Chloroalkyl ethers, selected (EHC 201, 1998)

UNITED NATIONS ENVIRONMENT PROGRAMME
INTERNATIONAL LABOUR ORGANISATION
WORLD HEALTH ORGANIZATION

INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

ENVIRONMENTAL HEALTH CRITERIA 201

SELECTED CHLOROALKYL ETHERS

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 Dr. R. Liteplo and Ms R. Gomes, Health Canada,
Canada

Published under the joint sponsorship of the United Nations
Environment Programme, the International Labour Organisation, and the
World Health Organization, and produced within the framework of the
Inter-Organization Programme for the Sound Management of Chemicals.

World Health Organization
Geneva, 1998

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WHO Library Cataloguing in Publication Data

Selected chloroalkyl ethers.

(Environmental health criteria ; 201)

1. Bis(Chloromethyl) ether - toxicity
2. Bis(Chloromethyl) ether - adverse effects
3. Environmental exposure 4. Occupational exposure
I. International Programme on Chemical Safety II.Series

ISBN 92 4 157201 9 (NLM Classification: QZ 202)
ISSN 0250-863X

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CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR SELECTED CHLOROALKYL ETHERS

PREAMBLE

ABBREVIATIONS

1. SUMMARY AND CONCLUSIONS

1.1. Identity, physical and chemical properties, analytical
methods
1.2. Sources of human exposure
1.3. Environmental transport, distribution and transformation
1.4. Environmental levels and human exposure
1.5. Kinetics and metabolism
1.6. Effects on laboratory animals and in vitro test systems
1.7. Effects on humans
1.8. Effects on other organisms in the laboratory and field
1.9. Conclusions
1.9.1. BCEE
1.9.2. BCME and CMME

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
2.4.1. BCEE
2.4.2. BCME
2.4.3. CMME

3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

3.1. Natural occurrence
3.2. Anthropogenic sources
3.2.1. Production
3.2.1.1 BCEE
3.2.1.2 BCME
3.2.1.3 CMME
3.2.2. Uses
3.2.2.1 BCEE
3.2.2.2 BCME
3.2.2.3 CMME
3.2.3. Sources in the environment
3.2.3.1 BCEE
3.2.3.2 BCME and CMME

4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

4.1. Transport and distribution between media
4.1.1. BCEE
4.1.2. BCME and CMME
4.2. Abiotic degradation
4.2.1. BCEE
4.2.2. BCME and CMME
4.3. Biodegradation, biotransformation and bioaccumulation
4.3.1. BCEE
4.3.2. BCME and CMME
4.4. Ultimate fate following use

5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

5.1. Environmental levels
5.1.1. BCEE
5.1.2. BCME and CMME
5.2. General population exposure
5.3. Occupational exposure
5.3.1. BCEE
5.3.2. BCME and CMME

6. KINETICS AND METABOLISM IN LABORATORY ANIMALS

6.1. Absorption and distribution
6.2. Metabolism
6.3. Elimination

7. EFFECTS ON EXPERIMENTAL MAMMALS AND IN VITRO TEST SYSTEMS

7.1. Single exposure
7.1.1. BCEE
7.1.2. BCME and CMME
7.2. Short-term exposure
7.2.1. BCEE
7.2.2. BCME
7.2.3. CMME
7.3. Long-term exposure/carcinogenicity
7.3.1. BCEE
7.3.2. BCME
7.3.3. CMME
7.4. Mutagenicity and related end-points
7.4.1. BCEE
7.4.2. BCME
7.4.3. CMME
7.5. Other toxicity studies

8. EFFECTS ON HUMANS

8.1. General population exposure
8.1.1. Human exposure studies
8.2. Occupational exposure
8.2.1. Case reports
8.2.2. Epidemiological studies

9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT

10.1. Evaluation of human health risks
10.1.1. BCEE
10.1.2. BCME and CMME
10.1.3. Guidance values
10.2. Evaluation of effects on the environment
10.2.1. BCEE
10.2.2. BCME and CMME

11. RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH AND THE
ENVIRONMENT

12. FURTHER RESEARCH

13. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

REFERENCES

RÉSUMÉ ET CONCLUSIONS

RESUMEN Y CONCLUSIONES

NOTE TO READERS OF THE CRITERIA MONOGRAPHS

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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.

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WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR SELECTED
CHLOROALKYL ETHERS

Members

Dr D. Anderson, BIBRA Toxicology International, Carshalton,
Surrey, United Kingdom

Dr R. Chhabra, Division of Intramural Research, Environmental

Toxicology Program, Toxicology Branch, National Institute of
Environmental Health Sciences, Research Triangle Park, North
Carolina, USA (Chairman)

Dr H. Ellis^a, Epidemiology Department, Rohm & Haas, Bristol,
Pennsylvania, USA

Dr B. Gilbert, FarManguinhos, FIOCRUZ, Institute of
Pharmaceutical Technology, Ministry of Health, Rio de Janeiro,
Brazil

Professor M. Jakubowski, Occupational and Environmental
Hygiene Division, Nofer Institute of Occupational Medicine, Lodz,
Poland

Dr S.K. Kashyap, National Institute of Occupational Health,
Meghani Nagar, Ahmedabad, India (Vice-chairman)

Dr R. Liteplo, Environmental Health Directorate, Health Protection
Branch, Environmental Health Centre, Ottawa, Ontario, Canada
(Co-rapporteur)

Dr E.E. McConnell, Laurdane Estates, Raleigh, North Carolina,
USA

Dr H. Naito, Ibaraki Prefecture University of Health Sciences,
Amimachi, Inashikigun, Japan

Dr W. Popp, Universitätsklinikum Essen, Institut für Hygiene und
Arbeitsmedizin, Essen, Germany

Dr R. Sram, Laboratory of Genetic Ecotoxicology, c/o Institute of
Experimental Medicine, Prague, Czech Republic

^a Invited, but unable to attend.

Dr Shou-Zheng Xue, Toxicology Programme, Shanghai Medical
University, Shanghai, China

Secretariat

Dr G.C. Becking, IPCS/IRRU, World Health Organization,
Research Triangle Park, North Carolina, USA

Ms R. Gomes, Health Canada, Environmental Health Directorate,
Tunney's Pasture, Ottawa, Ontario, Canada (Co-rapporteur)

IPCS TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR SELECTED
CHLOROALKYL ETHERS

A WHO Task Group on Environmental Health Criteria for Selected
Chloroalkyl Ethers met at the British Industrial Biological Research
Association (BIBRA) Toxicology International, Carshalton, Surrey,
United Kingdom, from 18 to 23 March 1996. Dr D. Anderson opened the
meeting and welcomed the participants on behalf of the host institute.
Dr G.C. Becking, IPCS, welcomed the participants on behalf of Dr M.
Mercier, Director of the IPCS and the three cooperating organizations
(UNEP/ILO/WHO). The Task Group reviewed and revised the draft
criteria monograph and made an evaluation of the risks to human health
and the environment from exposure to selected chloroalkyl ethers.

Financial support for this Task Group was provided by the United
Kingdom Department of Health as part of its contribution to the IPCS.

The first and second drafts of this monograph were prepared by Dr
R. Liteplo and Ms R. Gomes, Health Canada, Ottawa. The second draft
incorporated the comments received following circulation of the first
draft to the IPCS contact points for environmental health criteria
monographs.

Dr G.C. Becking (IPCS Central Unit, Interregional Research Unit)
and Dr P.G. Jenkins (IPCS Central Unit, Geneva) were responsible for
the overall scientific content and technical editing, respectively.

The efforts of all who helped in the preparation of the document
are gratefully acknowledged.

ABBREVIATIONS

BCEE bis(2-chloroethyl) ether

BCME bis(chloromethyl) ether

CMME chloromethyl methyl ether

MTD maximum tolerated dose

PMA phorbol myristate acetate

TDGA thiodiglycolic acid

1. SUMMARY AND CONCLUSIONS

1.1 Identity, physical and chemical properties, analytical methods

Bis(2-chloroethyl) ether (BCEE), bis(chloromethyl) ether (BCME)
and chloromethyl methyl ether (CMME) are chemicals from a large class
known as chloroalkyl ethers. The three ethers are colourless volatile
liquids at room temperature having characteristic odours. The vapour
pressure of these three compounds is high. The solubility of BCEE is
1.7% in water and its octanol/water partition coefficient is 1.46. The
alpha-chloroalkyl ethers BCME and CMME are reactive compounds,
hydrolysing rapidly in aqueous media (with half-lives of approximately
38 seconds and <0.007 seconds, respectively); hydrolysis of the more
stable ß-chloroether BCEE is slower (with a half-life in water of
about 20 years).

Sampling and analytical methods have been described for BCEE in
water and for BCME and CMME in air. Typically, determination is by
gas chromatography (GC-electron capture) or GC mass spectrometry.

1.2 Sources of human exposure

Natural sources of BCEE, BCME or CMME in the environment have not
been identified. The recent production data available are limited and
confined to the USA and Canada. Approximately 10⁴ tonnes of BCEE were
produced in the USA in 1986 for use as a solvent and in the production
of polymers and several industrial processes. Industrial uses of BCME
are currently restricted in the USA to specific intermediate chemical
reactions. BCME has also been produced for use in the production of
ion exchange resins, manufacture of other polymers, and as a solvent
in polymerization reactions. In China, some 200 tonnes of BCME are
produced annually as an intermediate in the manufacture of the
insecticide synergist, octachlorodipropyl ether. Technical grade CMME
contains from 1 to 8% BCME.

