This report contains the collective views of an international group of
    experts and does not necessarily represent the decisions or the stated
    policy of the United Nations Environment Programme, the International
    Labour Organisation, or the World Health Organization.

    Published under the joint sponsorship of
    the United Nations Environment Programme,
    the International Labour Organisation,
    and the World Health Organization

    World Health Orgnization
    Geneva, 1990

         The International Programme on Chemical Safety (IPCS) is a
    joint venture of the United Nations Environment Programme, the
    International Labour Organisation, and the World Health
    Organization. The main objective of the IPCS is to carry out and
    disseminate evaluations of the effects of chemicals on human health
    and the quality of the environment. Supporting activities include
    the development of epidemiological, experimental laboratory, and
    risk-assessment methods that could produce internationally
    comparable results, and the development of manpower in the field of
    toxicology. Other activities carried out by the IPCS include the
    development of know-how for coping with chemical accidents,
    coordination of laboratory testing and epidemiological studies, and
    promotion of research on the mechanisms of the biological action of

    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 

        ISBN 92 4 157115 2        (NLM Classification: QV 633)
        ISSN 0250-863X

         The World Health Organization welcomes requests for permission
    to reproduce or translate its publications, in part or in full.
    Applications and enquiries should be addressed to the Office of
    Publications, World Health Organization, Geneva, Switzerland, which
    will be glad to provide the latest information on any changes made
    to the text, plans for new editions, and reprints and translations
    already available.

    (c) World Health Organization 1990

         Publications of the World Health Organization enjoy copyright
    protection in accordance with the provisions of Protocol 2 of the
    Universal Copyright Convention. All rights reserved.

         The designations employed and the presentation of the material
    in this publication do not imply the expression of any opinion
    whatsoever on the part of the Secretariat of the World Health
    Organization concerning the legal status of any country, territory,
    city or area or of its authorities, or concerning the delimitation
    of its frontiers or boundaries.

         The mention of specific companies or of certain manufacturers'
    products does not imply that they are endorsed or recommended by the
    World Health Organization in preference to others of a similar
    nature that are not mentioned. Errors and omissions excepted, the
    names of proprietary products are distinguished by initial capital




     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       


     2.1. Identity             
     2.2. Physical and chemical properties 
     2.3. Conversion factors   
     2.4. Analytical methods   


     3.1. Natural occurrence   
     3.2. Man-made sources  
           3.2.1. Industrial production    
            Manufacturing processes    
            World production figures   
     3.3. Uses                     


     4.1. Transport and distribution between media 
     4.2. Biotransformation 


     5.1. Environmental levels 
     5.2. General population exposure  
     5.3. Occupational exposure    


     6.1. Absorption           
     6.2. Distribution      
     6.3. Metabolic transformation 
     6.4. Elimination and excretion    



     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  
            Oral exposure  
            Inhalation studies 
           8.5.2. Embryotoxicity and developmental effects 
           8.5.3. Teratogenicity   
            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  


     10.1. 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  











Dr W. Denkhaus,  Institute for Occupational and Social Medi-
   cine,  University  of  Mainz, Mainz,  Federal Republic of

Dr R.J. Fielder, Medical TEH Division, Department of Health,
   Hannibal House, Elephant and Castle, London, United King-

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


Dr A. Cicolella, Institut National de Recherche et de Sécur-
   ité, Vandoeuvre, France


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


    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).


    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.


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


1.1.  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-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

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

    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

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


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

    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-

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

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-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
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.

3.1.  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

3.2.  Man-Made Sources

3.2.1.  Industrial production  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).  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).


4.1.  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.


5.1.  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
  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)
  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)
  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)
  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)
  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

  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)


  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)

  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)

  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)


  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

  (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

  (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.

6.1.  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.


    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.


8.1.  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

    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

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
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
                 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               
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  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

    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.

    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.  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  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-

    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.  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  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).  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-

    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

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  et al. (1986) reported  that 2-methoxyacetaldehyde
(2-MALD),  a  possible  metabolite of  2-ME,  can  produce
specific  testicular effects  in vitro  and  in vivo  at doses
much lower than those required for MAA (0.2  and  0.5 mmol
per  litre  in vitro ).  In  more recent studies,  Foster et
al.  (1987)  compared the  in vivo  and  in vitro  testicular
effects  of MAA and EAA in rats.  Single oral doses of MAA
and EAA (equimolar with 100, 250, or 500 mg  2-ME/kg  body
weight)  were administered and  cell morphology was  moni-
tored  for 14 days.  MAA produced  damage to spermatocytes

undergoing  meiotic maturation and division within 24 h of
treatment,  whereas EAA produced these changes only at the
highest dose. Similar results were seen  in vitro  at a dose
(5 mmol/litre  medium)  equivalent  to  the  steady  state
plasma  level  of  MAA after  administration of 500 mg/kg.
Evidence  that MAA is  important in causing  2-ME  terato-
genicity was reported by Yonemoto et al. (1984).  MAA, but
not 2-ME, was found to interfere with  organogenesis  when
the two compounds were investigated using rat  embryos  in

    Results  from  in vivo  studies in mice  (Welsch et al.,
1987; Sleet et al., 1988) and rats (Ritter et  al.,  1985)
further  substantiate the hypothesis that monoalkyl glycol
ethers  are  metabolized  to acetic  acid  metabolites via
alcohol  dehydrogenase (ADH) and  aldehyde dehydrogenases,
and  that the ultimate toxin  is actually the alkoxy  acid
metabolite  of the glycol  ether or a  further metabolite.
In mice (Sleet et al., 1987), 2-ME and MAA were equipotent
in  producing teratogenic lesions leading to malformations
of  the digits of all paws.  Similar effects were noted by
Brown et al. (1984) and Ritter et al. (1985) in rats. Sub-
sequent  work showed that the  embryotoxic and teratogenic
effects of 2-ME in mice could be prevented by the concomi-
tant  administration of 0.12  or 1.2 mmol/kg of  4-methyl-
pyrazole,  an inhibitor of ADH,  but that 4-methylpyrazole
was  without effect after the administration of MAA (Sleet
et al., 1988).


    Only  limited information on the toxic effects of gly-
col ethers in humans is available.  This information comes
largely  from case reports in the early literature dealing
with accidental poisoning and/or workplace exposure.  Such
reports provide only minimal information relating specific
effects  to exposure levels.   Only a few  epidemiological
studies have been reported.

9.1  General Population Exposure

    The  widespread  use  of  consumer  products  such  as
paints,  stains,  inks,  lacquers, surface  coatings,  and
home/industrial  cleaners that contain one  or more glycol
ethers means that broad segments of the general population
could  be exposed.  However,  no reports quantifying  such
exposures have been found nor any that describe skin irri-
tation or sensitization from exposures to glycol ethers in
humans, despite widespread exposure.

9.1.1  Poisoning reports

    A 44-year-old man consumed 400 ml of 2-ME  mixed  with
brandy  and died without regaining consciousness 5 h after
he was admitted to hospital in a comatose state  (Young  &
Woolner,   1946).   Postmortem  findings   included  acute
haemorrhagic  gastritis, fatty degeneration of  the liver,
and   black  coloured  kidneys  with  marked  degenerative
changes in the renal tubules.

    Two non-fatal cases of poisoning by 2-ME in  men  aged
41  and  23 were  reported  by Nitter-Hauge  (1970).  Both
patients  consumed  100 ml  2-ME.  In  addition to nervous
system  disorders (agitation, confusion),  the predominant
clinical features were nausea, cyanosis, hyperventilation,
slight tachycardia, and metabolic acidosis. In one patient
there  were  suggestions  of moderate  kidney failure.  No
evidence of liver damage was found and both  patients  re-
covered within 4 weeks.

    Ingestion of approximately 40 ml 2-EE by a 44-year-old
women  led  to  vertigo, unconsciousness,  effects  on the
central  nervous  system,  and metabolic  acidosis (Fucik,
1969).   She recovered within  44 days from all  symptoms,
including  kidney insufficiency and signs of liver damage,
although neurasthenia was still evident at that time.

9.2  Occupational Exposure

9.2.1  Repeated exposure

    Reports on the effects of glycol ethers on humans fol-
lowing  repeated exposure are available  from occupational
studies. Early reports provided evidence that the repeated

exposure of humans to solvents containing 2-ME resulted in
such  effects  as  anaemia, leucopenia,  lethargy, general
weakness,  dizziness,  ataxia, and  unequal or exaggerated
reflexes.  A diagnosis of toxic encephalopathy was made by
Donley (1936) and Parson & Parsons (1938), but no reliable
estimation of exposure to 2-ME was given. Greenburg et al.
(1938) reported levels of 2-ME between 78 and  236 mg  per
m3    in  one  manufacturing plant  where 19 male subjects
(ages  16-26) were examined.   The median duration  of ex-
posure was 5 weeks and the maximum was 2 years.  Signs  of
nervous  system  dysfunction  (fatigue, hand  tremor,  and
lethargy)  were found, but  no clear relationship  between
the  incidence of symptoms  and the duration  of  exposure
could be ascertained in this small population.  No control
group was included in this study.

    The  development  of  macrocytic anaemia  has been de-
scribed in a case report of a worker exposed to  2-ME  and
other  solvents during microfilm  manufacturing.  Exposure
to 2-ME averaged 109 mg/m3   (35 ppm) (56-180 mg/m3,   18-
58 ppm),  to methyl ethyl ketone 1-5 ppm, and to propylene
glycol  monomethyl  ether 4-13 ppm  for  a duration  of 20
months. Follow-up analyses conducted 1 month after termin-
ating exposure indicated a return to normal limits for all
haematological parameters studied (Cohen, 1984).

    The  haematological effects of glycol ethers on humans
have  also been documented in  workplace surveys.  Obvious
symptoms  are not always  manifested in peripheral  blood.
The evaluation in a printing plant of seven  workers  with
dermal  and  respiratory  exposure to  dipropylene  glycol
monomethyl  ether, ethylene glycol monoethyl  ether, and a
range of aliphatic, aromatic, and halogenated hydrocarbons
used  for  offset  and multicolour  printing  revealed  no
alteration  in the peripheral blood (Cullen et al., 1983).
Although there was evidence of bone marrow injury in three
of  the  seven workers,  no  direct relationship  could be
drawn to glycol ether exposure. The exposure to other sol-
vents by this relatively small group of workers makes more
definitive  conclusions impossible.  Bone  marrow toxicity
had earlier been reported in two case studies  of  workers
exposed dermally to 2-ME (Ohi & Wegmann, 1978).

    Denkhaus  et al. (1986) investigated  the cellular im-
mune  response of nine  workers aged 25-58  years of  age,
heavily exposed to mixtures of organic solvents (including
2-ME and 2-EE) for 8-35 (mean 18.9) years, by the analysis
of  subpopulations of peripheral blood lymphocytes. A con-
trol  group of matched healthy controls was included.  The
mean  exposures to 2-ME  and 2-EE were  6.1 mg/m3  (peak
150 mg/m3)  and  4.8 mg/m3 (peak  53 mg/m3),  respect-
ively.  Based on samples taken during working shifts, mean
blood  levels  were  40.1 µg 2-ME/100 ml (peak: 965 µg/100
ml) and 2.0 µg 2-EE/100 ml   (peak: 92.7 µg/100 ml).    At

these levels (and in the presence of other  solvents  such
as 1-butanol, isobutanol, 2-butoxybutanol, toluene, m-xylene,
2-butanone,  and 2-hexanone), the exposed  workers had de-
creased  levels of helper T-cells, and increased levels of
natural  killer  cells and  human B-lymphocytes.  However,
the levels of suppressor cells were normal.   The  authors
noted  that  similar changes  in lymphocyte subpopulations
are  found in states  of general immunodeficiency  and  in
immunogenetic forms of aplastic anaemia.

9.2.2  Epidemiological studies

    In  a cross-sectional study, male employees in a plant
manufacturing  2-ME in the  USA were examined  for  haema-
tological  effects  and  possible sterility  (Cook et al.,
1982).  Personal air sampling indicated levels of exposure
of 1.3 mg/m3 or  less in one working location and 19-26 mg
per  m3   in another. Forty workers, engaged in production
and  distribution of 2-ME (75% of the possible total popu-
lation) and 25 controls (57% of total eligible population)
were  examined for haematological effects, and six exposed
and nine control workers participated in an examination of
testis  size,  semen  abnormalities, and  levels  of serum
follicle-stimulating  hormone  (FSH).  No increase  in the
incidence  of  leucopenia or  anaemia  was noted,  but de-
creases in white cell count and testicular size were noted
in the most highly exposed workers. These results were not
statistically significant but correlate with known effects
in experimental animals.

    A  cross-sectional evaluation of semen  quality (sperm
concentration,  pH, volume, viability, motility, velocity,
and morphology) was carried out in 37 workers  exposed  to
2-EE  used  as a  resin solvent in  a metal casting  plant
(NIOSH,  1986).  The study  population represented 50%  of
the exposed workforce.  A control group of 38 workers from
other  locations  in  the plant  was included.  Full-shift
breathing  zone airborne exposure to 2-EE ranged from non-
detectable to 88 mg/m3.   Dermal exposure was indicated by
urinary  excretion of EAA at levels from non-detectable to
163 mg/g creatinine.  Workers exposed to 2-EE had signifi-
cantly  lower  average  sperm counts  than  controls  (113
versus  154 million per ejaculate),  although both exposed
and control groups had lower sperm counts than those found
in  other occupational groups.  The two groups studied did
not  differ  significantly  with respect  to  other  semen
characteristics or testicular size.

    The  effect of 2-ME and  2-EE exposure on male  repro-
ductive  factors and blood  has been studied  in  shipyard
painters  by Sparer et al. (1988a,b), Welch et al. (1988),
and Welch & Cullen (1988).  Airborne levels (time-weighted
average:  TWA)  were determined  in  102 samples  over six
workshifts  and  were  0-80.5 mg 2-EE/m3    (mean 9.9  and

median  level 4.4 mg/m3),   and  0-17.7 mg 2-ME/m3   (mean
2.6  and median 1.4 mg/m3).     Given the methods  used by
Sparer et al. (1988a,b) the authors concluded  these  were
probably  underestimates of exposure, particularly  in the
mixing  room and inside large tanks.  Urinary excretion of
EAA  indicated  dermal exposure  as  well as  airborne ex-
posure  in some  workers.  In  73 painters,  from a  total
population of 153, an increased prevalence of oligospermia
and  azoospermia was noted and there was an increased odds
ratio  for a lower  sperm count per  ejaculate in  exposed
workers as compared to the 40 controls studied  (Welch  et
al., 1988).  In addition, when 94 painters from  the  same
population  were  examined  for haematological  effects of
chemical  exposures, 10% were found  to be anaemic and  5%
exhibited granulocytopenia (Welch & Cullen, 1988). None of
these  effects were noted in the 55 control subjects exam-
ined.  The reproductive effects observed were in agreement
with those reported previously by NIOSH (1986).


10.1.  Evaluation of Human Health Risks

10.1.1.  Exposure

    Many people may be exposed to 2-methoxyethanol (2-ME),
2-ethoxyethanol  (2-EE), and their acetates  (2-MEA and 2-
EEA),  at levels comparable to  industrial levels, through
the  use of  consumer and  trade products.   On the  other
hand,  exposure through food, water, or the ambient air is
probably  negligible.  This inference is based only on the
physical  and chemical properties  of these compounds  and
evidence of rapid environmental degradation.

    Significant  occupational  exposure  may  occur   both
through  inhalation and skin absorbtion.  Limited measure-
ments  of air levels in the workplace range from less than
0.1 mg/m3    to more than 150 mg/m3.   However, the avail-
able  monitoring is quite limited and large variations may
occur  both within and  among industries.  Because  of the
potential  for skin absorption,  air monitoring alone  may
underestimate  total exposure.  Total  uptake may be  best
estimated  from biological monitoring.   Occupations where
extensive  exposure  is  possible  include,  for  example,
painting, printing, and cleaning, but it should  be  borne
in  mind that there are many other occupations where these
compounds are also used and where exposure is of concern.

