one site
containing 90 µg/litre (HSDB, 1993). It was detected (detection limit
not specified) in 7% of 4972 samples of surface water from the Ohio
River basin in the USA in 1980-1981; concentrations ranged from 1 to
10 µg/litre in 44 samples (HSDB, 1993).
1,2-Dichloroethane was detected in 39 of 102 samples of surface
water from 14 of 34 sites in Japan in 1992 at concentrations ranging
from non-detectable (i.e., < 0.01 µg/litre) to 3.4 µg/litre
(Environment Agency Japan, 1993).
Concentrations of 1,2-dichloroethane in the influent of six
wastewater treatment plants in the Netherlands ranged from < 2 to
400 µg/litre, while levels in the effluents ranged from < 2 to
74 µg/litre. The variation was determined to be due to industrial
discharges (van Luin & van Starkenburg, 1984).
5.1.5 Food
1,2-Dichloroethane was not detected in any samples of 34 food
groups (consisting of dairy products, meats, eggs, fish, soup, bread,
cereal, pasta, fruit, vegetables, cooking oil, peanut butter,
sugar/jam, coffee/tea, soft drinks, wine/beer and tap water) collected
in Calgary, Canada, in 1991 (detection limit 50 µg/kg for solids and
1.0 µg/litre for liquids) (Enviro-Test Laboratories, 1991). In
January 1992, the study was repeated for the same 34 food groups
collected in Windsor, Canada, using more sensitive analytical
methodology (detection limit 5 µg/kg for solids and 1 µg/litre for
liquids). Based on preliminary results, 1,2-dichloroethane was not
detected in any of the samples analysed (Enviro-Test Laboratories,
1992).
In a Total Diet Study conducted by the US Food and Drug
Administration (FDA), 1,2-dichloroethane was not detected in 11
decaffeinated instant coffees or in 14 decaffeinated ground coffees
(detection limit not specified) (Heikes, 1987a).
1,2-Dichloroethane was detected only in one ready-to-eat cereal
(mean 0.31 µg/kg) out of 19 table-ready food items, including butter,
margarine, ready-to-eat cereals, cheese, peanut butter, processed
foods and drinking-water, which were selected to be representative of
the 234 table-ready food items examined in the Total Diet Study
(Heikes, 1987b, 1990). In further analysis of these foodstuffs,
1,2-dichloroethane was detected only in plain granola and shredded
wheat cereal at concentrations of 12 and 8.2 µg/kg, respectively
(Heikes, 1987b).
1,2-Dichloroethane was detected only in one item (whisky, at a
concentration of 30 µg/kg) in an additional Total Diet Study in the
USA of 231 different table-ready foods (quantification limit 9 µg/kg).
The food types examined included off-the-shelf cooked and uncooked
grain-based items, dairy products, fresh and canned fruits and
vegetables, meats and meat dishes, infant and junior blends, baked
goods, nuts and nut products, clear beverages, sugars, jams, and
candies (Daft, 1988). 1,2-Dichloroethane was not detected in four
earlier composite market basket surveys of dairy products, meats, oils
and fats, and beverage products (detection limit not specified) in the
USA (Entz et al., 1982).
In Germany, the mean concentrations of 1,2-dichloroethane in 12
samples of milk-products containing fruits (i.e. ice-cream, yoghurt,
curds and buttermilk) was 0.8 µg/kg fresh weight, with a maximum
concentration of 3.5 µg/kg fresh weight (detection limit not
specified) (Bauer, 1981).
Prior to 1984, 1,2-dichloroethane was used in Canada as a grain
fumigant (Lange, personal communication to the IPCS). In an early
survey, 1,2-dichloroethane concentrations ranged from 23 to 38 mg/kg
in wheat which had been treated with a fumigant containing
1,2-dichloroethane (Wit et al., 1969). 1,2-Dichloroethane could not
be "determined satisfactorily" in wheat which had been fumigated with
a mixture containing 30% of the compound (limit of detection specified
as 1.5 ng); similarly, it was not detected or determined only at trace
levels (not further specified) in samples of cereals (Berck, 1974).
1,2-Dichloroethane is currently not registered for use in
agricultural products in the USA. It was detected in wheat and
bleached flour samples at concentrations of 110 and 180 µg/kg and 6.1
and 6.5 µg/kg, respectively (limit of quantification 6 µg/kg), in a
survey of compounds used as fumigants in whole grains, milled grain
products and intermediate grain-based foods (Heikes & Hopper, 1986).
In 1979, it was detected at a concentration of 290 mg/kg in 1 out of
71 samples of wheat grown in the USA, but was not detected in 61
samples of wheat exported from England to the USA (Bailey et al.,
1982). Cooking (steaming, baking, etc.) tends to reduce levels of
1,2-dichloroethane in most foods contaminated during fumigation (Bond,
1984).
The use of 1,2-dichloroethane in agricultural products in the
United Kingdom has been discontinued. In earlier surveys, it was
detected in one out of 155 samples of wheat grown in the United
Kingdom in 1978-1979 at a concentration of 290 mg/kg and in none of
126 samples of imported wheat (MAFF, 1982); in 1981 and 1982,
1,2-dichloroethane was not detected in 47 and 59 samples of wheat,
respectively (MAFF, 1984). It was also not detected in 84 samples of
brown rice, 107 samples of rye products and 71 samples of processed
oats collected in 1985-1986 (MAFF, 1989). More recently,
1,2-dichloroethane was not detected (detection limit 0.4 mg/kg) in 24
samples of rice analysed in 1992 (UK HSE, 1992; MAFF/HSE, 1993).