1.3 Environmental transport, distribution and transformation

The mobility and distribution of the selected chloroalkyl ethers
is influenced by the high reactivity of BCME and CMME and the water
solubility and stability of BCEE. The alpha-chloroalkyl ethers BCME
and CMME are hydrolysed rapidly in aqueous media and degraded quickly
by photolysis. In aqueous media, the hydrolytic products of BCME and
CMME are formaldehyde and hydrochloric acid, and methanol,
formaldehyde and hydrochloric acid, respectively. The decomposition
products of BCME and CMME in air include hydrogen chloride,
formaldehyde and chloromethylformate, and chloromethyl and methyl
formate, respectively. BCEE is soluble in water; rainfall removes it
from the atmosphere and it tends to remain in water with very slow
hydrolysis. BCEE evaporates from surface water within a week and is
degraded in a little more than a day in the atmosphere by abiotic
processes.

Owing to the highly reactive nature of the alpha-chloroalkyl
ethers in water and air, CMME and BCME are not expected to be present
in the environment; however BCEE may be persistent due to the relative
stability of ß-chloroalkyl ethers.

1.4 Environmental levels and human exposure

Only limited data on levels of BCEE in environmental media are
available. It has been identified in air but not quantified; levels up
to 0.42 µg/litre have been found in drinking-water in the USA.
Reported levels of BCEE in groundwater have ranged from 0.001 µg/litre
at an industrial gypsum waste disposal site in Belgium to 840 µg/litre
near a waste disposal site in the USA. Higher concentrations have been
measured in landfill leachates. Information on levels of BCEE in
foodstuffs is not available, but bioaccumulation is not expected to
occur.

Quantitative data on levels of BCME or CMME in environmental
media are not available.

Based on the maximum reported level of BCEE in drinking-water,
i.e., 0.42 µg/litre, the average human (64 kg) consuming 1.4
litres/day would have an intake of about 0.01 µg/kg body weight per
day from this source, with unknown amounts from other environmental
sources. No estimates can be made on the daily intake of BCME and CMME
from environmental sources. However, based upon the lack of
persistence of BCME and CMME in the environment, average human
exposure to these compounds is likely to be very low.

Based on limited older data, workers in industries related to
plastics and textile production could have been exposed to between 1.2
and 72.9 µg BCME/m³ in workroom air. However, a recent study of a
resin-manufacturing plant reported average occupational exposures
ranging from 2.4 to 20.6 µg/m³. Data from other studies reported
levels of BCME as low as 0.01 µg/m³. Higher occupational exposure to
BCME occurred in China up until 1975 and still occurs on a lower level
in the manufacture of octachlorodipropyl ether. General population
exposure to BCME and CMME occurs where they are produced by the
widespread burning of this synergist in mosquito coils.

The highest reported concentrations of BCEE in the USA for
industrial effluents are 8 to 170 µg/litre and for municipal and
industrial waste landfill leachates 12 400 µg/litre.

1.5 Kinetics and metabolism

Quantitative information on the kinetics and metabolism of BCEE,
BCME and CMME in humans is not available. However, it is anticipated
that although in vivo BCME and CMME would be rapidly hydrolysed in
tissues to formaldehyde and hydrogen chloride, and methanol,
formaldehyde and hydrogen chloride, respectively, there should be
alkylation activity.

Limited data show that radioactive BCEE administered to rats by
inhalation or gavage is rapidly absorbed. Less than 3% of the
radioactivity was retained 48 h after gavage dosing.

BCEE is readily metabolized in rats. The principal metabolite is
thiodiglycolic acid (TDGA). After rats were given a single gavage dose
of [¹⁴C]-BCEE, approximately 12% of the administered radioactivity
was present as ¹⁴CO₂.

BCEE is eliminated quickly in both rats and rhesus monkeys. Less
than 2% of the radioactivity was recovered in the faeces of monkeys 72
h after oral administration of [¹⁴C]-BCEE; approximately 2.3% of the
administered radioactivity was found in rat tissues or faeces 48 h
after dosing. Over 50% of the radioactivity was recovered in the urine
and exhaled air 12 h after a gavage dose of [¹⁴C]-BCEE was
administered to rats. Less than 2% of the radioactivity expired
through the lungs was exhaled as the parent compound.

1.6 Effects on laboratory animals and in vitro test systems

BCEE is acutely toxic by the oral, inhalation or dermal routes of
exposure. Reported LD₅₀ values for the oral exposure of animal
species to BCEE range from 75 to 215 mg/kg body weight. BCME and CMME
are acutely toxic by inhalation or ingestion. Reported LC₅₀ values
for the inhalation exposure of laboratory animals to BCME or CMME
range from 25 to 48 mg/m³, and from 182 to 215 mg/m³, respectively.

Exposure of laboratory animals by inhalation to high single
concentrations of BCEE (>320 mg/m³) resulted in eye irritation as
well as congestion, oedema, and haemorrhage in the lungs. During
inhalation of BCME, irritation of the eyes and respiratory tract were
noted as well as necrotizing bronchitis. Skin application resulted in
erythema and necrosis, and application to the eye resulted in corneal
necrosis. Similar effects were noted after exposure to CMME.

Increased mortality and tracheal hyperplasia were observed in
rats and hamsters following multiple inhalation exposure to 4.7 mg
BCME/m³. Similar results were observed in rats repeatedly exposed by
inhalation to 3.3 or 33 mg CMME/m³.

In general, positive results were obtained when BCEE, BCME and
CMME were tested for mutagenicity in vitro. However, interpretation
of the results is difficult given the lack of details in the reports
available. BCME and CMME have been reported to increase unscheduled
DNA synthesis in vitro, and BCME increased the level of transformed
cells in in vitro assays.

In small groups of males from two strains of hybrid F₁ mice (and
in females from one F₁ strain) treated orally with BCEE
(time-weighted dose 41.3 mg/kg body weight over 18 months), there was
a significant increase in the incidence of hepatomas (combined benign
hepatomas and malignant tumours) compared to unexposed controls. Four

other limited studies in rats and mice using oral gavage, subcutaneous
or intraperitoneal injection and skin painting failed to confirm these
findings.

Carcinogenicity studies in experimental animals (mice and rats)
exposed to BCME showed significantly elevated incidence of pulmonary
adenomas and respiratory tumours. In mice, inhalation exposure also
showed evidence of an elevated incidence of lung tumours.

Studies with CMME have shown an increased incidence of tracheal
metaplasia and bronchial hyperplasia in a dose-dependent manner in
rats. However, results of carcinogenicity bioassays are inconclusive
in animal studies.

Information regarding the reproductive, developmental,
immunological or neurological toxicity of BCEE, BCME or CMME is not
available.

1.7 Effects on humans

BCEE was found to be irritating to the eyes and nasal passages of
humans at levels >150 mg/m³ following short-term exposure.

No epidemiological studies on the effects of long-term exposure
to BCEE have been reported.

In eight epidemiological studies, exposure of workers to BCME
(CMME) was associated with increased risk of lung cancer. Workers
exposed to commercial grade CMME were probably also exposed to BCME.
The predominant tumours in exposed workers were small cell carcinomas,
quite distinct from the chiefly squamous cell carcinomas usually found
in smokers. The association between exposure to BCME (CMME) and lung
cancer was strong, with standardized mortality ratios ranging up to
21. The type of lung cancer, latency period and average age of
appearance of lung tumours in workers exposed to BCME (CMME) have been
remarkably consistent. For CMME, there is also evidence of a positive
relationship between a qualitative measure of exposure and mortality
due to lung cancer.

Even concentrations of 0.01 µg BCME/m³ and 20 µg CMME/m³, in
the course of occupational exposure, increased the frequency of
chromosomal aberrations in the peripheral lymphocytes of exposed
workers.

Information has not been reported regarding the neurological,
immunological, developmental or reproductive effects of BCME or CMME
in humans.

1.8 Effects on other organisms in the laboratory and field

There have been few studies on the effects of BCEE on
environmental organisms; most are restricted to aquatic species. For
BCEE a 7-day LC₅₀ concentration in the guppy of 56.9 mg/litre, a 96-h
LC₅₀ in fish of 600 mg/litre and a 48-h LC₅₀ in Daphnia magna of
240 mg/litre have been reported.

Anaerobic microbial activity was not inhibited at concentrations
of BCEE up to 100 mg/litre and an LC₁₀ of 600 µg/litre has been
reported for microbes indigenous to waste stabilization ponds.

No information on the toxicological effects of BCME and CMME on
environmental organisms has been reported.

1.9 Conclusions

1.9.1 BCEE

- Exposure of terrestrial organisms to BCEE is considered to be
negligible because of the low rate of release and its short
persistence in the atmosphere.

- Although it is more persistent in water, the highest reported
concentration of BCEE in surface water is approximately five
orders of magnitude lower than the concentration found to induce
adverse effects in the guppy, the most sensitive aquatic species
identified among existing toxicity studies.

- Owing to the lack of available information on concentrations of
BCEE in several environmental media to which humans are exposed,
it is not possible to estimate quantitatively the total daily
intake of BCEE.

- Available data on the toxicity of BCEE in humans are limited.
Information on the developmental and reproductive effects of BCEE
in laboratory animals has not been identified, and none of the
long-term studies in laboratory animals is of sufficient quality
to provide quantitative information on either the potential of
BCEE to cause cancer or the toxicological effects produced by
long-term exposure to this substance.

- In the absence of adequate toxicological and carcinogenicity
data, it is prudent to minimize human exposure to BCEE.

1.9.2 BCME and CMME

- If these substances were to enter the environment, they would
both be rapidly broken down by hydrolysis and photo-oxidation.
Data concerning concentrations of BCME and CMME in the ambient
environment have not been reported.