10.1.2.  Health Effects

    The major effects of concern for humans  are  develop-
mental,  testicular,  and haematological  toxicity.  These
are  demonstrated by extensive and consistent data in ani-
mals and some human data.  All these effects can be caused
by  both short-term and longer-term exposures.  In experi-
mental  animals, very high  repeated exposure to  2-ME and
2-EE  (over  930 and  1450 mg/m3,   respectively) produces
neurobehavioural, hepatic, and renal toxic effects.  These
are also observed in human poisoning situations.

    These four glycol ethers exhibit very similar testicu-
lar  and developmental toxicities,  in all species  evalu-
ated,  and by all  routes of exposure  that have been  em-
ployed (inhalation, dermal, and oral). Mechanistic studies
indicate  that for both  testicular and developmental  ef-
fects, metabolism to the alkoxyacetic acid derivative is a
necessary activation step.  Metabolism takes place via the
alcohol  dehydrogenase system that is common to humans and
laboratory  animals.  The toxic metabolites, methoxyacetic
acid (MAA) and ethoxyacetic acid (EAA), have been detected
in the urine of humans exposed to these solvents. The con-
sistency  of  response  across laboratory  animal  species
studied,  combined  with  the similarity  of metabolism in
humans, makes it clear that humans should be  presumed  to

be  subject to the testicular and developmental effects of
these glycol ethers.  Available data on the  excretion  of
alkoxyacetic  acids by humans indicate prolonged retention
compared  with that in laboratory animals, suggesting that
humans may be more sensitive than the most  sensitive  ex-
perimental  animal species.  The rapid  skin absorbtion of
these  compounds is of particular concern.  Teratogenicity
and other developmental effects have been observed follow-
ing the application of 2-ME, 2-EE, and 2-EEA to the intact
skin of rats.

    Testicular damage has been observed in the rat, mouse,
and  rabbit  following  exposure to  these  glycol  ethers
through both the inhalation and the oral route. Single in-
halation exposures of rats to 1944 mg 2-ME/m3 or  more for
4 h  and repeated exposure to 933 mg 2-ME/m3   or more for
13 weeks  resulted in histological evidence  of testicular
damage. The NOEL for acute exposure was 933 mg/m3 and  for
repeated  exposure  was  311 mg/m3.    The  mouse appeared
somewhat  less sensitive, the  NOEL for repeated  exposure
being 933 mg/m3.   However, the rabbit was more sensitive,
with  marked testicular change  being seen after  repeated
exposure to 311 mg/m3   and a marginal effect (one in five
rabbits   affected)  being  seen  at  93 mg/m3.    Similar
effects  have been seen following oral exposure of rats to
2-ME, with short-term (including single dose)  exposure to
100 mg/kg producing testicular damage.  The NOEL in a sub-
acute  (11 days) study was 50 mg/kg. 2-EE is somewhat less
potent with regard to its testicular toxicity  than  2-ME;
effects  were only  seen at  dose levels  of 500 mg/kg  or
more, the NOEL being 250 mg/kg.

    Evidence  from  studies in  men exposed occupationally
to  2-ME and 2-EE is  consistent with the animal  data and
indicates  that these glycol ethers can produce testicular
toxicity  in  humans.   Epidemiological studies  on  small
groups  of workers  exposed to  2-EE in  a  metal  casting
plant  and in shipyard painters  exposed to both 2-ME  and
2-EE  consistently revealed an increased  incidence of re-
duced sperm counts.  Data on exposure levels were limited,
but there was evidence, in each case, of  dermal  exposure
as well as exposure via inhalation.

    Developmental  toxicity has been observed  in the rat,
mouse,  rabbit,  and  monkey following  exposure  to these
glycol  ethers using dermal, oral,  and inhalation routes.
Twelve  daily applications of undiluted 2-ME to the shaved
skin  of pregnant rats  (with 6-h occlusion)  was  lethal,
while  ten open applications of 2-EE (1.0 ml/day) or 2-EEA
(1.4 ml/day)  were  teratogenic but  not maternally toxic.
Twelve  occluded applications of 10% 2-ME in saline proved
developmentally  toxic, the NOEL  in this study  being  3%
2-ME. No-observed-effect levels have not been demonstrated

following  repeated oral dosing  of pregnant animals  with
2-ME.   The  lowest-observed-effect level  (LOEL) for oral
administration of 2-ME was 31.25 mg/kg per day  for  mice,
25 mg/kg  per day for rats,  and 0.16 mmol/kg per day  for
monkeys.   Single-dose studies have been reported only for
2-ME in mice, the results being that on gestation  day  11
(the  most sensitive day) the  NOEL was 100 mg/kg and  the
LOEL  was 175 mg/kg.  Both 2-EE and 2-EEA have been evalu-
ated by inhalation exposure in rats and rabbits. Rats were
exposed to 2-EE in two studies, resulting  in  teratogenic
effects  (743 mg/m3   for 7 h/day on  gestation days 1-19)
or fetotoxic effects (184 and 920 mg/m3   for 6  h/day  on
gestation days 6-15).  In the latter study, the  NOEL  was
37 mg/m3.      Rabbits  exposed  to  2-EE  also  exhibited
teratogenic  effects (589 mg/m3   for 7 h/day on gestation
days  1-18) or fetotoxic effects  (644 mg/m3   for 6 h/day
on gestation days 6-18). In the latter study, the NOEL was
184 mg/m3.     When  rabbits  were exposed  to  2-EEA  for
6 h/day  on gestation days 6-18,  teratogenic effects were
seen  at  2160 mg/m3   in  one  study and  1620 mg/m3   in
another.   Fetotoxicity appeared in both studies at 540 mg
per  m3   and the lowest exposure level in each study (135
and 270 mg/m3,   respectively) was the NOEL.  Rats exposed
to  2-EEA by inhalation for 6 h/day on gestation days 6-15
showed  the same pattern of response:  teratogenic effects
at  1620 mg/m3,   fetotoxicity at 1080 mg/m3,   and no ef-
fect at 270 mg/m3.

    Thus  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
per  m3.     Behavioural and  neurochemical alterations in
rats  followed  in  utero exposure  at 78 mg/m3,    with no
NOEL being identified.

    2-EE  and  2-EEA  were slightly  less potent. Develop-
mental effects in rats and rabbits followed all  2-EE  ex-
posures  at 368 mg/m3   or more.  Slight developmental ef-
fects were seen in rats exposed at 184  mg 2-EE/m3,    but
37 mg/m3 was  a clear NOEL. For 2-EEA, the NOEL was 170 mg
per m3 for both rats and rabbits.

    Haematological  effects  from  single acute  dose  ex-
posures have been observed in animals and in human poison-
ings.   Repeated inhalation exposure of the most sensitive
species,  the rabbit, to  2-ME for 13  weeks, 5 times  per
week, yielded a NOEL of 93 mg/m3.   Repeat doses  of  2-ME
also cause haematological toxicity in mice, rabbits, dogs,
hamsters, and guinea-pigs.  2-EE is less potent in causing
haematological  effects than 2-ME.  The NOEL for  haemato-
logical effects in rats and rabbits exposed to 2-EE for 13
weeks, 5 times per week for 6 h/day, is 368 mg/m3.    Dogs
and  mice also show  haematological effects from  repeated
2-EE exposure at higher levels.  Exposure to  the  acetate

esters of 2-EE and 2-ME would be expected to cause similar
effects  at similar exposure levels, but there are too few
data  on exposure and haematological effects of these com-
pounds to determine under what conditions single human ex-
posures will lead to haematological effects.

    Industrial  exposure levels have  been reported at  or
near  the NOEL for haematological effects in animals after
repeated doses of both 2-ME and 2-EE.  This fact, together
with  the probable greater  sensitivity of humans  and the
expected accumulation of metabolites in human blood, indi-
cates  that haematological effects may well occur from in-
dustrial and consumer exposure. This has been confirmed by
the haematological effects reported in some of the limited
number of studies of industrial workers with repeated 2-EE
and/or 2-ME exposure.

10.2.  Evaluation of Effects on the Environment

    Environmental  exposure  to  these glycol  ethers  can
arise  as a consequence of  their direct release into  the
atmosphere  from their use  as evaporative solvents.  Dis-
charges  to the land and water from accidental release may
also  result  in environmental  exposure.  Accumulation in
soil  and surface water could only occur in the absence of
degradation.   However,  these  glycol ethers  are rapidly
degraded  by chemical and biological processes and accumu-
lation  is not expected. 2-MEA and 2-EEA are also expected
to  hydrolyse  readily  and subsequently  biodegrade under
aerobic  conditions.  However, contamination  of anaerobic
soils and aquifers remains a potential problem,  but  this
condition is expected to be transitory resulting in negli-
gible risk.

    Both  2-ME and 2-EE demonstrate low toxicity to micro-
oganisms  and aquatic species.  The glycol ether acetates,
however,  are far more acutely  toxic.  No data exists  to
ascertain the potential for adverse effects from long-term
exposure to environmental species.


11.1.  Health Protection

1.  Alternative  less toxic solvents should  be identified
to  replace  2-methoxyethanol, 2-ethoxyethanol,  and their
esters,  particularly in consumer products.  Assessment of
the  effects of other  ethylene glycol ethers  is also  of
particular  importance,  because  some may  cause  effects
similar to the four glycol ethers evaluated here.

2.  In  view of the  known toxic effects  of these  glycol
ethers,  authorities should seriously consider appropriate
strategies  to  alert users  of  these chemicals  to their
hazards,   particularly  those  arising  from  dermal  ex-

3.  In view of recent toxicological data and the potential
for considerable dermal absorption of these glycol ethers,
national  occupational  exposure  limits should  be recon-
sidered  to insure that the total daily dose to workers by
all routes of administration does not pose an  undue  risk
to health.

4.  Single  dose effects occur  in animals at  fairly high
exposure levels. Prudent use of these compounds (attention
to  personal  hygiene,  suitable protective  devices,  and
adequate  ventilation) is recommended to reduce the health
risks.   The data indicate that  more extensive protection
may  be required to prevent developmental effects, as well
as effects on blood and testis, from repeated exposure.

11.2.  Further Research

1.  In view of the implication of methoxyacetic acid (MAA)
and  ethoxyacetic  acid  (EAA) (the  principal  identified
metabolites  of 2-ME, 2-EE,  and of their  esters) in  the
toxicity to the male reproductive  system, their mechanism
of action should be investigated.  If it  transpires  that
MAA  and EAA are not  the primary agents concerned,  these
should  be  identified  and  their  mechanism  of   action

2.  These  four  glycol  ethers  are  known  to  have both
haematological  effects  and  male  reproductive   effects
(sperm  count  reduction).   The available  data, although
limited,  appear to suggest  that the two  effects  become
evident at similar dose levels.  The mechanism  of  action
should  be  investigated  for  both  organ  systems,   and
haematological effects and sperm counts should be examined
in  parallel to determine if  haematological changes offer
warning signs for other effects of these compounds.

3.  Air monitoring alone is not sufficient to  assure  low
exposure.   Biological  monitoring  can aid  in  detecting
failures   in   protective   measures.   At   present  the
relationship  between  biological indicators  of exposure,
total  body uptake, and  observed health effects  have not
been  sufficiently established.  Further work is necessary
to  provide the basis  for using biological  monitoring in
determining safe exposures.

4.  Epidemiological  studies  and/or targeted  health sur-
veillance in populations subject to high exposure to these
glycol  ethers  should be  designed  in order  to estimate
exposure-effect relationships for the purpose of determin-
ing safe exposures, providing that overall exposure can be
properly  and adequately evaluated by appropriate environ-
mental and biological monitoring.

5.  The possibility that these compounds may cause effects
on  the  female  gonads  should  be  investigated  through
multigeneration reproductive studies in animals.

6.  Available  research  indicates that  humans may metab-
olize  these  glycol  ethers to  the corresponding alkoxy-
acetic acids to a greater extent than rats, and  that  the
half-life for urinary excretion of these toxic metabolites
is  about  four  times longer  in  humans  than  in  rats.
Furthermore,  rats conjugate a  large portion of  the acid
metabolites,  whereas  humans  do not.   These differences
might  contribute to the relatively  higher sensitivity of
humans  to these glycol ethers.  Detailed knowledge of the
metabolism   and  excretion  kinetics  would  improve  the
ability to predict safe exposure levels.

7.  The results obtained from short-term (13-week) studies
indicate effects on various organ systems.  However, there
have  been no studies  of sufficient duration  that  would
allow  the reversibility of  such effects to  be assessed.
Therefore, it is suggested that stop-studies be undertaken
in  which experimental animals are exposed to these glycol
ethers  for at  least 13  weeks, followed  by  a  suitable
recovery   period.   Important   physiological  parameters
should  then be evaluated in order to determine whether or
not these effects are transient.


    Regulatory standards for 2-ME, 2-MEA, and 2-EE, estab-
lished by national bodies in different countries  and  the
European  Economic Community, are  summarized in the  data
profile of the International Register of Potentially Toxic
Chemicals (IRPTC, 1987).


D.M., &  GANGOLLI, S.D.  (1987) Effect of ethylene glycol monomethyl ether
on spermatogenesis,  dominant lethality,  and F1  abnormalities in the rat
and the mouse after treatment of F0 males.  Teratog. Carcinog. Mutagen., 

ANDREW, F.D.  & HARDIN, B.D. (1984) Developmental effects after inhalation
exposure of  gravid rabbits  and rats  to ethylene glycol monoethyl ether.
 Environ. Health Perspect., 57: 13-23.

BAILEY,  H.C.,   LIU,  D.H.W.,   &  JAVITZ,   H.A.  (1985)   Time/toxicity
relationships in  short-term static, dynamic, and plug-flow bioassays. In:
Bahner, R.C. & Hansen, D.J., ed.  Aquatic toxicology and hazard assessment:
 Eighth  Symposium,   Philadelphia,  American   Society  for   Testing  and
Materials, pp. 193-212 (ASTM STP 891).

BARBEE, S.V.,  TERRILL,  J.B.,  DESOUSA,  D.J.,  &  CONAWAY,  C.C.  (1984)
Subchronic inhalation toxicology of ethylene glycol monoethyl ether in the
rat and rabbit.  Environ. Health Perspect., 57: 157-163.

BASLER, A.  (1986) Aneuploidy-inducing chemicals in yeast evaluated by the
micronucleus test.  Mutat. Res., 174: 11-13.

BOTTA, D.,  CASTELLANI PIRRI,  L.,  &  MANTICA,  E.  (1984)   Ground  water
 pollution by  organic solvents  and their  microbial degradation products,
Luxembourg, Commission  of the  European Communities,  pp.  261-275  (EUR-

BRINGMANN, G.  & KUHN,  R. (1978) Testing of substances for their toxicity
threshold:  Model   organisms   Microcystis  (Diplocystis)  Aeruginosa  and
 Scenedesmus quadricauda.  Mitt. intern.  Ver. theor.  angew. Limnol.,  21:

BROWN,  N.A.,   HOLT,  D.,   &  WEBB,  M.  (1984)  The  teratogenicity  of
methoxyacetic acid in the rat.  Toxicol. Lett., 22: 93-100.

SMITH, H.F.  (1956) The  toxicity of  butyl cellosolve solvent.  Arch. ind.
 Health, 14: 114-131.

CHAPIN, R.E.,  DUTTON, S.L.,  ROSS, M.D.,  & LAMB, J.C. (1985a) Effects of
ethylene  glycol   monomethyl  ether  (EGME)  on  mating  performance  and
epididymal sperm  parameters in F344 rats.  Fundam. appl. Toxicol., 5: 182-

(1985b) The  recovery of  the testis  over 8 weeks after short-term dosing
with ethylene  glycol monomethyl  ether: histology, cell specific enzymes,
and rete testis fluid protein.  Fundam. appl. Toxicol., 5: 515-525.

CHEEVER, K.L.,  PLOTNICK, H.B.,  RICHARDS, D.E.,  &  WEIGEL,  W.W.  (1984)
Metabolism and  excretion  of  2-ethoxyethanol  in  the  adult  male  rat.
 Environ. Health Perspect., 57: 241-248.