No information on concentrations of 1,2-dichloroethane in breast
milk of women in the general population is available.
5.1.6 Soils and sediments
1,2-Dichloroethane was not detected (detection limit 0.01 mg/kg)
in 30 samples of soil taken from "typical" urban residential and
parkland locations in southern Ontario, Canada in 1987 (Golder
Associates, 1987). The mean concentration of 1,2-dichloroethane in
soil near 20 homes in areas of the Netherlands with "uncontaminated"
soil was 11 mg/kg, while samples of soil in the vicinity of a garage
and a waste site contained < 5 and 30 mg/kg, respectively (Kliest et
al., 1989). The US EPA (1988) reported that 1,2-dichloroethane has
been detected in soil samples from 1.5% of 2783 hazardous waste sites
sampled in the USA (concentrations and detection limits were not
reported).
1,2-Dichloroethane was not detected (detection limit, 0.01 µg/kg)
in sediments downstream of two facilities in Canada which manufactured
the compound (Oliver & Pugsley, 1986; AEC, 1989). It was detected in
11 out of 99 samples of sediment from 5 out of 33 areas surveyed in
Japan in 1992 at concentrations ranging from non-detectable (i.e.,
< 0.4 µg/kg) to 0.7 µg/kg (dry weight) (Environment Agency Japan,
1993).
5.1.7 Consumer products
In studies conducted in the USA, 1,2-dichloroethane was released
from cleaning agents and pesticides, glued wallpaper and glued carpets
in environmental chambers, while it was not emitted by painted
sheetrock (detection limit not specified) (Wallace et al., 1987).
More recently, 1,2-dichloroethane was detected in 5 out of 1043
household products tested in the USA; concentrations ranged up to 0.1%
(by weight) in automotive products, oils, greases and lubricants, and
miscellaneous products (Sack et al., 1992). It should be noted that
the use of 1,2-dichloroethane in products such as upholstery and
carpet fumigants, soap and scouring compound ingredients, wetting and
penetrating agents and degreasing fluid has been largely discontinued
in the USA. In addition it is not used in any registered drug
products in the USA (Drury & Hammons, 1979).
In a survey in Germany, 1,2-dichloroethane was not detected in
facial soap, mouthwash or toothpaste (detection limit not specified).
However, it was detected in shampoo and shaving cream at levels
ranging up to 7.6 µg/litre and 122 µg/litre, respectively, and in 1
out of 7 cough-syrups at a concentration of 12.9 µg/kg (Bauer, 1981).
No data on concentrations of 1,2-dichloroethane in cigarettes are
available. No difference was reported between the median air
concentrations of 1,2-dichloroethane in air in the offices of smokers
and those in the offices of non-smokers in southern England (Proctor
et al., 1989).
5.2 General population exposure
Based on estimates of mean exposure from various media, the
principal source of exposure to 1,2-dichloroethane by the general
population is indoor and outdoor air (< 0.03 to 0.1 µg/kg body weight
per day and 0.004 to 0.02 µg/kg body weight per day, respectively),
with only minor amounts being contributed by drinking-water (< 0.001
to 0.003 µg/kg body weight per day). Intake of 1,2-dichloroethane
from food is probably negligible. For some individuals residing in
the vicinity of industrial sources of airborne 1,2-dichloroethane,
intake from ambient air may be substantially greater than that for the
general population.
5.2.1 Ambient air
Based on a daily inhalation volume for adults of 22 m3, a mean
body weight for males and females of 64 kg, the assumption that 4 out
of 24 h are spent outdoors (IPCS, 1994), and the range of mean
1,2-dichloroethane levels found in a recent survey of cities across
Canada (0.07-0.28 µg/m3 as presented in section 5.1.1), mean intake
of 1,2-dichloroethane from ambient air for the general population is
estimated to range from 0.004 to 0.02 µg/kg body weight per day.
5.2.2 Indoor air
Based on a daily inhalation volume for adults of 22 m3, a mean
body weight for males and females of 64 kg, the assumption that 20 out
of 24 h are spent indoors (IPCS, 1993), and the range of
1,2-dichloroethane concentrations in indoor air or "personal" air in
surveys in Canada and the USA (< 0.1 to 0.5 µg/m3 as presented in
section 5.1.2), mean intake of 1,2-dichloroethane from indoor air for
the general population is estimated to range from < 0.03 to 0.1 µg/kg
body weight per day.
5.2.3 Drinking-water
Based on a daily volume of water consumption for adults of 1.4
litres, a mean body weight for males and females of 64 kg (IPCS,
1993), and the mean levels of 1,2-dichloroethane in provincial surveys
in Canada (< 0.05 to 0.139 µg/litre as presented in section 5.1.3),
mean intake of 1,2-dichloroethane from drinking-water for the general
population is estimated to range from < 0.001 to 0.003 µg/kg body
weight per day.
5.2.4 Food
Based on its low octanol/water partition coefficient,
1,2-dichloroethane is unlikely to bioaccumulate, and therefore it is
considered that food does not represent a significant source of
exposure for the general population. It has only rarely been detected
in individual samples of foodstuffs in North America (see section
5.1.5). Even if the compound was assumed to be present in foods at
concentrations up to the limit of detection in the surveys with the
more sensitive analytical methodology, the daily intake of
1,2-dichloroethane from food would still be negligible compared to
that from air.
5.2.5 Other media
Available data were considered insufficient to estimate intake of
1,2-dichloroethane from soil or consumer products.