- BCME and technical grade CMME (which contains BCME) are proven
human carcinogens. In addition, both of these chemicals are
carcinogens in laboratory animals. Both chemicals cause
chromosomal aberrations in occupationally exposed workers.
Occupational and general population exposure to these compounds
should be eliminated.

- Based on the fate of these substances in the environment and the
lack of exposure, there is no reason to suspect that adverse
effects on aquatic and terrestrial organisms would occur.

2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL
METHODS

2.1 Identity

Bis(2-chloroethyl) ether (BCEE), bis(chloromethyl) ether (BCME)
and chloromethyl methyl ether (CMME) are included in a large class of
chemical substances known as the chloroalkyl ethers. Identifying
features of BCEE, BCME and CMME are summarized in Table 1.

2.2 Physical and chemical properties

BCEE, a ß-chloroalkyl ether, is a colourless, volatile liquid
with a "chlorinated solvent-like" odour (Sittig, 1981). BCME and CMME,
both alpha-chloroalkyl ethers, are also colourless, volatile liquids
with characteristic odours. The odour of BCME has been described as
"suffocating" (Sittig, 1981; Verschueren, 1983), while that of CMME
has been described as "irritating" (Verschueren, 1983). Technical
grade CMME contains from 1 to 8% BCME (Travenius, 1982) and, unless
otherwise indicated in this monograph, CMME refers to the technical
grade material. In general, the vapour pressure and water solubility
of these compounds are high, and the log octanol/water partition
coefficients (log K_ow) are low. The ß-chloroalkylethers like BCEE are
only slightly reactive towards water, but the alpha-chloroalkyl ethers
like BCME and CMME are rapidly hydrolysed by water, and their
solubility, K_ow, K_oc and Henry's Law constant cannot be
experimentally determined. The physical and chemical properties of the
selected chloroalkyl ethers are presented in Table 2.

2.3 Conversion factors

At 25°C and 101.3 kPa, the conversion factors for BCEE, BCME and
CMME in air are as follows:

BCEE: 1 ppm (v/v) = 5.85 mg/m³; 1 mg/m³ = 0.17 ppm
BCME: 1 ppm (v/v) = 4.7 mg/m³; 1 mg/m³ = 0.21 ppm
CMME: 1 ppm (v/v) = 3.3 mg/m³; 1 mg/m³ = 0.30 ppm

2.4 Analytical methods

2.4.1 BCEE

One method for the analysis of BCEE in water involves solvent
extraction (using diethyl ether in pentane, methylene chloride, or
ethyl ether in hexane), concentration with a Kuderna-Danish (K-D)
apparatus, and separation and analysis by gas chromatography with
electron capture detection (GC/EC) or gas chromatography mass
spectrometry (GC/MS) (Dressman et al., 1977; Quaghebeur et al., 1986).
This method has been expanded to include clean-up with Florisil and
K-D concentration of the sorbed fraction prior to analysis by GC/EC
(McMillin et al., 1984). Vapour stripping using helium or nitrogen gas
has also been used to extract BCEE from samples of ground and surface

Table 1. Information on the identity of BCEE, BCME and CMME (US NLM, 1996)

Compound Identification Molecular Chemical structure Relative Synonyms
(CAS number)^a formula molecular mass

Bis(2-chloroethyl) ether BCEE C₄H₈Cl₂O Cl-(CH₂)2-O-(CH₂)₂-Cl 143.02 dichloroethyl ether,
(111-44-4) dichloroethyl oxide,
bis (ß-chloroethyl) ether,
dichloroether,
1,1'-oxybis(2-chloro)ethane,
1,5-dichloro-3-oxapentane,
1-chloro-2-(ß-chloroethoxy)-
ethane,
2,2'-dichloroethyl ether,
ß,ß'-dichlorodiethyl ether,
bis(chloro-2-ethyl) oxide,
di(ß-chloroethyl) ether,
di(2-chloroethyl) ether,
ether, bis(2-chloroethyl),
sym-dichloroethyl ether,
diethylene glycol dichloride.

Bis(chloromethyl) ether BCME C₂H₄Cl₂O Cl-CH₂-O-CH₂-Cl 114.97 chloro(chloromethoxy) methane,
(542-88-1) sym-dichloro-dimethyl ether,
oxybis(chloromethane),
dichloromethyl ether,
bichloromethyl ether,
dichlorodimethyl ether,
1,1'-dichlorodimethyl ether.

Table 1. (continued)

Compound Identification Molecular Chemical structure Relative Synonyms
(CAS number)^a formula molecular mass

Chloromethyl methyl ether CMME C₂H₅ClO Cl-CH₂-O-CH₃ 80.52 chloromethoxymethane,
(107-30-2) monochlorodimethyl ether,
methoxymethyl chloride,
chlorodimethyl ether,
methyl chloromethyl ether,
monochloromethyl methyl ether.

^a Chemical Abstracts Services registry number.

Table 2. Physical and chemical properties of BCEE, BCME and CMME

Physical/chemical property BCEE BCME CMME

Melting point (°C) -50^a -41.5^a -103.5^b
Boiling point (°C) 178.67^a 104^a 59.5^b
Vapour pressure (mmHg) 0.71 at 20°C^b 30 at 22°C^c 122 at 20°C^d
Vapour density 4.93^b 3.97^b 2.8^d
Water solubility (mg/litre) 10 200^b NA NA
Log octanol/water partition
coefficient (log K_ow) 1.46^c NA NA
Henry's Law constant
(atm.m³/mol) 1.31 x 10^-5c NA NA
Soil sorption coefficient
(log K_oc) 1.1^c NA NA
Hydrolysis rate constant
in water 4 x 10^-6 h^-1 at 25°C^c 0.05 sec^-1h >90 sec^-1 at 25°C^e
in air not available 1.7 x 10-1 sec^-1 at 45°Cⁱ 0.0018 min^-1 at 29°C^k

Photolysis rate constant
in water 24 to <360 mol^-1.h^-1c 3 to <360 mol^-1.h^-1c not available
in air 1.79 x 10-11 cm³.mol^-1.sec^-1f not available 1.0 x 10-10 mol^-1.sec^-1e

Half-life
in water 20 years at 25°C (hydrolysis)^c 38 sec at 20°C (hydrolysis)^j <0.007 sec at 25°C^e
in air 13.44 h at 25°C (indirect photolysis)^f >25 h at 25°C (hydrolysis)^k 3.5 to 6 min at 25°C
(hydrolysis)i

in soil 1 to 6 months (estimate)^g not available not available

Table 2 (continued)

^a Weast & Astle (1985) ^g Howard et al. (1991)
^b Verschueren (1983) ^h Tou & Kallos (1974a)
^c Mabey et al. (1982) ⁱ Nichols & Merritt (1973)
^d CCINFO (1991) ^j US EPA (1980)
^e Radding et al. (1977) ^k Tou & Kallos (1974b)
^f US EPA (1987b)

NA = not applicable. Due to the extremely rapid hydrolysis of this substance in water, it is not possible to obtain an experimental
value, and calculated values are meaningless.

water. Typically, this step is followed by concentration of the
extract with a cold or lipophilic vapour trap, and analysis by GC/MS
(Hites et al., 1979; DeWalle & Chian, 1981). An additional technique
has been described by Kleopfer & Fairless (1972), in which samples of
water are passed through an activated carbon filter, followed by
Soxhlet extraction of the carbon, drying of the extract with sodium
sulfate, K-D concentration, Shriner-Fuson separation of the acidic,
basic and neutral fractions, and analysis of the last by GC/MS.
Determination of BCEE in air involves passing air samples through a
sorbent, followed by elution and analysis by gas chromatography
(NIOSH, 1984).

Reported detection limits for these methodologies differ by up to
two orders of magnitude. Detection limits for the procedure described
by Dressman et al. (1977) and Quaghebeur et al. (1986) range from
0.005 to 0.04 µg/litre, respectively. Limits of detection for the
methods described by McMillin et al. (1984) and Kleopfer & Fairless
(1972) are 0.3 and 0.2 µg/litre, respectively.

2.4.2 BCME

While information concerning the sampling and analysis of BCME in
water, soil or foodstuffs was not available, considerable data on
techniques for the analysis of low levels (µg/m³) of BCME in air have
been identified (Collier, 1972; Evans et al., 1975; Frankel & Black,
1976; Parkes et al., 1976; Kallos, 1981; Muller et al., 1981; Galvin &
House, 1988; Blease et al., 1989). Typically, air samples are drawn
into a (Poropak or Tenax) sorption tube, thermally eluted, and
analysed by GC/MS or GC/EC. Two additional methods have been described
which involve the direct derivatization of BCME (with
2,4,6-trichlorophenol or sodium pentafluorophenolate), and subsequent
analysis by GC/EC (Sawicki et al., 1976; Langelaan & Nielen, 1989).
Norpoth et al. (1981) reported a spectrophotometric method for the
determination of BCME.

Collier (1972), Frankel & Black (1976) and Galvin & House (1988)
reported a detection limit of 470 ng/m³ for BCME in air, while Evans
et al. (1975) and Langelaan & Nielen (1989) achieved detection limits
as low as 50 and 14 ng/m³, respectively. Muller et al. (1981) did not
report a detection limit, but quantified BCME at a concentration of
2.35 µg/m³ in air. A detection limit of 0.94 µg/m³ was reported for
the spectrophotometric quantification method described by Norpoth et
al. (1981). The methods described by Sawicki et al. (1976) and Parkes
et al. (1976) have a detection limit of 2.35 µg/m³, while a detection
limit of approximately 4.7 ng/m³ was established for the method
described by Blease et al. (1989), in which high resolution was
achieved with the combined use of gas chromatography and tandem mass
spectrometry (GC/MS/MS).

