INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
ENVIRONMENTAL HEALTH CRITERIA 115
2-METHOXYETHANOL, 2-ETHOXYETHANOL,
AND THEIR ACETATES
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Labour Organisation, or the World Health Organization.
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the International Labour Organisation,
and the World Health Organization
World Health Orgnization
Geneva, 1990
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WHO Library Cataloguing in Publication Data
2-Methoxyethanol, 2-ethoxyethanol, and their acetates.
(Environmental health criteria ; 115)
1.Ethylene glycols - adverse effects 2.Ethylene glycols - toxicity
I.Series
ISBN 92 4 157115 2 (NLM Classification: QV 633)
ISSN 0250-863X
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CONTENTS
ENVIRONMENTAL HEALTH CRITERIA FOR 2-METHOXYETHANOL, 2-ETHOXYETHANOL,
AND THEIR ACETATES
1. SUMMARY AND CONCLUSIONS
1.1. Identity, physical and chemical properties, analytical methods
1.2. Sources of human and environmental exposure
1.3. Environmental transport, distribution, and transformation
1.4. Environmental levels and human exposures
1.5. Kinetics and metabolism
1.6. Effects of organisms in the environment
1.7. Effects on experimental animals and in vitro test systems
1.7.1. Systemic toxicity
1.7.2. Carcinogenicity and mutagenicity
1.7.3. Male reproductive system
1.7.4. Developmental toxicity
1.8. Effects on man
1.9. Conclusions
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, 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. Man-made sources
3.2.1. Industrial production
3.2.1.1 Manufacturing processes
3.2.1.2 World production figures
3.3. Uses
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION
4.1. Transport and distribution between media
4.2. Biotransformation
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1. Environmental levels
5.2. General population exposure
5.3. Occupational exposure
6. KINETICS AND METABOLISM
6.1. Absorption
6.2. Distribution
6.3. Metabolic transformation
6.4. Elimination and excretion
7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT
8. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS
8.1. Single exposures
8.2. Short-term exposures
8.2.1. Haematological and immunological effects
8.2.2. Effects on liver and kidney
8.2.3. Behavioural and neurological effects
8.3. Skin and eye irritation; sensitization
8.4. Long-term exposures
8.5. Effects on reproduction and fetal development
8.5.1. Effects on the male reproductive system
8.5.1.1 Oral exposure
8.5.1.2 Inhalation studies
8.5.2. Embryotoxicity and developmental effects
8.5.2.1 2-Methoxyethanol
8.5.2.2 2-Ethoxyethanol
8.5.3. Teratogenicity
8.5.3.1 2-Methoxyethanol
8.5.3.2 2-Ethoxyethanol and 2-ethoxyethanol acetate
8.6. Mutagenicity and related end-points
8.7. Carcinogenicity
8.8. Mechanism of toxicity - mode of action
9. EFFECTS ON MAN
9.1. General population exposure
9.1.1. Poisoning reports
9.2. Occupational exposure
9.2.1. Repeated exposure
9.2.2. Epidemiological studies
10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT
10.1. Evaluation of human health risks
10.1.1. Exposure
10.1.2. Health effects
10.2. Evaluation of effects on the environment
11. RECOMMENDATIONS
11.1. Health protection
11.2. Further research
12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES
REFERENCES
RESUME ET CONCLUSIONS
EVALUATION DES RISQUES POUR LA SANTE HUMAINE ET DES EFFETS SUR
L'ENVIRONNEMENT
RECOMMANDATIONS
RESUMEN Y CONCLUSIONES
EVALUACION DE LOS RIESGOS Y EFECTOS EN EL MEDIO AMBIENTE
RECOMENDACIONES
WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR 2-METHOXYETHANOL,
2-ETHOXYETHANOL, AND THEIR ACETATES
Members
Dr W. Denkhaus, Institute for Occupational and Social Medi-
cine, University of Mainz, Mainz, Federal Republic of
Germany
Dr R.J. Fielder, Medical TEH Division, Department of Health,
Hannibal House, Elephant and Castle, London, United King-
dom
Dr B. Gilbert, Company for the Development of Technology
Transfer (CODETEC), Cidade Universitaria, Campinas,
Brazil (Vice-Chairman)
Dr B. Hardin, Division of Standards Development and Tech-
nology Transfer, National Institute for Occupational
Safety and Health, Cincinnati, Ohio, USA
Dr M. Ikeda, Department of Public Health, Kyoto University
Faculty of Medicine, Kyoto, Japan (Chairman)
Dr S.K. Kashyap, National Institute of Occupational Health,
Ahmedabad, India
Dr L. Rosenstein, Office of Toxic Substances, US Environ-
mental Protection Agency, Washington DC, USA
Dr J. Sokal, Institute of Occupational Medicine, Division of
Industrial Toxicology, Lodz, Poland
Dr H. Veulemans, Laboratory for Occupational Hygiene, De-
partment of Occupational Medicine, University of Leuven,
Leuven, Belgium
Representatives of other Organizations
Dr K. Miller, International Commission on Occupational
Health, British Industrial Biological Research Associ-
ation, Carshalton, Surrey, United Kingdom
Observers
Dr A. Cicolella, Institut National de Recherche et de Sécur-
ité, Vandoeuvre, France
Secretariat
Dr G. Becking, International Programme on Chemical Safety,
Interregional Research Unit, World Health Organization,
Research Triangle Park, North Carolina, USA (Secretary)
Dr H. Teitelbaum, US Environmental Protection Agency,
Office of Toxic Substances, Washington DC, USA
(Rapporteur)
NOTE TO READERS OF THE CRITERIA DOCUMENTS
Every effort has been made to present information in
the criteria documents as accurately as possible without
unduly delaying their publication. In the interest of all
users of the environmental health criteria documents,
readers are kindly requested to communicate any errors
that may have occurred to the Manager of the International
Programme on Chemical Safety, World Health Organization,
Geneva, Switzerland, in order that they may be included in
corrigenda, which will appear in subsequent volumes.
* * *
A detailed data profile and a legal file can be
obtained from the International Register of Potentially
Toxic Chemicals, Palais des Nations, 1211 Geneva 10,
Switzerland (Telephone No. 7988400 or 7985850).
ENVIRONMENTAL HEALTH CRITERIA FOR 2-METHOXYETHANOL, 2-ETHOXYETHANOL,
AND THEIR ACETATES
A WHO Task Group on Environmental Health Criteria for
2-Methoxyethanol, 2-Ethoxyethanol, and their Acetates met
at the British Industrial Biological Research Association
(BIBRA), Surrey, United Kingdom, from 4 to 7 April 1989.
The meeting was sponsored by the United Kingdom Department
of Health and Social Services. Dr S.D. Gangoli, Director,
BIBRA, welcomed the participants on behalf of the host
institution, and Dr G.C. Becking opened the meeting on
behalf of the three co-operating organizations of the IPCS
(ILO/UNEP/WHO). The Task Group reviewed and revised the
draft document and made an evaluation of the risks for
humans and the environment from exposure to these four
glycol ethers.
The first and second drafts of this document were
prepared by Dr H. TEITELBAUM, US Environmental Protection
Agency, Washington DC, USA.
The efforts of all who helped in the preparation and
finalization of the document are gratefully acknowledged.
Dr G. Becking and Dr P.G. Jenkins, both members of the
IPCS Central Unit, were responsible for the overall
scientific content and technical editing, respectively.
ABBREVIATIONS
ADH alcohol dehydrogenase
EAA ethoxyacetic acid
ECG electrocardiogram
2-EE 2-ethoxyethanol
2-EEA 2-ethoxyethyl acetate
GC-FID gas chromatography with flame ionization detector
HPLC high performance liquid chromatography
LOEL lowest-observed-effect level
MAA methoxyacetic acid
2-ME 2-methoxyethanol
2-MEA 2-methoxyethyl acetate
NIOSH National Institute for Occupational Safety and Health (USA)
NOEL no-observed-effect level
ODC ornithine decarboxylase
OSHA Occupational Safety and Health Administration (USA)
PCB polychlorinated biphenyl
SCE sister chromatid exchange
TWA time-weighted average
UDS unscheduled DNA synthesis
1. SUMMARY AND CONCLUSIONS
1.1. Identity, Physical and Chemical Properties, Analytical Methods
This monograph considers only the methyl and ethyl
ethers of ethylene glycol, i.e. 2-methoxyethanol (2-ME)
and 2-ethoxyethanol (2-EE), and their respective acetate
esters, 2-methoxyethyl acetate (2-MEA) and 2-ethoxyethyl
acetate (2-EEA). These four compounds are all stable,
colourless, flammable liquids with a mild ethereal odour
and are all miscible with (or in the case of 2-EEA very
soluble in) water and miscible with a large number of
organic solvents.
Analytical methods are available for the detection of
these glycol ethers or their metabolites in various media
(air, water, blood, and urine). They often employ adsorp-
tion or extraction procedures to concentrate the sample,
followed by gas chromatographic analysis. Using gas or
high performance liquid chromatography, 2-methoxyacetic
acid (MAA) and 2-ethoxyacetic acid (EAA), (metabolites of
2-ME and 2-EE) can be measured in urine, usually after
derivatization, at concentrations between 5 and 100 µg/ml.
1.2. Sources of Human and Environmental Exposure
The four glycol ethers reviewed are all produced by
the reaction of ethylene oxide with the appropriate
alcohol, followed, when required, by esterification with
ethanoic acid.
Data for world production of these glycol ethers are
not available. However, the combined annual production
in Western Europe, USA, and Japan is approximately 79 x
103 tonnes of 2-ME and 205 x 103 tonnes of 2-EE. A
large proportion is used in the coatings industry (paints,
stains, and lacquers) and as solvents for printing inks,
resins and dyes, and home and industrial cleaners. They
are also used as anti-icing additives in hydraulic fluids
and jet fuel.
1.3. Environmental Transport, Distribution, and Transformation
The solubility of these glycol ethers in water and
their relatively low vapour pressure could result in their
build-up in water in the absence of degradation. However,
degradation by microorganisms in soil, sewage sludge, and
water appears to prevent this possibility.
Atmospheric emissions resulting from the use of glycol
ethers as evaporative solvents result in the greatest
environmental exposure. In the general environment, photo-
lytic degradation appears to be rapid, and levels below
0.0007 mg/m3 (2 x 10-4 ppm) would be expected.
Under aerobic conditions glycol ethers are degraded
rapidly by microorganisms to carbon dioxide and water,
whereas under anaerobic conditions methane and carbon
dioxide are the major end-products.
1.4. Environmental Levels and Human Exposures
The use of glycol ethers can result in significant
widespread emissions to the environment. There is particu-
lar concern for direct human exposure in industry, in
small work-shops, and during home use of products con-
taining glycol ethers. Occupational exposure values of
< 0.1 mg/m3 to > 150 mg/m3 have been reported. Signifi-
cant exposure could occur to users of consumer products
but no data are available.
In addition to exposure from airborne glycol ethers,
humans may be exposed dermally. Blood analyses confirm
rapid absorption by this route, which may contribute more
than airborne exposure to the total body burden.
1.5. Kinetics and Metabolism
All four glycol ethers have been shown to be readily
absorbed through the skin, lungs, and gastrointestinal
tract. The highest levels detected in distribution studies
on 2-ME in pregnant mice were in the maternal liver,
blood, and gastrointestinal tract, and in the placenta,
yolk sac, and numerous embryonic structures.
The metabolic transformation of 2-ME gives two primary
metabolites: MAA and 2-methoxyacetyl glycine. Metabolism
to carbon dioxide represents a secondary, minor route.
The conversion in plasma of 2-ME to MAA is rapid, with a
half-life of 0.6 h in rats, but the excretion of MAA is
slow, with a half-life of about 20 h in the rat and 77 h
in man.
In laboratory animals, administration of 2-EE led to
the production of EAA and 2-ethoxyacetyl glycine, EAA
being the major metabolite appearing in the presumptive
target organ, the testes. In a human study using 2-EEA, a
similar metabolic pathway was seen, the acetate being
hydrolyzed first to 2-EE and subsequently oxidized to EAA.
The resultant EAA was excreted with an estimated half-life
of 21-42 h. Experimental work suggests that the retention
or accumulation of metabolites could be toxicologically
significant assuming that these metabolites are respon-
sible for the observed target-organ toxicity.