COHEN, R.  (1984) Reversible  subacute ethylene  glycol  monomethyl  ether
toxicity associated  with microfilm production: a case report.  Am. J. ind.
 Med., 6: 441-446.

G.S., &  FLANAGAN, K.  (1982) A  cross-sectional study  of ethylene glycol
monomethyl ether process employees.  Arch. environ. Health, 37: 346-351.

CREASY, D.M.  & FOSTER,  P.M.D. (1984)  The morphological  development  of
glycol ether-induced testicular atrophy in the rat.  Exp. mol. Pathol., 40:

CREASY,  D.M.,  FLYNN,  J.C.,  GRAY,  T.J.B.,  &  BUTLER,  W.H.  (1985)  A
quantitative  study   of  stage-specific   spermatocyte  damage  following
administration of  ethylene glycol  monomethyl ether in the rat.  Exp. mol.
 Pathol., 43: 321-336.

CREASY, D.M.,  JONES, H.B., BEECH, L.M., & GRAY, T.J.B. (1986) The effects
of two  testicular toxins  on  the  ultrastructural  morphology  of  mixed
cultures of  Sertoli and  germ cells:  a comparison  with  in vivo  effects.
 Food chem. Toxicol., 24: 655-656.

CULLEN, M.R.,  RADO, T.,  WALDRON, J.A.,  SPARER, J., & WELCH, L.S. (1983)
Bone marrow  injury in  lithographers exposed to glycol ethers and organic
solvents  used  in  multicolor  offset  and  ultraviolet  curing  printing
processes.  Arch. environ. Health, 38(6): 347-354.

DAWSON, G.W., JENNINGS, A.L., DROZDOWSKI, D., & RIDER, E. (1977) The acute
toxicity of  47 industrial  chemicals to  fresh and  saltwater fishes.   J.
 hazard. Mater., 1: 303-318.

DE DELBARRE,  F., KAHAN,  A., DE  GERY, A.,  & KONRAD,  K.  (1980)  Action
immunomodulatrice du  méthoxy-2 éthanol  et de  dérivés homologues chez le
rat.  C.R. Acad. Sci. Paris, 291: 215-218.

Lymphocyte subpopulations  in solvent-exposed  workers.  Int.  Arch. occup.
 environ. Health, 57: 109-115.

DOE, J.E.  (1984a) Ethylene  glycol monoethyl  ether and  ethylene  glycol
monoethyl ether acetate teratology studies.  Environ. Health Perspect., 57:

DOE, J.E.  (1984b) Further  studies on the toxicology of the glycol ethers
with emphasis  on rapid  screening and  hazard assessment.  Environ. Health
 Perspect., 57: 199-206.

Comparative aspects  of the  reproductive toxicology by inhalation in rats
of ethylene glycol monomethyl ether and propylene glycol monomethyl ether.
 Toxicol. appl. Pharmacol., 69: 43-47.

DONLEY,  D.E.   (1936)  Toxic  encephalopathy  and  volatile  solvents  in
industry.  J. ind. Hyg. Toxicol., 18: 571-577.

DUGARD, P.H.,  WALKER, M., MAWDSLEY, S.J., & SCOTT, R.C. (1984) Absorption
of some  glycol ethers through human skin  in vitro .  Env. Health Perspect.,
57: 193-197.

ECETOC (1985)   The toxicology  of glycol  ethers and its relevance to man,
Brussels,  European   Chemical  Industry  Ecology  and  Toxicology  Centre
(Technical Report No. 17).

GANGOLLI, S.D.  (1983) Testicular  toxicity of  ethylene glycol monomethyl
and monoethyl ethers in the rat.  Toxicol. appl. Pharmacol., 69: 385-399.

FOSTER,  P.M.D.,  CREASY,  D.M.,  FOSTER,  J.R.,  &  GRAY,  T.J.B.  (1984)
Testicular toxicity  produced by  ethylene glycol monomethyl and monoethyl
ethers in the rat.  Environ. Health Perspect., 57: 207.

FOSTER, P.M.D.,  BLACKBURN,  D.M.,  MOORE,  R.B.,  &  LLOYD,  S.C.  (1986)
Testicular toxicity  of 2-methoxyacetaldehyde,  a possible  metabolite  of
ethylene glycol monomethyl ether, in the rat.  Toxicol. Lett., 32: 73-80.

FOSTER, P.M.D., LLOYD, S.C., & BLACKBURN, D.M. (1987) Comparison of the  in
 vivo and  in vitro testicular effects produced by methoxy-, ethoxy-, and  n-
butoxy acetic acids in the rat. Toxicology, 43: 17-30.

FUCIK, J. (1969) Poisoning by ethylene glycol monoethyl ether.  Prac. Lek.,
21: 116-118.

MARGOLIN,  B.H.,   RESNICK,  M.A.,  ANDERSON,  B.,  &  ZEIGER,  E.  (1987)
Chromosome aberrations  and sister  chromatid exchanges in Chinese hamster
ovary cells: evaluations of 108 chemicals.  Environ. mol. Mutagen., 10(10):

GOLDBERG, M.E.,  HARN, C.,  & SMYTH, H.F. (1962) Toxicological implication
of altered  behaviour induced  by an  industrial  vapour.   Toxicol.  appl.
 Pharmacol., 4: 148-164.

GRANT, D.,  SULSH, S.,  JONES, H.B., GANGOLLI, S.D., & BUTLER, W.H. (1985)
Acute toxicity  and recovery  in the  hemopoietic  system  of  rats  after
treatment with  ethylene glycol  monomethyl and monobutyl ethers.  Toxicol.
 appl. Pharmacol., 77: 187-200.

GRAY, T.J.B., MOSS, E.J., CREASY, D.M., & GANGOLLI, S.D. (1985) Studies on
the toxicity  of some  glycol ethers  and alkoxyacetic  acids  in  primary
testicular cell cultures.  Toxicol. appl. Pharmacol., 79: 490-501.

(1938) Health hazards in the manufacture of "fused collars". 1. Exposure
to ethylene glycol monomethyl ether.  J. ind. Hyg. Toxicol., 20: 134-147.

GREENE, J.A.,  SLEET, R.B.,  MORGAN, K.T.,  & WELSCH,  F. (1987) Cytotoxic
effects of  ethylene glycol  monomethyl ether  in the  forelimb bud of the
mouse embryo.  Teratology, 36: 23-34.

Gas chromatographic  determination of  methoxyacetic and ethoxyacetic acid
in urine.  Br. J. ind. Med., 43: 62-65.

GROESENEKEN, D.,  VEULEMANS, H.,  & MASSCHELEIN,  R.  (1986b)  Respiratory
uptake  and   elimination  of   ethylene  glycol   monoethyl  ether  after
experimental human exposure.  Br. J. ind. Med., 43: 544-549.

GROESENEKEN,  D.,   VEULEMANS,  H.,  &  MASSCHELEIN,  R.  (1986c)  Urinary
excretion of  ethoxyacetic  acid  after  experimental  human  exposure  to
ethylene glycol monoethyl ether.  Br. J. ind. Med., 43: 615-619.

Ethoxyacetic acid: a metabolite of ethylene glycol monoethyl ether acetate
in man. Br. J. ind. Med., 44: 488-493.

Comparative urinary  excretion of  ethoxyacetic acid  in man and rat after
single low  doses of  ethylene glycol monoethyl ether.  Toxicol. Lett., 41:

Experimental human  exposure to  ethylene glycol  monomethyl  ether.   Int.
 Arch. occup. environ. Health, 61: 243-247.

improved method for the determination in urine of alkoxyacetic acids.  Int.
 Arch. occup. environ. Health, 61: 249-254.

Pulmonary and  percutaneous absorption  of 2-propoxyethyl  acetate and  2-
ethoxyethyl acetate  in beagle  dogs.  Environ.  Health Perspect., 57: 177-

HAMLIN, J.W.,  HUDSON, B.,  SHEEN,  A.D.,  &  SAUNDERS,  K.J.  (1982)  The
measurement of  glycol ether  levels in the workplace.  Polym. Paint Colour
 J., October 13: 61-63.

HANLEY, T.R.,  Jr,  YANO,  B.L.,  NITSCHKE,  K.D.,  &  JOHN,  J.A.  (1984)
Comparison  of  the  teratogenic  potential  of  inhaled  ethylene  glycol
monomethyl ether  in rats,  mice, and  rabbits.  Toxicol. appl. Pharmacol.,
75: 409-422.

HARDIN,  B.D.   (1983)  Reproductive   toxicity  of   the  glycol  ethers.
 Toxicology, 27: 91-102.

WEAVER,  T.F.   (1982)  Teratogenicity   of  2-ethoxyethanol   by   dermal
application.  Drug chem. Toxicol., 5(3): 277-294.

HARDIN, B.D.,  GOAD, P.T.,  & BURG,  J.R. (1984) Developmental toxicity of
four glycol ethers applied cutaneously to rats.  Environ. Health Perspect.,
57: 69-74.

HEALTH AND  SAFETY EXECUTIVE  (1988)   Methods  for  the  determination  of
 hazardous substances:  Glycol ethers  and glycol  acetate vapours  in air,
London, UK Health and Safety Executive, pp. 1-7 (MDHS-23).

HERMENS, J.,  CANTON, H.,  JANSSEN, P.,  & DEJONG,  R. (1984) Quantitative
structure-activity relationships  and toxicity  of mixtures  of  chemicals
with anaesthetic  potency: Acute  lethal and sublethal toxicity to  Daphnia
 magna. Aquat. Toxicol., 5: 143-154.

HORTON,  V.L.,  SLEET,  R.B.,  JOHN-GREENE,  J.A.,  &  WELSCH,  F.  (1985)
Developmental  phase-specific  and  dose-related  teratogenic  effects  of
ethylene glycol  monomethyl ether in CD-1 mice.  Toxicol. appl. Pharmacol.,
80: 108-118.

HOUSE, R.V.,  LAUER, L.D.,  MURRAY, M.J.,  WARD, E.C., & DEAN, J.H. (1985)
Immunological studies in B6C3F1 mice following exposure to ethylene glycol
monomethyl ether and its principal metabolite methoxyacetic acid.  Toxicol.
 appl. Pharmacol., 77: 358-362.

HURTT, M.E.  & ZENICK,  H. (1986)  Decreasing  epididymal  sperm  reserves
enhances the  detection of ethoxyethanol-induced spermatotoxicity.  Fundam.
 appl. Toxicol., 7: 348-353.

IRPTC (1987)   IRPTC legal  file 1986  - Volume  1,  Geneva,  International
Register  of  Potentially  Toxic  Chemicals,  United  Nations  Environment

JUHNKE, I. & LUDEMANN, D. (1978) The results obtained with the Golden Orfe
test during  the examination  of 200  chemical compounds  for  acute  fish
toxicity.  Wasser Abwasser Forsch., 11: 161-164.

KAREL, L.,  LANDING, B.H.,  &  HARVEY,  T.S.  (1947)  The  intraperitoneal
toxicity of  some glycols,  glycol ethers, glycol esters and phthalates in
mice.  J. Pharmacol. exp. Ther., 90: 338-347.

KIRK-OTHMER (1980)   Encyclopedia of chemical technology: Vol. 9 - Ethanol,
3rd ed., New York, Chichester, Brisbane, Toronto, John Wiley & Sons.

KIRK-OTHMER (1980)   Encyclopedia of chemical technology: Vol. 11 - Glycols
 (Ethylene  and  Propylene),  3rd  ed.,  New  York,  Chichester,  Brisbane,
Toronto, John Wiley & Sons.

LAILLER, J.,  PLAZONNET, B.,  LE  DOUAREC,  J.C.,  &  GONIN,  M.J.  (1975)
Evaluation of  ocular irriation in the rabbit: Development of an objective
method of studying eye irritation.  Proc. Eur. Soc. Toxicol., 17: 336-350.

(1984) Reproductive  toxicity of ethylene glycol monoethyl ether tested by
continuous breeding of CD-1 mice.  Environ. Health Perspect., 57: 85-90.

LAUG, E.P.,  CALVERY,  H.O.,  MORRIS,  H.J.,  &  WOODARD,  G.  (1939)  The
toxicology of  some glycols  and derivatives.   J. ind.  Hyg. Toxicol., 21:

LEE, K.H.  & WONG,  H.A. (1979) Toxic effects of some alcohol and ethylene
glycol derivatives on Cladosporium resinae.  Appl. environ. Microbiol., 38:

& NIEMEIER,  R.W. (1983)  Genetic effects  of 2-methoxyethanol  and bis(2-
methoxyethyl)ether.  Toxicol. appl. Pharmacol., 70: 303-316.

MELLAN, I.  (1977) Glycol  ethers  and  esters.  In:   Industrial  Solvents
 Handbook, 2nd  ed., Park  Ridge, New  Jersey, Noyes  Data Corporation, pp.
346-399, 513-551.

(1981) Comparative  short-term  inhalation  toxicity  of  ethylene  glycol
monomethyl ether  and propylene  glycol monomethyl ether in rats and mice.
 Toxicol. appl. Pharmacol., 61: 368-377.

MILLER, R.R.,  CARREON, R.E., YOUNG, J.T., & MCKENNA, M.J. (1982) Toxicity
of methoxyacetate acid in rats.  Fundam. appl. Toxicol., 2: 155-160.

B.A. (1983a)  Comparative metabolism  and disposition  of ethylene  glycol
monomethyl ether  and propylene  glycol monomethyl  ether  in  male  rats.
 Toxicol. appl. Pharmacol., 67: 229-237.

MILLER, R.R.,  AYRES, J.A.,  YOUNG, J.T., & MCKENNA, M.J. (1983b) Ethylene
glycol monomethyl  ether. I.  Subchronic vapor  inhalation study with rats
and rabbits.  Fundam. appl. Toxicol., 3: 49-54.

CREASY, D.M.,  &  GRAY,  T.J.B.  (1985)  The  role  of  metabolism  in  2-
methoxyethanol-induced testicular toxicity.  Toxicol. appl. Pharmacol., 79:

T. (1979)  Testicular atrophy of mice induced by ethylene glycol monoalkyl
ethers.  Jpn. J. ind. Health, 21: 29-35.

YAMAZAKI, K.  (1981) Embryotoxic  effects of  ethylene  glycol  monomethyl
ether in mice.  Toxicology, 20: 335-343.

YAMAZAKI, K.  (1984) Experimental  studies on  toxicity of ethylene glycol
alkyl ethers in Japan.  Environ. Health Perspect., 57: 75-84.

NAKAAKI, K.,  FUKABORI, S.,  & TADA,  O. (1980)  An experimental  study on
percutaneous absorption  of some organic solvents.  J. Sci. Labour, 56(12):

NEIHOF, R.A.  & BAILEY,  C.A. (1978)  Biocidal  properties  of  anti-icing
additives for aircraft fuels.  Appl. environ. Microbiol., 35: 698-703.

R.W.  (1981)   Ethoxyethanol  behavioral   teratology  in   rats.    Neuro-
 toxicology., 2(2): 231-249.

NELSON,  B.K.,   BRIGHTWELL,  W.S.,   &  SETZER,   J.V.  (1982)   Prenatal
interactions between ethanol and the industrial solvent 2-ethoxyethanol in
rats: maternal  and behavioral  teratogenic effects.   Neurobehav. Toxicol.
 Teratol., 4: 387-394.

NELSON, B.K.,  BRIGHTWELL, W.S.,  BURG,  J.R.,  &  MASSARI,  V.J.  (1984a)
Behavioral and  neurochemical alterations  in the  offspring of rats after
maternal or  paternal inhalation  exposure to  the industrial  solvent  2-
methoxyethanol.  Pharmacol. Biochem. Behav., 20: 269-279.

M.H.,  WEAVER,   T.E.,  &   GOAD,  P.T.   (1984b)  Comparative  inhalation
teratogenicity of four glycol ether solvents and amino derivative in rats.
 Environ. Health Perspect., 57: 261-271.

Reproductive toxicity  of the  industrial solvent  2-ethoxyethanol in rats
and interactive  effects of  ethanol.  Environ.  Health Perspect., 57: 255-

NIOSH  (1986)    Health  hazard   evaluation  report:  Precision  Castparts
 Corporation, Portland,  Oregon, Cincinnati,  Ohio, National  Institute for
Occupational Safety and Health (Report No. HETA-84-415-1688).