5.3 Occupational exposure during manufacture, formulation or use
Based on a review of available information, current occupational
exposure to 1,2-dichloroethane in North America occurs predominantly
during the manufacture of other chemicals, such as vinyl chloride,
where 1,2-dichloroethane is used as an intermediate. In a 1982
National Occupational Exposure Survey by the US National Institute for
Occupational Safety and Health (NIOSH), 28% of employees working with
adhesives and solvents were exposed to 1,2-dichloroethane, while
between 5 and 9% of workers were exposed to the substance in the
medicinals and botanicals, biological products, petroleum refining and
organic chemicals industries, and in museums and art galleries (US
Department of Labour, 1989).
Mean concentrations of 1,2-dichloroethane at three production
plants in the United Kingdom in 1990 were 2.8, 3.2 and 6.8 mg/m3
(0.7, 0.8 and 1.7 ppm); 95% of samples contained less than 20 mg/m3
(5 ppm), while maximum values at the plants were 18, 80 and
160 mg/m3 (4.5, 20 and 40 ppm) (UK HSE, 1992).
The time-weighted average concentration of 1,2-dichloroethane in
an electron microscopy preparation laboratory in Hong Kong, in which
the chemical was used as a solvent, was 19.8 mg/m3 (4.9 ppm). The
concentration in the breathing zone of the operator was 52.87 mg/m3
(13.06 ppm) while the average concentration in the preparation room
was 35.1 mg/m3 (8.67 ppm) (Li & Cheng, 1991).
6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS
6.1 Absorption
Case reports of acute effects following inhalation exposure to
1,2-dichloroethane in the workplace indicate that it is readily
absorbed (Nouchi et al., 1984).
In experimental animals, absorption following ingestion of
1,2-dichloroethane is rapid and complete. Spreafico et al. (1980) and
Reitz et al. (1982) reported that peak levels in blood (13 to
67 mg/litre) occurred within 10 or 15 min in rats administered single
oral doses of 25, 50 or 150 mg/kg body weight in corn oil. A plot of
administered dose against peak blood level appeared linear up to
50 mg/kg, with a perceptible decrease in steepness thereafter,
possibly indicating a relative saturation in gastrointestinal
absorption at doses of 100 to 150 mg/kg body weight. (The authors
noted that there were no significant differences in kinetic parameters
following single and 10 daily administrations of 50 mg/kg body
weight). Gastrointestinal absorption in rats was more rapid and
efficient following administration in water, compared to corn oil
(Withey et al., 1983).
Absorption following inhalation in experimental animals is also
rapid. In rats, levels of 1,2-dichloroethane in the blood peaked (8
to 10 mg/litre) within 1-2 h of continuous inhalation of 600 mg/m3
(150 ppm) for 6 h (Reitz et al., 1982).
The rate of dermal absorption of 1,2-dichloroethane by mice was
479.3 ± 38.3 nmol/min per cm2 following covered application of 0.5 ml
of the undiluted solvent (Tsuruta, 1975), while the rate of absorption
of 1,2-dichloroethane in 0.9% NaCl in vitro in excised skin of rats
was 169 ± 0.44 nmoles/min per cm2 (Tsuruta, 1977). Dermal
absorption of 1,2-dichloroethane in aqueous solution (1000 mg/litre)
was found to be similar in human and rat epidermis in vitro within
one hour of occluded application (20.3 µg/cm2 per h versus 33.1 µg/cm2
per h), whereas when the substance was applied neat (uncovered),
absorption within the first 15 min was approximately four to ten-fold
greater in the rat epidermis than in the human epidermis. In
addition, absorption increased with applied dose in the rat epidermis,
whereas absorption was not dependent upon dose in the human epidermis
(Ward, 1992).
The concentration of 1,2-dichloroethane in the blood of
guinea-pigs increased rapidly (up to approximately 7 mg/litre) during
the first 30 min following covered application of 1.0 ml of the
undiluted compound to shaved skin; the level in blood then began to
decrease abruptly to a minimum (approximately 5 mg/litre) after one
hour, at which point it began to gradually increase again (up to about
17 mg/litre after 12 h) (Jakobson et al., 1982). 1,2-Dichloroethane
was also rapidly absorbed when applied in aqueous solution to the skin
of rats in vivo, with the levels in blood being directly related to
the concentration of the solution (Morgan et al., 1991).
6.2 Distribution
Absorbed 1,2-dichloroethane is widely distributed throughout the
human body, based on analysis of several tissues of humans who died
following acute oral poisonings with the substance. Concentrations
ranged from 1 to 50 mg/kg in the spleen and 100 to 1000 mg/kg in the
stomach; levels in the liver and kidney were approximately 10 times
less than those in the stomach (Luznikov et al., 1985). The
metabolite 2-chloroacetaldehyde was not detected; detectable
quantities of 2-chloroethanol and monochloroacetic acid were reported,
though levels were too low to compare among tissues.
1,2-Dichloroethane has been detected in the breast milk of women
occupationally exposed via inhalation and dermal contact (Urusova,
1953).
Similarly, 1,2-dichloroethane is widely distributed throughout
the body in experimental animals exposed via inhalation or ingestion.
The highest concentrations were usually found in adipose tissue,
although it was also detected in blood, liver, kidney, brain and
spleen. 1,2-Dichloroethane accumulated most rapidly in the liver of
rats administered single oral doses of 25, 50 or 150 mg/kg body weight
in corn oil, although concentrations were greatest in adipose tissue.