1.6. Effects on Organisms in the Environment
The toxicity of 2-ME and 2-EE to microorganisms and
aquatic animals appears to be low. For microorganisms,
the lethal concentration in the medium is greater than 2%.
Growth inhibition of green algae by 2-ME was noted at 104
mg/litre and of cyanobacteria (blue-green algae) at 100 mg
per litre. The acute toxicity of 2-EE is very low for arthro-
pods (LC50 > 4 g/litre) and freshwater fish (LC50 > 10 g per
litre). The glycol ether acetates (2-MEA and 2-EEA) are
far more toxic to fish. The LC50 of 2-EEA for fathead
minnows is 46 mg/litre and that of 2-MEA for tidewater
silverfish and bluegills is 45 mg/litre. There have been
no long-term studies.
1.7. Effects on Experimental Animals and In Vitro Test Systems
1.7.1. Systemic toxicity
The toxicity of 2-ME and 2-EE to experimental animals
has been much more widely studied than that of 2-MEA and
2-EEA.
2-ME and 2-EE and their acetates have similar
lethalities after single exposures and they show low acute
lethality whether exposure is via the dermal, oral, or
inhalation route. Oral LD50 values for a variety of
species range between 900 and 3400 mg/kg body weight for
2-ME, 1400 and 5500 mg/kg for 2-EE, 1250 and 3930 mg/kg
for 2-MEA, and 1300 and 5100 mg/kg for 2-EEA. Inhalation
LC50 values of 4603 mg/m3 (2-ME) and 6698 mg/m3 (2-EE)
have been reported in mice.
Only limited data on skin and eye irritation or on the
sensitization potential of these glycol ethers in animals
is available. It would appear that they are not irritating
to the skin, but that they can cause eye irritation. No
skin irritation or skin sensitization has been reported in
humans in spite of extensive exposures.
Short-term inhalation exposure (up to 90 days) of
experimental animals to high concentrations (> 9313 mg
2-ME/m3 and > 1450 mg 2-EE/m3) has been shown to lead
to adverse effects on blood parameters, the nervous
system, and testes, thymus, kidney, liver, and lung. At
lower exposure levels, effects are observed on the
haemopoietic system and testes. For example, rats exposed
by inhalation to 2-ME for 13 weeks at levels between 93
and 930 mg/m3 exhibited reduced packed cell volume and
white blood cell, haemoglobin, platelet, and serum protein
concen-trations at the highest dose only, while similarly
exposed rabbits had decreased thymus size, in addition to
the decreased blood parameters, at 930 mg/m3. 2-EE
exhibited similar but less severe effects in rats and
rabbits when animals were exposed for 13 weeks at a level
of 1450 mg/m3. No data are available from long-term
studies.
1.7.2. Carcinogenicity and mutagenicity
The mutagenicity of 2-ME has been investigated in a
range of in vitro systems using bacteria and mammalian
cells. Although most studies yielded negative results,
there were reports of positive mutagenicity results at
very high 2-ME concentrations in CHO cells when investi-
gated for chromosome aberration (at 6830 µg/ml or more)
and sister chromatid exchange (3170 µg/ml or more).
However, in vivo studies for chromosome aberrations and
micronuclei were negative. Only very limited information
on the mutagenic potential of 2-EE is available, and there
are no carcinogenicity data for these glycol ethers.
1.7.3. Male reproductive system
The effect of 2-ME on the male reproductive system has
been intensively investigated following both oral and
inhalation exposure in rodents. Degenerative changes in
the germinal epithelium of the seminiferous tubules were
consistently noted. Similar effects were seen with 2-EE
but at somewhat higher dose levels.
Oral dosing of rats with 2-ME for 1-11 days resulted
in a dose-related decrease in sperm count and changes in
sperm motility and morphology at dose levels of 100 mg/kg
body weight or more. Marked histological damage was seen
in the testes at autopsy. The no-observed-effect level
(NOEL) was 50 mg/kg. Reduced fertility was still evident
8 weeks after exposure to 200 mg/kg. Similar effects were
seen at dose levels of 500 mg 2-EE/kg or more, given for
up to 11 days, the NOEL for 11-day treatment being
250 mg/kg. However, when sperm reserves were depleted by
repeated mating, some reduction in sperm counts was seen
at the lowest dose investigated (150 mg/kg). Fertility
studies following a single oral dose of 250 mg 2-ME/kg or
more revealed complete sterility in both rats and mice at
5 weeks post dosing, some decrease in fertility being seen
at 125 mg/kg.
When the inhalation route was investigated, similar
degenerative changes in the testes were seen with 2-ME.
Effects were observed following a single exposure (4 h) to
1944 mg/m3 or more but not to 933 mg/m3. NOEL values
were 311 mg/m3 in rats following exposure for 13 weeks (6
h/day, 5 day/week) and 933 mg/m3 (6 h/day) in mice fol-
lowing exposure on 9 occasions over 11 days. Exposure of
rabbits to 2-ME for 13 weeks (6 h/day, 5 days/week) re-
sulted in marked effects on the testes at 311 mg/m3 or
more; marginal effects were seen at 93 mg/m3, and a
NOEL was not identified.
1.7.4. Developmental toxicity
Developmental toxicity has been observed in several
species of laboratory animals following exposure by all
routes of administration, i.e. oral, inhalation, and
dermal. 2-ME produced teratogenic effects in mice, rats,
rabbits, and monkeys. 2-EE and 2-EEA were teratogenic in
rats and rabbits. Although 2-MEA has not been tested for
developmental toxicity, metabolic profiles (see section 6)
suggest that it is reasonable to expect that 2-MEA would
have a toxicity similar to that of 2-ME.
The widest range of dose/response data (doses of 31.25
to 1000 mg/kg per day) is available for 2-ME. In this
gavage study using mice, (2-ME was administered on days 7
to 14 of gestation), the NOEL for maternal toxicity was
125 mg/kg per day. However, malformations were observed
at 62.5 mg/kg per day and skeletal variations at 31.25
mg/kg per day. A NOEL for developmental toxicity was not
reported. In single-dose studies, mice were treated with
2-ME by gavage on gestation day 11; 100 mg/kg was not
fetotoxic, while 175 mg/kg produced digit defects without
other signs of maternal or fetal toxicity. Cardiovascular
defects and ECG abnormalities were observed in neonatal
rats following treatment on days 7 to 13 of gestation with
25 mg/kg per day. Since that was the lowest dose tested,
this study yielded no developmental NOEL (maternal
toxicity was not observed at that dose). Similarly, no
NOEL for developmental toxicity could be determined when
monkeys were treated by gavage with 2-ME at 0.16, 0.32, or
0.47 mmol/kg per day on days 20 to 45 of gestation.
Fetotoxicity in mice and rats and malformations in
rabbits were observed following exposure by inhalation to
2-ME at 156 mg/m3. For all three species, the NOEL for
developmental effects was 31 mg/m3. However, behavioural
and neurochemical alterations were seen in the offspring
of rats exposed to 78 mg 2-ME/m3 on days 7-13 or 14-20 of
gestation.
Following inhalation exposure of rats (743 mg/m3) and
rabbits (589 mg/m3), 2-EE was found to be teratogenic
(in the presence of slight maternal toxicity). Another
study reported fetotoxicity but no malformations in rats
exposed to 184 or 920 mg 2-EE/m3, and in rabbits exposed
to 644 mg 2-EE/m3. NOEL values for developmental effects
were 37 mg/m3 for rats and 184 mg/m3 for rabbits. Behav-
ioural and neurochemical alterations were seen in the off-
spring of rats exposed to 368 mg 2-EE/m3 on days 7-13 or
14-20 of gestation.
Rats treated by dermal application of 0.25 ml undi-
luted 2-EE (four times daily on gestation days 7-16)
exhibited marked fetotoxicity and a high incidence of
malformation in the absence of maternal toxicity. Similar
effects were noted following 2-EEA treatment of rats,
using the same protocol, at an equimolar dose (0.35 ml,
four times daily).
Inhalation exposure of rabbits to 2-EEA on gestation
days 6-18 produced teratogenic responses at 2176 mg/m3 and
544 mg/m3 in two different studies, the developmental
NOEL values in these two studies being 135 mg/m3 and 270
mg/m3. Exposure of rats to 2-EEA on days 6-15 of ges-
tation produced fetotoxicity at 540 mg/m3 and malfor-
mation at 1080 mg/m3. The developmental NOEL was 170
mg/m3.
1.8. Effects on man
Information on the toxic effects of these four glycol
ethers on humans is limited. The results from the few
case reports and workplace epidemiological studies are
consistent with the adverse effects seen in experimental
animals. No reports quantifying general population
exposure and health effects have been found.
In two non-fatal cases of poisoning by ingestion of
100 ml 2-ME, the predominant signs and symptoms were
nausea, vertigo, cyanosis, tachycardia, hyperventilation,
and metabolic acidosis, with some evidence of renal
failure. Similar but less severe symptoms were found in a
person ingesting 40 ml 2-EE. In a fatal poisoning
resulting from the ingestion of 400 ml 2-ME, postmortem
findings showed acute haemorrhagic gastritis, fatty
degeneration of the liver, and degenerative changes in
renal tubules.
Repeated exposure of workers to 2-ME and 2-EE, in
addition to other solvents, resulted in anaemia,
leucopenia, general weakness, and ataxia. No reliable
estimation of exposure was made in many of these reported
studies. Haematological effects of glycol ethers on humans
have been documented and the development of macrocytic
anaemia in a worker exposed to 2-ME (average 105 mg/m3),
along with other solvents, has been described.
Bone marrow toxicity has been reported in workers
exposed dermally to 2-ME, and immunological effects have
been noted in workers following prolonged exposure (8-35
years) to 2-ME and 2-EE (mean exposures being 6.1 mg/m3
and 4.8 mg/m3, respectively).
Epidemiological studies of workers exposed to 2-ME and
2-EE have shown some evidence of adverse effect on the
male reproductive system, with an increased frequency of
reduced sperm counts. Exposure to 2-EE (37 workers) at
levels up to 88.5 mg/m3 led to change in semen indices.
Among 73 workers exposed to 2-ME (up to 17.7 mg/m3) and
2-EE (up to 80.5 mg/m3), there was an increased fre-
quency of reduced sperm counts and also evidence of haema-
tological effects when exposures (TWA) were 2.6 mg/m3 for
2-ME and 9.9 mg/m3 for 2-EE.
The adverse effects noted in humans exposed occu-
pationally are consistent with those noted in experimental
animals. However, due to deficiencies in exposure
assessments and to mixed exposures, no dose-response
relationships can be determined.
1.9. Conclusions
Many people may be exposed to these four glycol ethers
at levels comparable to industrial levels through the use
of consumer and trade products. Significant occupational
exposure may occur both through inhalation and skin
absorption. Limited measurements of air levels in the
workplace range from < 0.1 mg/m3 to > 150 mg/m3.
Both 2-ME and 2-EE demonstrate low toxicity to micro-
organisms and aquatic species. No data exist to ascertain
the potential for adverse effects on environmental
species from long-term exposure.
In rats, the NOEL in acute studies for testicular
effects was 933 mg 2-ME/m3, and the NOEL for repeated
exposure was 311 mg/m3. In repeated exposure studies using
the most sensitive species, the rabbit, a clear effect was
detected at 311 mg/m3, whereas at 93 mg/m3 there was a
marginal effect (1 in 5 animals). Evidence from studies
on men exposed occupationally to 2-ME and 2-EE indicates
that these glycol ethers can produce testicular toxicity
in humans.
Developmental toxicity has been observed in all
species (mice, rats, and rabbits exposed to 2-ME at 156
mg/m3 or more. The NOEL for all three species was 31
mg/m3. Behavioural and neurochemical alterations in
rats followed in utero exposure to 78 mg/m3, no NOEL
being identified. 2-EE and 2-EEA were slightly less
potent. Developmental effects were observed in rats and
rabbits following exposure to 2-EE at 368 mg/m3 or
more. These effects were slight in rats exposed to 184 mg
2-EE/m3, but 37 mg/m3 was a clear NOEL for both rats
and rabbits.