NIOSH (1987a)  Alcohols  IV.  In:   NIOSH  manual  of  analytical  methods,
Cincinnati, Ohio,  National Institute  for Occupational Safety and Health,
p. 1403.

NIOSH  (1987b)   Esters  I.   In:   NIOSH  manual  of  analytical  methods,
Cincinnati, Ohio,  National Institute  for Occupational Safety and Health,
p. 1450.

NITTER-HAUGE, S.  (1970) Poisoning  with ethylene glycol monomethyl ether:
report of two cases.  Acta med. Scand., 188: 277-280.

OHI, G.  & WEGMANN,  D.H. (1978) Transcutaneous ethylene glycol monomethyl
ether poisoning in the work setting.  J. occup. Med., 20: 675-676.

OUDIZ, D.  & ZENICK,  H. (1986)   In  vivo  and   in  vitro  evaluations  of
spermatotoxicity induced  by  2-ethoxyethanol  treatment.   Toxicol.  appl.
 Pharmacol., 84: 576-583.

PARSONS,  C.E.   &  PARSONS,   M.E.M.  (1938)   Toxic  encephalopathy  and
"granulopenic anaemia"  due to  volatile solvents in industry: report of
two cases.  J. ind. Hyg. Toxicol., 20: 124-135.

PAUSTENBACH, D.J.  (1988) Assessment  of the developmental risks resulting
from  occupational   exposure  to   selected  glycol   ethers  within  the
semiconductor industry.  J. Toxicol. environ. Health, 23: 29-75.

PISKO, G.T.  & VERBILOV, A.A. (1988) Toxicity of monomethyl, monoethyl and
monobutyl ethers of ethylene glycol.  Gig. Tr. prof. Zabol., 3: 48-49.

PRICE, K.S.,  WAGGY, G.T., & CONWAY, R.A. (1974) Brine shrimp bioassay and
seawater BOD of petrochemicals.  J. Water Pollut. Control Fed., 46: 63-77.

JOHN, J.A.,  & MILLER,  R.R. (1983)  Ethylene glycol  monomethyl ether II.
Reproductive and  dominant lethal studies in rats.  Fundam. appl. Toxicol.,
3: 80-85.

RITTER,  E.J.,   SCOTT,  W.J.,   RANDALL,  J.L.,  &  RITTER,  J.M.  (1985)
Teratogenicity   of   dimethoxyethyl   phthalate   and   its   metabolites
methoxyethanol and methoxyacetic acid in the rat.  Teratology, 32: 25-31.

ROMER,  K.G.,   BALGE,  F.,   &  FREUNDT,   K.J.  (1985)   Ethanol-induced
accumulation of  ethylene glycol  monoalkyl ethers  in  rats.   Drug  chem.
 Toxicol., 8(4): 255-264.

ROWE, V.K. & WOLF, M.A. (1982) Derivatives of glycols. In: Clayton, G.D. &
Clayton, F.E.,  ed.  Patty's  industrial hygiene  toxicology, Vol.  2,  pp.

SAPARMAMEDOV, E.  (1974) [Toxicity  of some  simple ethylene glycol ethers
(single  experiments).]   Zdravookhr  Turkm.,  18(9):  26-31  (in  Russian)
(English translation from US NIOSH.).

SAVOLAINEN, H.  (1980) Glial  cell toxicity  of ethyleneglycol  monomethyl
ether vapour.  Environ. Res., 22: 423-430.

SCOTT, W.J.,  FRADKIN, R.,  NAU, H.,  & WITTFOHT,  W.  (1987)  Teratologic
potential of  2-methoxyethanol (2-ME)  in non-human  primates.  Teratology,
35(2): 66 (abstract).

SLEET, R.B.,  JOHN-GREENE, J.A.,  &  WELSCH,  F.  (1986)  Localization  of
radioactivity from  2-methoxy[1,2-14C]ethanol in  maternal  and  conceptus
compartments of CD-1 mice.  Toxicol. appl. Pharmacol., 84: 25-35.

SLEET, R.B.,  GREENE, J.A.,  & WELSCH,  F. (1987)  The teratogenicity  and
disposition of the glycol ether 2-methoxyethanol and their relationship in
CD-1 mice.  In: Welsch,  F., ed.   Approaches to  elucidate  mechanisms  in
 teratogenesis, New York, Hemisphere Publishing Co., pp. 33-57.

SLEET, R.B.,  GREENE, J.A.,  &  WELSCH,  F.  (1988)  The  relationship  of
embryotoxicity to  disposition of 2-methoxyethanol in mice.  Toxicol. appl.
 Pharmacol., 93: 195-207.

SMALLWOOD, A.W.,  DEBORD, K.E.,  & LOWRY, L.K. (1984) Analyses of ethylene
glycol monoalkyl ethers and their proposed metabolites in blood and urine.
 Environ. Health Perspect., 57: 249-253.

SMALLWOOD, A.W.,  DEBORD, K.,  BURG, J.,  MOSELEY, C.,  & LOWRY, L. (1988)
Determination  of   urinary  2-ethoxyacetic   acid  as   an  indicator  of
occupational exposure to 2-ethoxyethanol.  Appl. ind. Hyg., 3(2): 47-50.

SMYTH, H.F.,  SEATON, J., & FISCHER, L. (1941) The single dose toxicity of
some glycols and derivatives.  J. ind. Hyg. Toxicol., 23: 259-268.

SPARER, J.,  WELCH, L.S.,  MCMANUS, K.,  & CULLEN, M.R. (1988a) Effects of
exposure to glycol ethers in shipyard painters. I. Evaluation of exposure.
 Am. J. ind. Med., 14: 497-507.

(1988b) Effects  of exposure  to glycol  ethers in  shipyard painters. II.
Male reproduction.  Am. J. ind. Med., 14: 509-526.

Toxicology of  ethylene glycol  monoethyl ether.  Arzneim Forsch., 21: 880-

STOTT, W.T.  & MCKENNA,  M.J. (1985)  Hydrolysis of  several glycol  ether
acetates and  acrylate esters  by nasal mucosal carboxylesterase  in vitro .
 Fundam. appl. Toxicol., 5: 399-404.

SZYBALSKI, W.  (1958) Special  microbiological systems II. Observations on
chemical mutagenesis in microorganisms.  Ann. N.Y. Acad. Sci., 76: 475-488.

TANAKA, K.,  MIKAMI, E.,  & SUZUKI,  T. (1986)  Methane fermentation of 2-
methoxyethanol by  mesophilic  digesting  sludge.   J.  Ferment.  Technol.,
64(4): 305-309.

TORAASON,  M.,   STRINGER,  B.,   STOBER,  P.,   &  HARDIN,   B.D.  (1985)
Electrocardiographic study  of rat  fetuses  exposed  to  ethylene  glycol
monomethyl ether (EGME).  Teratology, 32: 33-39.

TORAASON, M.,  BREITENSTEIN, M.J.,  & SMITH,  R.J. (1986a) Ethylene glycol
monomethyl ether  (EGME) inhibits rat embryo ornithine decarboxylase (ODC)
activity.  Drug chem. Toxicol., 9: 191-203.

TORAASON, M.,  STRINGER, B.,  & SMITH,  R. (1986b) Ornithine decarboxylase
activity in the neonatal rat heart following prenatal exposure to ethylene
glycol monomethyl ether.  Drug chem. Toxicol., 9(1): 1-14.

TYL, R.W.,  PRITTS, I.M., FRANCE, K.A., FISHER, L.C., & TYLER, T.R. (1988)
Developmental toxicity  evaluation of  inhaled 2-ethoxyethanol  acetate in
Fischer 344  rats and  New Zealand  white rabbits.  Fundam. appl. Toxicol.,
10: 20-39.

US  EPA   (1987)   Environmental   health  criteria:  2-methoxyethanol,  2-
 ethoxyethanol,  and  their  acetates,  Washington,  DC,  US  Environmental
Protection Agency, Office of Toxic Substances.

VERSCHUEREN, K.  (1977) Ethylene  glycol monomethyl ether. In:  Handbook of
 experimental data  on organic  chemicals, New  York, Van Nostrand-Reinhold
Company, 327 pp.

Field study  of the urinary excretion of ethoxyacetic acid during repeated
daily exposure  to the  ethyl ether of ethylene glycol and the ethyl ether
of ethylene glycol acetate.  Scand. J. Work Environ. Health, 13: 239-242.

Survey of  ethylene glycol  ether  exposures  in  Belgian  industries  and
workshops.  Am. Ind. Hyg. Assoc. J., 48(8): 671-676.

WEIL, C.S.  & SCALA,  R.A. (1971)  Study of  intra-  and  inter-laboratory
variability in  the results  of rabbit  eye  and  skin  irritation  tests.
 Toxicol. appl. Pharmacol., 19: 276-360.

WELCH, L.S.  & CULLEN, M.R. (1988) Effects of exposure to glycol ethers in
shipyard painters.  III. Hematologic  effects.  Am.  J. ind. Med., 14: 527-

WELCH, L.S.,  SCHRADER, S.M.,  TURNER, T.W., & CULLEN, M.R. (1988) Effects
of exposure  to ethylene  glycol ethers  on shipyard  painters:  II.  Male
reproduction.  Am. J. ind. Med., 14: 509-526.

WELSCH,  R.,  SLEET,  R.B.,  &  GREENE,  J.A.  (1987)  Attenuation  of  2-
methoxyethanol and  methoxyacetic acid-induced digit malformations in mice
by simple  physiological compounds:  implications for  the role of further
metabolism of  methoxyacetic acid  in developmental  toxicity.  J. biochem.
Toxicol., 2: 225-240.

Effects of  repeated exposure  of dogs  to monoalkyl ethylene glycol ether
vapors.  J. ind. Hyg. Toxicol., 25(9): 409-414.

WICKRAMARATNE, G.A.,  de S.  (1986) The  teratogenic potential  and  dose-
response of  dermally administered ethylene glycol monomethyl ether (EGME)
estimated in  rats with  the Chernoff-Kavlock  assay.  J.  appl.  Toxicol.,
6(3): 165-166.

YONEMOTO, J.,  BROWN, N.A.,  & WEBB,  M. (1984)  Effects of dimethoxyethyl
phthalate, monomethoxyacetic  acid on  post implantation  rat  embryos  in
culture.  Toxicol. Lett., 21: 97-102.

YOUNG, E.G.  & WOOLNER,  L.B. (1946)  A case  of fatal  poisoning from  2-
methoxyethanol.  J. ind. Hyg. Toxicol., 28: 267-268.

ZIMMERMANN, F.K., MAYER, V.W., SCHEEL, I., & RESNICK, M.A. (1985) Acetone,
methyl ethyl  ketone, ethyl  acetate, acetonitrile and other polar aprotic
solvents are  strong inducers  of aneuploidy  in Saccharomyces cerevisiae.
 Mutat. Res., 149: 339-351.


1.  Identité, propriétés physiques et chimiques, méthodes d'analyse

    La  présente  monographie  ne traite  que  des  éthers
méthyliques  et éthyliques de  l'éthylène-glycol, c'est-à-
dire  le  méthoxy-2  éthanol  (2-ME),  l'éthoxy-2  éthanol
(2-EE)  et  leurs  esters acétiques  respectifs,  à savoir
l'acétate   de  méthoxy-2  éthyle  (2-MEA)   et  l'acétate
d'éthoxy-2 éthyle (2-EEA). Ces composés se présentent tous
les  quatre sous la forme de liquides stables incolores et
inflammables,  dotés d'une légère odeur éthérée;  ils sont
tous  miscibles à l'eau (ou  tout au moins dans  le cas du
2-EAA  très soluble dans celle-ci) et miscibles à un grand
nombre de solvants organiques.

    Il existe des méthodes d'analyse permettant la mise en
évidence de ces éthers du glycol et de  leurs  métabolites
dans  divers  milieux  (air,  eau,  sang  et  urine).  Ces
méthodes  font souvent appel à des techniques d'adsorption
ou  d'extraction afin de concentrer l'échantillon, suivies
d'une  analyse par chromatographie  en phase gazeuse.   La
chromatographie  en  phase  gazeuse ou  la chromatographie
liquide  à haute performance  permettent de doser  l'acide
méthoxy-2   acétique  (MAA)  ainsi  que  l'acide  éthoxy-2
acétique  (EAA) (qui sont des métabolites du du 2-ME et du
2-EE)  dans  les  urines, généralement  après obtention de
dérivés  convenables,  à  des concentrations  entre  5  et
100 µg/ml.

2.  Sources d'exposition humaine et environnementale

    Les  quatre éthers du glycol étudiés s'obtiennent tous
par réaction de l'oxyde d'éthylène sur l'alcool convenable
puis,  si nécessaire, par estérification  à l'aide d'acide

    On  ne dispose pas de données concernant la production
mondiale  de  ces  éthers  du  glycol.  Toutefois  on peut
avancer  que  la  production annuelle  globale de l'Europe
occidentale, des Etats-Unis et du Japon se situe aux envi-
rons  de 79 x 103 tonnes  de 2-ME et de 205 x 103   tonnes
de  2-EE.  Ils  sont en  grande partie  utilisés  pour  la
production  industrielle de divers revêtements (peintures,
teintures, laques, vernis, etc.) et comme solvants pour la
préparation   d'encres  d'impression,  de  résines  et  de
colorants,  ainsi  que  pour la  fabrication de détachants
domestiques et industriels. On les utilise également comme
additifs  de dégivrage dans  les liquides hydrauliques  et
les carburéacteurs.

3.  Transport, distribution et transformation dans l'environnement

    Du  fait de  leur solubilité  dans l'eau  et  de  leur
tension   de   vapeur   relativement  basse,   ces  éthers
pourraient,  en  l'absence  de décomposition,  s'accumuler
dans  l'eau.  Toutefois, il  semble que cette  éventualité
soit  exclue du fait  de leur dégradation  par des  micro-
organismes  présents dans le sol, les boues d'effluents et

    C'est l'utilisation de ces éthers comme solvants vola-
tils  qui, du fait des émissions atmosphériques auxquelles
elle donne lieu, entraîne l'exposition environnementale la
plus   importante.   Dans  l'environnement   général,  ils
subissent une photolyse rapide et l'on pourrait s'attendre
à  des  concentrations  inférieures à  0,0007 mg/m3   (2 x
10-4 ppm).

    En  aérobiose,  les  éthers du  glycol  subissent  une
dégradation microbienne rapide en dioxyde de carbone et en
eau,  alors  qu'en  anaérobiose, les  principaux  produits
finals sont le méthane et le dioxyde de carbone.

4.  Concentrations dans l'environnement et exposition humaine

    L'utilisation  d'éthers  du glycol  peut entraîner des
nombreuses émissions dans l'environnement. C'est en parti-
culier l'exposition humaine directe dans l'industrie, dans
les  petits ateliers et  au cours de  l'utilisation domes-
tique de produits à base d'éthers du glycol qui est spéci-
alement préoccupante. En ce qui concerne l'exposition pro-
fessionnelle, les valeurs signalées vont de concentrations
< 0,1 mg/m3 à  des concentrations > 150 mg/m3.    L'utili-
sation  de  certains  produits  de  consommation  à   base
d'éthers  du  glycol  pourrait  provoquer  une  exposition
notable des usagers mais on ne dispose pas de données à ce

    Outre  l'exposition par la voie atmosphérique, l'homme
peut également être exposé par la voie dermique. L'analyse
du sang confirme que ces produits sont rapidement absorbés
par  cette voie, qui contribue probablement davantage à la
charge  totale  de  l'organisme que  l'exposition par voie

5.  Cinétique et métabolisme

    Ces  quatre éthers sont rapidement  absorbés au niveau
de  la peau,  des poumons  et des  voies digestives.   Des
études  de répartition portant sur le 2-ME chez des souris
gravides ont montré que c'est dans le foie  maternel,  les
voies  digestives,  le placenta,  le  sac vitellin  et  de
nombreuses  structures embryonnaires que  se rencontraient
les concentrations les plus fortes.