Peak levels in adipose tissue, at 45 to 60 min, exceeded those in
blood by 3.9 to 8.3 times, whereas peak levels in the liver, 10 min
after exposure, exceeded those in the blood by 1.3 to 2.2 times
(Spreafico et al., 1980). Accumulation was less than expected at the
two higher exposure levels, indicating saturation of the tissues.
Similar accumulation in adipose tissue in rats was noted following
inhalation of 200 or 1000 mg/m3 (50 or 250 ppm) for up to 6 h.
During inhalation, steady state levels were reached within 2 to 3 h
and increased 20-to 30-fold when the exposure increased from 202 to
1012 mg/m3, suggesting saturable metabolic capacity. Levels of
1,2-dichloroethane in the spleen, brain and kidney were similar to
those in the blood, irrespective of the route of exposure (Spreafico
et al., 1980).
Reitz et al. (1982) reported that the relative distribution of
radioactivity at 48 h (assumed to be primarily in the form of
metabolites) was similar in rats administered [14C]-labelled
1,2-dichloroethane orally (single dose of 150 mg/kg body weight) or by
inhalation (600 mg/m3 or 150 ppm for 6 h). Residual reactivity in
selected tissues was 1.5 to 2 times higher after oral exposure than
following inhalation. There was also a higher residual activity in
the forestomach after the oral exposure. The distribution pattern for
macromolecular binding was similar, as determined 4 h after oral
ingestion or directly after inhalation. Oral exposure produced lower
(i.e. 1.5 to 2 times less) levels of total macromolecular binding but
higher (i.e. 3 to 5 times more) levels of DNA alkylation than
inhalation, though the absolute levels were considered low.
Arfellini et al. (1984) reported a greater degree of binding to
DNA in organs (liver, kidneys, lung and stomach) of mice than in those
of rats (1.45 to 2.26 fold) 22 h after intraperitoneal administration
of equivalent single doses of 8.7 µmoles/kg body weight.
In periods from 1 min to 4 days following intravenous
administration of a single dose (0.73 mg/kg body weight) of
radiolabelled 1,2-dichloroethane to mice, the highest levels of
radioactivity (non-volatile and bound metabolites) determined by whole
body autoradiography were present in the nasal olfactory mucosa and
the tracheo-bronchial epithelium. Low levels of metabolites were also
present in the epithelium of the upper alimentary tract, vagina and
eyelid and in the liver and kidney. Mucosal and epithelial binding
was decreased by pretreatment with metapyrone, indicating that binding
might be due to oxidative metabolism. In in vitro studies in
tissues from the same strain of mice, reactive products of
1,2-dichloroethane were irreversibly bound to the nasal mucosa, lung
and liver but not to the oesophagus, forestomach or vagina. The level
of binding in the nasal mucosa was twice that in the lung and 1.4
times that in the liver. On the basis of their results, the authors
suggested that the epithelium of the respiratory tract may be a
potential target for the toxic effects of 1,2-dichloroethane due to in
situ metabolism to reactive intermediates (Brittebo et al., 1989).
1,2-Dichloroethane was detected in fetal tissue of rats following
maternal exposure to airborne concentrations ranging from 612-
7996 mg/m3 (153-1999 ppm) on day 17 of gestation, the detected
concentrations in fetal tissues being related to the level of exposure
as well as the position on the uterine horn (Withey & Karpinski,
1985).
6.3 Metabolic transformation
1,2-Dichloroethane is metabolized extensively in rats and mice.
It is principally sulfur-containing metabolites that are eliminated in
the urine. Mitoma et al. (1985) reported slightly more complete
metabolism in mice than in rats, based on 100% recovery of metabolites
as expired CO2 and in the excreta and carcasses of mice administered
an oral dose of 150 mg/kg body weight [14C]-labelled
1,2-dichloroethane, compared to about 85% in rats administered
100 mg/kg body weight. This difference may have been due to
experimental variation or error. Reitz et al. (1982) reported 70 and
91% transformation of 1,2-dichloroethane in the rat following oral
(150 mg/kg body weight) and inhalation (607 mg/m3, 6 h) exposures,
respectively, with 85% of the metabolites appearing in the urine.
Proposed metabolic pathways for 1,2-dichloroethane are
illustrated in Fig. 1. Metabolism appears to occur via two principal
pathways for which the reactions and subsequent metabolism of the
products can account for all of the identified sulfur-containing
metabolites in the urine of 1,2-dichloroethane-exposed animals. One
pathway begins with cytochrome P-450-mediated oxidation, and the other
with glutathione conjugation. In the first pathway, cytochrome P-450
enzymes catalyse an oxidative transformation of 1,2-dichloroethane to
form reactive intermediates, which result in the formation of
2-chloroacetal-dehyde and 2-chloroethanol (Guengerich et al., 1980),
which are conjugated both enzymatically and non-enzymatically with
glutathione (GSH) and excreted in the urine. Guengerich et al. (1991)
concluded that cytochrome P-450 IIE1 is a major catalyst in the
oxidation of 1,2-dichloroethane in human microsomes.
The other pathway involves direct conjugation with glutathione to
form S-(2-chloroethyl)-glutathione, which is a half mustard with a
half-life of 69 min at 20°C (Schasteen & Reed, 1983) and less than 15
min at 37°C (Foureman & Reed, 1985). Non-enzymic conversion of the
half mustard to the corresponding episulfonium ion gives a putative
alkylating agent (episulfonium ion) that has several fates. Reaction
can occur with water to form S-(2hydroxyethyl) glutathione, with
thiols such as GSH to form ethene bis-glutathione, or with DNA to form
adducts. With the exception of the precursors which form DNA adducts,
the reaction products are considered non-toxic and undergo further
metabolism.