2.4.3 CMME

Identified methods for the sampling and analysis of CMME in
environmental media are limited to techniques developed for monitoring
low levels (µg/m³) in air. Several methods have been described which
involve the derivatization of CMME (with 2,4,6-trichlorophenol or
sodium pentafluorophenolate) and subsequent analysis by GC/EC (Sawicki
et al., 1976; Kallos et al., 1977; Langhorst et al., 1981; Langhorst,
1985; Langelaan & Nielen, 1989). The limits of detection for these
methodologies are 49 ng/m³ (Langelaan & Nielen, 1989), 1.65 µg/m³
(Sawicki et al., 1976; Langhorst et al., 1981) and 3.29 µg/m³ (Kallos
et al., 1977).

3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

3.1 Natural occurrence

Natural sources of BCEE, BCME or CMME in the environment have not
been identified. While BCME could be formed spontaneously from the
reaction of formaldehyde and chloride ions in an acidic atmosphere,
this reaction is unlikely in the general environment, although it may
be important in occupational settings (Durkin et al., 1975; Tou &
Kallos, 1976; Kallos & Tou, 1977; Travenius, 1982).

3.2 Anthropogenic sources

3.2.1 Production

Only limited information on the production of BCEE, BCME or CMME
has been reported.

3.2.1.1 BCEE

BCEE used to be prepared commercially in the USA as a by-product
in the manufacture of ethylene oxide by the chlorohydrin process, but
this process went out of use in the USA in 1973 (IARC, 1975). Other
methods of production also involving ethylene glycol or ethylene,
ethylene chlorohydrin and chlorine as reagents have been mentioned
(Durkin et al., 1975; IARC, 1975; ATSDR, 1989a). In 1975, two US
companies, one German and one Japanese company manufactured BCEE for
captive use as a solvent or chemical intermediate (IARC, 1975).

3.2.1.2 BCME

BCME is formed when formaldehyde reacts with chloride ions in an
acidic medium (Travenius, 1982). In China, BCME is produced by the
reaction of paraformaldehyde and hydrogen chloride gas as an
intermediate in the synthesis of the insecticide synergist S-2,
octachlorodipropyl ether [bis(1,2,3,3-tetrachloropropyl)ether] to
which it is converted in a one-part process. The scale of S-2
production is believed to be around 700 tonnes/year, which would
require over 200 tonnes of BCME. Specific synthesis reactions include
the reaction between paraformaldehyde and chlorosulfonic acid (Durkin
et al., 1975) and the saturation of a paraformaldehyde solution in
cold sulfuric acid with hydrogen chloride (US EPA, 1980). Small
amounts (several percent) of BCME are also produced during the
synthesis of CMME from gaseous hydrogen chloride and heated methanol
and formaldehyde (Durkin et al., 1975). In addition, the decomposition
products of commercial forms of CMME can combine to produce 1 to 8%
BCME as an impurity (Travenius, 1982). While BCME is not produced in
commercial quantities in Canada or the USA, it has been produced in
small quantities for use as a chemical intermediate in laboratory
applications (IARC, 1974).

3.2.1.3 CMME

CMME is produced by the reaction of anhydrous hydrogen chloride,
methanol and formaldehyde (Fishbein, 1979) or by the direct
chlorination of dimethyl ether (Durkin et al., 1975). An additional
method, which is designed to produce CMME that is free of BCME
impurities, involves the addition of actinium chloride to a slight
excess of anhydrous dimethoxymethane at room temperature (CCINFO,
1991). Production of CMME in the USA was estimated to be at least 4590
tonnes in 1977 and about 2.27 tonnes in 1982 (HSDB, 1996).

3.2.2 Uses

Only information concerning the use of BCEE, BCME or CMME in
Canada and the USA is available.

3.2.2.1 BCEE

In the USA, BCEE was formerly used in the process for the
manufacture of methyldithiocarbamic acid fungicide commonly known as
metham-sodium. Besides this use, approximately 20% of the BCEE sold in
the USA was used in the production of polymers, and 7% was either used
to synthesize a derivative of diquat or recycled for use as a
co-solvent (S. Helmhout, personal communication to the IPCS, 1992).
Other applications have included its use as a solvent for fats, waxes,
greases and esters; as a constituent of paints, varnishes and
lacquers; as a solvent for the removal of fatty substances from
various textiles, and as a penetrant and wetting agent in the textile
industry. It has also been used in the purification of oils and
gasoline, as a soil fumigant, insecticide and acaricide, and as an
intermediate in the manufacture of pharmaceuticals and other chemicals
(Durkin et al., 1975; IARC, 1975; US EPA, 1987a; ATSDR, 1989a).

3.2.2.2 BCME

In the USA, industrial use of BCME has been restricted since the
early 1980s to specific intermediate chemical reactions (Travenius,
1982). In China, BCME is an intermediate in the production of the
insecticide synergist S-2, octachlorodipropylether (see section
3.2.1.2). In the past, BCME has been used as a chloromethylating agent
in the production of ion exchange resins, water repellents and other
textile-treating agents, the manufacture of polymers, and a solvent
for polymerization reactions (Fishbein, 1979). Specific minor uses of
BCME have included the crosslinking of cellulose, the preparation of
three-block styrene-butadiene-styrene polymers, and the surface
treatment of vulcanized rubber to increase adhesion of epoxy resin and
polyurethane elastomers (Durkin et al., 1975).

Available data indicate that there is currently no commercial
activity involving more than one kilogram of BCME in Canada
(Government of Canada, 1993b).

3.2.2.3 CMME

In the USA, industrial use of CMME has been restricted since the
early 1980s to specific intermediate chemical reactions (Travenius,
1982). Based on available data, there is currently no commercial
activity in Canada involving more than one kilogram of CMME
(Government of Canada, 1993b).

In the past, CMME has been used as a chloromethylating agent in
many synthetic processes, most notably in the production of anion
exchange resins (Durkin et al., 1975). It has also been used as a
solvent for polymerization reactions (Fishbein, 1979), in the
synthesis of methoxymethyl ethers of phenols, the crosslinking of
polystyrene, and the surface treatment of vulcanized rubber (Durkin et
al., 1975).

3.2.3 Sources in the environment

Information on the release of BCEE, BCME and CMME in countries
other than the USA and Canada has not been reported.

3.2.3.1 BCEE

BCEE may enter the environment as a by-product from the
chlorination of waste streams containing ethylene or propylene, and as
a contaminant in the fungicide metam-sodium. It has been estimated,
based on the quantities imported and the known level of contamination,
that less than 100 g of BCEE would have been released into the
Canadian environment in 1990 from metam-sodium (Government of Canada,
1993a). In the USA, a total of 2700 kg/year was estimated to be
released into the environment from chemical plants in 1989. Seventy
percent of this amount was reported to be emitted to the air, while
the remaining 30% was released in water (US EPA, 1990). The
chlorination of drinking-water containing diethyl ether can result in
the formation of BCEE (NRC, 1977); however, quantitative data have not
been identified.

3.2.3.2 BCME and CMME

It was reported in the Toxic Release Inventory Database (US EPA,
1990) that less than 1 kg of BCME and 50 kg of CMME were released into
the atmosphere in the USA from industrial producers and users during
1989. However, release occurred in the two-step production of
octachlorodipropyl ether in China (Chen et al., 1996). This process
ceased in 1975, but manufacture of octachlorodipropyl ether was
revived in 1987 using a one-step process, from which gas releases and
accidental liquid spills occur. There is no information on the amount
of BCME that may remain as a contaminant of the product, which
contains formaldehyde and hydrogen chloride (BCME's precursors). There
is, however, gas-chromatographic evidence that CMME and BCME are
released into the air by the burning of octachlorodipropyl ether in
mosquito coils. No information is available from these sources

concerning the release of BCME or CMME into other media (water, soil,
underground injection), but, owing to their rapid rate of hydrolysis,
these compounds are not expected to remain as such for prolonged
periods in waste streams from plants where they are produced or used
(IARC, 1974).

The spontaneous formation of BCME or CMME in drinking-water from
the chlorination of ethers has not been investigated. However, in view
of their rapid rate of hydrolysis (see section 4.2.2), it is unlikely
that BCME or CMME would be present as contaminants in drinking-water
(Durkin et al., 1975).

No information has been identified concerning the quantities of
BCME or CMME released into the environment during storage or
transportation. However, these amounts are likely to be insignificant
since BCME and CMME have been usually produced and used in "closed
system" operations where containment prevents the release of these
chemicals into the environment (Durkin et al., 1975).

4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

4.1 Transport and distribution between media

4.1.1 BCEE

Based on the low-to-moderate Henry's Law constant (1.3 × 10^-5
atm.m³/mol), BCEE would tend to remain in water. The air/water ratio,
as well as the Henry's Law constant, will determine the amounts of
BCEE distributed between the two compartments. Rainfall would probably
result in the removal of BCEE from the atmosphere (Durkin et al.,
1975). Using the approach of Mackay & Wolkoff (1973), Durkin et al.
(1975) calculated the half-life with respect to volatilization of BCEE
from a body of water to be 5.78 days at 25°C. Similarly, a
volatilization half-life of 3.4 days (from water) was calculated by
the US EPA (1987b). Thus the removal of BCEE from surface water will
probably occur within a week, although it will persist in bottom
water. Based upon its low log K_oc (organic carbon partition
coefficient) and high water solubility, BCEE is not expected to adsorb
to soil or sediment and is therefore considered to be mobile in these
media (US EPA, 1987b). The US EPA (1987b) reported that, because of
its vapour pressure, BCEE should volatilize relatively rapidly from
dry surfaces. In the only study dealing with soil volatilization (a
7-day microcosm study by Piwoni et al. (1986) in which the soil was
kept moist), an insignificant amount (3%) of applied BCEE was
calculated to have volatilized.