Haematological effects are produced by these glycol
ethers in mice, rat, rabbits, dogs, hamsters, and guinea-
pigs. This agrees with haematological effects reported in
some of the limited number of studies of industrial
workers exposed repeatedly to 2-EE and/or 2-ME. In
repeated-exposure animal studies, the NOEL was 93 mg
2-ME/m3 in rabbits and 368 mg 2-EE/m3 in rats and
rabbits. No data have been found to evaluate quantitat-
ively the haematological effects that follow acute
exposure.
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS
2.1. Identity
The four glycol ethers discussed in this monograph,
i.e. 2-methoxyethanol (2-ME), 2-methoxyethyl acetate
(2-MEA), 2-ethoxyethanol (2-EE), and 2-ethoxyethyl acetate
(2-EEA), are stable flammable liquids with a slight odour
at normal room temperature and pressure. Their structural
formulae are:
H H H
| | |
H - C - O - C - C - OH 2-methoxyethanol
| | |
H H H
H H H H
| | | |
H - C - C - O - C - C - OH 2-ethoxyethanol
| | | |
H H H H
H H H O H
| | | || |
H - C - O - C - C - O - C - C - H 2-methoxyethyl acetate
| | | |
H H H H
H H H H O H
| | | | || |
H - C - C - O - C - C - O - C - C - H 2-ethoxyethyl acetate
| | | | |
H H H H H
Information on the identity of the four selected
glycol ethers is presented in Table 1.
2.2. Physical and Chemical Properties
A summary of the physical and chemical properties of
these four glycol ethers (2-ME; 2-MEA; 2-EE; 2-EEA) is
given in Table 2.
2.3. Conversion Factors
2-Methoxyethanol (2-ME) 1 ppm = 3.11 mg/m3
2-Methoxyethyl Acetate (2-MEA) 1 ppm = 4.83 mg/m3
2-Ethoxyethanol (2-EE) 1 ppm = 3.68 mg/m3
2-Ethoxyethyl Acetate (2-EEA) 1 ppm = 5.40 mg/m3
2.4. Analytical Methods
Several analytical procedures used for the determi-
nation of 2-ME, 2-MEA, 2-EE, and 2-EEA in various environ-
mental media are summarized in Table 3. In some reports,
the useful range was indicated but not the limit of
detection.
In reporting the methods validated by NIOSH (1987a,
1987b), only the range that has been confirmed as accurate
is shown. However, these methods may be capable of
measuring much lower levels of glycol ethers in air pro-
viding adequate sampling times are employed and desorption
efficiencies ascertained.
Variations on the basic NIOSH sampling and gas chroma-
tographic methods have been reported by Denkhaus et al.
(1986), and the measurement of glycol ethers in the
workplace using diffusive monitors has been described by
Hamlin et al. (1982).
Metabolites of 2-EE and 2-ME in urine have been
measured using either gas chromatography (Groeseneken et
al., 1986a, 1989b; Smallwood et al., 1984, 1988), or HPLC
analysis (Cheever et al., 1984).
Using methylene chloride extractions of acidified
urine, followed by derivatization with pentafluorobenzyl
bromide, average recoveries of 78 and 91% were obtained
for methoxyacetic acid (MAA) and ethoxyacetic acid (EAA),
respectively. Detection limits for GC-FID analysis were
11.4 µg/ml for MAA and 5.0 µg/ml for EAA (Smallwood et
al., 1984). Smallwood et al. (1988) have reported that a
range of 5 to 100 µg EAA/ml in urine can be analysed.
Preliminary results indicate that this procedure can be
used to detect exposure to 2-EE in shipyard workers using
2-EE-containing paints. Groeseneken et al. (1986a)
utilized similar extraction procedures and GC-FID analysis
after diazomethane derivatization. Although recoveries
were low (50-60%), the method could quantify 0.15 mg MAA
per litre and 0.07 mg EAA/litre. Groeseneken et al.
(1989b) have recently described an improved method for
detecting MAA and EAA in urine. Recoveries were in excess
of 90%, linear standard curves were obtained over a broad
range (0.1-200 mg/litre), and the possible interference by
gly-colic acid in the assay previously described
(Groeseneken et al. 1986a) was eliminated. Cheever et al.
(1984) ana-lysed urine samples, directly at pH 3 by HPLC,
for EAA after animals were dosed with 230 mg 2-EE/kg body
weight, but no limit of detection or appropriate range for
use was reported. However, this method may be useful for
biological monitoring of exposed populations.
Table 1. The identity of selected glycol ethers
----------------------------------------------------------------------------------------------------
Chemical CAS Number Molecular Common Some common
formula synonyms trade names
----------------------------------------------------------------------------------------------------
2-Methoxyethanol 109-86-4 C3H8O2 Ethylene glycol Methyl Cellosolve;
(2-ME) monomethyl ether; Jeffersol EM;
ethanol, 2-methoxy; Dowanol EM; Poly-solv
EGM ether EM; Methyl oxitol.
2-Methoxyethyl 110-49-6 C5H10O3 Ethylene Methyl Cellosolve
acetate glycol monomethyl acetate
(2-MEA) ether acetate;
ethanol, 2-methoxy-
acetate
2-Ethoxyethanol 110-80-5 C4H10O2 Ethylene glycol Cellosolve, Dowanol
(2-EE) monoethyl ether EE; Oxitol; Ethoxol
2-Ethoxyethyl 111-15-9 C6H12O3 Ethylene glycol Cellosolve acetate;
acetate monoethyl ether Ethyl Cellosolve
(2-EEA) acetate; acetic acetate; Oxitol
acid, 2-ethoxyethyl acetate; Poly-Solv EE
ester.
----------------------------------------------------------------------------------------------------
Table 2. Physical and chemical properties of selected glycol ethersa
---------------------------------------------------------------------------------------------------------
Chemical Relative Density Boiling Vapour Relative Flash Water
molecular (g/ml at point pressure vapour point solubility
mass 20 °C) (°C) (mmHg) density (°C)
(air=1 )
---------------------------------------------------------------------------------------------------------
2-Methoxyethanol 76.09 0.960 124 6.2 at 20 °C 2.6 46.1 open cup infinite
(2-ME) 9.7 at 25 °C 41.7 closed cup
2-Methoxyethyl 118.13 1.005 145 2.0 at 20 °C 4.07 55.6 closed cup infinite
Acetate 5.3 at 25 °C
(2-MEA)
2-Ethoxyethanol 90.12 0.93 135 3.8 at 20 °C 3.0 49 open cup infinite
(2-EE) 5.3 at 25 °C 44 closed cup
2-Ethoxyethyl 132.16 0.975 156 1.2 at 20 °C 4.72 51.1 closed cup 23 g/100g
Acetate 1.1 at 25 °C at 20 °C
(2-EEA)
---------------------------------------------------------------------------------------------------------
a Data from: Rowe & Wolf (1982) and Mellan (1977).
Table 3. Analytical methods for selected glycol ethers and their metabolites
---------------------------------------------------------------------------------------------------------
Matrix Sampling method Analytical Limit of detection Reference
extraction/cleanup methoda or useful range
---------------------------------------------------------------------------------------------------------
Air Adsorption on charcoal, GC-FID range (mg/m3): NIOSH (1987a, 1987b)
elution with methylene 2-ME 44-160;
chloride, carbon 2-MEA 51-214;
disulfide or methylene 2-EE 340-1460
chloride; methanol
Air Inhaled or expired air GC-FID NR Groeseneken et al.
(2-EE) pumped through silica (1986b)
gel, desorbed with
methanol (88% efficient)
Air Diffusive sampling, GC-FID range: 5-20 mg/m3 Hamlin et al. (1982)
(2-ME, 2-EE) adsorption on Tenax
thermal desorption
Air Personal monitors with GC-FID range: 0.5-250 mg/m3 Health and Safety
(2-ME, 2-EE) pump adsorption on Executive (1988)
Tenex thermal desorption
Water Direct analysis of HPLC-UV 5 mg/litre; Bailey et al. (1985)
(2-EEA) aqueous solutions range: 5-1000 mg/litre
Blood Methylene chloride GC-FID 2-ME 8.8 mg/kg; range Smallwood et al.
(2-ME, 2-EE) extraction in presence 8-946 mg/kg (1984)
of anhydrous sodium 2-EE 5.0 mg/kg; range
sulfate. Average 6-895 mg/kg
recoveries 2-ME (78%),
2-EE (84%)
Blood Head-space elution GC-FID NR Denkhaus et al.
(2-ME, 2-EE) (1986)
Urine Methylene GC-FID MAA 11.4 mg/litre; range Smallwood et al.
(MAA, EAA) extraction followed 11.4-1140 mg/litre (1984)
by derivatization with EAA 5.0 mg/litre; range
pentafluorobenzyl bromide 10-1000 mg/litre
Table 3 (contd)
---------------------------------------------------------------------------------------------------------
Matrix Sampling method Analytical Limit of detection Reference
extraction/cleanup methoda or useful range
---------------------------------------------------------------------------------------------------------
Urine Lyophilization followed GC-FID MAA 0.03 mg/litre; range Groeseneken et al.
(MAA, EAA) by derivatization 0.1-200 mg/litre (1989b)
with pentafluorobenzyl EAA 0.03 mg/litre; range
0.1-200 mg/litre
-----------------------------------------------------------------------------------------------------------
a GC-FID = gas chromatography-flame ionization detector;
HPLC-UV = high performance liquid chromatography with ultraviolet light detection;
NR = not reported.
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1. Natural Occurrence
The two glycol ethers and their acetates (2-ME, 2-MEA,
2-EE, 2-EEA) have not been reported to occur as natural
products.
3.2. Man-Made Sources
3.2.1. Industrial production
3.2.1.1 Manufacturing processes
The production process for 2-ME and 2-EE involves the
reaction of the relevant alcohol with ethylene oxide to
produce the required glycol ether (Kirk-Othmer, 1980).
The acetates, 2-MEA and 2-EEA, are produced by standard
esterification techniques using 2-ME or 2-EE, the acid
anhydride or chloride, and an acid catalyst (Kirk-Othmer,
1980).
3.2.1.2 World production figures
The use of 2-ME and 2-EE has declined over the past
few years because they have been partially replaced in
some countries by less toxic substances. Estimates of
production levels for three major industrialized areas are
shown in Table 4. Production figures for other regions of
the world have not been found.
Table 4. Estimated production (in tonnes) of 2-EE and 2-ME in 1981a
-----------------------------------------------------------
Region or Country 2-ME 2-EE
-----------------------------------------------------------
Western Europe 37 000 116 000
Japan 3100 9800
United States 39 000 79 000
-----------------------------------------------------------
a These are estimates taken from US EPA (1987);
production figures for the rest of the world have not
been found.
3.3. Uses
2-ME, 2-EE, 2-MEA, and 2-EEA have a wide range of uses
as solvents with particular applications in paints,
stains, inks, lacquers, and the production of food-contact
plastics. The major function of these agents is to
dissolve various components of mixtures, in both aqueous
and non-aqueous systems, and to keep them in solution
until the last stages of evaporation. It is these
dispersive applications that cause the greatest concern
for widespread human and environmental exposure.
In addition, these four glycol ethers are used as
resin solvents, in surface coatings and inks for silk-
screen printing and in photographic and photolithographic
processes, as solvents for dyes in textile and leather
finishing, and as general solvents in a wide variety of
home and industrial cleaners. 2-ME is used extensively as
an anti-icing additive in hydraulic fluids and jet fuel
for military and small civilian jet aircraft, as well as
in hydraulic brake fluids (Mellan, 1977).
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION
4.1. Transport and Distribution Between Media
The greatest environmental exposure to glycol ethers
results from their direct release into the atmosphere
when they are used as evaporative solvents. Given the
amounts synthesized and transported, there is also a great
potential for environmental exposure from accidental
releases and the disposal of cleaning products and con-
tainers. Discharges of this type result in the transport
of these chemicals to land and water. Because of their
water solubility and low vapour pressure, they could build
up in water in the absence of degradation. However, their
levels in soil and water would be expected to decrease
fairly quickly because of rapid hydrolysis and/or oxi-
dation. Also, adapted sludge has been reported to digest
these compounds (Verschueren, 1977), giving 90% degra-
dation of 2-EE after 5.5 days.
Since all of the major degradation processes in soil
and water are oxidative, the potential exists for persist-
ent contamination of anaerobic soils, such as landfills,
and their underlying anaerobic aquifers. Contamination of
ground water by 2-EE and 2-EEA from leaking storage tanks
has been observed (Botta et al., 1984). However, 2-ME can
apparently serve as a substrate for anaerobic methane fer-
mentation and is digested by anaerobic sludge (Tanaka et
al., 1986). Under such conditions, contamination of soil
and ground water would be transitory.