Although some DNA damage has been induced via the P-450 pathway
in vitro (Banerjee et al., 1980; Guengerich et al., 1980; Lin et
al., 1985), several lines of evidence suggest that the GSH conjugation
pathway is probably of greater significance than the P-450 pathway as
the major route for DNA damage (Guengerich et al., 1980; Rannug, 1980;
Sundheimer et al., 1982; Inskeep et al., 1986; Koga et al., 1986).
The P-450-dependent pathway can, however, presumably form
considerable quantities of 2-haloacetaldehydes, which readily bind to
protein and non-protein thiols, as shown for vinyl bromide and vinyl
chloride (Guengerich et al., 1981) and dibromoethane (DBE) (van
Bladeren et al., 1981). However, these authors concluded that 2H
and 18O studies on the formation of 2-haloethanols and
2-haloacetaldehydes from 1,2-dihaloethanes are inconsistent with a
major role of such a mechanism for DNA damage (Guengerich et al.,
1986; Koga et al., 1986).
The 1,2-dichloroethane-induced mutation frequency of two human
cell lines has been correlated with the difference in levels of
glutathione- S-transferase activities. AHH-1 cell line mutation
frequency was 25 times that in the TK6 cell line in the presence of
1,2-dichloroethane. The difference was attributed to the fact that
the AHH-1 cell line possesses 5 times more glutathione- S-transferase
activity than the TK6 cell line (Crespi et al., 1985).
Moreover, although the significance of the reported results is
uncertain, the results of an additional study by Storer & Conolly
(1985) are not inconsistent with the hypothesis that reduction of GSH
levels is associated with a reduction in DNA damage. Male B6C3F1
mice pretreated with piperonyl butoxide (PIB), a P-450 inhibitor, were
examined for the extent of hepatic DNA damage produced 4 h after
1,2-dichloroethane administration. Hepatic DNA damage, as measured by
alkali-labile lesions, was potentiated by PIB. Treatment of mice with
high doses of 2-chloroethanol failed to produce DNA damage, as
measured by this assay. Diethylmaleate, a GSH depletor, potentiated
the hepatotoxicity of 2-chloroethanol but not DNA damage.
In addition, Cheever et al. (1990) reported that although the
levels of hepatic DNA covalent binding of metabolites of
14C-1,2-dichloroethane injected (single dose) to rats which had been
exposed by inhalation to 1,2-dichloroethane in a long-term bioassay
were significant (p < 0.05), these levels were not different in rats
with concomitant exposure to disulfiram in the diet over two years.
Evidence suggests that the putative episulfonium ion, resulting
from non-enzymatic conversion of S-(2-chloroethyl) glutathione, is a
major intermediate in the formation of DNA adducts in vivo from
1,2-dichloroethane exposure (Inskeep et al., 1986). When rats were
administered single does of 14C-1,2-dichloroethane in vivo and the
liver was analysed 8 h later, 78% of the DNA adducts (0.25 nmol/mg
DNA) could be released by neutral thermal hydrolysis. A major adduct
and several minor adducts were present; the major adduct
co-chromatographed with S-[2-(N7-guanyl)ethyl] glutathione. The
postulated adduct of liver DNA after 14C-1,2-dichloroethane
exposure, S-[2-(N7-guanyl)ethyl] glutathione, appears to be
chromatographically identical to the major adduct in rats after
exposure to 1,2-dibromoethane (Koga et al., 1986). This
1,2-dibromoethane adduct, which has been isolated and characterized by
NMR and mass spectrometry, gives strong support to an identical adduct
being the principal DNA adduct from exposure to 1,2-dihaloethanes.
Reitz et al. (1982) found (based on consideration of results of
their own work as well as that of Spreafico et al., 1980) that
metabolism of 1,2-dichloroethane appears to be saturated or limited in
rats at levels of exposure resulting in blood concentrations of 5 to
10 mg/litre, based on an observed non-linear relationship between
levels in blood and administered doses or concentrations.
Administration by gavage resulted in the formation of about twice the
amount of "total" metabolites as did exposure by inhalation, based on
recovery in excreta, expired air and the carcass. Oral exposure
produced 1.5- to 2-fold lower levels of total macromolecular binding
but 3- to 5-fold higher levels of DNA alkylation than inhalation,
though the absolute levels of DNA alkylation were considered low.
Based on examination of DNA binding in the liver and lung of rats
exposed by inhalation to a low constant concentration (0.3 mg/litre)
of 1,2-dichloroethane for 12 h or to a peak concentration (up to
18 mg/litre) for a few minutes, Baertsch et al. (1991) concluded that
DNA damage by 1,2-dichloroethane depends upon the concentration time
profile, with bolus doses causing disproportionately greater damage.
6.4 Elimination and excretion
Unmetabolized 1,2-dichloroethane is eliminated in expired air,
while its metabolites are largely excreted in the urine. Unchanged
1,2-dichloroethane was detected in the exhaled breath of women exposed
dermally and to airborne concentrations of 0.252 mg/m3 (0.063 ppm)
in the workplace; the amount of 1,2-dichloroethane expired was greater
immediately following exposure and decreased over time (Urusova,
1953).