4.1.2 BCME and CMME

Information regarding the mobility and distribution of BCME and
CMME in environmental media is limited. Callahan et al. (1979)
suggested that BCME could volatilize rapidly from an aquatic system
only if it were discharged in a water-immiscible solvent with a high
vapour pressure. Once in the atmosphere, these substances would be
rapidly degraded by photo-oxidation or hydrolysis. Very little
information was identified concerning the behaviour of BCME or CMME in
soil. It is unlikely that BCME and CMME are mobile in soil as both
compounds hydrolyse rapidly in an aqueous environment.

4.2 Abiotic degradation

4.2.1 BCEE

At a temperature of 20°C in water, a hydrolysis half-life of 20
to 22 years was estimated for BCEE (Mabey et al., 1982; Milano et al.,
1989). The US EPA estimated the half-life for the reaction of BCEE
with hydroxyl radicals in the atmosphere to be approximately 2.8 days
(A. Leifer, Office of Toxic Substances, US EPA, personal
communication, 1992). A half-life of 13.4 h has been reported for the
indirect photolysis of BCEE in the gaseous phase (US EPA, 1987b).
Photolysis products of BCEE include 2-chloroethanol, ethyl alcohol,
methyl alcohol, 2-chloroethyl ethyl ether, peracetic acetic acid,

1-(2-chloroethoxy)-1,2-epoxyethane, acetaldehyde and chloracetaldehyde
(Milano et al., 1989).

4.2.2 BCME and CMME

BCME and CMME are removed from environmental media via abiotic
processes. In the atmosphere, these substances are degraded by
photo-oxidation or hydrolysis. Cuppit (1980) reported atmospheric
half-lives of < 2.9 days for BCME and < 3.9 days for CMME. Tou &
Kallos (1974a) reported half-lives for atmospheric hydrolysis of
> 1 day for BCME and between 0.0024 (Nichols & Merritt, 1973) and
0.27 days for CMME, in humid air. At low humidity levels, however,
BCME may be degraded by oxidative as well as hydrolytic pathways. In
air, the decomposition products for BCME include hydrogen chloride,
formaldehyde and chloromethylformate, while those of CMME include
chloromethyl and methyl formate (Cupitt, 1980).

BCME and CMME hydrolyse rapidly in water. At 20°C, half-lives in
water of 38 seconds for BCME and < 1 second for CMME have been
reported (Tou et al., 1974; Radding et al., 1977; US EPA, 1980).
Although BCME may be degraded by oxidation, the extremely rapid
hydrolysis of BCME in aqueous media precludes any significant
oxidative degradation of this substance in aquatic systems (Callahan
et al., 1979). BCME is hydrolysed to formaldehyde and hydrogen
chloride (ATSDR, 1989b), while CMME is hydrolysed to hydrogen
chloride, methanol and formaldehyde (Travenius, 1982).

4.3 Biodegradation, biotransformation and bioaccumulation

4.3.1 BCEE

In the only study identified, Tabak et al. (1981) reported that
BCEE was completely biodegraded within 7 days in an aqueous medium
inoculated with sewage sludge. Although data on the biodegradation of
BCEE in soil are limited, this process may play some role in the fate
of this substance in soil. Kincannon & Lin (1986) reported a half-life
of BCEE in soil of approximately 16.7 days, based on the results of a
97-day soil column study in which the degradation of BCEE mixed with
hexachloroethane (as a constituent of a hazardous waste sludge) was
quantified.

For biota, Barrows et al. (1978) reported a bioconcentration
factor (BCF) of 11 and a biological half-life of between 4 and 7 days
for BCEE in bluegill sunfish (Lepomis marochirus) based on the
results of a study in which the fish were exposed to BCEE (under
flow-through conditions) for 14 days at a mean water concentration of
10 µg/litre.

4.3.2 BCME and CMME

No information on the biodegradation of either BCME or CMME in
soil was identified. However, their high rates of hydrolysis in
aqueous media preclude any possibility of BCME or CMME bioaccumulating
in organisms.

4.4 Ultimate fate following use

Owing to the highly reactive nature of the
alpha-chloroalkylethers in water and air, CMME and BCME are not
expected to be present in the general environment (Durkin et al.,
1975). However, owing to the relative stability of ß-chloroalkylethers
in environmental media, BCEE may be persistent in the general
environment (Durkin et al., 1975).

5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

5.1 Environmental levels

5.1.1 BCEE

Quantitative information on the levels of BCEE in air is limited
to a single study in the USA in which this substance was detected (but
not quantified) in the atmosphere above two landfill sites in New
Jersey (US NLM, 1996).

Available data concerning the levels of BCEE detected in surface
water and drinking-water are summarized in Tables 3 and 4,
respectively. BCEE has been detected in samples of municipal
drinking-water at mean concentrations of up to 0.42 µg/litre in the
USA (Kraybill, 1977). The highest concentration reported for selected
surface waters was 58 µg/litre in Belgium, in the vicinity of
industrial discharges (Quaghebeur et al., 1986).

Identified studies concerning the levels of BCEE in groundwater
were limited to surveys conducted in the vicinity of contaminated
areas; concentrations of BCEE ranged from 0.001 µg/litre in samples
collected at an industrial gypsum waste disposal site in Belgium
(Quaghebeur et al., 1986) to 840 µg/litre in samples collected near a
municipal and industrial waste landfill site in the USA (DeWalle &
Chian, 1981).

Identified studies on the levels of BCEE in soil were limited to
two investigations in which this compound was detected in samples
collected from contaminated areas in the USA. BCEE was monitored (but
not quantified) in samples of soil collected at Love Canal, New York
(Hauser & Bromberg, 1982), and measured at a mean concentration of 140
mg/kg in samples of soil from waste disposal sites in the USA (ATSDR,
1989a).

No information is available on the levels of BCEE in foodstuffs.
Based on its high water solubility and low K_ow, BCEE is not expected
to bioaccumulate in fish or other aquatic species (ATSDR, 1989a).

The concentration of BCEE in in-plant effluents in Canada has
been reported to range from 6.1 to 1057 µg/litre (Government of
Canada, 1993a). These effluents are diluted with cooling water before
being discharged to the environment and, although levels of BCEE at
the outflow pipe were not monitored, they were probably below the
limit of detection.

The highest concentrations of BCEE in the USA were reported for
industrial effluents (8 to 170 µg/litre), and municipal and industrial
waste landfill leachates (12 400 µg/litre) (DeWalle & Chian, 1981).

Table 3. Bis(2-chloroethyl) ether levels in surface water

Location Number of Concentration^b Remarks Reference
samples^a mean (range)
(µg/litre)

Philadelphia, USA NR ND samples collected from April 1975 to July 1975 Manwaring et al. (1977)
from the Delaware River, upstream from a
water treatment plant

NR trace samples collected in April 1975 from the
Delaware River, upstream from a chemical plant Manwaring et al. (1977)

2 trace samples collected in October 1976 from the
Delaware River Sheldon & Hites (1978)

5 (ND - trace) samples collected in March 1977 from the
Delaware River Sheldon & Hites (1978);
US EPA (1980)
New Orleans and
Baton Rouge, USA 3 0.11 (0.04 - 0.16) Pellizzari et al. (1979)

Houston, USA 1 (1) 1.4 Pellizzari et al. (1979)

Nitro, USA NR 0.041 samples collected from the Kanawha River Rosen et al. (1963);
Durkin et al. (1975)

USA^c 808 (3) < 10.0 median limit of detection, 10.0 µg/litre Staples et al. (1985)

Belgium^c NR (7 - 58) samples collected from Haine River adjacent to
industrial discharges Quaghebeur et al. (1986)

Belgium^c NR (trace - 7.9) samples collected from Durme River, Scheldt
River and Gheut-Terneuzen Channel
downstream from industrial discharges Quaghebeur et al. (1986)

^a Value in parenthesis indicates the number of samples with detectable levels of bis(2-chloroethyl) ether.
^b Mean and/or (range) of concentrations, unless otherwise indicated; detection limits were reported, when possible.
^c Locations were not specified.
NR = not reported; ND = not detected

Table 4. Bis(2-chloroethyl) ether levels in drinking water

Location Number of Concentration^b Detection Remarks Reference
samples^a mean (range) limit
(µg/litre) (µg/litre)

Toronto, Canada 50 (0) ND 0.00003 finished drinking-water Kendall (1990)

Toronto, Canada 8 (0) ND 0.001 bottled spring water Kendall (1990)

Alberta, Canada^c 1512 (1) ND (ND - trace) 1 samples of treated (from 215 Alberta Ministry of the
sites) and raw (from 14 sites) Environment (1991)
drinking-water
collected from January 1986
to June 1991

Nitro, USA 1 (1) 0.2 NR tap water DeWalle & Chian (1981)

Evansville, USA 1 NQ NR finished drinking-water Kleopfer & Fairless (1972)

Philadelphia, USA NR NQ NR finished drinking-water Suffet et al. (1980)
collected between 1975
and 1977

Philadelphia, USA NR < 0.1 (0.04 - 0.6) NR finished drinking-water Manwaring et al. (1977)
collected between February
1975 and July 1975

New Orleans, USA NR (0.04 - 0.16) NR finished drinking-water Keith et al. (1976)
collected in August 1974

Philadelphia, USA NR (0.03 - < 1) NR raw drinking-water collected Manwaring et al. (1977)
between April 1975 and
July 1975

Philadelphia, USA NR (0.4 - 0.5) NR raw drinking-water Durkin et al. (1975)

Table 4. (continued)