    La  métabolisation  du  2-ME donne  naissance   à deux
métabolites  primaires :  le  MAA et  la méthoxy-2 acétyl-
glycine.  La transformation en dioxyde  de carbone corres-
pond   à  une  voie  métabolique   secondaire  de  moindre
importance.   La  conversion  plasmatique du  2-ME  en MAA
s'effectue rapidement, avec une demi-vie de 0,6 heure chez
le rat;  en revanche l'excrétion de la MAA est  lente,  sa
demi-vie  étant d'environ 20 heures chez  le rat et de  77
heures chez l'homme.

    L'administration  à des animaux de laboratoire de 2-EE
a  conduit  à la  production  d'EAA et  d'éthoxy-2 acétyl-
glycine,  l'EAA étant le principal métabolite qui se mani-
feste  dans l'organe supposé être l'organe cible, à savoir
les  testicules.  Chez l'homme, une  étude sur le 2-EAA  a
permis d'observer une voie métabolique analogue, l'acétate
étant  d'abord hydrolysé en 2-EE  puis oxydé en EAA.   Cet
EAA  a été ensuite excrété avec une demi-vie estimative de
21  à  42 heures.   L'expérience semble  indiquer  que  la
rétention  ou l'accumulation des métabolites pourrait être
toxicologiquement  importante dans la mesure  où ces méta-
bolites  seraient responsables de la  toxicité observée au
niveau de l'organe cible.

6.  Effets sur les êtres vivants dans leur milieu naturel

    Il semble que le 2-ME et le 2-EE présentent une faible
toxicité  pour les micro-organismes  et les animaux  aqua-
tiques.   En ce qui concerne les micro-organismes, la con-
centration létale dans le milieu est supérieure à 2 %.  On
a  constaté  une inhibition  de  la croissance  des algues
vertes par le 2-ME à la concentration de 104 mg/litre   et
de celle des cyanobactéries (algues bleu/vert) à  la  con-
centration de 100 mg/litre.  La toxicité aiguë du 2-EE est
très faible pour les arthropodes (CL50 >  à 4 g/litre)  et
les poissons d'eau douce (CL50 >  à 10 g/litre).  Les acé-
tates  des éthers du glycol (2-MEA et 2-EAA) sont beaucoup
plus toxiques pour les poissons.  Ainsi la CL50   du 2-EEA
pour  le vairon  Pimephales promelas est de 46 mg par litre
tandis  que celle  du 2-MAA  est de  45 mg/litre  pour  le
tarpon  et  pour  Lepomis machrochirus.   Il  n'y a  pas eu
d'études à long terme.

7.  Effets sur les animaux d'expérience et les systèmes d'épreuve
 in vitro 

7.1  Toxicité générale

    La toxicité du 2-ME et du 2-EE chez l'animal d'expéri-
ence  a été beaucoup plus étudiée que celle du 2-MEA et du

    En  ce qui concerne le 2-ME et le 2-EE ainsi que leurs
acétates,  la dose létale  après exposition unique  est du
même  ordre et ces composés présentent une faible toxicité
aiguë,  que l'exposition ait lieu par voie dermique, orale
ou  par inhalation.  Pour diverses espèces, les valeurs de
la DL50 vont  de 900 à 3400 mg/kg de poids  corporel  pour
le  2-ME,  de 1400  à 5500 mg/kg pour  le 2-EE, de  1250 à
3900 mg/kg pour le 2-MEA et de 1300 à 5100 mg/kg  pour  le
2-EAA.  Des  valeurs  de 4603 mg/m3 (2-ME)   et de 6698 mg
par m3 (2-EE)  ont été signalées pour la CL50 par  inhala-
tion chez la souris.

    On ne possède que peu de données concernant les effets
irritants au niveau des yeux et de la peau ou  le  pouvoir
de  sensibilisation de ces éthers du glycol chez l'animal.
Il semblerait qu'ils ne soient pas irritants pour la peau,
mais  qu'ils puissent l'être  pour l'oeil.  Chez  l'homme,
malgré  de  fortes  expositions,  on  n'a  jamais  signalé
d'irritation cutanée ni de sensibilisation à ce niveau.

    On a montré qu'en exposant par voie  respiratoire  des
animaux  d'expérience pendant des périodes  allant jusqu'à
90 jours, à de fortes  concentrations (> 9313 mg  de  2-ME
par  m3   et >  1450 mg de  2-EE/m3)   on déterminait  des
effets   nocifs  sur  les  paramètres  hématologiques,  le
système  nerveux, les testicules, le thymus, les reins, le
foie et les poumons.  A des concentrations  plus  faibles,
les  effets  ne  s'observaient  qu'au  niveau  du  système
hématopoïétique  et des testicules. Par  exemple, des rats
exposés par inhalation à du 2-ME pendant 13 semaines à des
doses  comprises entre 93 et 930 mg/m3,   présentaient une
réduction  de l'hématocrite, du  nombre de leucocytes,  de
l'hémoglobine,  des plaquettes et des  protéines sériques,
mais seulement à la dose la plus forte.  Chez  des  lapins
exposés  de la même manière, on notait une réduction de la
taille  du thymus et une altération des paramètres hémato-
logiques, à la dose de 903 mg/m3.    Le 2-EE a produit des
effets  analogues, mais moins  graves, chez le  rat et  le
lapin  lors d'une exposition  de 13 semaines à  la concen-
tration  de 1450 mg/m3.    On  ne dispose d'aucune  donnée
résultant d'études à long terme.

7.2  Cancérogénicité et mutagénicité

    On  a étudié  la mutagénicité  du 2-ME  sur toute  une
série  de systèmes  in vitro  constitués de  bactéries ou de
cellules  mammaliennes.  La plupart des  études ont fourni
des  résultats  négatifs,  toutefois  on  a  tout  de même
signalé  des résultats positifs  à de très  fortes concen-
trations  de  2-ME sur  des  cellules CHO.   Il s'agissait
d'aberrations chromosomiques (à des concentrations supéri-
eures  à  6830 µg/ml)    et d'échanges  entre  chromatides
soeurs (à des concentrations supérieures à 3170  µg    par
ml).  La  recherche  d'aberrations  chromosomiques  et  de

micronoyaux n'a rien donné  in vivo .   On ne dispose que de
données  limitées  sur le  pouvoir  mutagène du  2-EE;  en
outre, il n'existe pas de données sur  la  cancérogénicité
de ces éthers du glycol.

7.3  Organes mâles de la reproduction

    On a étudié de manière approfondie l'effet du 2-ME sur
l'appareil reproducteur mâle après administration par voie
orale  ou respiratoire de  ces substances à  des rongeurs.
La  présence de modifications  dégénératives au niveau  de
l'épithélium  germinal des tubes séminifères  à été systé-
matiquement  observée.  Des effets analogues  ont été con-
statés avec le 2-EE, mais à des doses un peu inférieures.

    L'administration  par voie orale  à des rats  de  2-ME
pendant  1 à 11 jours a  provoqué une réduction du  nombre
des  spermatozoïdes et des modifications  de leur mobilité
et  de leur  morphologie, liées  à la  dose, à  partir  de
100 mg/kg  de  poids  corporel.  L'autopsie  a  révélé une
atteinte  histologique  marquée  des testicules.   La dose
sans  effet  observable  (NOEL)  était  de  50 mg/kg.   La
réduction  de  la  fertilité était  encore  manifeste huit
semaines  après  une  exposition à  200 mg/kg.  Des effets
analogues ont été observés dans le cas du 2-EE à des doses
supérieures  ou  égales à  500 mg/kg, administrées pendant
des périodes allant jusqu'à 11 jours, la dose  sans  effet
observable  sur  11 jours  étant de  250 mg/kg.  Toutefois
l'épuisement  des  réserves  de spermatozoïdes,  par suite
d'accouplements  répétés,  s'est  accompagné à  la dose la
plus  faible étudiée (150 mg/kg), d'une  réduction de leur
nombre.   Après avoir administré par voie orale à des rats
et  à des souris une dose unique de 250 mg ou davantage de
2-ME/kg de poids corporel, on a observé chez  les  animaux
une  stérilité  complète  cinq semaines  après   l'admini-
stration,  une  certaine  réduction de  la fécondité étant
observée dès 125 mg/kg.

    L'administration  du 2-ME par  la voie respiratoire  a
donné  lieu à des modifications dégénératives analogues au
niveau  des testicules.  Les  effets en question  ont  été
observés après exposition unique de 4 heures à  des  doses
supérieures  ou égales à 1944 mg/m3,   aucun effet n'étant
observé  à 933 mg/m3.    Les valeurs de la dose sans effet
observable  étaient  de  311 mg/m3   chez  les  rats après
exposition  de 13 semaines (6 heures par jour, 5 jours par
semaine)  et de 933 mg/m3   (6  heures par jour) chez  les
souris  après  exposition à  neuf  reprises sur  une durée
totale  de  11 jours.  L'exposition  de  lapins à  du 2-ME
pendant  13 semaines  (6  heures  par  jour,  5  jours par
semaine)  a  entraîné des  effets  marqués au  niveau  des
testicules  à la dose de  311 mg/m3   ou davantage;  à  la
dose de 93 mg/m3,   on a observé des effets  limites;   il
n'a  pas été  possible de  déterminer la  dose sans  effet

7.4  Toxicité foetale

    On  a observé des effets toxiques sur le développement
de   plusieurs  espèces  d'animaux  de  laboratoire  après
exposition  par  toutes les  voies possibles, c'est-à-dire
orale,  respiratoire et dermique.   Le 2-ME a  produit des
effets  tératogènes chez la souris, le rat, le lapin et le
singe.   Le 2-EE et le  2-EEA se sont révélés  tératogènes
chez  le  rat et  le lapin.  Bien  que le 2-MEA  n'ait pas
encore  été étudié de  ce point de  vue, son profil  méta-
bolique  (voir  section  6)  incite  à  penser   qu'il   a
vraisembleblement une toxicité analogue à celle du 2-ME.

    C'est  dans le cas du 2-ME que l'on possède l'ensemble
le  plus complet de données dose-réponse (doses de 31,25 à
1000 mg/kg/j).  Lors de cette étude portant sur des souris
auxquelles  le  2-ME  avait  été  administré  par   gavage
(administration les jours 7 et 14 de la gestation),  on  a
obtenu  une dose sans  effet observable de  125 mg/kg  par
jour en ce qui concerne la toxicité maternelle.  Toutefois
des  malformations  ont été  observées  à partir  de doses
quotidiennes  de 62,5 mg/kg et des modifications au niveau
du  squelette à partir de  31,25 mg/kg par jour.  La  dose
sans effet observable relative à la toxicité  foetale  n'a
pas  été indiquée.  Lors  d'études portant sur  des  doses
uniques, des souris ont reçu par gavage du 2-ME au onzième
jour  de la gestation;  la  dose de 100 mg/kg n'était  pas
foetotoxique tandis que celle de 175 mg/kg a  produit  des
anomalies  digitales, mais sans autres  signes de toxicité
maternelle ou foetale.  Des anomalis cardio-vasculaires et
électrocardiographiques  ont  été  observés chez  les rats
nouveau-nés  après administration les 7ème  et 13ème jours
de la gestation d'une dose quotidienne de 25 mg/kg.  Etant
donné qu'il s'agissait de la dose la plus  faible  expéri-
mentée,  l'étude n'a pas  permis d'établir une  dose  sans
effet  observable sur  le foetus  (on n'a  pas observé  de
toxicité maternelle à cette dose).  De même,  aucune  dose
de ce type n'a pu être déterminée après administration par
gavage  à  des  guenons  de  2-ME  aux  doses quotidiennes
respectives  de 0,16, 0,32, ou  0,47 mmol/kg, du 20ème  au
45ème jour de la gestation.

    Après  exposition par voie respiratoire à du 2-ME à la
dose  de 156 mg/m3,   on  a observé une  toxicité  foetale
chez  des rats et des souris et des malformations chez des
lapins. Pour l'ensemble de ces trois espèces, la dose sans
effet observable sur le développement foetal était  de  31
mg/m3.    Toutefois  des  anomalies  comportementales   et
neurochimiques  ont été observées  dans la descendance  de
rattes exposées du 7ème au 13ème jour ou du 14ème au 20ème
jour de leur gestation à une dose de 78 mg de 2-ME par m3.

    Après  avoir exposé des rats à des doses de 743 mg par
m3   de 2-EE et des lapins à des doses 589 mg/m3    de  la
même substance, on a constaté que ce produit était térato-
gène  (avec  en  outre une  certaine toxicité maternelle).
Dans  une autre étude, on a constaté une toxicité foetale,
mais sans malformations, chez des rats exposés à des doses
de 184 ou 920 mg de 2-EE par m3   et chez des  lapins  ex-
posés à la dose de 644 mg/m3   de la même substance.  Pour
ce  qui est  des effets  sur le  développement foetal,  la
valeur de la dose sans effet observable était de 37 mg par
m3 pour  le rat et de 184 mg/m3 pour  le lapin. On  a  ob-
servé  des  anomalies  comportementales et  neurochimiques
dans  la descendance de rattes  exposées du 7ème au  13ème
jour et du 14ème au 20ème jour de leur gestation à la dose
de 360 mg de 2-EE par m3.

    Des rattes soumises à une application dermique de 0,25
ml de 2-EE non dilué quatre fois par jour du 7ème et 16ème
jour  de la  gestation, ont  eu une  descendance  où  l'on
notait une foetotoxicité marquée et une forte incidence de
malformations malgré l'absence de toxicité maternelle. Des
effets  analogues ont été observés à la suite d'un traite-
ment  indentique par le 2-EEA  selon le même protocole  au
moyen  d'une  dose  équimolaire (0,35 ml,  quatre fois par

    En  exposant par la voie respiratoire des lapines à du
2-EEA du 6ème au 18ème jour de la gestation, on  a  obtenu
au  cours de deux études différentes, des réponses térato-
gènes  aux doses de 2176 mg/m3   et 544 mg/m3,   la valeur
de  la  dose sans  effet  observable sur  le développement
foetal  étant respectivement de 135 mg/m3    et 270 mg par
m3.   L'exposition de rattes du 6ème au 15ème jour de leur
gestation  à du 2-EEA a entraîné dans leur descendance une
toxicité foetale à la dose de 540 mg/m3   et  des  malfor-
mations  à la dose de 1080 mg/m3.   La dose sans effet ob-
servable sur le développement foetal était de  170 mg  par

8.  Effets sur l'homme

    On  ne dispose que  de renseignements limités  sur les
effets  toxiques  chez l'homme  de  ces quatre  éthers  du
glycol.   Les résultats fournis par quelques études de cas
ou études épidémiologiques sur les lieux de  travail  sont
dans  la ligne  des effets  observés chez  les animaux  de
laboratoire.  On n'a pas eu connaissance de  rapports  qui
chiffrent  l'exposition de la population en général ni les
effets sur la santé.

    Lors  de  deux  cas non  mortels  d'empoisonnement par
ingestion  d'un volume de  100 ml de 2-ME,  on a noté  les
principaux symptômes suivants : nausée, vertiges, cyanose,
tachycardie,  hyperventilation et acidose métabolique avec

quelques  signes  d'insuffisance  rénale.   Des   sympômes
analogues  mais  moins graves  ont  été observés  chez une
personne  qui  avait  ingéré  40 ml  de  2-EE.   Lors d'un
empoisonnement  mortel  par  ingestion de  400 ml de 2-ME,
l'autopsie  a révélé une gastrite  hémorragique aiguë, une
dégénérescence   graisseuse  du  foie  et  une  altération
dégénérative des tubules rénaux.

    L'exposition réitérée de travailleurs à du 2-ME  et  à
du 2-EE, en plus d'autres solvants, a entraîné chez eux de
l'anémie,  un  leucopénie,  une faiblesse  générale et une
ataxie. Dans nombre de ces études, il n'a pas été possible
de  trouver  une  estimation fiable  de  l'exposition  des
sujets.  On a rapporté des effets hématologiques  dus  aux
éthers  du glycol chez  l'homme et on  a notamment  décrit
l'apparition d'une anémie macrocytaire chez un travailleur
exposé  à du 2-ME  (dose moyenne 105 ml/m3),    ainsi qu'à
d'autres solvants.