4.2. Biotransformation
Under normal aerobic conditions, 2-ME, 2-EE, and their
acetates would be expected to be degraded readily to car-
bon dioxide and water by microorganisms. Under anaerobic
conditions, 2-ME is degraded by mesophilic sludge through
at least two pathways, depending on temperature and pH,
with methane and carbon dioxide being the end products in
both cases (Tanaka et al., 1986). Optimal conditions for
degradation are pH 7.5 and 30-35°C.
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1. Environmental Levels
The patterns of use of these four glycol ethers can
result in significant, widespread emissions to the environment.
Therefore, there is a great potential for exposure to
people in the workplace, as well as to the general pop-
ulation and to the environment. However, no data on the
levels of 2-ME, 2-EE, and their acetates in the general
environment have been found. As a result of the rates of
degradation and the physical and chemical properties of
these compounds, it is highly unlikely that food chain
accumulation would occur.
5.2. General Population Exposure
No data have been found that would allow an estimate
to be made of the exposure to the general population using
these evaporative solvents. However, there is particular
concern for direct human exposure in small workshops and
by individual users, where the products are being used in
environments with either poor or non-existent ventilation,
or where skin exposure may not be controlled adequately.
5.3. Occupational Exposure
Workers, other than those in large industrial estab-
lishments, constitute the largest population group subject
to high exposure. In the USA, airborne exposures have been
measured for some of the trades, many of the industrial
uses, and for workers involved in the manufacture of these
compounds (Table 5). In a survey of European manufacturing
sites, the time-weighted averages (TWAs) for workers ex-
posed to 2-ME, 2-MEA, 2-EE, and 2-EEA were reported as
28.9, 4.3, 15.8, and 14.6 mg/m3 (9.3, 0.9, 4.3, and 2.7
ppm), respectively (ECETOC, 1985). As estimates of ex-
posure, these measurements do not take into account dermal
or aerosol exposures, which may be very significant (see
section 9.2). A summary of the exposure of workers in the
semiconductor industry to 2-ME, 2-MEA, 2-EE, or 2-EEA
(Table 6) (Paustenbach, 1988) reports exposures lower than
those in other industries within the USA (Table 5). These
measurements do not accurately reflect exposure during
uses such as maintenance painting (as opposed to
industrial production), because here there is a wide vari-
ation in exposure conditions. Modelling of the possible
range of exposures in trade and consumer uses might pro-
vide some useful data.
The exposure data available from large industries
suggest that the majority of exposures are "low", i.e.
exposures for 2-ME are below 0.1 mg/m3 (0.03 ppm) and for
2-EE are below 1.8 mg/m3 (0.5 ppm). However, in almost
all industries studied there are some workers exposed to
much higher levels (see section 9). For example, monitor-
ing carried out in a number of industries using glycol
ethers (Hamlin et al., 1982) involved both personal and
area monitoring and covered a range of applications in
flexographic and gravure printing, car refinishing, film
coating, and printing ink manufacture. Although atmos-
pheric concentrations were generally low, levels of up to
74 mg 2-EE/m3 (20 ppm) and 146 mg 2-ME/m3 (47 ppm) were
reported in some poorly ventilated areas. There was wide
variation in the exposure between different plants, even
when these plants used the same process.
Air samples (2654 total) from 336 plants in Belgium
have been analysed for glycol ethers (including 2-ME,
2-EE, and their acetates) (Veulemans et al., 1987b). One
or more glycol ethers were detected in 262 air samples
covering 78 plants, 2-EE and its acetate being detected
most often. Detectable levels were of the order of 9.2 mg
per m3, 25% being above 18.4 mg/m3.
Engineering models have been used to estimate ex-
posure resulting from the use of paint, coatings, stains,
etc., containing 2-ME, 2-EE, and their acetates. Such
models indicate that peak exposure values of > 30 ppm and
1-h average exposures of > 5 ppm will occur when paints
and similar products containing more than 2% of these sol-
vents are used (US EPA, 1987). Much higher exposure levels
are possible when the concentration of 2-ME or 2-EE in the
paint is higher. These estimates apply to situations where
protective equipment or special engineering controls were
not available. Under industrial conditions, exposure may
be lower than these models predict if ventilation, exhaust
hoods, or other protective equipment are used.
Table 5. Summary of occupational exposures (mg/m3) to glycol ethers in the USAa
------------------------------------------------------------------------------------------------------------
Chemical and Arithmetic Arithmetic Standard Geometric Geometric
job category rangeb mean deviation mean deviation
------------------------------------------------------------------------------------------------------------
2-MEc
Operator 0.31-188.5 (0.1 -60.6) 59.28 (19.06) 8.40 (2.70) 23.10 (7.43) 56.98 (18.32)
Miscellaneous 9.33 (3.00) 3.11 (1.00) 9.33 (3.00)
Painter 0.31- 10.3 (0.1 - 3.3) 6.87 (2.21) 7.43 (2.39) 2.08 (0.67) 7.43 (2.39)
Painter/screener 0.31- 12.1 (0.1 - 3.9) 6.22 (2.00) 7.15 (2.30) 1.95 (0.63) 5.91 (1.90)
2-MEd
Painter 3.76- 18.7 (1.21- 6.01) 11.23 (3.61) 5.69 (1.83) 8.40 (2.70) 7.46 (2.40)
Operator 5.19- 7.68 (1.67- 2.47) 6.44 (2.07) 3.76 (1.21) 6.31 (2.03) 1.24 (0.40)
2-MEe
Operator 0.31- 35.14 (0.1 -11.3) 7.28 (2.34) 9.39 (3.02) 1.37 (0.44) 11.26 (3.62)
2-MEAc
Miscellaneous 0.48- 40.57 (0.1 - 8.4) 12.94 (2.68) 13.09 (2.71) 1.69 (0.35) 16.81 (3.48)
Operator 0.48- 26.56 (0.1 - 5.5) 7.87 (1.63) 13.04 (2.70) 1.98 (0.41) 10.19 (2.11)
Printer/screener 0.48- 5.07 (0.1 - 1.05) 2.13 (0.44) 16.23 (3.36) 0.87 (0.18) 3.86 (0.80)
Painter 0.48- 14.49 (0.1 - 3.0) 1.88 (0.39) 15.94 (3.30) 0.77 (0.16) 3.31 (0.70)
2-EEc
Painting 0.37-313.9 (0.1 -85.3) 71.21 (19.35) 13.69 (3.72) 2.72 (0.74) 74.30 (20.19)
Printer 0.37- 87.95 (0.1 -23.9) 17.77 (4.83) 9.09 (2.47) 4.49 (1.22) 19.95 (5.42)
Coating/adhesive 0.37- 36.80 (0.1 -10.0) 5.89 (1.60) 13.14 (3.57) 0.99 (0.27) 11.85 (3.22)
Mechanical industry 0.37 (0.10) 3.68 (1.00) 0.04 (0.01)
Leather 0.37 (0.10) 3.68 (1.00) 0.04 (0.01)
Operation/prod. 0.37 (0.10) 3.68 (1.00) 0.04 (0.01)
--------------------------------------------------------------------------------------------------------------
Table 5. (contd.)
--------------------------------------------------------------------------------------------------------------
Chemical and Arithmetic Arithmetic Standard Geometric Geometric
job category rangeb mean deviation mean deviation
--------------------------------------------------------------------------------------------------------------
2-EEd
Printer/screener 6.92-161.9 (1.88-44.0) 84.90 (23.07) 6.92 (1.88) 59.80 (16.25) 59.28 (16.11)
2-EEe
Printer/screener 0.37- 54.10 (0.1-14.79) 16.74 (4.55) 9.02 (2.45) 3.35 (0.91) 18.58 (5.05)
2-EEAc
Leather 6.75- 51.30 (1.25-9.5) 30.89 (5.72) 9.34 (1.73) 22.90 (4.24) 18.36 (3.40)
& coating 0.54-272.38 (0.1-50.44) 20.79 (3.85) 21.98 (4.07) 2.70 (0.50) 51.68 (9.57)
Prod./maint. 0.54- 27.0 (0.1- 5.0) 9.50 (1.76) 13.77 (2.55) 2.59 (0.48) 11.29 (2.09)
2-EEAd
Painter 1.03- 5.08 (0.19-0.94) 3.08 (0.57) 9.88 (1.83) 2.27 (0.42) 2.05 (0.38)
2-EAe
Miscellaneous 15.12-230.04 (2.8-42.6) 67.61 (12.52) 14.04 (2.60) 36.72 (6.80) 82.57 (15.29)
--------------------------------------------------------------------------------------------------------------
a From: US EPA (1987). Values were reported as ppm in the original report and are given in parentheses.
b Values of 0.1 ppm or less are reported as 0.1 ppm.
c Federal (USA) OSHA data.
d California OSHA data.
e NIOSH data.
Table 6. Exposure to glycol ethers within the semiconductor industry in the USA (mg/m3)a
------------------------------------------------------------------------------------------------------------
2-EEA 2-EEA 2-ME 2-ME 2-MEA 2-MEA
Sampling data No. Range Mean + SD No. Range Mean + SD No. Range Mean + SD
------------------------------------------------------------------------------------------------------------
Personal (TWA) 96 0.0054-2.7 0.27±0.43 6 0.12 -3.11 0.68±1.18 16 ND 0.048±0.00
Personal
(Short-term) 21 0.0054-97.2 15.23±29.2 1 NA 80.0 1 NA 82.0
Area (TWA) 128 0.0054-9.72 0.27±0.86 4 0.093-2.49 0.72±1.18 20 ND 0.048±0.00
Area
(Short-term) 10 0.027-81.0 8.42±25.49 1 NA 80.9 1 NA 87.0
------------------------------------------------------------------------------------------------------------
a From: Paustenbach (1988).
No. = number of samples.
Analytical limit of detection: 2-EEA, 0.0054 mg/m3; 2-ME, 0.093 mg/3; and 2-MEA, 0.048 mg/m3.
TWA = time-weighted average.
NA = not applicable.
ND = not detectable.
SD = standard deviation.
6. KINETICS AND METABOLISM
6.1. Absorption
As would be expected from their chemical structures
and solubilities, all four glycol ethers are readily
absorbed through the skin, lungs, and gastrointestinal
tract. Utilizing in vitro techniques, a rate of absorption
of 2-EEA through beagle skin of 2.3 mg/cm2 per h has been
measured (Guest et al., 1984). For isolated human epider-
mis, the following absorption rates have been determined:
2-ME, 2.8 mg/cm2 per h; 2-EE, 0.8 mg/cm2 per h; and
2-EEA, 0.8 mg per cm2 per h (Dugard et al., 1984).
In vivo studies in humans showed rapid absorption of
2-ME after dermal application of 15 ml of solvent (Nakaaki
et al., 1980). Two hours after application, blood levels
reached 200-300 µg/ml. This rate of absorption was ap-
proximately 10 times greater than that of methanol,
acetone, or methyl acetate.
Indirect evidence exists to show that 2-EE is well
absorbed from the gastrointestinal tract of rats. After a
single oral dose of 14C-2EE (230 mg/kg body weight), 76-
80% of the dose was excreted in the urine within 96 h
(Cheever et al., 1984).
6.2. Distribution
Glycol ethers are rapidly metabolized and eliminated
in the mammalian species that have been studied (see sec-
tions 6.3 and 6.4). Very few studies have therefore been
conducted to examine tissue distribution.
Using radioactive 2-ME, Sleet et al. (1986) noted that
radioactivity was present throughout the maternal and con-
ceptus compartments only 5 min after oral administration
of a tracer dose to pregnant mice. The highest levels
were noted in maternal liver, blood, and gastrointestinal
tract, and in the placenta, yolk sac, and embryonic struc-
tures such as limb buds, somites, and neuroepithelium.
Maternal blood levels declined to between 2 and 10% of
peak levels after 24 h. At 6 h post-administration, 69% of
the radioactivity in maternal liver and 33% of that in the
embryo were acid soluble.