Location Number of Concentration^b Detection Remarks Reference
samples^a mean (range) limit
(µg/litre) (µg/litre)

USAc NR 0.42 NR finished drinking-water Kraybill (1977)

NR ND 5 finished drinking-water US EPA (1980)
collected (between March
1976 and April 1976) from
112 cities during the
National Organics Monitoring
Survey (NOMS) (Phase I)

NR 0.0115 (ND - 0.36) 0.005 finished drinking-water Dressman et al. (1977)
collected (between May 1976
and June 1976) from 113
cities during the NOMS
(Phase II); BCEE was detected
in drinking-water from 13
cities at a mean concentration
of 0.10 µg/litre

USA^c NR 0.0017 NR finished drinking-water US EPA (1980)
collected (between November
1976 and June 1977) from 110
cities during the NOMS (Phase
III); BCEE was detected in
drinking-water from 8 cities
at a mean concentration of
0.024 µg/litre

NR (0.02 - 0.12) NR drinking-water from 80 cities Fishbein (1979)

Netherlands^c NR 0.1 maximum NR Kraybill (1977)

Table 4 (continued)

^a Values in parenthesis indicate the number of samples with detectable levels of bis(2-chloroethyl) ether.
^b Mean and/or (range) of concentrations, unless otherwise indicated.
^c Locations were not specified
ND = not detected
NR = not reported
NQ = not quantified

5.1.2 BCME and CMME

No information has been reported on levels of BCME or CMME in
ambient air or the indoor air of homes or offices. In a small survey
of outdoor air in the Netherlands, BCME and CMME were not detected
(detection limits, 14.1 µg/m³ and 49.5 µg/m³, respectively) in
samples collected in the neighbourhood of a potential emission source
(distance and source were not specified) (Langelaan & Nielen, 1989).

Available data on the levels of BCME or CMME in drinking-water,
surface water or ground water are limited to one investigation in
which BCME was not detected (detection limit, 10 µg/litre) in a total
of 317 samples of surface and groundwater from unspecified locations
in the USA (Staples et al., 1985).

Quantitative data concerning the levels of BCME or CMME in soil
have not been reported. However, in view of their rapid rate of
hydrolysis, these compounds are not expected to persist as
contaminants in moist soil (US NLM, 1996). Similarly, while no studies
on the levels of BCME or CMME in foodstuffs have been reported, the
high rates of hydrolysis reduce the likelihood of BCME or CMME
bioaccumulating in the food chain (US NLM, 1996).

No reliable data on levels of either BCME or CMME in industrial
effluents have been reported.

5.2 General population exposure

Quantitative data concerning the levels of BCEE in the general
environment are restricted to the results of studies in which the
levels of this substance in surface water and drinking-water have been
assessed. Based on a daily volume of ingestion for adults of 1.4
litres, a mean body weight for males and females of 64 kg (IPCS,
1994), and the highest mean concentration of BCEE in drinking-water
presented in Table 4 (0.42 µg/litre), the estimated intake of BCEE
from drinking-water for adults would be approximately 0.01 µg/kg body
weight per day.

Adequate information on the concentrations of BCME and CMME in
air, drinking-water, soil, or foodstuffs have not been reported, and
therefore it is not possible to estimate the intake of these
substances. No quantitative data are available for the exposure of
populations that use mosquito coils containing octachlorodipropyl
ether (see section 3.2.3.2), but the number of users of such coils is
of the order of millions in China.

5.3 Occupational exposure

5.3.1 BCEE

Occupational exposure to BCEE (via inhalation or dermal contact)
may occur in individuals involved in the dry cleaning and textile
industries, or in the processing of gum, lacquer, oil, paint, soap and
tar (Tabershaw et al., 1977). However, no investigations concerning
quantitative levels of exposure to BCEE in the workplace have been
reported.

5.3.2 BCME and CMME

Occupational exposure to BCME or CMME may occur in laboratory and
textile workers, and in individuals involved in the production of
anion-exchange resins, organic chemicals and polymers (Lemen et al.,
1976; US EPA, 1980). In China, occupational exposure to BCME occurs in
the manufacture of octachlorodipropyl ether. Under conditions where
vapours of formaldehyde and hydrochloric acid co-exist, BCME may form
spontaneously in air. Available quantitative data concerning
occupational exposure to either BCME or CMME are limited to
investigations of the levels of BCME in workroom air (Table 5).

BCME may be produced in solution from a variety of sources of
formaldehyde and chloride ions, and has been detected in the vapours
above these solutions (Frankel et al., 1974). In one study, the
concentration of BCME in the headspace above formalin slurries
containing Freidel-Crafts (chloride) salts ranged from 0.99 to
7.1 mg/m³ (210 to 1500 ppb) (Frankel et al., 1974).

While no recent studies have been identified where levels of
occupational exposure to CMME have been reported, it has been
estimated that in the past, concentrations of CMME in workroom air may
have ranged from 4.7 to 47 mg/m³ (1-10 ppm) (Travenius, 1982).

Table 5. Concentrations of bis(chloromethyl) ether in workroom air

Industry Sampling period Concentration^a Detection limit Reference
(µg/m³) (µg/m³)

Dye auxiliaries (resin) production; Jan. 1976 - Aug. 1976 ND 0.5 or 0.9 Yao & Miller (1979)
dye manufacture; fertilizer
production; textile finishing on
woven goods; hospital procedures;
foundry products (research plant);
foundry products (full-scale plant)
(USA)

Plastics industry^b (USA) Jan. 1973 <4.7 - 72.9 NR Eisner (1974)

Textile finishing plants (4) (USA) Nov. 1974 - Dec. 1974 <0.5 - 37.6 0.5 Marceleno (1974)

Chemical plant (UK) 1978 <4.7 NR Travenius (1982)

Chemical plant (Netherlands) NR 1.2 - 3.8 0.5 van der Ven & Venema
(1979)

Resin manufacturing plant^d (France) 1979 - 1984 2.8 - 20.6 NR Gowers et al. (1993)

^a Concentrations of bis(chloromethyl) ether measured in workroom air
^b Samples of air collected at the Diamond Shamrock Chemical Company in California, in the vicinity of reactors used to condense
phenol and formaldehyde
^c Unspecified industrial operations; location of sample acquisition was not reported
^d Range of average concentrations from various areas in the plant
ND - not detected
NR - not reported

6. KINETICS AND METABOLISM IN LABORATORY ANIMALS

Quantitative information on the absorption, distribution,
elimination and metabolism of BCEE, BCME or CMME in humans is not
available.

6.1 Absorption and distribution

Gwinner et al. (1983) reported that more than 95% of the total
[¹⁴C]-BCEE vapour (calculated to be approximately 75 mg) introduced
into an inhalation chamber containing three male Wistar rats was
absorbed by the animals after an 18-h exposure. When the tissue
(protein)-associated radioactivity (per gram of tissue) was examined
after this exposure period, approximately 0.32% of the administered
radioactivity was present in the liver, while 0.17 and 0.12% were
found in the kidney and small intestine, respectively. Only 0.07% of
the administered radioactivity was present in the lungs. Lingg et al.
(1982) administered by gavage a single dose of [¹⁴C]-BCEE (40 mg/kg
body weight, dissolved in corn oil) to male Sprague-Dawley rats and
monitored the amount of radioactivity present in a limited number of
tissues during the subsequent 48-h period. After 48 h, the percentage
of administered ¹⁴C was found to be 11.5 in expired CO₂, 64.7 in
urine, 2.4 in faeces, and 2.3 in organs and tissues. In tissues,
approximately 1, 0.56, 0.49 and 0.19% of the radioactivity was
retained in muscle, kidney, blood and liver, respectively.
Quantitative data on the absorption and distribution of BCME or CMME
in animal species have not been reported.

6.2 Metabolism

BCEE is readily metabolized following absorption. Thiodiglycolic
acid (TDGA) was the principal metabolic product (representing 50 to
80% of the total metabolites) in the urine of rats administered BCEE
either orally, by intraperitoneal injection or by inhalation (Lingg et
al., 1979, 1982; Muller et al., 1979; Norpoth et al., 1986).
2-Chloroethoxy-acetic acid, N-acetyl-S-[2-(2-chloroethoxy)-ethyl]-L-
cysteine, 1-(2-chloroethyl)-ß-D-glucopyranosiduronic acid and
S-carboxymethyl-L-cysteine have been reported to be minor metabolites
(each comprising less than 10% of the total) in the urine of rats
administered BCEE (Lingg et al., 1979, 1982; Muller et al., 1979).
Lingg et al. (1982) reported that in male Sprague-Dawley rats
administered (by gavage) a single dose of [¹⁴C]-BCEE (40 mg/kg body
weight, dissolved in corn oil), approximately 12% of the radioactivity
was metabolized to ¹⁴CO₂.

The formation of TDGA from BCEE involves a number of steps (Lingg
et al., 1979, 1982; Muller et al., 1979; Gwinner et al., 1983; Norpoth
et al., 1986). BCEE is believed to undergo oxidative degradation
(involving ether cleavage) to produce chloroacetaldehyde and
chloroethanol (which itself is rapidly converted to
chloroacetaldehyde) (Gwinner et al., 1983). It is believed that
chloroacetaldehyde is subsequently converted to chloroacetic acid,
which after conjugation with glutathione and further modification,

produces TDGA. The formation of N-acetyl-S-[2-(2-chloroethoxy)ethyl]-
L-cysteine is believed to involve the direct substitution of one of
the chlorine atoms in BCEE with cysteine (Lingg et al., 1982).
S-Carboxymethyl-L-cysteine, although not detected in all studies in
which the metabolism of BCEE was examined, has been postulated to be
an intermediate in the synthesis of TDGA (Lingg et al., 1982).
1-(2-Chloroethyl)-ß-D-glucopyranosiduronic acid is evidence of the
occurence of 2-chloroethanol among metabolic products, while
S-carboxymethyl- n-cysteine may be produced by alkylation of
glutathione by chloroacetaldehyde (Lingg et al., 1982), and
2-chloroethoxy-acetic acid is believed to be produced via the
oxidative dehalogenation of BCEE (Lingg et al., 1982).