    Il  a été fait état d'une toxicité médullaire chez des
ouvriers  dont l'épiderme était exposé  à du 2-ME, et  des
effets immunologiques ont été également notés à  la  suite
d'une exposition prolongée (8 à 35 années) au 2-ME  et  au
2-EE (doses moyennes d'exposition 6,1 mg/m3 et  4,8 mg par
m3 respectivement).

    Des   études   épidémiologiques  effectuées   sur  des
ouvriers  exposés à du  2-ME et à  du 2-EE ont  révélé des
anomalies au niveau de la fonction de  reproduction,  avec
une  fréquenc accrue des cas d'oligospermie.  L'exposition
à  du  2-EE  (37 ouvriers) à  des  concentrations  pouvant
atteindre 88,5 mg/m3 a  entraîné une modification du sper-
mogramme.  Parmi 73 ouvriers  exposés à du  2-ME  (jusqu'à
17,7 mg/m3)    et à du  2-EE (jusqu'à 80,5 mg/m3),    on a
constaté  une  fréquence  accrue de  cas d'oligospermie et
observé  certains  effets  hématologiques, pour  des doses
d'exposition (TWA) de 2,6 mg/m3 dans  le cas du 2-ME et de
9,9 mg/m3 dans celui du 2-EE.

    Les  effets  indésirables  constatés chez  l'homme par
suite  d'une  exposition  professionnelle correspondent  à
ceux qui ont été observés chez les animaux de laboratoire.
Cependant,  l'évaluation  de  l'exposition  présentant  un
certain nombre d'insuffisances et du fait qu'il s'agissait
d'expositions  simultanées à plusieurs substances,  il n'a
pas été possible d'en déduire une relation dose-réponse.

9.  Conclusions

    De  nombreuses personnes peuvent  être exposées à  ces
quatre éthers du glycol à des concentrations comparables à
celles que l'on rencontre dans l'industrie, par  suite  de
l'utilisation  de certains produits de  consommation ou de

produits  commerciaux.  Une exposition professionnelle non
négligeable peut se produire par inhalation ou par résorp-
tion  cutanée.  Des mesures  faites en petit  nombre  dans
l'air  des lieux de travail indiquent des teneurs allant <
0,1 mg/m3 à > 150 mg/m3.

    Le 2-ME et le 2-EE sont tous deux d'une  faible  toxi-
cité  pour les micro-organismes et les espèces aquatiques.
Il  n'existe  aucune  donnée qui  permettrait d'évaluer le
risque  d'effets indésirables sur  les êtres vivants  dans
leur milieu naturel par suite d'une exposition  de  longue

    Chez le rat, la dose de 2-ME sans effets aigus observ-
ables au niveau testiculaire, est de 933 mg/m3;    en  cas
d'exposition répétée, la dose sans effet observable est de
311 mg/m3.    En exposant de manière répétée  l'espèce  la
plus  sensible, à savoir le  lapin, on a observé  un effet
net dès 311 mg/m3;   cet effet était limite à la  dose  de
93 mg/m3   (un animal sur cinq).  Les données fournies par
des  études effectuées sur  des sujets humains  exposés de
par  leur profession à du  2-ME et à du  2-EE montrent que
ces  éthers  du  glycol  exercent  une  certaine  toxicité

    Chez  toutes  les  espèces étudiées  (souris,  rats et
lapins)  on a observé après exposition au 2-ME à des doses
égales ou supérieures à 156 mg/m3,   une  toxicité  vis-à-
vis  du développement foetal.  Des anomalies comportement-
ales et neurochimiques ont été observées chez le rat après
exposition  in  utero à 78 mg/m3   de  cette substance sans
qu'on puisse déterminer de dose sans effet observable.  Le
2-EE  et le 2-EEA se sont révélés légèrement moins actifs.
Des effets ont été également observés sur le développement
de  foetus de rats et de lapins après exposition à du 2-EE
à des doses égales ou supérieures 368 mg/m3.    Ces effets
étaient  légers chez les rats exposés à 184 mg de 2-EE par
m3   mais on a pu néanmoins fixer nettement la  dose  sans
effet  observable chez le rat  et le lapin à  la valeur de
38 mg/m3.

    Ces  éthers du glycol produisent  des effets hématolo-
giques  chez  la souris,  le rat, le  lapin, le chien,  le
hamster et le cobaye.  Ces résultats sont en  accord  avec
les  anomalies hématologiques observées lors  des quelques
études  consacrées à des  travailleurs de l'industrie  qui
avaient subi des expositions répétées à du 2-EE  et/ou  du
2-ME.   Lors  d'études  sur l'animal  comportant une expo-
sition  répétée à ces deux  substances, on a fixé  à 93 mg
par  m3   la dose  de 2-ME sans  effet observable chez  le
lapin et à 368 mg/m3   la dose de 2-EE sans  effet  obser-
vable chez le rat et le lapin.  On n'a pas pu  obtenir  de
données  qui  permettent  une évaluation  quatitative  des
effets hématologiques aigus consécutifs à une exposition.


1.  Evaluation des risques pour la santé humaine

1.1  Exposition

    Nombreuses   sont  les  personnes  qui   peuvent  être
exposées au méthoxy-2 éthanol (2-ME), à l'éthoxy-2 éthanol
(2-EE)  et à leurs acétates (2-MEA et 2-EEA) à des concen-
trations  comparables  à  celles que  l'on  rencontre dans
l'industrie,  lors de l'utilisation de produits de consom-
mation  et de produits  commerciaux.  En revanche  l'expo-
sition  par  l'intermédiaire des  denrées alimentaires, de
l'eau  ou de l'air  ambiant est probablement  négligeable.
Cette   hypothèse  ne  repose   que  sur  les   propriétés
physiques  et chimiques  de ces  composés et  sur le  fait
qu'ils se dégradent rapidement dans l'environnement.

    Une exposition professionnelle non négligeable peut se
produire   par  inhalation  ou  résorption  cutanée.   Les
quelques mesures de concentrations dans l'air des lieux de
travail  ont donné des valeurs qui vont de moins de 0,1 mg
par  m3   à plus de 150 mg/m3.    Toutefois les données de
surveillance  existantes sont très  limitées et il  peut y
avoir  d'importantes  variations  entre  les   différentes
industries et dans une même industrie. En raison du risque
de  résorption cutanée, une  simple surveillance de  l'air
des lieux de travail risque de sous  estimer  l'exposition
totale.   Pour évaluer la charge totale de l'organisme, la
meilleure méthode consiste à faire un contrôle biologique.
Une forte exposition peut se produire lors de travaux tels
que la peinture, l'impression ou le nettoyage mais il faut
se  souvenir que ces  composés sont utilisés  à l'occasion
d'un  grand nombre d'autres activités  au cours desquelles
on pourrait craindre une exposition.

1.2  Effets sur la santé

    Les principaux effets qu'on peut craindre chez l'homme
tiennent  à  l'action  toxique  de  ces  composés  sur  le
développement  foetal,  les  testicules et  les paramètres
hématologiques.  La réalité de ces effets est attestée par
des  données nombreuses et cohérentes obtenues chez l'ani-
mal  ainsi  que  par quelques  données concernant l'homme.
Tous  ces effets peuvent appraître par suite d'expositions
à  court ou à long  terme.  Chez l'animal de  laboratoire,
une  exposition répétée à des très fortes doses de 2-ME et
de  2-EE  (plus  de 930  ou  1450 mg/m3,   respectivement)
entraîne  des effets toxiques  qui se traduisent  par  des
anomalies  neuro-comportementales, hépatiques et  rénales.
On  les  observe  également dans  les  cas  d'intoxication

    Ces  quatre  éthers  du  glycol  exercent  des  effets
toxiques très voisins tant sur les testicules que  sur  le
développement  du foetus, et  ce, chez toutes  les espèces
étudiées  et par toutes les voies d'exposition qui ont été
utilisées   (voie  respiratoire,  voie   percutanée,  voie
orale).   L'étude du mécanisme  de ces effets  montre  que
dans  les deux cas, une phase d'activation est nécessaire,
à savoir la métabolisation en un dérivé de l'acide alkoxy-
acétique  correspondant.  La métabolisation  s'effectue en
présence  du  système  de l'alcool  déshydrogénase qui est
commun à l'homme et aux animaux de laboratoire.  Des méta-
bolites toxiques, l'acide méthoxyacétique (MAA) et l'acide
éthoxyacétique  (EAA)  ont  été décelés  dans  l'urine  de
sujets  exposés à ces  solvants.  La régularité  de  cette
réponse toxique d'une espèce animale à l'autre,  jointe  à
l'analogie   du  métabolisme  chez  l'homme  et  l'animal,
montrent à l'évidence que l'homme pourrait être  la  cible
des  mêmes  effets  toxiques  sur  les  testicules  et  le
développement foetal. Les données dont on dispose au sujet
de  l'excrétion  des  acides alkoxyacétiques  chez l'homme
indiquent que leur durée de rétention est plus longue chez
celui-ci  que chez l'animal,  ce qui incite  à penser  que
l'homme  pourrait  être plus  sensible  à ces  effets  que
l'animal  de  laboratoire  le  plus  sensible.   C'est  la
résorption cutanée rapide de ces composés qui  est  parti-
culièrement préocccupante. On a observé des effets térato-
gènes et autres anomalies du developpement à la  suite  de
l'application  de 2-ME, de  2-EE et de  2-EAA sur la  peau
intacte du rat.

    Des  lésions testiculaires ont  été observées chez  le
rat, la souris et le lapin à la suite d'une  exposition  à
ces éthers du glycol, soit par la voie  respiratoire  soit
par  la voie orale.  Chez le rat, une seule exposition par
voie  respiratoire  à des  doses  de 2-ME  supérieures  ou
égales  à 1944 mg/m3   pendant 4 heures  et une exposition
répétée  à des doses  supérieures ou égales  à 933 mg  par
m3 pendant  13 semaines ont déterminé des anomalies histo-
logiques  au niveau testiculaire.  Dans le cas  de l'expo-
sition  unique, la dose sans effet observable était de 933
mg/m3;    elle était 311 mg/m3   dans le cas d'expositions
répétées.   La souris a semblé  un peu moins sensible,  la
dose  sans effet observable dans  son cas étant, pour  des
expositions  répétées, de 933 mg/m3.    Toutefois le lapin
l'était  davantage,  avec  des  altérations  testiculaires
marquées  qu'on  pouvait  observer après  des  expositions
répétées à 311 mg/m3   et la présence d'effets limites (un
lapin sur cinq) dès la dose de 93 mg/m3.   Des effets ana-
logues  ont été observés  à la suite  de l'exposition  par
voie  orale de rats  à du 2-ME,  une exposition de  courte
durée (et notamment à une dose unique) ayant déterminé des
lésions  testiculaires à partir  de 100 mg/m3.    Dans  le
cas d'une étude portant sur les effets subaigus (11 jours)
la  dose sans effet observable a été de 50 mg/kg.  Le 2-EE
présente  une  toxicité  testiculaire un  peu  moindre que

celle du 2-ME;  ces effets n'apparaissent qu'à  des  doses
de 500 mg/kg ou davantage et la dose sans effet observable
se situe à 250 mg/kg.

    Les  données fournies par  les études menées  sur  des
sujets humains exposés de par leur profession à du 2-ME et
à du 2-EE cadrent avec les données obtenues  sur  l'animal
et  montrent que ces éthers du glycol peuvent produire des
effets  toxiques au niveau testiculaire chez l'homme.  Des
études  épidémiologiques portant sur de  petits groupes de
travailleurs exposés au 2-EE dans un atelier de  fonte  de
métaux  et chez des peintres d'un chantier naval exposés à
ces  deux composés, ont  révélé une oligospermie  systéma-
tique. Les données relatives aux niveaux d'exposition sont
limitées mais dans chaque cas, il y a lieu de penser qu'il
y a eu exposition par voie cutanée et respiratoire.

    On a observé  chez le rat, la souris, le lapin  et  le
singe  des effets toxiques  sur le développement  embryon-
naire  après exposition à  ces éthers du  glycol par  voie
percutanée,  orale  ou  respiratoire.  Du  2-ME  non dilué
appliqué  à 12 reprises au cours d'une journée sur la peau
rasée  de  rattes  gravides (zone  d'application  couverte
pendant  6 heures)  s'est  révélé mortel  pour les animaux
alors  qu'appliqué à 10 reprises  sans pansement, du  2-EE
(1,0 ml/jour)  ou du 2-EEA  (1,4 ml/jour) ont produit  des
effets  tératogènes mais n'ont  pas été toxiques  pour les
femelles  gravides.  Au cours d'une autre étude, 12 appli-
cations  de 2-ME à 10 % dans du soluté physiologique, avec
pansement  sur  le  site d'application,  ont  entraîné des
effets toxiques sur le développement embryonnaire, la dose
sans  effet observable se  situant à la  concentration  de
3 %.   Après administration répétée par voie orale de 2-ME
à  des animaux gravides, on  n'a pas observé de  dose sans
effet toxique.  La dose la plus faible produisant un effet
observable  dans le cas de l'administration par voie orale
était de 31,5 mg/kg par jour pour la souris,  de  25 mg/kg
pour le rat et de 0,16 mmol/kg pour le singe.  En  ce  qui
concerne l'administration d'une dose unique, on ne possède
des  résultats que pour le  2-ME chez la souris,  avec une
dose  sans  effet  observable pour  le  11ème  jour de  la
gestation (le jour le plus sensible) de 100 mg/kg  et  une
valeur de 175 mg/kg pour la dose la plus faible avec effet
observable.  Le 2-EE et le 2-EEA ont fait l'objet d'études
au cours desquelles des rats et des lapins ont été exposés
à  ces deux composés  par la voie  respiratoire.   L'expo-
sition  des rats au 2-EE a fait l'objet de deux études qui
ont  révélé des effets tératogènes  (743 mg/m3,   7 heures
par jour, du premier au 19ème jour de la gestation) ou des
effets  foetotoxiques  (184  et 920 mg/m3,    6 heures par
jour,  du 6ème au 15ème jour de la gestation).  Dans cette
dernière étude, on a trouvé une dose sans effet observable
de  37 mg/m3.    Chez des  lapins exposés à  du 2-EE on  a

également  observé des effets tératogènes  (589 mg/m3,   7
heures  par jour du premier au 18ème jour de la gestation)
et  des  effets  foetotoxiques (644 mg/m3,    6 heures par
jour,  du 6ème au 18ème jour de la gestation).  Dans cette
dernière  étude, la dose  sans effet observable  était  de
184 mg/m3.   Chez des lapines exposées à du 2-EEA 6 heures
par  jour du  6ème au  18ème jour  de la  gestation, on  a
observé  des effets tératogènes  à la dose  de  2160 mg/m3
dans   une  étude et  à la dose  de 1620 mg/m3   dans  une
autre.   Les  deux  études ont  montré  l'apparition d'une
foetotoxicité à 540 mg/m3;   la dose sans effet observable
correspondant, dans chaque étude, à la dose la plus faible
étudiée  (respectivement  135  et 270 mg/m3).     Des rats
exposés par voie respiratoire à du 2-EEA 6 heures par jour
du 6ème au 15ème jour de la gestation ont présenté le même
de  type de réactions :  effets tératogènes à  1620 mg par
m3,  foetotoxicité  à 1080 mg/m3   et aucun effet à 260 mg
par m3.