6.3. Metabolic Transformation
The glycol ether acetates, 2-EEA and 2-MEA, are rap-
idly hydrolysed in vivo to the free glycol ether (2-EE and
2-ME, respectively) and acetate in rats (Romer et al.,
1985). The metabolism of 2-ME has been studied by Miller
et al. (1983a) and Moss et al. (1985), who found that
methoxyacetic acid (MAA) and methoxyacetyl glycine are the
primary metabolites. MAA accounted for 50 to 60% of the
urinary radioactivity and methoxyacetyl glycine for 18 to
25% during the 48-h observation period following a single
intraperitoneal dose of 2-[methoxy-14C]ethanol (250 mg per
kg body weight) (Moss et al., 1985). The conversion in
plasma of 2-ME to 2-MAA was rapid, the half-life for the
disappearance of 2-ME being 36 min. In the study reported
by Miller et al. (1983a) using 14C labelled 2-ME, 12% of
the dose was eliminated as 14CO2 after 48 h, suggesting
that either 2-ME or its metabolite 2-MAA underwent further
oxidative metabolism.
2-Ethoxyacetic acid (EAA) and 2-ethoxyacetyl glycine
have been found in the urine of rats that had been admin-
istered a single oral dose of 230 mg 2-EE/kg body weight
(Cheever et al., 1984).
Fig. 1 shows the proposed pathway for the metabolism
of 2-ME in the rat (Miller et al., 1983a; Moss et al.,
1985; Foster et al., 1986). This route of metabolism
involves the enzyme alcohol dehydrogenase (ADH), as shown
by the blocking of 2-ME metabolism by the known ADH in-
hibitor 4-methylpyrazole (Moss et al., 1985). In addition,
the administration of ethanol before exposure of rats to
2-ME or 2-EE has been found to prolong the retention of
these glycol ethers in the blood (Romer et al., 1985).
This effect was noted at ethanol blood levels above
3 mmole/litre. The retention of 2-ME or 2-EE in the body
was attributed to the competitive inhibition by ethanol of
the common metabolizing enzyme, alcohol dehydrogenase.
When rats were administered 2-EE at doses from
0.5 mg/kg to 100 mg/kg, Groeseneken et al. (1988) found
increasing relative amounts of EAA in urine (from 13.4% to
36.8% of the total dose). This could be the result of
competition by other metabolic pathways, which would
become more easily saturated at the higher dosage levels.
At 2-EE doses equivalent to the lowest doses in these
animal studies, it was estimated that humans excrete 30-
35% as EAA. Furthermore, 27% (on average) of the EAA was
excreted as the glycine conjugate in the rat, whereas no
glycine conjugation was observed in humans.
The in vitro nasal mucosal carboxylesterase activity
of mice was compared to the activity of other mice tissues
and to the nasal mucosal carboxylesterase activity of
rats, rabbits, or dogs when exposed to 2-MEA or 2-EEA
(Stott & McKenna, 1985). The specific activity in nasal
carboxylase was found to be similar to that of the liver
in mice, but it was greater than the activity found in the
kidney, lung, or blood of mice. Nasal mucosal carboxyl-
esterase activity of mice was comparable to that of dogs,
slightly higher than the activity in rats, and nearly six-
fold higher than the activity in rabbits. These in vitro
studies suggest that considerable hydrolysis may occur in
the intact animal, resulting in the formation of acetic
acid at the initial route of entry.
6.4. Elimination and Excretion
Although 2-ME is rapidly metabolized to 2-MAA after an
intraperitoneal dose of 250 mg/kg body weight in the rat,
the excretion of 2-MAA is fairly slow (half-life of ap-
proximately 20 h) (Moss et al., 1985). In humans, an elim-
ination half-life for 2-MAA of 77.1 h has been reported
(Groeseneken et al., 1989a). The elimination of radioac-
tive 2-EAA (ethyl 1,214C) has been reported in the rat
(half-life of approximately 8 h) (Guest et al., 1984) and
in humans (half-life of approximately 21-42 h)
(Groeseneken, 1986b,c, 1988; Veulemans, 1987a). In rats,
the administration of an oral dose of 230 mg 2-EE/kg body
weight led to the production of EAA and N -ethoxyacety gly-
cine (> 76% of the dose), EAA being the major metabolite
found in testes after 2 h (Cheever et al., 1984).
The urinary excretion of EAA during and after single
4-h exposures to 14, 28, or 50 mg 2-EEA/m3 in human
volunteers has been reported by Groeseneken et al. (1987).
The distribution/excretion time course during and after
2-EEA exposure was similar to that observed for 2-EE.
This indicates that humans, like rodents, hydrolyse the
acetate to 2-EE, which is then converted to the EAA metab-
olite and excreted. The excretion of the EAA metabolite
was observed to be biphasic. A second peak of excretion
occurred approximately 3 h after the first, suggesting
some type of redistribution of the glycol ethers, or of a
metabolite, from a peripheral compartment.
The urinary excretion of EAA was evaluated under field
conditions in which women volunteers were exposed daily to
2-EE or 2-EEA in the process of silk-screen printing
(Veulemans et al., 1987a). Urinary EAA was measured during
5 days of normal production and was also detectable after
a 12-day stop in production. The excretion of EAA in-
creased during the work week, yet it was still detectable
after 12 days without exposure. These data suggest that
the retention of EAA, or of other 2-EE or 2-EEA metab-
olite, may be toxicologically significant if EAA is the
active metabolite responsible for the observed toxicity.
7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT
Given the physical and chemical properties of these
four glycol ethers and the known rates of degradation in
the environment (section 4), there is minimal concern that
hazardous levels of these substances will occur. Although
only a few studies have been reported, the available data
support this conclusion. For example, both 2-ME and 2-EE
have been tested for effects on microorganisms and aquatic
animals. The lethal concentration of 2-ME and 2-EE to
microorganisms (Cladosporium resinae, Pseudomonas aeru-
ginosa, Gliomastix sp, and Candida sp is > 2% in the
medium (Neihof & Bailey, 1978; Lee & Wong, 1979). The
exposure of C. resinae lasted 30 to 42 days, whereas the
other organisms were exposed for 4 months. Very low
toxicity was shown by 2-ME to the green alga Scenedesmus
quadricauda (growth inhibition only at > 10 g/litre) and
the cyano-bacterium (blue-green alga) Microcystis aerugin-
osa (growth inhibition only at > 100 mg/litre) (Bringmann
& Kuhn, 1978). 2-EE has very low toxicity to the brine
shrimp (Artemia salina) (LC50 > 4 g/litre) (Price et
al., 1974) and to another arthropod Daphnia magna
(Hermens et al., 1984). The toxicity of 2-EE to fresh-
water fish is also very low, the LC50 (96 h) for the
bluegill (Lepomis macrochirus) being > 10 g/litre. However,
2-EEA is far more toxic to fish in this assay, LC50 (96 h)
values of 60 mg/litre (Bailey et al., 1985) and 46 mg per
litre in fathead minnows (Pimephales promelas) (Purdy,
1987) having been reported. These results confirm those of
Juhnke & Ludemann (1978), who reported an LC50 (48 h)
value of 107-141 mg per litre when using the Golden Orfe
(Leuciscus idus melanotus) test. The reason for this low
LC50 has not been studied, but Dawson et al. (1977) re-
ported similarly low LC50 values for 2-MEA in fish (45 mg
per litre in tidewater silverfish (Menidia beryllina)
and bluegill (Lepomis chirus).
Effects on other organisms have not been reported.
8. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS
8.1. Single Exposures
Data indicating the acute oral, dermal, intraperito-
neal, and inhalation toxicities of 2-ME and 2-EE are given
in Table 7. As shown, these two glycol ethers have similar
toxicities, and are of low acute toxicity whether animals
are exposed via the dermal, oral, or respiratory routes.
Even after intraperitoneal injection, the reported levels
of acute toxicity are still low (1.7-2.46 g per kg body
weight).
Dyspnoea, somnolence, ataxia, and prostration were re-
ported after near lethal doses of 2-EE were given to rats,
mice, guinea-pigs, or rabbits (Stenger et al., 1971).
Haemoglobinuria and/or haematuria were reported after a
single oral administration of 2-EE with a dose approaching
the LD50 (Laug et al., 1939). Microscopic examination of
the kidneys of rats, mice, guinea-pigs, or rabbits given
2-EE orally revealed severe tubular degeneration, conges-
tion, and cast formation; in some animals most of the
cortical tubules were necrotic (Laug et al., 1939). No
data on the purity of the 2-EE used in these early studies
were reported.
Single 4-h inhalation exposures of rats to 1866 mg 2-ME
per m3 or more led to testicular atrophy as early as 24 h
after exposure (Doe, 1984b).
8.2. Short-term Exposures
Repeated exposure of experimental animals to 2-ME and
2-EE by various routes of administration (7-90 days) have
revealed adverse effects on the haematological and nervous
systems and on the testes, thymus, kidney, liver, and
lung. From data on the metabolic transformation and
elimination of 2-MEA and 2-EEA in animals and man (see
section 6), it is probable that the toxicities of these
glycol ether acetates are similar to those of the parent
chemicals 2-ME and 2-EE.
8.2.1. Haematological and immunological effects
Following repeated exposures to 2-ME and 2-EE using
various routes of administration, haematological effects
have been observed in several species. A summary of the
most relevant studies is given in Tables 8 (2-ME) and 9
(2-EE).
Table 7. Acute toxicity data for 2-methoxyethanol and 2-ethoxyethanol and their acetatesa
-------------------------------------------------------------------------------------------------------------
Compound Species Intra- Oral LD50 Dermal Inhalation References
peritoneal LD50 LC50
LD50
-------------------------------------------------------------------------------------------------------------
2-Methoxyethanol Rat 2460 2460-3400 Smyth et al. (1941); Goldberg et al.
(1962); Pisko & Verbilov (1988)
Mouse 2200 2167-2560 4603 Werner et al. (1943); Saparmamedov
(1480) (1974); Pisko & Verbilov (1988)
Guinea-pig 950 Karel et al. (1947)
Rabbit 890-1450 1300 Carpenter et al. (1956); Pisko &
Verbilov (1988)
2-Ethoxyethanol Rat 2000 2125-5500 Smyth et al. (1941); Laug et al.(1939)
Stenger et al. (1971); Pisko & Verbilov
(1988)
Mouse 1700 4000-4800 6698 Werner et al. (1943); Laug et al.(1939)
(1820) Stenger et al. (1971); Saparmemedov
(1974); Pisko & Verbilov (1988)
Guinea-pig 1400-2600 Karel et al. (1947); Laug et al.(1939)
Rabbit 3300- Stenger et al. (1971); Smyth et al.
15 200 (1941)
2-Methoxyethanol Rat 3930 Smyth et al. (1941)
acetate Guinea-pig 1250 Kirk-Othmer (1980)
Rabbit 5557
2-Ethoxyethanol Rat 5100 Smyth et al. (1941)
acetate Guinea-pig 1910 Kirk-Othmer (1980)
Rabbit 10 333
-------------------------------------------------------------------------------------------------------------
a Doses are given as mg/kg body weight except for inhalation doses,
which are in mg/m3 (values in parentheses are ppm)
Concerning changes in blood parameters, a comparison
of Tables 7, 8, and 9 indicates clearly that 2-ME is more
toxic than 2-EE in several species, although 2-EE has been
less widely studied. For example, Nagano et al. (1979)
showed that 2-EE administered orally for 5 weeks at 2000
mg/kg body weight per day did not result in changes in
haematological parameters other than a reduced leucocyte
count. No effects were observed at 1000 mg/kg. Under a
similar dosing regimen, 2-ME caused a dose-related re-
duction in leucocytes at 500 mg/kg per day, other haemato-
logical parameters being unaffected at 250 mg/kg per day
(Nagano et al., 1979).
Some of the doses used in the studies summarized in
Tables 7 and 8 resulted in histological and functional
changes in the bone marrow and thymus. In an inhalation
study, Miller et al. (1983b) noted thymic atrophy and de-
creased thymus weights in male and female rats exposed to
933 mg 2-ME/m3 for 13 weeks. Miller et al. (1981) also
noted decreased weights of thymus, spleen, and mesenteric
lymph nodes in rats exposed to 933 or 3110 mg 2-ME/m3 for
9 days, and reduced bone marrow cellularity was observed
at 3110 mg/m3. In one study there was at least partial
reversal of these effects 22 days after an exposure last-
ing 4 days (Grant et al., 1985).