Information on the metabolism of BCME or CMME in laboratory
animals has not been reported; however it is anticipated that BCME and
CMME would be rapidly hydrolysed in the aqueous environment of
tissues, forming formaldehyde and hydrogen chloride, and methanol,
formaldehyde and hydrogen chloride, respectively. However, the effects
of BCME (CMME) are most likely attributable to their direct alkylating
activity (van Duuren, 1989).

6.3 Elimination

Although quantitative information on the elimination of BCME or
CMME in laboratory animals is not available, limited quantitative data
concerning the elimination of BCEE (administered orally) in laboratory
animals have been reported. Lingg et al. (1982) administered (by
gavage) a single dose of [¹⁴C]-BCEE (40 mg/kg body weight, dissolved
in corn oil) to male Sprague-Dawley rats and monitored the amount of
radioactivity appearing in the faeces, urine and expired air during
the subsequent 48-h period. Twelve hours after the administration of
[¹⁴C]-BCEE, 50% of the radioactivity had been lost in the urine and
exhaled air (as ¹⁴CO₂). Lingg et al. (1979) estimated that less than
2% of the administered radioactivity that was expired through the
lungs was exhaled as the parent compound. Forty-eight hours after the
oral administration of [¹⁴C]-BCEE, approximately 65% of the
radioactivity was excreted in the urine and 11.5% exhaled from the
lungs (total loss of 76%); approximately 2.3 and 2.4% of the
administered radioactivity remained in the organs (and tissues) and
faeces, respectively.

Smith et al. (1985) reported that 24, 48 and 72 h after the oral
administration (by gavage) of [¹⁴C]-BCEE (10 mg/kg body weight, in a
solution containing ethanol, Emulphor and distilled water) to two
female Rhesus monkeys, approximately 43, 56 and 58% of the
administered radioactivity had been eliminated in the urine.
Seventy-two hours after the administration of [¹⁴C]-BCEE, less than
2% of the radioactivity was recovered in the faeces.

7. EFFECTS ON EXPERIMENTAL MAMMALS AND IN VITRO TEST SYSTEMS

7.1 Single exposure

Information on the acute toxicity of BCEE, BCME and CMME is
summarized in Table 6.

7.1.1 BCEE

Although the acute toxicity of BCEE has been examined in a number
of studies, complete experimental details were not always provided.
Reported LD₅₀ values for the oral exposure of animal species to BCEE
range from 75 to 215 mg/kg body weight. An LC₅₀ of 5850 mg/m³ (1000
ppm) was estimated from studies in which Sherman strain rats were
exposed to BCEE for 0.75 h (Smyth & Carpenter, 1948). The exposure of
guinea-pigs to 5850 mg/m³ for 3.8 to 5.5 h resulted in the death of
the animals (Schrenk et al., 1933). Exposure to 1521 mg/m³ (260 ppm)
resulted in the death of the animals after 7.5 to 12.3 h of continuous
exposure. No deaths were observed after exposure to 205 mg/m³ (35
ppm) for up to 13.5 h, although slight nasal irritation was observed
within 3 to 10 min of exposure to this concentration. Acute exposure
of guinea-pigs to BCEE vapour (320 mg/m³) caused eye irritation (as
indicated by squinting and lacrimation) as well as congestion, oedema
and haemorrhage in the lungs; liver, kidney and brain congestion was
also noted (Schrenk et al., 1933). The severity of the toxicological
effects produced by exposure to the higher concentrations of BCEE was
also related to the length of the exposure period. Effects in
Sprague-Dawley rats or CD-1 mice administered a single oral dose of
BCEE (dissolved in cottonseed oil) included ptosis, increased
salivation, diarrhoea, decreased activity and ataxia (Drake & Myer,
1992).

Smyth & Carpenter (1948) reported that the dermal exposure of
guinea-pigs to BCEE caused skin irritation; the LD₅₀ was 366 mg/kg
body weight.

7.1.2 BCME and CMME

Reported LC₅₀ values for the exposure (by inhalation) of
laboratory animals to BCME range from 25 to 48 mg/m³ (5.3 to 10.3
ppm). The acute exposure (by inhalation) of animals to BCME produced
severe irritation of the eyes and respiratory tract (congestion,
oedema and haemorrhage (mainly of the lungs) and acute necrotizing
bronchitis (Union Carbide, 1968; Drew et al., 1975). The median life
span of rats exposed (by inhalation) to 0, 3.3, 9.9, 32.4 or 44.7
mg/m³ (0, 0.7, 2.1, 6.9 or 9.5 ppm) was 462, 420, 36, 2 and 2 days,
respectively. For hamsters exposed (by inhalation) to these
concentrations of BCME, the median life span was 675, 657, 68, 16 and
4 days, respectively (Drew et al., 1975). Exposure to 9.9 mg/m³
(2.1 ppm) for 7 h increased the incidence of tracheal and bronchial
hyperplasia 2- to 3-fold in rats and 4- to 5-fold in hamsters,
compared to unexposed controls (Drew et al., 1975).

Table 6. Acute toxicity of BCEE, BCME and CMME

Species^a Route LC₅₀ or LD₅₀ Reference
(duration)

BCEE
Rat (Sherman) inhalation (0.75 h) LC₅₀: 5850 mg/m³ (1000 ppm) Smyth & Carpenter (1948)
Rat (Sherman) oral LD₅₀: 75 mg/kg bw Smyth & Carpenter (1948)
Rat oral LD₅₀: 105 mg/kg bw Spector (1956)
Rat (Sprague-Dawley) oral LD₅₀: 175 mg/kg bw Drake & Myer (1992)
Mouse oral LD₅₀: 136 mg/kg bw Spector (1956)
Mouse (CD-1) oral LD₅₀: 215 mg/kg bw Drake & Myer (1992)
Rabbit oral LD₅₀: 126 mg/kg bw Spector (1956)
Guinea-pig dermal (poultice; 24 h) LD₅₀: 366 mg/kg bw Smyth & Carpenter (1948)

BCME
Rat (Sprague-Dawley) inhalation (7 h) LC₅₀: 33 mg/m³ (7 ppm) Drew et al. (1975)
Rat inhalation^b LC₅₀: 48 mg/m³ (10.3 ppm) Union Carbide (1968)
Mouse (A/Heston) inhalation (6 h) LC₅₀: 25 mg/m³ (5.3 ppm) Leong et al. (1971)
Hamster (Syrian) inhalation (7 h) LC₅₀: 33 mg/m³ (7 ppm) Drew et al. (1975)
Rat (Wistar) oral (undiluted) LD₅₀: 0.21 ml/kg bw (278 mg/kg bw) Union Carbide (1968)
Rabbit (New Zealand) dermal (undiluted; 24 h) LD₅₀: 0.28 ml/kg bw (370 mg/kg bw) Union Carbide (1968)

CMME^c
Rat inhalation (7 h) LC₅₀: 182 mg/m³ (55 ppm) Drew et al. (1975)
Hamster inhalation (7 h) LC₅₀: 215 mg/m³ (65 ppm) Drew et al. (1975)
Rat oral LD₅₀: 817 mg/kg bw NIOSH (1974)

^a Data on strain presented if reported in study.
^b Duration not specified.
^c Containing BCME.

Reported LC₅₀ values for the exposure (by inhalation) of
laboratory animals to CMME range from 182 to 215 mg/m³ (55 to 65
ppm). Exposure to CMME produced pulmonary congestion, oedema,
haemorrhage and acute necrotizing bronchitis (Drew et al., 1975);
however the toxic effects produced by CMME may be due, at least in
part, to contaminating BCME.

Application of BCME to the skin of rabbits produced erythema and
necrosis, while exposure of the eye to this substance produced severe
corneal necrosis (Union Carbide, 1968).

7.2 Short-term exposure

7.2.1 BCEE

Information on the effects of short-term or subchronic exposure
of animals to BCEE is limited primarily to range-finding studies for
carcinogenicity bioassays. Theiss et al. (1977) reported that the
maximum tolerated dose (MTD) of BCEE in A/St male mice (receiving 6
intraperitoneal injections over a 2-week period) was 40 mg/kg body
weight. The administration (route not clearly specified) of 19 daily
doses (100 mg/kg body weight) of BCEE (deemed to be the MTD) to two
strains of hybrid F₁ mice [strain (C57BL/6 × C3H/Anf)F₁ and strain
(C57BL/6 × AKR)F₁] had no effect on mortality, although other
toxicological effects were not reported (Innes et al., 1969).