A single dose of 150 mg/kg body weight radiolabelled
1,2-dichloroethane was injected into rats that had been exposed via
inhalation at a concentration of 200 mg/m3 (50 ppm) for 2 years. The
proportion of radioactivity present in the urine within 24 h was 42.5
and 33.9% (in males and females, respectively), while 27.3 and 40.3%
were eliminated as the unchanged parent compound in the breath. Only a
very small amount of radioactivity was detected as 14CO2 or in the
faeces. In rats that had been concomitantly exposed to disulfiram
during the 2-year period, the proportion of unchanged
1,2-dichloroethane eliminated in the breath increased significantly
(i.e. 57.6 and 57.7%; p < 0.05), while the proportion eliminated in
the urine decreased correspondingly (27.6 and 24.9%). Levels of
unchanged 1,2-dichloroethane in blood were significantly (p < 0.05)
increased in rats exposed to 1,2-dichloroethane and disulfiram
compared to those exposed to 1,2-dichloroethane alone (see section
7.10) (Cheever et al., 1990).
The pattern of elimination of metabolites was similar in rats and
mice 48 h after administration of oral doses of radiolabelled
1,2-dichloroethane (100 and 150 mg/kg body weight, respectively). In
rats, 8.2 and 69.51% of the radiolabelled dose was recovered as CO2
and in the excreta (principally urine), respectively, compared to
18.21 and 81.11% in mice. The overall recovery was less in rats than
in mice (96.26 versus 110.12%) (Mitoma et al., 1985).
In rats exposed to 600 mg/m3 (150 ppm) 1,2-dichloroethane for
6 h or administered 150 mg/kg body weight by gavage, there was no
significant difference in the route of excretion of non-volatile
metabolites. After 48 h, in each case, more than 84% of total
metabolites was eliminated in the urine, 7-8% was excreted as carbon
dioxide in expired air, 2% was excreted unchanged in the faeces, and
4% remained in the carcass (Reitz et al., 1982). The major urinary
metabolites identified following exposure of rats by either route were
thiodiacetic acid (70%) and thiodiacetic acid sulfoxide (26 to 28%).
The rate of elimination following oral (gavage) administration or
inhalation was such that 1,2-dichloroethane was not detected in the
blood a few hours after exposure and only small amounts were detected
in tissues (liver, kidney, lung, spleen, forestomach, stomach and
carcass) 48 h after exposure (Reitz et al., 1982). The rate of
elimination from blood and tissues appeared to depend on the exposure
level; the higher the exposure level, the lower the elimination rate
of 1,2-dichloroethane, after both oral and inhalation exposure.
Elimination from the liver was reported to be biphasic, a higher
elimination rate occurring just after the peak levels of
1,2-dichloroethane were reached. Elimination from other organs was
monophasic. Following inhalation up to an exposure level of
1012 mg/m3, elimination was slowest in adipose tissue and most rapid
in the lung (Spreafico et al., 1980).
Withey & Collins (1980) also reported that the elimination of
1,2-dichloroethane was dose-dependent. After intravenous
administration of from 3 to 15 mg/kg body weight to male Wistar rats,
the authors found that the elimination fitted a twocompartment model
at a low dose level and a three-compartment model at high dose levels.
The percentage of administered radioactivity excreted in the
urine over a 24-h period in rats decreased with increasing single
doses (0.25 to 8.08 mmol 1,2-dichloroethane/kg body weight)
administered by gavage in mineral oil (Payan et al., 1993). The
authors attributed these results to saturation of metabolism rather
than kidney damage, as there were no variations in biochemical
parameters of nephrotoxicity between the controls and groups exposed
to doses up to 4.04 mmol/kg body weight. Urinary thiodiglycolic acid
increased as a linear function of the dose of 1,2-dichloroethane until
at least 1.01 mmol/kg body weight; it accounted for 63% of the total
metabolites in urine at this dose.
6.5 Retention and bioaccumulation
Although 1,2-dichloroethane is eliminated more slowly from
adipose tissue than from blood or other tissues (lung and liver)
following exposure, it is unlikely to bioaccumulate significantly, as
no difference was observed between levels in blood or tissues (data
not presented) following single or repeated (10 days) oral doses of
50 mg/kg body weight in rats (Spreafico et al., 1980). Only 71 and
75%, respectively, of an administered oral dose of radiolabelled
1,2-dichloroethane was recovered in the excreta and exhaled breath of
rats administered 150 mg/kg body weight by gavage following 2 years of
exposure via inhalation (200 mg/m3 or 50 ppm); the authors
speculated that the remainder may have been sequestered in the body
fat. Recovery in the excreta and exhaled breath was complete in
younger rats (4 months old) receiving the same oral dose (Cheever et
al., 1990).
7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS
7.1 Single exposure
Data on the acute toxicity of 1,2-dichloroethane in experimental
animals are summarized in Table 3. These data indicate that
1,2-dichloroethane is of relatively low acute toxicity.
LC50 values in rats exposed to 1,2-dichloroethane for 6 or
7.25 h ranged from 4000 mg/m3 (1000 ppm) (Spencer et al., 1951) to
6600 mg/m3 (1650 ppm) (Bonnet et al., 1980). The 6-h LC50 in mice
was 1050 mg/m3 (Gradiski et al., 1978). LC50 values decreased
with increasing duration of exposure in rats exposed to concentrations
ranging from 1200 to 80 000 mg/m3 (300 to 20 000 ppm)
1,2-dichloroethane for 1 to 8 h (Spencer et al., 1951). Various
non-lethal effects have been reported in animals following acute
exposure to 1,2-dichloroethane, including central nervous system
depression, cardiovascular collapse, altered behaviour, pulmonary
congestion and oedema, histological damage in the liver, kidneys and
adrenal glands and myocardial failure, at concentrations ranging from
4000 mg/m3 for 1.5 or 4 h to 80 000 mg/m3 (20 000 ppm) for 30 min
(Heppel et al., 1945; Spencer et al., 1951; Alumot et al., 1976a;
Wolff et al., 1979; ATSDR, 1989). Central nervous system depression
occurred at much higher concentrations than those which induce effects
in other organs.