When MAA, the metabolite of 2-ME, was administered to
rats by gavage at 300 mg/kg body weight per day for 8
days, it resulted in reduced erythrocyte counts, haemo-
globin concentrations, and packed cell volumes, and a
marked reduction in leucocyte counts. Thymus and spleen
weights were also decreased and a severe lymphoid
depletion was seen in the thymus. Similar, but less
marked, effects on blood and thymus were seen in some
animals administered 100 mg/kg per day. No treatment-
related effects were reported at 30 mg/kg per day (Miller
et al., 1982).
Studies on immunological function show that 2-ME and
2-EE yield different results. De Delbarre et al. (1980)
studied the effect of 2-ME and 2-EE on the humoral respon-
siveness to antigenic stimuli and on adjuvant arthritis in
the rat. 2-ME had an inhibitory effect on adjuvant ar-
thritis at doses greater than 18.6 mg/kg body weight per
day administered subcutaneously, whereas 2-EE was not
effective at doses up to 150 mg/kg. A dose of 150 mg 2-ME
per kg per day delayed rejection of skin grafts and 75 mg
2-ME/kg per day (for 28 days) significantly depressed
antibody production. Again, 2-EE had no effect on these
parameters. House et al. (1985) administered 2-ME to mice
by gavage (10 doses of 250, 500, or 1000 mg 2-ME/kg body
weight per day for 2 weeks) and noted a 48% reduction in
thymus weight at 500 and 1000 mg/kg. However, there was no
significant alteration in immune function or host resist-
ance. Similar findings were reported when the same dose
levels of MAA, the major metabolite of 2-ME (section 6),
were administered.
Table 8. Haematological effects of 2-methoxyethanol in animalsa
--------------------------------------------------------------------------------------------------------
Species Route No. Dose frequency; Effect References
time; level
--------------------------------------------------------------------------------------------------------
Rat inhalation 10 males 6 h/day; 9 days; RBC fragility, no effect at Miller et al.
10 females 311, 933, 3110 mg/m3 3110 mg/m3 but reduced RBC, (1981)
Hb, and PCV levels and bone
marrow cellularity seen in M
and F; similar findings in F
at 933 mg/m3; reduced WBC
at 3110 and 933 mg/m3;
reduced thymus weight
Rat inhalation 10 males 6 h/day; 5 days/week only effect at 2 lowest Miller et al.
10 females for 13 weeks; doses was reduced body (1983b)
93.3, 311, 933 mg/m3 weight gain in F; at 933
mg/m3 reduced WBC, Hb,
PCV, and platelets in both
sexes after 4 and 12 weeks;
reduced serum proteins at 13
weeks, thymic atrophy
Rabbit inhalation 5 males 6 h/day; 5 days/week decreased thymus size and Miller et al.
5 females for 13 weeks; body weight, PCV, WBC, (1983b)
93.3, 311, 933 mg/m3 platelets and Hb at 933
mg/m3; slight to moderate
decrease in lymphoid tissue
at 311 mg/m3
Dog inhalation 2 treated 7 h/day; 5 days/week decreased RBC, Hb and Hct; Werner et al.
2 controls for 12 weeks; increased immature (1943)
750 mg/m3 granulocytes
Mouse oral 5 males 5 times/week for 4/5 mice at 2000 mg/kg died Nagano et al.
5 weeks; 62.5, 125, before completion; doses at (1979)
250, 500, 1000, 2000 or above 500 mg/kg resulted
mg/kg body weight/day in reduced WBC, RBC, and PCV
Table 8 (contd.)
--------------------------------------------------------------------------------------------------------
Species Route No. Dose frequency; Effect References
time; level
--------------------------------------------------------------------------------------------------------
Rat oral 24 males once per day for reduced thymus and spleen Grant et al.
4 days; 100 and 500 weight at 500 mg/kg on days (1985)
mg/kg body weight/day; 1-8, recovery by day 22;
sacrificed reduced WBC at both 100 and
500 mg/kg, largely
reversible by day 22
Hamster oral 4 males once daily, 5 days/week decrease in WBC at 500 mg/kg Nagano et al.
for 5 weeks; 62.5, 125, the only effect on blood (1984)
500 mg/kg body weight/day
Guinea oral 3 males once daily, 5 days/week about 50% decrease in WBC at Nagano et al.
-pig for 5 weeks; 250 and 500 both doses (1984)
mg/kg body weight/day
--------------------------------------------------------------------------------------------------------
a M = male; F = female; PCV = packed cell volume; Hct = haematocrit; RBC = red blood cell count;
WBC = white blood cell count; Hb = haemoglobin; No. = number of animals per group
Table 9. Haematological effects of 2-ethoxyethanol in animalsa
-------------------------------------------------------------------------------------------------------
Species Route No. Dose frequency; Response Reference
time; level
-------------------------------------------------------------------------------------------------------
Rat inhalation 15 males 6 h/day; 5 days/week decreased leucocyte count Barbee et al.
15 females for 13 weeks; 92, 368, in females at 1472 mg/m3, (1984)
1472 mg/m3 no other significant
biological effect reported
Rabbit inhalation 10 males 6 h/day; 5 days/week for decreased Hb, Hct, and Barbee et al.
10 females 13 weeks; 92, 368, 1472 RBC in both males and (1984)
mg/m3 females only at 1472
mg/m3
Dog inhalation 2 treated 7 h/day; 5 days/week for slight reduction in RBC, Werner et al.
2 control 12 weeks; 3091 mg/m3 Hb, and PCV, microcytosis, (1943)
hypochromia, and poly-
chromatophilia were seen,
marked increase in
immature granulocytes
Mouse oral 5 males 5 times/week for 5 lower WBC at 2000 mg/kg, Nagano et al.
weeks; 62.5, 125, 250, but no effect on (1979)
500, 3110, 2000 mg/kg erythrocyte parameters
body weight/day
-------------------------------------------------------------------------------------------------------
a PCV = packed cell volume; Hct = haematocrit;
RBC = red blood cell count; WBC = white blood cell count; Hb = haemoglobin
No. = number of animals per group
8.2.2 Effects on liver and kidney
Effects on the liver, such as reduced cytoplasmic den-
sity, disruption of lobular structure, elevated plasma
fibrinogen, reduced serum proteins, and elevated liver
weights, have been reported in certain studies in which
rats, mice, or rabbits were exposed to 2-ME or 2-EE at
levels in excess of 300 ppm (933 and 1104 mg/m3, respect-
ively), for periods of up to 13 weeks. Many of the effects
observed were reversible, and no consistent pattern was
noted among the various studies (Miller et al., 1981;
1983b; Stenger et al., 1971). Hepatic changes have been
observed at inhalation exposures to 2-ME and 2-EE in ex-
cess of 300 ppm (933 and 1104 mg/m3, respectively).
No pathological changes could be detected in the kid-
neys of rats exposed to approximately 933 mg 2-ME/m3 for
6 or 7 h per day, 5 days a week, for 13 weeks (Miller et
al., 1981, 1983b). In studies with 2-EE, no treatment-
related pathology was reported after inhalation exposure
of rats to 1362 mg/m3 (370 ppm) for 5 weeks or dogs to
3091 mg/m3 (840 ppm) for 12 weeks (Werner et al., 1943).
8.2.3 Behavioural and neurological effects
There have been few reports on the effects of 2-ME
and 2-EE on the function of the nervous system in animals.
Ataxia was reported after inhalation exposure of rats to
18.96 g 2-EE/m3 (5152 ppm) for 8h. After exposure of rats
to levels of 2-ME between 1555 and 12 440 mg/m3, 4 h per
day for up to 7 days, inhibition of an avoidance-escape
conditioned response was observed without any alteration
of motor function (Goldberg et al., 1962). The same
authors reported also a significant inhibition of this
response after 14 days exposure to 1210-4836 mg 2-ME per
m3 (389-1555 ppm). After 3 weeks recovery, rats whose
avoidance response had been inhibited on the 14th day
showed a return to normal. Savolainen (1980) reported a
partial loss of motor function in the hind limbs of rats
after exposure to 1244 mg 2-ME/m3 (400 ppm) for 6 h/day,
5 days per week, for 2 weeks. This hindlimb paralysis
coincided with the glial cell toxicity noted during the
second week of exposure. Recovery was incomplete after 2
weeks post-exposure, the animals receiving the highest
dose showing minor paresis.
8.3 Skin and Eye Irritation; Sensitization
No satisfactory data on the sensitization potential of
2-ME and 2-EE in animals, and only limited data on their
irritant properties to eyes, have been reported. Weil &
Scala (1971) found 2-ME to be an eye irritant. Lailler et
al. (1975) reported that 0.1 ml of undiluted 2-ME led to
corneal and conjunctival oedema and increased vascular
leakage in the conjunctiva and aqueous humour. A 25% aque-
ous solution was much less active.
8.4 Long-term Exposures
No adequate long-term animal studies on 2-ME and 2-EE
or their acetates have been reported to date.
8.5 Effects on Reproduction and Fetal Development
The effects of glycol ethers, particularly 2-ME, on
animal reproduction, fertility, and teratogenicity have
been extensively studied. Some of the early studies on
reproduction have been reviewed by Hardin (1983). The many
studies conducted in several countries and in several
animal species are in general agreement on the nature of
developmental and reproductive effects.
8.5.1 Effects on the male reproductive system
8.5.1.1 Oral exposure
The pathological changes observed in the testes of
rats after the administration of 2-ME have been well
characterized by Foster et al. (1983). The severe degener-
ative changes noted in the germinal epithelium of the
seminiferous tubules of different laboratory animals were
similar, irrespective of species or route of adminis-
tration. Daily doses of 2-ME were administered orally to
rats (50, 100, 250, or 500 mg/kg) for periods between 1
and 11 days, and 250, 500, or 1000 mg 2-EE/kg body weight
per day was administered in a similar regimen (Foster et
al., 1983; Creasy & Foster, 1984; Creasy et al., 1985).
After 2-ME administration, testicular damage was observed
1 day post dosing with 100 mg/kg or more, the lesion being
localized in the late primary spermatocytes. Continuous
dosing with 2-ME resulted not only in progressive deletion
of the primary spermatocytes but also in degenerative
changes in secondary spermatocytes and dividing sper-
matids. Changes in sperm motility, morphology, and concen-
tration were also reported. The cessation in maturation
of early primary spermatocytes led to a depletion of the
spermatid population, resulting in tubules containing only
Sertoli cells, spermatogonia, and early primary spermato-
cytes. Decreased testicular weight was reported at 250 mg
per kg or more. Although most of the effects seen after a
4-day treatment with 2-ME were reversible within 8 weeks,
a small proportion of tubules showed incomplete recovery
indicating a non-reversible, long-term effect. Similar
findings were reported after 2-EE administration, but only
after 11 days of dosing with 500 and 1000 mg/kg. No
effects on the testes were observed following oral admin-
istration of 250 mg 2-EE/kg per day or 50 mg 2-ME/kg per
day.
Subsequent work by Chapin et al. (1985a,b) supports
the hypothesis that 2-ME administered to male rats at
doses of 100 or 200 mg/kg daily for 5 days affects the
spermatogonia. In these studies male rats were given doses
of 0, 50, 100, or 200 mg/kg per day for 5 days, and recov-
ery was investigated by evaluating the testicular damage
in sacrificed animals at 8 subsequent weekly intervals or
alternatively by investigating fertility through mating
with two females per week for 8 weeks. Treatment with 100
or 200 mg/kg resulted in widespread testicular damage and
cell death immediately after treatment, with only very
mild effects being noted at 50 mg/kg (this was thus a
marginal-effect level rather than a no-effect level).
There was some evidence of recovery from testicular damage
towards the end of the study period, but reduced fertility
was still apparent weeks after the cessation of treatment
with 200 mg/kg. Thus, the recovery was neither as
complete nor as rapid as that noted by Foster et al.
(1983).
The in vivo and in vitro effects of 2-ME and MAA ex-
posures, respectively, were compared by evaluating effects
using electron microscopy (Creasy et al., 1986). 2-ME
caused cell death in the pachytene spermatocytes in vivo ,
as well as focal breakdown of the plasma membranes be-
tween spermatocytes and Sertoli cells. Similar, but less
frequent, breaks were seen in vitro when mixed cultures of
Sertoli and germ cells were treated with MAA.