7.2.2 BCME

In one study (Drew et al., 1975) on the short-term toxicity of
BCME, groups of 50 male Sprague-Dawley rats and Syrian hamsters were
exposed by inhalation to 0 or 4.7 mg/m³ (0 or 1 ppm) for 1, 3, 10 or
30 multiple 6-h exposures (duration between exposures not specified),
after which time the animals were observed for their entire life span
and the trachea and bronchi examined histopathologically. In groups of
rats exposed to BCME for 0, 1, 3, 10 or 30 occasions, 50% mortality
was observed after 66, 66, 20, 4 and 4 weeks, respectively. The
incidence of tracheal hyperplasia, with and without atypias, increased
from 27% after 1 exposure to 89% after 30 exposures to BCME. The
incidence of tracheal squamous metaplasia increased after 3 to 30
exposures. The incidence of bronchial hyperplasia and squamous
metaplasia increased with greater exposure to BCME. In hamsters
subjected to 0, 1, 3, 10 or 30 exposures (6-h) to BCME, 50% mortality
was observed after 95, 95, 70, 22 and 8 weeks, respectively. The
incidence of tracheal hyperplasia, with and without atypias, tracheal
squamous metaplasia and alveolar metaplasia with atypia increased with
more frequent exposure to BCME. Exposure to BCME also produced
bronchoalveolar metaplasia, squamous metaplasia with atypia and
atypical alveolar epithelium. Evidence of subarachnoid haemorrhage was
observed in 24% of the rats and 8% of the hamsters that received 30
exposures (6-h) to 4.7 mg/m³ (1 ppm) (Drew et al., 1975).

7.2.3 CMME

In one study on the short-term toxicity of CMME, groups of 25
male Sprague-Dawley rats were exposed (by inhalation) to 3.3 or 33
mg/m³ (1 or 10 ppm) for 30 days (duration and frequency of exposure
not specified) (Drew et al., 1975). Exposure to 3.3 mg/m³ resulted in
8% mortality, but no effect on body weight, within 30 days (data for
unexposed controls were not presented). Regenerative hyperplasia and
squamous metaplasia in bronchial epithelium were observed in rats
killed 2 weeks after the last exposure. Exposure to 33 mg/m³ resulted
in 88% mortality within 30 days (data for controls not presented);
marked (not quantified) weight decrease was observed with some
recovery towards the end of exposure. Significant (not quantified)
increases in lung/body weight ratios were observed in rats that died
after exposure to CMME; regenerative hyperplasia of bronchial
epithelium was also observed.

7.3 Long-term exposure/carcinogenicity

Studies on long-term exposure and carcinogenicity are given in
Table 7.

7.3.1 BCEE

Studies on the toxicological effects produced by the long-term
exposure of laboratory animals to BCEE have focused on its
carcinogenic potential. However there are numerous deficiencies in all
of these studies, compared to the more stringent protocols used in
current carcinogenicity bioassays.

Innes et al. (1969) assessed the carcinogenicity of BCEE in mice
following ingestion. Groups of 18 males and 18 females from two
strains of hybrid F₁ mice [(C57BL/6 × C3H/Anf) and (C57BL/6 × AKR)]
were administered by stomach tube approximately 100 mg/kg body weight
BCEE (dissolved in distilled water) from the age of 7 to 28 days
(although the amount of BCEE was not adjusted during this period to
account for weight gain). Once the mice had reached four weeks of age,
the BCEE was then provided in the diet at a concentration of 300 mg/kg
diet until the mice were 18 months of age, after which time they were
killed and necropsied. The time-weighted average dose for these
studies was calculated to be 41.3 mg/kg body weight per day (US EPA,
1987a). There were multiple groups of controls consisting of animals
of both strains and sexes. "Hepatomas" (representing benign hepatomas
and malignant tumours), tumours of the pulmonary system (adenomas and
adenocarcinomas) and lymphomas (Type-B reticulum cell sarcomas and
leukaemias) were the predominant types of tumours observed in these
animals. Compared to unexposed controls, the incidence of "hepatomas"
was significantly (p = 0.01) increased in the treated (C57BL/6 ×
C3H/Anf)F₁ mice (in males, 8/79 versus 14/16; in females, 0/87 versus
4/18; in control and exposed animals, respectively) and in (C57BL/6 ×
AKR)F₁ males (5/90 versus 9/17 in control and exposed animals,
respectively). However the incidence of pulmonary tumours or lymphomas
was not significantly increased in the BCEE-exposed animals of either

Table 7. Long-term exposure/carcinogenicity of BCEE, BCME and CMME

Protocol Result Comments Reference

BCEE

Groups of 18 males and 18 females from The incidence of "hepatomas" (benign Evidence of Innes et al.
two strains of F₁ hybrid mice [(C57BL/6 x and malignant tumours), "pulmonary increased incidence (1969)
C3H/Anf) and (C57BL/6 x AKR)] were tumours" and lymphomas in the male of liver tumours.
given (by gavage) approximately 100 control and BCEE-exposed (C57BL/6 x However, study
mg/kg bw BCEE (dissolved in distilled C3H/Anf)F₁ mice was 8/79 and 14/16 limited owing to
water) from the age of 7 to 28 days. Once (p = 0.01), 5/79 and 0/16 and 5/79 small number of
the mice had reached four weeks of age, and 2/16, respectively; the incidence BCEE-exposed
BCEE was then provided in the diet at a of these tumours in the female control animals, use of
concentration of 300 mg/kg until the mice and (C57BL/6 x C3H/Anf)F₁ mice was single dose level
were 18 months of age, after which time 0/87 and 4/18 (p = 0.01), 3/87 and and inadequate
they were sacrificed and necropsied. The 0/18 and 4/87 and 0/18, respectively. reporting of tumour
time-weighted-average dose for these The incidence of "hepatomas" (benign pathology. Amount
studies was calculated to be 41.3 mg/kg and malignant tumours), "pulmonary of BCEE was not
bw/day (US EPA, 1987a). Controls tumours" and lymphomas in the male adjusted during
consisted of multiple groups of animals of control and BCEE-exposed (C57BL/6 x initial period to
both strains and sexes. C3H/AKR)F₁ mice was 5/90 and 9/17 account for weight
(p = 0.01), 10/90 and 2/17 and 1/90 gain.
and 0/17, respectively; the incidence
of these tumours in the female control
and BCEE-exposed mice was 1/82 and
0/18, 3/82 and 0/18 and 4/82 and 1/18,
respectively.

Table 7. (continued)

Protocol Result Comments Reference

BCME (dissolved in a solution containing The authors reported that BCEE was not No reported Weisburger et
sodium chloride, Polysorbate 80, carcinogenic in these male or female evidence of al., 1981
carboxy-methylcellulose and benzyl rats; however, there was a "substantial carcinogenicity.
alcohol) was administered by gavage to difference" between the mean weight of However, study
groups of 26 male and 26 female Charles the females administered BCEE and limited due to
River CD rats (at doses of 50 and corresponding controls, as well as "a small number of
25 mg/kg bw) twice weekly for 78 weeks, reduction" in the mean weight of the BCEE-exposed
after which time the animals were high-dose male rats, compared to the animals and
observed for a further 26-week period. controls. Notably, survival after 52 relatively short
The animals were necropsied and tissues weeks on the study was only 65% for the exposure period.
examined histopathologically, either at high-dose females and 96-100% for the The size of
the end of the study or when the animals other BCEE-exposed animals. The survival control groups
became moribund. Groups of controls of for the control animals at 52 weeks was was not clearly
each sex were administered vehicle alone. 97% and 99% for males and females, stated, and
respectively. quantitative data
on tumour
incidence were
not presented.

Groups of 20 male A/St mice were injected The incidence of lung tumours (expressed No evidence of Theiss et al.,
intraperitoneally three times a week with as the number of lung tumours/mouse) in carcinogenicity 1977
8, 20 or 40 mg/kg bw BCEE (dissolved in the BCEE-exposed animals (approximately in a limited
tricaprylin). Mice injected with 8 and 0.13 lung tumours/mouse) was lower than study of
20 mg/kg bw BCEE received a total of 24 that observed in animals injected with carcinogenic
injections while animals administered vehicle alone (0.39 lung tumours/mouse). potential.
40 mg/kg bw BCEE only received 4 injections.
Controls (n = 20) were injected with
vehicle alone. The mice were sacrificed
24 weeks after the initial injection and
the number of surface lung tumours
(adenomas) determined.

Table 7. (continued)

Protocol Result Comments Reference

Thirty female ICR/Ha Swiss mice were Compared to animals injected with vehicle Inconclusive van Duuren et
injected subcutaneously with 1 mg BCEE alone, where no tumours developed at the evidence of al., 1972
(suspended in 0.05 ml mineral oil) once site of injection, 2/30 animals injected carcinogenicity
a week for life (median survival time with BCEE developed sarcomas at the site in a limited study
of animals was 656 days). Controls of injection. involving small
(n = 30) were administered vehicle alone. numbers of animals
administered one
dose-level with
inadequate
reporting of data
on other effects.

Groups of 50 male and 50 female The incidence of all malignant and No evidence of Norpoth et al.,
Sprague-Dawley rats were injected benign tumours (e.g., mesenchymal, carcinogenicity 1986
subcutaneously with either 4.36 µmole epithelial, sarcomas, carcinomas, in a study
(0.62 mg) or 13.1 µmole(1.87 mg) BCEE unclassified) in the untreated controls, involving limited
(dissolved in 0.25 ml DMSO) once a vehicle-treated controls, low- and exposure to
week for two years. Controls were high-dose males and females was 2/35, BCEE with limited
administered DMSO or left untreated. 4/35, 4/50 and 6/50, and 24/50, 24/50, reporting of
23/50 and 22/50, respectively. The toxicological
median survival time of the untreated effects.
control, vehicle-treated control, low-
and high-dose groups was 696, 605, 590
and 643 (for males), and 639, 668, 629
and 654 days (for females), respectively.

Table 7. (continued)

Protocol Result Comments Reference

One milligram of BCEE (in 0.1 ml The incidence of skin papillomas at No evidence of Van Duuren et
benzene) was applied to the skin of 20 the site of application was 2/20 and skin tumour al., 1972
female ICR/Ha Swiss mice. Two weeks 3/20 in the control and BCEE-initiated initiating
later the secondary (promotion) animals, respectively. activity by
treatment (2.5 µg phorbol myristate