Oral LD50 values for rats, mice, dogs and rabbits ranged from
413 mg/kg body weight in female mice to 2500 mg/kg body weight in dogs
(Barsoum & Saad, 1934; McCollister et al., 1956; Smyth, 1969; Larionov
& Kokarovtseva, 1976; Munson et al., 1982; NIOSH, 1994). Non-lethal
effects observed in rats and rabbits following single oral doses of
1,2-dichloroethane ranging from 615 to 1476 mg/kg body weight include
hepatic effects (fatty degeneration, cloudy swelling, congestion,
haemorrhagic lesions, dystrophy in the cytoplasm and hyperchromatosis
in the nuclei of hepatocytes), degeneration of the renal tubular
epithelium, altered levels of enzymes in the serum and liver, oedema
and haemorrhaging in the walls of the coronary vessels, stasis and
thrombi in the myocardium, altered fibrinolytic activity in the blood,
and altered haematological parameters. A single dose of 0.5 ml
altered the ratio of the oxidized and reduced forms of nicotinamide
coenzymes in the liver and myocardium of rats (Natsyuk & Chekman,
1975). Electrocardiographic changes were reported at doses of 1, 1.5
and 2 mg/kg body weight, although these effects have not been
confirmed in other studies (Saitanov & Arsenieva, 1969).
The LD50 for dermal exposure in rabbits was estimated to be
between 2.8 and 4.9 g/kg (Torkelson & Rowe, 1981; NIOSH,
1994).
Table 3. Acute toxicity of 1,2-dichloroethane in experimental animals
Species Numbers/sex Duration/vehicle LC50 or LD50 Reference
Inhalation
Rats (Wistar equal no. of m & f) 10-54 0.53 h 48 000 mg/m3 (12 000 ppm) Spencer et al. (1951)
20-51 2.75 h 12 000 mg/m3 (3000 ppm)
31-32 7.20 h 4000 mg/m3 (1000 ppm)
Rats (albino, strain, number and sex not not specified 30 000 mg/m3 Nevrotsky et al. (1971)
specified)
Rats (Sprague-Dawley, 12 per group, sex not 6 h 6600 mg/m3 (1646 ppm) Bonnet et al. (1980)
specified)
Mice (OF1, 20 f per group) 6 h 1050 mg/m3 (262 ppm) Gradiski et al. (1978)
Ingestion
Rats (strain, number and sex not specified) not specified 850 mg/kg body weight Larionov &
Kokarovtseva (1976)
Rats (6 per group, strain and sex not not specified 770 mg/kg body weight Smyth (1969)
specified)
Rats (young adult albino, 80 m & f) corn oil 680 mg/kg body weight McCollister et al. (1956)
Mice, 6-week old (CD-1, number not male water 489 mg/kg body weight Munson et al. (1982)
specified) female 413 mg/kg body weight
Table 3. (cont'd).
Species Numbers/sex Duration/vehicle LC50 or LD50 Reference
Dogs (strain, number and sex not specified) acacia gum 2500 mg/kg body weight Barsoum & Saad (1934)
Rabbits (strain, number and sex not not specified 860 mg/kg body weight NIOSH (1994)
specified)
Dermal
Rabbits (strain, number and sex not not specified 2800 mg/kg body weight NIOSH (1994)
specified)
Rabbits (strain, number and sex not olive oil; duration 2800-4900 mg/kg body weight Torkelson & Rowe
specified) and area of skin (1981)
exposed not
specified
7.2 Skin and eye irritation
When 1.0 ml undiluted 1,2-dichloroethane was applied directly to
the clipped skin of guinea-pigs for up to 12 h in occluded patch
tests, no gross skin reactions were visible (Jakobson et al., 1982).
Microscopic changes appeared 4 h after application, comprising
karyopyknosis, perinuclear oedema, spongiosis and junctional
separation (Kronevi et al., 1981). In Draize tests on rabbits,
moderate erythema and oedema were observed 24 h after
application (dose not specified). Microscopy on the third day
revealed necrosis and other lesions such as ulcerations and
acanthosis. The severity of the changes was not indicated (Duprat et
al., 1976).
Instillation of 0.1 ml undiluted 1,2-dichloroethane into the
conjunctival sac of the eye of rabbits generated reversible, mild
irritation characterized by conjunctivitis and epithelial abrasion.
Epithelial keratitis, described as being "in a state of repair", was
observed microscopically 7 days after application (Duprat et al.,
1976). Reversible clouding of the cornea was observed in dogs within
10 h of subcutaneous administration of undiluted 1,2-dichloroethane at
0.9 mg/kg body weight. The clouding continued up to 48 h, but the
corneas appeared clear after 5 days. Histological changes, including
necrosis of the corneal endothelium, partially denuded Descemet's
membrane, formation of excess basement membrane, and swelling of the
corneal stroma, were also observed in dogs, cats and rabbits after
ocular injection of 1.8 mg 1,2-dichloroethane (0.15 ml of a 1%
solution) into the anterior chamber (Kuwabara et al., 1968).