Subsequent studies by Foster et al. (1987), in which
the alkoxyacetic acids of 2-ME and 2-EE (MAA and EAA,
respectively) were given orally in doses equimolar to the
studies described earlier (Foster et al., 1983), yielded
similar patterns of testicular degeneration and effects on
spermatocyte development. The similarity of effects at
equimolar concentrations between the two acetic acid de-
rivatives and their respective glycol ethers suggests that
these metabolites may either be the causative factors or
at least play a role in the production of the observed
degenerative effects.
The assessment of the effects of low doses of poten-
tial toxicants on sperm fertility and production is diffi-
cult because of the large amount of sperm usually produced
by most test species and the large sperm reserves. Using
an experimental design that required bi-daily matings of
Long-Evans male rats, the effects of orally administered
2-EE (0, 150, or 300 mg/kg body weight per day; 5 days per
week for 6 weeks) on sperm reserves and on pachytene sper-
matocytes was evaluated (Hurtt & Zenick, 1986). Further
groups of rats received the same doses of 2-EE, but were
not subjected to repeated mating. After 6 weeks of treat-
ment, the animals were sacrificed and the effect of 2-EE
administration on organ weight, testicular spermatid
count, cauda epididymal sperm count, and sperm morphology
was determined. Exposures to 2-EE resulted in significant
decreases in testicular weight, spermatid count, and epi-
didymal sperm count for both mated and unmated animals at
the highest dose level. However, the effects were also
seen at 150 mg/kg per day in repeatedly mated animals.
Adult male rats treated orally with 2-EE (936 mg/kg
body weight, 5 days/week for 6 weeks) were found to have
decreased sperm counts and altered sperm morphologies
after 5 and 6 weeks of exposure when compared with
vehicle-control animals, and sperm motility was decreased
at week 6 (Oudiz & Zenick, 1986). These data indicate that
the pachytene spermatocyte is the target cell most sensi-
tive to the effects of 2-EE.
The reproductive toxicity of 2-EE in CD-1 mice has
been evaluated in a continuous breeding protocol (Lamb et
al., 1984). Male and female mice (20 males and 20 females
per dose group) were given access to drinking-water con-
taining 0.5, 1.0, or 2.0% 2-EE and housed as breeding
pairs continuously for 14 weeks. Treated animals were then
paired with controls for breeding. At 1 and 2% 2-EE, sig-
nificant adverse effects on fertility were seen, the re-
productive capacity of both males and females being af-
fected. Testicular atrophy, decreased sperm motility, and
increased abnormal sperm levels were seen in treated
males, but no treatment-related pathological effects were
seen in females even though reduced fertility was noted in
the cross-mating phase.
The reproductive toxicity of a single oral dose of
2-ME (0, 500, 750, 1000, or 1500 mg/kg) was assessed in
adult male CD rats and CD-1 mice by Anderson et al.
(1987). Animals from each group were sacrificed at weekly
intervals during weeks 3-8 post exposure and evaluated for
sperm counts, sperm morphology, and testicular histology.
A dose-related toxicological response in spermatocytes was
observed in both species. In a companion study, male rats
and mice were exposed to 2-ME (0, 125, 250, or 500 mg/kg)
and permitted to mate during weeks 1-10 post exposure.
Following mating, pregnant females were sacrificed on day
17 of pregnancy and each uterus was evaluated for dominant
lethal effects. The only effect noted was a decrease in
total number of implants at week 6 following treatment
with 500 mg/kg. In a study in which both rats and mice
were given single doses at 0, 500, 750, 1000, or 1500 mg
per kg and mated 5 and 6 weeks later, dominant lethal
studies showed a dose-related decrease in fertility in
rats, with complete sterility in all but the lowest dose
group after 6 weeks. No effects on the reproductive
capacity of mice were noted. There was no statistically
significant evidence for the induction of dominant lethal
mutations or abnormalities in the F1 generation of either
species.
8.5.1.2 Inhalation studies
Testicular damage has been reported in rats exposed to
2-ME by inhalation for a single 4-h period (Doe, 1984b).
Exposure to 1944 mg/m3 resulted in histological evidence
of damage to the maturing spermatids, testicular atrophy
occurring at 3887 mg/m3 or more. The NOEL was 933 mg/m3.
The effect of repeated exposure to 2-ME has also been
investigated using the inhalation route. Exposure of rats
to 3110 mg/m3 (6 h/day) for 9 out of 11 days resulted in
degenerative changes and necrosis in the germinal epi-
thelium of the seminiferous tubules, but no effects on the
testes were observed with a dose of 933 mg/m3. However,
Doe et al. (1983) reported pronounced atrophy of the sem-
iniferous tubules in rats exposed to 933 mg 2-ME/m3 or
more (6 h/day, 5 days/week) for 13 weeks. The NOEL was
311 mg/m3 (Miller et al., 1983b). Studies were also car-
ried out in rabbits, using exposure levels of 93.3, 311,
and 933 mg/m3 (6 h/day, 5 days/week), and most animals
exposed to 311 mg/m3 showed reduced testis size and
severe degenerative changes in the tubules. Reduced testis
weight was also seen in two out of five animals exposed to
93.3 mg/m3, and one animal showed histological changes
in the germinal epithelium. A NOEL could not be ident-
ified, but 93.3 mg/m3 was near the minimal effective dose
in rabbits.
In addition, an increased incidence of sperm abnor-
malities (principally sperm with banana shaped or amorph-
orous heads) has been noted in mice exposed to 1555 mg
2-ME/m3 (7 h per day for 5 days) but not to 78 mg per
m3 (McGregor et al., 1983).
8.5.2 Embryotoxicity and developmental effects
8.5.2.1 2-Methoxyethanol
2-ME has been shown to lead to embryotoxic and devel-
opmental effects in laboratory animals following inha-
lation, oral, or dermal exposure. The effects of 2-ME
exposure over the entire organ-forming period of gestation
have been studied in rabbits, rats, and mice, the rabbit
being the most sensitive species.
The embryotoxicity of 2-ME after gastric intubation
was evaluated in mice (31.25, 62.5, 125, 250, 500, or 1000
mg/kg body weight) on days 7-14 of gestation (Nagano et
al., 1981). No maternal deaths were observed, but maternal
weight gain was reduced in the mice that received doses of
250 mg/kg per day or more. Maternal toxicity was not seen
at 123 mg/kg or less. On day 18 of gestation, fetuses were
examined and an increase in fetal death rate was observed
at doses of 250 mg/kg or more. At doses of 500 and 1000 mg
per kg, all fetuses were dead at caesarean section, except
for one in the 500-mg/kg group. Approximately 44% (57/130)
of the live fetuses in the 250-mg/kg group were found to
have gross anomalies, including exencephaly (24), umbili-
cal hernia (3), and abnormal digits (29). One fetus had
both exencephaly and abnormal digits. The lone surviving
fetus in the 500-mg/kg group had exencephaly and abnormal
digits. Minimal skeletal malformations were also observed
at the lowest dose of 31.25 mg/kg body weight (a matern-
ally non-toxic dose). Thus, a NOEL could not be ascer-
tained.
Dose-dependent electrocardiographic changes were
detected on gestation day 20 in the rat fetuses of mothers
exposed orally to 2-ME (0, 25, or 50 mg/kg body weight) on
days 7 to 13 of gestation (Toraason et al., 1985). Cardio-
vascular malformations were observed, including right
ductus arteriosus and ventricular septal defects. QRS in-
tervals were significantly prolonged, particularly in the
highest dose group, suggesting intra-ventricular conduc-
tion delays.
Ornithine decarboxylase (ODC) activity is highest
during rapid growth and development in fetuses and is
sensitive to maternal exposure to chemicals and drugs.
Toraason et al. (1986a,b) evaluated the effect on ODC ac-
tivity in the fetuses of pregnant rats that received 25 mg
2-ME/kg by gavage during gestation days 7-13 or 13-19. The
activity was most affected in fetuses exposed during ges-
tation days 7 to 13. It was highest in 3-day old rats and
declined sharply thereafter. No functional or morphologi-
cal effects were observed in fetuses exposed at maternal
dose levels of 25 mg/kg during gestation days 7-13 or in
fetuses exposed at that level during days 13-19.
Nelson et al. (1984a) treated male rats by inhalation
(78 mg 2-ME/m3 for 7 h/day, 7 days/week for 6 weeks) and
subsequently bred these to untreated females. In addition,
groups of 15 pregnant rats were treated with the same dose
(7 h/day on gestation days 7-13 or 14-20) and allowed to
deliver and rear their young. Neuromotor function activity
and simple learning ability were assessed on days 10-90
after birth. Offspring from dams treated between gestation
days 7-13 showed significant changes in avoidance con-
ditioning, and changes in neurochemical levels were ob-
served in the brains of 21-day-old offspring from the
paternally exposed group as well as from both maternally
exposed groups.
8.5.2.2 2-Ethoxyethanol
A dose-finding study in pregnant rats revealed that no
offspring survived inhalation exposures of 3312 mg 2-EE
per m3, 7 h/day, during gestation days 7-13 or 14-20
(Nelson et al., 1981). The authors reported 34% neonatal
deaths at 736 mg/m3 under similar exposure conditions.
Offspring from dams exposed to 368 mg/m3 on gestation
days 7-13 or 14-20 showed impaired performance in behav-
ioural tests and neurochemical alterations in brain samples.
Using inhalation exposures of 478, 1435, and 2208 mg
2-EE/m3 on gestation days 7-15 (7 h/day), Nelson et al.
(1984b) reported complete resorption of all rat fetuses at
2208 mg/m3, reduced fetal weight at 1435 mg/m3, and a
NOEL of 478 mg/m3. Andrew & Hardin (1984), exposed preg-
nant rats to 733 and 2823 mg/m3 for 7 h/day throughout
gestation and observed increased fetal resorptions at 733
mg/m3 as well as skeletal and cardiovascular abnormali-
ties. At 2823 mg/m3 the resorption frequency reached 100%.
Developmental toxicity has been noted in rats after
dermal application of 2-EE (0.25 or 0.5 ml, four times per
day) (Hardin et al., 1982) or 2-EEA (0.35 ml, four times
per day) (Hardin et al., 1984) on gestation days 7-16.
Increased resorption rates and fetal deaths, decreased
viable fetus weights, and increased cardiovascular defects
and skeletal malformations were seen, even at the lowest
dose tested.
The effect of simultaneous administration of ethanol
(10% in drinking water) and 2-EE (368 mg/m3 by inha-
lation) has been investigated, in view of their related
metabolism (via the enzyme alcohol dehydrogenase) (Nelson
et al., 1982, Nelson et al., 1984c). Although the results
obtained are difficult to interpret, ethanol adminis-
tration early in gestation tended to reduce the behav-
ioural effects induced by 2-EE, whereas ethanol given late
in gestation enhanced these effects.
8.5.3 Teratogenicity
8.5.3.1 2-Methoxyethanol
The teratogenic potential of dermally administered
2-ME was estimated in pregnant rats with the Chernoff-
Kavlock screening test (Wickramaratne, 1986). Various con-
centrations (0, 3, 10, 30, or 100%) of 2-ME in physiologi-
cal saline were applied to shaved skin and occluded for
6 h of exposure on gestation days 6-17. Animals were per-
mitted to have their litters and rear the pups until 5
days postpartum, when the study was terminated. No adverse
effects were noted at the 3% dose level. Small litter
sizes and decreased fetal survival were observed at the
10% level. At 30%, lethality was observed in all fetuses,
and all pregnant females died when exposed dermally to
100% 2-ME.
The teratogenicity of 2-ME in mice, rats, and rabbits
has been evaluated by Hanley et al., (1984). Pregnant rats
and rabbits were exposed by inhalation to 0, 9, 31, or 156
mg/m3 for 6 h/day on gestation days 6-18 (rabbits) or 6-
15 (rats), and mice were exposed to 0, 31, or 156 mg per
m3 for 6 h/day on days 6-15 of gestation. No teratogenic
effects were found in CF-1 mice and Fischer-344 rats under
the conditions of this study, although slight fetotoxicity
was noted in both species. In New Zealand white rabbits
exposed to 156 mg/m3 there was a significant increase in
resorption rate and incidence of malformations involving
all organ systems, as well as a significant decrease in
mean fetal body weight when compared to controls. Of the
fetuses from dams exposed to 156 mg per m3, 63% exhibi-
ted at least one malformation and 91% of the litters had
at least one fetus with a malformation. There were no
teratogenic or fetotoxic effects in any of the three
species evaluated at 31 mg/m3.