    Des  effets toxiques sur le développement embryonnaire
ont  donc été observés  chez toutes les  espèces  (souris,
rats  et  lapins), exposées  à  des doses  supérieures  ou
égales  à 156 mg de 2-ME.  Pour ces trois espèces, la dose
sans  effet  observable  était de  31 mg/m3.   Après expo-
sition  in utero à 78 mg/m3,   on a observé chez la descen-
dance  des altérations comportementales  et neurochimiques
sans  qu'il soit possible de déterminer la dose sans effet

    Le 2-EE et le 2-EEA se sont révélés  légèrement  moins
actifs.  Des effets toxiques sur le développement embryon-
naire ont été observés chez des rats et des  lapins  après
exposition  à des doses supérieures ou égales à 368 mg par
m3 de  2-EE. De légers effets de ce type ont été également
observés chez des rats exposés à 184 mg de  2-EE/m3,    la
dose  sans  effet  observable étant  clairement  établie à
37 mg/m3.     En ce qui  concerne le 2-EEA,  la dose  sans
effet observable était de 170 mg/m3   pour les rats et les

    Des effets hématologiques consécutifs à une exposition
à une dose unique on été observés chez l'animal ainsi qu'à
la  suite  d'intoxications  chez  l'homme.    L'exposition
répétée par voie respiratoire, de lapins, l'espèce la plus
sensible,   à  du  2-ME  5 fois  par  semaine  pendant  13
semaines,  a permis de fixer la dose sans effet observable
à  93 mg/m3.    Administré à  répétition, le 2-ME  produit
également  des anomalies hématologiques chez la souris, le
lapin,  le chien, le  hamster et le  cobaye.  Le 2-EE  est
moins actif à cet égard que le 2-ME.  En ce  qui  concerne
les effets hématologiques chez le rat et le  lapin,  après
exposition  à  du  2-EE pendant  13 semaines,  5 fois  par
semaine et 6 heures par jour, on peut fixer la  dose  sans
effet  observable  à 368 mg/m3.     Chez  le chien  et  la

souris,  on observe également après,  exposition répétée à
des doses plus élevées, un certain nombre d'effets hémato-
logiques.   L'exposition aux acétates  de 2-EE et  de 2-ME
devrait  provoquer  des  effets analogues,  toutes  choses
égales  d'ailleurs, mais les  données dont on  dispose sur
l'exposition  et les effets hématologiques de ces composés
sont  trop  limitées pour  qu'on  puisse établir  les con-
ditions  dans lesquelles une seule exposition conduirait à
des effets hématologiques chez l'homme.

    On a observé dans l'industrie des niveaux d'exposition
voisins de la dose sans effet hématologique observable que
l'on  a  pu  déterminer chez  l'animal  après  expositions
répétées  à du 2-ME  et à du  2-EE.  On peut  en conclure,
compte  tenu de la sensibilité probablement plus grande de
l'homme  et de l'accumulation vraisemblable de métabolites
dans  le sang, que l'exposition résultant de l'utilisation
de   produits   de   consommation  ou   d'activités   dans
l'industrie  pourrait entraîner des  effets hématologiques
de  ce genre.  A l'appui de cette hypothèse, on peut citer
les  effets hématologiques effectivement signalés  lors de
quelques   études  effectuées  chez  des  travailleurs  de
l'industrie  ayant subi des  expositions répétées au  2-EE
et/ou au 2-ME.

2.  Evaluation des effets sur l'environnement

    La  libération  directe dans  l'atmosphère ou l'utili-
sation de ces produits comme solvants volatils  peut  con-
duire  à une exposition dans  le milieu ambiant.  Ce  peut
être  également le cas par suite d'une libération acciden-
telle  sur le sol ou  dans l'eau.  L'accumulation dans  le
sol et les eaux superficielles ne peut se  produire  qu'en
l'absence de dégradation de ces composés.  Or, on sait que
ces  éthers  du  glycol  se  décomposent  rapidement  sous
l'effet  de  processus  chimiques et  biologiques;  ils ne
devraient  donce pas s'accumuler.   Le 2-MEA et  le  2-EAA
devraient  également  s'hydrolyser  rapidement  et   subir
ensuite  une  biodégradation aérobie.   Toutefois dans des
conditions   d'anaérobiose,   on  pourrait   craindre  une
contamination  des sols et  des nappes phréatiques  encore
que  le phénomène soit vraisemblablement transitoire et le
risque correspondant négligeable.

    Le 2-ME et le 2-EE sont peu toxiques pour  les  micro-
organismes  et les espèces aquatiques.  Leurs acétates, en
revanche,  présentent  une  toxicité aiguë  beaucoup  plus
forte.  On ne dispose pas de données à  partir  desquelles
on puisse déterminer leur potentiel nocif pour les espèces
vivantes en cas d'exposition prolongée.


1.  Protection de la santé

1.  Il   conviendrait  de  recercher  des  solvants  moins
toxiques  que le méthoxy-2 éthanol,  l'éthoxy-2 éthanol et
leurs esters, en particulier pour les remplacer  dans  les
produits  de  consommation.    Il est  également important
d'évaluer  les  effets  des autres  éthers  de l'éthylène-
glycol  car certains d'entre  eux pourraient excercer  des
effets analogues aux quatre éthers qui ont fait l'objet de
la présente évaluation.

2.  Du  fait des effets toxiques reconnus de ces éthers du
glycol, les autorités responsables devraient se préoccuper
sérieusement  de trouver les moyens  d'avertir les consom-
mateurs  des  dangers  que présente  l'utilisation  de ces
produits,  en  particulier  en cas  d'exposition  par voie

3.  Compte  tenu des données toxicologiques récentes et de
la  possibilité d'une très forte absorption percutanée des
ces  éthers du glycol,  il importe de  revoir les  limites
nationales  d'exposition  professionnelle  pour  faire  en
sorte  que  la dose  quotidienne  totale à  laquelle  sont
exposés  les  travailleurs  par n'importe  quelle voie, ne
menace pas leur santé.

4.  Lorsqu'elle est assez importante, une dose unique peut
produire  des  effets  sur  l'animal.   Pour  réduire  les
risques,  il est recommandé  d'utiliser ces produits  avec
prudence  (veiller  à l'hygiène  personnelle, utiliser des
dispositifs  protecteurs appropriés et assurer  une venti-
lation  suffisante).  Les données montrent  que les effets
toxiques  sur le développement embryonnaires ainsi que sur
le  sang et les  testicules, consécutifs à  une exposition
répétée,  pourraient exiger des mesures de protection plus

2.  Recherches à affectuer

1.  Du  fait que l'acide méthoxyacétique  (MAA) et l'acide
éthoxyacétique  (EAA), qui sont les principaux métabolites
du 2-ME, du 2-EE et de leurs esters, exercent  des  effets
toxiques  sur les organes reproducteurs mâles, il faudrait
en étudier le mode d'action.  S'ils apparaît que le MAA et
EAA ne sont pas les véritables responsables de ces effets,
ceux-ci  devront  être  identifiés et  leur  mode d'action

2.  Ces quatre éthers du glycol ont des effets sur le sang
et  sur  la  fonction de  reproduction  masculine  (oligo-
spermie).   Les  données  disponibles, bien  qu'en  nombre
limité, indiquent que ces deux effets se manifestent à des
doses  analogues.  Il faudrait étudier le mode d'action de

ces  composés  sur ces  deux  types d'organes  et  étudier
parallèlement  le nombre de  spermatozoïdes et les  effets
hématologiques  afin de voir si ces derniers sont suscept-
ibles  de jouer le rôle  de signal d'alarme pour  d'autres
effets toxiques de ces composés.

3.  La surveillance de l'air ne suffit pas à  assurer  une
faible  exposition.  Un contrôle biologique peut permettre
de déceler les insuffisances des mesures de protection.  A
l'heure  actuelle  on n'a  pas  établi avec  une certitude
suffisante  la relation qui  existe entre les  indicateurs
biologiques  de l'exposition, la charge totale de l'organ-
isme  et les effets physiologiques  observés.  Des travaux
sont  encore nécessaires pour pouvoir  établir les limites
de sécurité en fonction des résultats de  la  surveillance

4.  Il  faudrait envisager des études  épidémiologiques ou
une  surveillance  sanitaire  spécifique au  sein de popu-
lations qui sont fortement exposées à ces éthers du glycol
afin   d'obtenir  des  relations   exposition-effets;   on
pourrait  alors  déterminer  les limites  de  sécurité,  à
condition  toutefois que l'exposition globale  puisse être
correctement  et suffisamment évaluée par  la surveillance
de l'environnement et des contrôles biologiques.

5.  Il  conviendrait d'étudier l'éventualité  d'effets sur
l'appareil  reproducteur féminin en procédant à des études
de  reproduction  sur  plusieurs générations  d'animaux de

6.  Les   résultats  disponibles  indiquent   que  l'homme
pourrait  métaboliser dans une plus  grande proportion que
le  rat  ces éthers  du  glycol en  acides alkoxyacétiques
correspondants,  la demi-vie des ces  métabolites toxiques
s'étant environ quatre fois plus longue chez l'homme.  Par
ailleurs l'organisme du rat est capable de  conjuguer  une
fraction  plus importante des métabolites acides que ne le
fait   celui  de  l'homme.   Ces   différences  pourraient
entraîner  une sensibilité relativement plus importante de
l'homme  aux  éthers  du glycol.   Une  connaissance  plus
précise du métabolisme et de la cinétique  d'excrétion  de
ces composés permettrait de mieux prévoir les  limites  de

7.  Les  résultats fournis par  des études à  court  terme
(13 semaines)  montrent  que  des  effets  s'exercent  sur
divers organes.  Toutefois, il n'a pas été procédé  à  des
études  suffisamment longues pour qu'on  puisse déterminer
si  ces  effets  sont réversibles  ou  non.   Il est  donc
recommandé  de procéder à  des études au  cours desquelles
des  animaux de laboratoire  subiront une exposition  d'au
moins  13 semaines à ces composés, suivie d'une période de
récupération.   A  l'issue  de  cette  période,  on  devra
déterminer  les paramètres physiologiques  importants afin
de voir si les effets sont passagers ou non.


1.  Identidad, propiedades físicas y químicas, métodos analíticos

    En esta monografía sólo se tienen en cuenta los éteres
metílico y etílico del etilenglicol, es decir el 2-metoxi-
etanol  (2-ME)  y el  2-etoxietanol  (2-EE), así  como sus
ésteres  acéticos respectivos, el acetato de 2-metoxietilo
(2-MEA) y el acetato de 2-etoxietilo (2-EEA). Estos cuatro
compuestos  son todos ellos líquidos estables, incoloros e
inflamables con un olor levemente etéreo y todos ellos son
miscibles con (o, en el caso del 2-EEA, muy  solubles  en)
agua y miscibles con numerosos solventes orgánicos.

    Se  dispone de métodos analíticos  para detectar estos
éteres  glicólicos  o  sus metabolitos  en diversos medios
(aire, agua, sangre y orina).  En muchos casos se basan en
el empleo de métodos de adsorción o extracción  para  con-
centrar la muestra, seguidos de un análisis  por  cromato-
grafía  de gases.  Mediante la cromatografía de gases o la
cromatografía  de  líquidos  de alto  rendimiento, cabe la
posibilidad  de  determinar  cuantitativamente  el   ácido
2-metoxiacético  (MAA) y el  ácido 2-etoxiacético (EAA)  -
metabolitos del 2-ME y del 2-EE - en la orina, por lo gen-
eral  tras derivación, a concentraciones de 5-100 µg   por

2.  Fuentes de exposición humana y ambiental

    Los  cuatro  éteres glicólicos  examinados están todos
ellos producidos por la reacción del óxido  etilénico  con
el  alcohol apropiado, seguida, si procede, de esterifica-
ción con ácido etanoico.

    No  se dispone de datos sobre la producción mundial de
estos éteres glicólicos.  Sin embargo, la producción anual
combinada de Europa occidental, los Estados Unidos de Amé-
rica y el Japón es aproximadamente del 79 x 103 toneladas de
2-ME y 205 x 103 toneladas  de 2-EE. Una  proporción  con-
siderable se utiliza en la fabricación de pinturas, color-
antes y lacas así como en forma de solventes para tinta de
imprenta, resinas y tintes, y como productos  de  limpieza
domésticos  e industriales. También se utilizan estos com-
puestos  como aditivos anticongelantes en los líquidos hi-
dráulicos y el combustible de los reactores.

3.  Transporte, distribución y transformación en el medio ambiente

    La  hidrosolubilidad de estos  éteres glicólicos y  su
presión de vapor relativamente baja podrían dar lugar a su
acumulación  en el agua  en ausencia de  degradación.  Sin
embargo,  esta  posibilidad  queda aparentemente  excluida
debido  a la degradación por los microorganismos presentes
en el suelo, los cienos de alcantarilla y el agua.

    Las  emisiones  atmosféricas  causadas por  el  uso de
éteres  glicólicos  como  solventes volátiles  originan la
máxima exposición ambiental. En el medio ambiente general,
la  degradación fotolítica parece ser rápida y cabe prever
niveles inferiores a 0,0007 mg/m3 (2 x 10-4 ppm).

    En  condiciones aeróbicas los microorganismos degradan
rápidamente los éteres glicólicos en forma de  dióxido  de
carbono y agua, mientras que en condiciones  de  anaerobi-
osis  los principales productos finales son el metano y el
dióxido de carbono.

4.  Niveles en el medio ambiente y exposición humana

    El uso de éteres glicólicos puede dar lugar  a  emisi-
ones  considerables y muy extendidas en el medio ambiente.
Suscita especial preocupación la exposición humana directa
en la industria, en los talleres de dimensiones modestas y
como  consecuencia del empleo  doméstico de productos  que
contienen dichos éteres.  Se han señalado valores de expo-
sición profesional comprendidos entre < 0,1 mg/m3 y  > 150
mg/m3.    Los  usuarios  de productos  de  consumo  pueden
sufrir  una exposición considerable, aunque  no se dispone
de datos al respecto.

    Además  de la exposición a los éteres glicólicos pres-
entes en la atmósfera, las personas pueden estar expuestas
por  vía cutánea.  Los análisis de sangre confirman que la
absorción es rápida por esta vía, que puede contribuir más
que  la exposición atmosférica a la carga total que recibe
el organismo.

5.  Cinética y metabolismo

    Se  ha  demostrado  que los  cuatro  éteres glicólicos
pueden  absorberse rápidamente a  través de la  piel,  los
pulmones  y el tracto  gastrointestinal.  Los valores  más
elevados  que se  han obtenido  en los  estudios sobre  la
distribución del 2-ME en ratonas gestantes se sitúan en el
hígado,  la  sangre y  el  tracto gastrointestinal  de  la
madre,  así  como en  la placenta, el  saco vitelino y  en
numerosas estructuras del embrión.

    La  transformación  metabólica  del 2-ME  produce  dos
metabolitos  primarios:  MAA y glicina de 2-metoxiacetilo.
La  metabolización a dióxido de carbono representa una vía
secundaria  de menor importancia.  La  conversión del 2-ME
en MAA en el plasma se produce rápidamente, con  una  vida
media  de 0,6 h en las ratas, pero la secreción del MAA es
lenta,  con una vida media  de 20 h aproximadamente en  la
rata y de 77 h en el hombre.

    En  los animales de laboratorio,  la administración de
2-EE  da lugar  a la  producción de  EAA y  de glicina  de
2-etoxiacetilo;  el  EAA  es el  principal  metabolito que
aparece  en los testículos,  que son el  "órgano  diana"
presunto.  En un estudio humano en el que se utilizó 2-EEA
se  observó una vía metabólica análoga:  el acetato se hi-
drolizó primero en 2-EE y luego se transformó en  EAA  por
oxidación. El EAA resultante se excretó con una vida media
estimada  en  21-42 h.  Los  estudios experimentales hacen
pensar que la retención o acumulación de  los  metabolitos
podrían  ser importantes desde  el punto de  vista toxico-
lógico  en el supuesto de  que dichos metabolitos sean  la
causa de la toxicidad observada en el "órgano diana".

6.  Efectos en los organismos presentes en el medio ambiente

    La toxicidad del 2-ME y del 2-EE para  los  microorga-
nismos y animales acuáticos parece ser baja.  En  el  caso
de los microorganismos, la concentración letal en el medio
es superior al 2%.  Con el 2-ME se ha observado inhibición
del crecimiento de las algas verdes a 104 mg/litro   y  de
las  cianobacterias (algas verde azuladas) a 100 mg/litro.
La  toxicidad aguda del 2-EE es muy baja para los artrópo-
dos  (CL50 >  4 g/litro) y  para los peces  de agua  dulce
(CL50 >   10 g/litro).  Los acetatos  de éteres glicólicos
(2-MEA  y 2-EEA) son mucho más tóxicos para los peces.  La
CL50 del  2-EEA para el Phoxinus cabezudo es 46 mg/litro y
la  del  2-MEA para  el pez plateado  de la pleamar  y los
Lepomis  de agallas azules es  de 45 mg/litro.  No  se han
hecho estudios a largo plazo.