7.3 Short-term exposure
Small groups of Wistar rats, rabbits, guinea-pigs, dogs and pigs
(n = 1 to 21) were exposed to 6000 mg/m3 (1500 ppm)
1,2-dichloroethane, 7 h/day for 6 days. Sections of the liver, heart,
lungs, kidney adrenal glands and spleen were examined microscopically.
In most animals, degeneration or necrosis of the kidney and liver,
along with congestion and haemorrhage of the lungs and adrenal glands,
were observed (Heppel et al., 1945).
No significant changes in organ or body weights, histology or
clinical chemistry and haematological parameters were observed in rats
administered 1,2-dichloroethane doses of up to 150 mg/kg body weight
per day in corn oil by gavage, 5 times/week for 2 weeks (van Esch et
al., 1977; Reitz et al., 1982).
7.4 Subchronic exposure
7.4.1 Inhalation
The subchronic toxicity of inhaled 1,2-dichloroethane was
investigated in three early limited studies in multiple species, as
presented in Table 4. Heppel et al. (1946) exposed groups of rats,
mice, rabbits, guinea-pigs, dogs, cats and monkeys to 4000 mg/m3
(1000 ppm) for up to 66 days. Mice, rats, rabbits and guinea-pigs
were the most sensitive species, based on mortality after only one or
a few exposures. Various effects were noted in these animals,
including pulmonary congestion (guinea-pigs, cats and rats), fatty
changes in the kidney (rats and monkeys), fatty changes in the
livera (cats, dogs and monkeys) and clouded corneas (dogs). At
1600 mg/m3 (400 ppm), observed effects included fatty degeneration
of the liver, kidney or heart (guinea-pigs and one rat), fatty changes
in the liver (dogs) and pulmonary congestion (rats), while at
800 mg/m3 (200 ppm), rats and guinea-pigs had mild pulmonary
congestion and one rat had fatty degeneration in the kidneys. No
effects on growth were noted in mice and rats exposed to 400 mg/m3
(100 ppm).
In a similar study, rats, guinea-pigs, rabbits and monkeys were
exposed to 400, 800 or 1600 mg/m3 (100, 200 or 400 ppm)
1,2-dichloroethane for 6 to 9 months (Spencer et al., 1951). Severe
effects, including hepatotoxicity, and deaths were observed in rats
and guinea-pigs exposed at the highest level, while monkeys also
showed degeneration of the liver and kidneys at this concentration.
No effects were noted in rabbits. At 800 mg/m3 (200 ppm) no adverse
effects were observed in rats, but slight degeneration of the liver
was noted in guinea-pigs. At 400 mg/m3 (100 ppm), no adverse
effects were observed in any of the four species. The authors
considered the "maximum concentrations without adverse effects" to be
1600 mg/m3 (400 ppm) in the rabbit, 800 mg/m3 (200 ppm) in the
rat, and 400 mg/m3 (100 ppm) in the monkey and guinea-pig, based on
a limited range of end-points.
a It has been suggested, on the basis of in vitro investigations,
that fatty accumulation in the liver may be due to the ability of
1,2-dichloroethane to block the secretion of hepatocellular
(Cotalasso et al., 1994).
Table 4. Subchronic toxicity of 1,2-dichloroethane in experimental animals
Species Protocol Results Reference
Inhalation
Rats (26, strain and animals were exposed to 0 or There was high mortality in exposed rats (20/26), rabbits (5/6) and Heppel
sex not specified) 4000 mg/m3 (0 or 1000 ppm), guinea-pigs (36/41) after a few exposures. All mice died after one et al.
Mice (22, strain and 7 h/day, 5 days/week for up exposure. Survival was higher among cats and dogs (4/6 of either (1946)
sex not specified) to 66 exposures; sections of species survived more than 23 exposures). One monkey died after 2
Rabbits (5 m & 1 f, liver, heart, lungs, kidney, days and the other after 32 exposures. Pulmonary congestion was
strain not specified) adrenal glands and spleen noted in guinea-pigs, cats and rats. Rats and monkeys had fatty
Guinea-pigs (10-16, strain were examined changes in the kidney. Cats and monkeys had fatty changes in the
and sex not specified) microscopically; haematological liver. Dogs had cloudy corneas; one dog had fatty degeneration of
Dogs (3 f, strain not and urinary parameters were the liver. No effects on haematological or urinary parameters were
specified) assessed in dogs observed in dogs. Rabbits had no obvious effects on postmortem.
Cats (6 f, strain not
specified)
Monkeys (Rhesus, 2,
sex not specified)
Rats (15 m & 1 f, animals were exposed to 0 or All dogs and puppies survived 177 exposures. All rabbits died, after Heppel
strain not specified) 1600 mg/m3 (0 or 400 ppm), 1 to 97 exposures; 14/20 and 9/16 guinea-pigs and rats died by the et al.
Rabbits (2 m & 3 f, 7 h/day, 5 days/week for up to 60th exposure. Rats had pulmonary congestion and 1 rat and 6 (1946)
strain not specified) 177 exposures; sections of guinea-pigs had fatty degeneration of the liver, kidney and heart.
Guinea-pigs (8-10 m & liver, heart, lungs, kidney, Dogs had slight fatty changes in the liver. No effects were noted in
2 f, strain not specified) adrenal glands and spleen were rabbits on postmortem. There were no significant differences in
Dogs (6 f, strain not examined microscopically; haematological parameters in exposed dogs and rabbits compared
specified) and puppies haematological parameters to controls.
(3 m, strain not were also assessed in dogs
specified) and rabbits
Table 4. (cont'd).
Species Protocol Results Reference