Developmental phase-specific and dose-related terato-
genic anomalies in CD-1 mice resulting from 2-ME exposure
have been evaluated (Horton et al., 1985). 2-ME was admin-
istered by gavage to pregnant females at doses of 250 mg
per kg (during gestation days 7 to 9, 8 to 10, or 9 to 11;
during days 7 to 8, 9 to 10, or 10 to 11; or once a day on
gestation days 9, 10, 11, 12, or 13) in order to identify
the most sensitive developmental phases for the anomalies
under study. Resulting malformations were specifically re-
lated to the developmental stage at the time of exposure,
with exencephaly being observed between days 7 to 10 and
paw anomalies (syndactyly, oligodactyly, and stunted digit
number 1) during the later stages of development (days 9-
12). The dose dependency of digit malformation was studied
by administering single doses by gavage (100, 175, 250,
300, 350, 400, or 450 mg 2-ME/kg) on gestation day 11.
Dose-related paw malformations were noted in all litters,
with forepaws being more susceptible than hindpaws in
terms of the number and severity of malformations. At 175
mg/kg digit anomalies were induced without concurrent
reductions in fetal weight, while at 250 mg/kg or more
digit anomalies occurred concurrently with reduced fetal
body weight. In this study, the NOEL for the single ex-
posure (day 11) was 100 mg/kg. Although in this same
strain of mice digital malformations were not detected in
near-term fetuses given 100 mg 2-ME/kg body weight by
gavage on gestation day 11 (Greene et al., 1987), there
was a slight increase in the amount of cell death in
approximately 50% of the limb buds from embryos collected
24 h after dosing.
In a preliminary study, the teratogenic potential of
2-ME was determined in Cynomolgus monkeys using doses of
0.16, 0.32, and 0.47 mmol/kg administered by gavage
throughout the period of organogenesis (Scott et al.,
1987). Fetal death was dose-related (2/13 at 0.16 mmol
per kg; 3/10 at 0.32 mmol/kg; and 8/8 at 0.47 mmol/kg).
At the highest dose level, four fetuses were lost through
abortion and one of the remaining four, which was re-
covered by hysterotomy, demonstrated malformation (ectro-
dactyly) of the forelimbs. The MAA content of maternal
sera was followed throughout the treatment period. By the
25th day of treatment, MAA levels had more than doubled in
all treatment groups, compared to the values determined on
day one, indicating that multiple exposure to 2-ME can
lead to accumulation of the potentially embryotoxic metab-
olite MAA, the possible causative factor in the embryonic
deaths and teratogenicity observed (see section 8.8).
8.5.3.2 2-Ethoxyethanol and 2-Ethoxyethanol acetate
Andrew & Hardin (1984) have studied the teratogenic
potential of 2-EE in rats and rabbits. Rats (29-38 per
group) were exposed by inhalation to 0, 552, or 2388 mg
per m3 5 days per week for 3 weeks immediately prior to
mating and then to 0, 743, or 2823 mg/m3 for 7 h/day from
gestation day 1 to 19. Pregnant rabbits received 589 or
2271 mg/m3 for 7 h/day from gestation day 1 to 18. In
the New Zealand white rabbits exposed to 2271 mg/m3, the
rate of early resorptions was 100%. Even at 689 mg/m3, the
number of early resorptions per litter was 6 times that in
the control group. There was no evidence of severe intra-
uterine growth retardation in surviving fetuses, but a
significant increase in the incidence of major malfor-
mations (ventral wall defects and fusion of the aorta with
the pulmonary artery), minor anomalies, and skeletal vari-
ants. Teratogenic effects of 2-EE and also 2-EEA were re-
ported in Dutch Belted Rabbits after inhalation exposures
of 644 mg 2-EE/m3 and 2160 mg 2-EEA/m3 (Doe, 1984a).
In this study the author considered the NOEL in rabbits to
be 184 mg/m3 for 2-EE and 135 mg/m3 for 2-EEA.
In the study by Andrew & Hardin (1984), the highest
2-EE dose (2823 mg/m3) in rats led to 100% resorption,
as in rabbits. The resorption rate per litter in the
group gestationally exposed to 743 mg/m3 was about twice
the control value. Fetal body size was significantly
decreased, indicating retardation of intrauterine growth.
The significant increase in the incidence of cardiovascu-
lar defects (transposed and retrotracheal pulmonary
artery) and the increased incidence of common skeletal
variants and anomalies over control values were indicative
of a teratogenic effect of 2-EE in rats. Doe (1984a)
reported fetotoxicity without teratogenicity in rats after
inhalation exposure to 184 and 920 mg/m3, but no adverse
effects were reported after exposure to 37 mg/m3.
The teratogenic potential of 2-EE was evaluated in
pregnant Sprague-Dawley rats using dermal application
(0.25 or 0.50 ml, four times/day during gestation days 7
to 16) (Hardin et al., 1982). No signs of maternal
toxicity were noted except for ataxia on the last day of
dosing in the high-dose group, as well as a significant
decrease in body weight gain in the last half of ges-
tation. All fetuses in the high-dose group suffered intra-
uterine death. In the low-dose group, there was a signifi-
cant increase in the number of females with 100% dead
implants (p < 0.001), and in the incidence of skeletal
variations (p < 0.05). Also, reductions in fetal body
weight (p < 0.001) and cardiovascular malformations
(p < 0.05) were observed, as were significant decreases in
the number of live fetuses per litter (p < 0.001).
Hardin et al. (1984) studied the developmental tox-
icity of 2-EEA in rats after dermal application of 0.35 ml
2-EEA four times per day on days 7 to 16 of gestation
(daily application 1.37 g). 2-EEA was strongly embryo-
toxic, as reflected by significantly increased frequencies
of completely resorbed litters and dead implants per
litter. Also, the body weight of live fetuses was reduced
relative to water-treated controls. The spectrum and fre-
quency of malformations and variations noted in 2-EEA-
treated animals was similar to that described by Hardin et
al. (1982) in a previous study.
The developmental toxicity (including teratogenicity)
of 2-EEA in rats and rabbits following inhalation ex-
posure has been evaluated by Tyl et al. (1988). Fischer
344 rats (30 animals/group) and New Zealand white rabbits
(24 animals/group) were exposed to 2-EEA concentrations of
0, 270, 540, 1080, or 1620 mg/m3, 6 h/day on gestational
days 6-15 (rats) and 6-18 (rabbits). Fetuses were examined
for external, visceral, and skeletal malformations and
variations on gestational day 21 (rats) and 29 (rabbits).
In both rats and rabbits, maternal toxicity and develop-
mental toxicity were observed at exposures of 540 mg/m3 or
more. Teratogenic responses were increased at 1080 and
1620 mg/m3 with a 100% incidence of total malformations
being observed at the highest dose. An exposure of 270 mg
per m3 was considered a NOEL in both species, no evi-
dence of maternal or developmental toxicity being reported
at this dose.
8.6 Mutagenicity and Related End-Points
The only published data on 2-EE concerns a point mu-
tation test using Escherichia coli, which was reported to
be negative (Szybalski, 1958). However, 2-ME has been
tested in several in vitro and in vivo systems for its
genotoxic potential. The mutagenicity of 2-ME has been
evaluated in the following test systems: Salmonella typhi-
murium, unscheduled DNA synthesis (UDS) in human embryo
fibroblasts, bone marrow metaphase analysis in male and
female rats, dominant lethality in male rats, and a sex-
linked recessive lethal test in Drosophila melanogaster.
No evidence of mutagenicity in S. typhimurium was found
using five strains, with and without metabolic activation,
and dose levels up to 33 mg 2-ME per plate. When 2-ME was
tested in the presence of alcohol dehydrogenase no evi-
dence was found that metabolites of 2-ME were mutagenic in
S. typhimurium. Similarly, the addition of 2-ME at con-
centrations up to 10 mg/ml of medium did not lead to
changes in UDS in human embryo fibroblasts (McGregor et
al., 1983).
The production in CHO cells of sister chromatid ex-
changes (SCEs) and chromosome aberrations by 2-EE was
studied by Galloway et al. (1987). Both assays were
carried out with and without activation by an exogenous
enzyme system from rat liver chemically induced with the
PCB mixture Aroclor 1254. Aberrations were found only in
the absence of metabolic activation when using 2-EE con-
centrations between 4780 and 9510 µg/ml of medium. The
lowest effective concentration was 6830 µg/ml. SCEs were
found with and without activation, the lowest effective
concentration being 3170 µg/ml when the range studied
was 951-9510 µg/ml.
Aneuploidy was induced in the diploid yeast strain
D61.M ( Saccharomyces cerevisiae ) at 2-MEA levels of 3-
5.7% in the medium (Zimmermann et al., 1985). However,
there were no chemically related effects in this yeast
strain on point mutation or recombination after exposure
to 2-MEA. The relevance to mammals of these findings in
yeast is not clear.
No statistically significant increase in chromosome
aberrations was seen in male or female rats after exposure
by inhalation to 2-ME (78 or 1555 mg/m3), 7 h/day, for 1
or 5 days. Where possible 50 metaphases per rat were
scored from groups of 10 animals (McGregor et al., 1983).
Basler (1986) dosed Chinese hamsters intraperitoneally (10
animals) with two thirds of the LD50 of 2-MEA (approxi-
mately 1333 mg/kg body weight in corn oil) and the animals
were sacrificed 12, 24, 48, and 72 h after the single
dose. No statistically significantly increase in micro-
nucleated erythrocytes was noted.
Two dominant lethal studies in rats have been carried
out using 2-ME. McGregor et al. (1983) exposed groups of
10 male CD rats by inhalation to 78 or 1555 mg/m3, 7 h
per day, for 5 days. Control and low-dose groups gave
similar results, but the results at 1555 mg/m3 were
difficult to interpret. A high proportion of early deaths
was noted, which could be partly explained in terms of the
low implantation frequency reported. Therefore, a dominant
lethal effect at 1555 mg/m3 could not be demonstrated
conclusively. Rao et al. (1983), using male Sprague-
Dawley rats exposed to 93, 311, or 933 mg 2-ME/m3 by in-
halation 6 h/day, 5 days/week for 13 weeks, found no domi-
nant lethal effect at 93 or 311 mg/m3. An assessment of
dominant lethality was impossible at 933 mg/m3 due to
almost complete infertility. No positive control was in-
cluded.
In a sex-linked recessive lethal test in Drosophila
melanogaster reported by McGregor et al. (1983), the
results were inconclusive. Given the low absolute number
of mutants (low sample size), the inconsistency with which
various broods were affected, and the lack of a dose-
response relationship, a firm conclusion on the mutagen-
icity of 2-ME in D. melanogaster cannot be made.
8.7 Carcinogenicity
No carcinogenicity data are available on these glycol
ethers.
8.8 Mechanism of Toxicity - Mode of Action
The metabolic fate of 2-ME, 2-EE, and their acetates
has been well studied in both animals (Miller et al., 1983a;
Moss et al., 1985) and man (NIOSH, 1986, Groeseneken et
al., 1987, Veulemans, 1987a). Due to rapid hydrolysis of
the acetates to the monoalkyl glycol ether (see section
6), the putative toxic metabolite are the same for 2-ME or
2-MEA and for 2-EE or 2-EEA.
Both in vitro and in vivo studies have supported the
hypothesis that the toxic effects of 2-ME and 2-EE are
elicited by the toxicity of 2-methoxyacetaldehyde and
methoxyacetic acid (MAA) from 2-ME and ethoxyacetaldehyde
and ethoxyacetic acid (EAA) from 2-EE.
Gray et al. (1985) studied the effects in vitro of
2-ME, 2-EE, MAA, and EAA on mixed cultures of Sertoli and
germ cells from rat testes. At concentrations up to 50
mmol/litre medium, no morphological damage was noted for
2-ME or 2-EE, whereas administration of MAA or EAA at 2-10
mmol/litre led to degeneration of the pachytene and div-
iding spermatocytes, the probable target cells of the
parent ethers in vivo (Chapin et al., 1985b, Creasy et
al., 1985; Foster et al., 1986, Oudiz and Zenick, 1986).
Foster