7.  Efectos en los animales de experimentación y en los
    sistemas de experimentación  in vitro 

7.1  Toxicidad sistémica

    La  toxicidad del 2-ME y  del 2-EE en los  animales de
experimentación  se ha estudiado en medida mucho mayor que
la del 2-MA y del 2-EEA.

    El 2-ME y el 2-EE y sus acetatos dan tasas análogas de
letalidad tras una exposición única y producen una letali-
dad  aguda baja cuando la  exposición tiene lugar por  vía
dérmica u oral o por inhalación. Los valores de la DL50 oral
en  las diversas especies  estudiadas oscilan entre  900 y
3400 mg/kg  de peso corporal  en el caso  del 2-ME,  entre
1400  y 5500 mg/kg en el del 2-EE, entre 1250 y 3930 mg/kg
en el del 2-MEA, y entre 1300 y 5100 mg/kg en el de 2-EEA.
En  los ratones se han  obtenido valores de la  CL50   por
inhalación de 4603 mg/m3 (2-ME) y 6698 mg/m3 (2-EE).

    Sólo  se dispone de datos limitados acerca de la irri-
tación cutánea u ocular o del potencial de sensibilización
de  estos éteres glicólicos  en los animales.  Al parecer,
no son irritantes para la piel, pero pueden  causar  irri-
tación en los ojos.  En el hombre no se ha observado irri-
tación  ni sensibilización cutáneas ni siquiera en caso de
gran exposición.

    La exposición por inhalación a corto plazo  (hasta  90
días) de los animales de experimentación a concentraciones
elevadas  (> 9313 mg de 2-ME/m3 y  > 1450 mg  de  2-EE/m3)
ejerce,  según se ha demostrado, efectos adversos  en  los
parámetros  sanguíneos, el sistema nervioso y los testícu-
los, el timo, el riñón, el hígado y los pulmones.  Utiliz-
ando  niveles más bajos  de exposición, se  han  observado
efectos  en el sistema hematopoyético y en los testículos.
Así, por ejemplo, las ratas expuestas durante 13 semanas a
la inhalación de 2-ME a concentraciones comprendidas entre
93  y  930 mg/m3 presentaron   una reducción  del  volumen
hematocrito y de los glóbulos blancos, la hemoglobina, las
plaquetas y las concentraciones de proteínas séricas sola-
mente cuando se aplicaba la dosis máxima, mientras que los
ratones  expuestos del mismo modo  presentaron disminución
del  tamaño del timo además de la disminución de los pará-
metros  sanguíneos con concentraciones de 930 mg/m3.   Las
ratas  y  conejos  expuestos al  2-EE  presentaron efectos
análogos  pero menos intensos cuando soportaron durante 13
semanas  una concentración de 1450 mg/m3.    No se dispone
de datos sobre estudios a largo plazo.

7.2  Carcinogenicidad y mutagenicidad

    La  mutagenicidad del 2-ME se ha estudiado en una gama
de  sistemas  in vitro   utilizando bacterias y  células  de
mamífero.   Aunque la mayor parte de los estudios han dado
resultados  negativos, algunos informes  acusan resultados
positivos en cuanto a la mutagenicidad de las concentraci-
ones  muy altas de 2-ME en células CHO estudiadas desde el
punto de vista de las aberraciones cromosómicas (a 6830 µg
por ml o más) o del intercambio de cromátides equiparables
(3170  µg/ml   o más). En cambio, la investigación  in vivo 
de   aberraciones  cromosómicas  y  micronúcleos  ha  dado
siempre  resultados  negativos.   Sólo se  dispone  de una
información muy limitada sobre el potencial mutagénico del
2-EE y no se dispone de ningún dato sobre  la  carcinogen-
icidad de estos éteres glicólicos.

7.3  Sistema reproductor masculino

    Los  efectos del 2-ME en el sistema reproductor mascu-
lino  se han estudiado detenidamente en roedores expuestos
por vía oral o por inhalación.  En el epitelio germinal de
los  tubos  seminíferos  se han  observado  constantemente
alteraciones degenerativas. Análogos efectos se han obten-
ido  con el 2-EE, si bien con niveles de dosificación algo
más elevados.

    En  la rata, la administración oral de 2-ME durante 1-
11 días ha dado lugar a un descenso del recuento de esper-
matozoides  con cambios de la motilidad y la morfología de
éstos  en relación con la dosis utilizada; como niveles de
dosificación  se utilizaron 100  mg/kg de peso  corporal o
más.   En la autopsia se encontraron acusadas alteraciones
histológicas  en los testículos.   El nivel de  efecto  no
observado  (NENO) fue de 50 mg/kg. La reducción de la fer-
tilidad  seguía siendo patente a las 8 semanas de la expo-
sición  a 200 mg/kg.  Análogos  efectos se observaron  con
dosificaciones  de 500 mg de 2-EE/kg  o más, administrados
durante  11 días como máximo; en el tratamiento de 11 días
el  NENO fue de 250 mg/kg.  En cambio, cuando las reservas
de  espermatozoides están reducidas  por la frecuencia  de
los  acoplamientos,  se  observó cierta  reducción  de los
recuentos con la dosis más baja estudiada.   Los  estudios
de fertilidad consecutivos a la administración de una sola
dosis oral de 250 mg de 2-ME/kg o más mostraron una ester-
ilidad completa, tanto en las ratas como en los ratones, a
partir de las 5 semanas de administración; con  125  mg/kg
se observó ya cierto descenso de la fertilidad.

    En los experimentos de inhalación se observaron alter-
aciones  degenerativas análogas en  los testículos con  el
2-ME.   Los efectos se observaron tras una sola exposición
(4 h) a 1944 mg/m3 o  más pero no con 933 mg/m3.   El NENO
fue de 311 mg/m3 en  la rata tras la exposición durante 13
semanas (6 h/día, 5 días/semana) y de 933 mg/m3 (6  h/día)
en  los ratones tras  la exposición en  9 ocasiones en  el
curso de 11 días. En los conejos expuestos al 2-ME durante
13  semanas (6 h/día, 5 días/semana) se observaron efectos
marcados  en  los  testículos con  concentraciones  de 311
mg/m3 o   más y efectos marginales  con 93 mg/m3;   no  se
determinó el NENO.

7.4  Toxicidad para el desarrollo

    En  varias especies de  animales de laboratorio  se ha
observado  toxicidad para el desarrollo tras la exposición
a  los compuestos utilizando todas las vías de administra-
ción: oral, inhalatoria y dérmica. El 2-ME produjo efectos
teratógenos en ratones, ratas, conejos y monos.  El 2-EE y
el  2-EEA  resultaron  teratógenos  en  las  ratas  y  los
ratones.   Aunque no se ha estudiado la toxicidad sobre el
desarrollo  del 2-MEA, los perfiles  metabólicos (véase la
sección 6)  hacen pensar que es posible que el 2-MEA tenga
una toxicidad análoga a la del 2-ME.

    En  relación  con el  2-ME se dispone  de la gama  más
amplia de datos dosis/respuesta (dosis de 31,25  por  1000
mg/kg por día). En este estudio de  administración  inten-
siva  en el que  se utilizaron ratones  (2-ME administrado
entre  el 7° y el 14° día de gestación) el NENO correspon-
diente  a la toxicidad materna  fue de 125 mg/kg  por día.

No  obstante, se observaron malformaciones  con 62,5 mg/kg
por  día y variaciones  esqueléticas con 31,25  mg/kg  por
día.  No se señaló ningún NENO de toxicidad para el desar-
rollo.  En el marco de estudios de dosis única, se trató a
ratones  con 2-ME administrado por alimentación forzada el
11°  día  de la  gestación; la dosis  de 100 mg/kg no  era
fetotóxica  mientras que la de 175 mg/kg produjo anomalías
digitales sin otros signos de toxicidad materna  o  fetal.
En  la ratas recién nacidas se observaron defectos cardio-
vasculares  y anomalías del ECG tras el tratamiento de las
madres con 25 mg/kg por día durante los días 7° a  13°  de
la  gestación.   Como ésta  fue la dosis  más baja que  se
ensayó,  este estudio no  ha permitido establecer  un NENO
para  el desarrollo (con esa dosis no se observó toxicidad
materna).  De igual modo, no pudo determinarse ningún NENO
de  toxicidad para el desarrollo  en un estudio de  trata-
miento  de monos por alimentación forzada con 2-ME a 0,16,
0,32  o 0,47 mmol/kg por día durante los días 20° a 45° de
la gestación.

    Tras  la exposición a la  inhalación de 2-ME a  156 mg
por  m3 se  ha observado  fetotoxicidad en los  ratones  y
ratas y malformaciones en los conejos. En las  tres  espe-
cies,  el  NENO correspondiente  a  los efectos  sobre  el
desarrollo fue de 31 mg/m3.   Sin embargo, en  la  descen-
dencia de las ratas expuestas a 78 mg 2-ME/m3 durante  los
días  7-13 o 14-20 de  la gestación se observaron  altera-
ciones conductuales y neuroquímicas.

    Tras la exposición por inhalación de ratas (743 mg por
m3)   y conejos (589 mg/m3),   el 2-EE se  reveló  terató-
geno  (en presencia de ligera toxicidad materna).  En otro
estudio se observó fetotoxicidad pero no malformaciones en
las  ratas expuestas a 184 ó 920 mg de 2-EE/m3,   así como
en los conejos expuestos a 644 mg de 2-EE/m3.    Los  val-
ores  del NENO para los efectos en el desarrollo fueron de
37 mg/m3 en   las ratas y de 184 mg/m3 en  los conejos. En
la  descendencia de las ratas  expuestas a 368 mg  de 2-EE
por  m3   durante los días 7-13 ó 14-20 de la gestación se
observaron alteraciones conductuales y neuroquímicas.

    Las ratas tratadas por aplicación dérmica de  0,25  ml
de 2-EE sin diluir (cuatro veces al día en los  días  7-16
de la gestación) acusaron una considerable fetotoxicidad y
una  elevada incidencia de  malformaciones en ausencia  de
toxicidad materna.  Análogos efectos se observaron tras el
tratamiento  de las ratas  con 2-EEA, utilizando  el mismo
protocolo, a una dosis equimolar (0,35 ml, cuatro veces al

    La  exposición  por  inhalación de  2-EEA  de  conejas
durante los días 6-18 de la gestación  provocó  respuestas
teratógenas  con 2176 mg/m3 y  544 mg/m3   en dos estudios
diferentes,  en los cuales  los valores del  NENO para  el

desarrollo fueron de 135 mg/m3   y 270 mg/m3.    Las ratas
expuestas al 2-EEA durante los días 6-15 de  la  gestación
acusaron  fetotoxicidad  a 540 mg/m3    y malformaciones a
1080 mg/m3.   El NENO para el desarrollo fue de 170 mg por

8.  Efectos en el hombre

    La información disponible sobre los efectos tóxicos de
estos cuatro éteres glicólicos en el ser humano  es  limi-
tada.   Los resultados de los escasos informes sobre casos
individuales  y  estudios  epidemiológicos en  el lugar de
trabajo  corroboran los efectos adversos observados en los
animales  de experimentación.  No se  ha encontrado ningún
informe  en el  que se  cuantifique la  exposición  y  los
efectos adversos en la población general.

    En  dos casos no mortales de envenenamiento por inges-
tión  de 100 ml de  2-ME, los signos  y síntomas  predomi-
nantes  fueron  náuseas,  vértigo, cianosis,  taquicardia,
hiperventilación  y acidosis metabólica, con algunos indi-
cios  de  insuficiencia  renal. Síntomas  análogos, aunque
menos graves, se observaron en un sujeto que ingirió 40 ml
de 2-EE.  En un caso de intoxicación mortal causada por la
ingestión de 400 ml de 2-ME, la autopsia reveló  una  gas-
tritis hemorrágica aguda con degeneración grasa del hígado
y alteraciones degenerativas de los túbulos renales.

    La exposición repetida de los trabajadores al  2-ME  y
al  2-EE, así  como a  otros solventes,  ha dado  lugar  a
anemia, leucopenia, debilidad general y ataxia.  En muchos
de  estos estudios no se ha hecho ninguna estimación fide-
digna  de la exposición.  Los efectos hematológicos de los
éteres glicólicos en el ser humano están bien documentados
y  se ha descrito la aparición de anemia macrocítica en un
trabajador  expuesto al 2-ME (promedio:  105 mg/m3),   así
como a otros solventes.

    En  los trabajadores expuestos por vía dérmica al 2-ME
se han observado efectos tóxicos en la médula ósea, y tam-
bién  se han observado  efectos inmunológicos en  trabaja-
dores sometidos a una exposición prolongada (8-35 años) al
2-ME  y al 2-EE (los promedios de exposición fueron de 6,1
mg/m3 y 4,8 mg/m3, respectivamente).

    Los  estudios  epidemiológicos realizados  en trabaja-
dores  expuestos al 2-ME  y al 2-EE  han revelado  algunos
indicios  de  efectos  adversos en  el sistema reproductor
masculino,  con un aumento  de la frecuencia  de recuentos
reducidos  de espermatozoides.  La exposición  al 2-EE (37
trabajadores) a concentraciones de hasta 88,5 mg/m3   pro-
vocaron  una alteración de  los índices seminales.   En un
grupo  de 73 trabajadores expuestos al 2-ME (hasta 17,7 mg
por  m3)   y al 2-EE  (hasta 80,5 mg/m3)   se  observó una

mayor frecuencia de recuentos reducidos de espermatozoides
y también signos de efectos hematológicos con exposiciones
de  2,6 mg/m3   para el 2-ME y de 9,9 mg/m3   para el 2-EE

    Los  efectos adversos observados en  las personas pro-
fesionalmente expuestas coinciden con los señalados en los
animales de experimentación. Sin embargo, debido a defici-
encias  en las evaluaciones de la exposición y a las expo-
siciones  mixtas, no se  han podido determinar  relaciones

9.  Conclusiones

    Muchas  personas  pueden estar  expuestas a concentra-
ciones de estos cuatro éteres glicólicos comparables a las
industriales a consecuencia del empleo de productos comer-
ciales  y de consumo. Tanto por inhalación como por absor-
ción  cutánea pueden producirse exposiciones profesionales
importantes.   En un número limitado de determinaciones de
la  concentración atmosférica en los lugares de trabajo se
han  obtenido valores comprendidos entre < 0,1 mg/m3   y >
150 mg/m3.

    Tanto  el 2-ME como el  2-EE se muestran poco  tóxicos
para  los microorganismos y las especies acuáticas.  No se
dispone de datos que permitan precisar la capacidad poten-
cial  de las exposiciones prolongadas para ejercer efectos
adversos sobre las especies presentes en el medio ambiente.

    En las ratas se ha obtenido un NENO para  los  efectos
testiculares de 933 mg de 2-ME/m3,   así como un NENO para
la exposición repetida de 311 mg/m3.   En los experimentos
de  exposición repetida con  la especie más  sensible,  el
conejo, se ha detectado un efecto neto con 311 mg/m3, mien-
tras que a 93 mg/m3 se  observaba un efecto marginal (1 de
5 animales). En las personas expuestas profesionalmente al
2-ME  y al 2-EE  se han encontrado  indicios de que  estos
éteres  glicólicos pueden producir toxicidad testicular en
el ser humano.

    En todas las especies (ratones, ratas y  conejos)  ex-
puestas  al 2-ME a 156 mg/m3   o más se ha observado toxi-
cidad para el desarrollo. Para las tres especies  se  tuvo
un NENO de 31 mg/m3.   En las ratas expuestas  in  utero  a
78 mg/m3 se  produjeron alteraciones conductuales y neuro-
químicas,  pero no se estableció ningún valor de NENO.  El
2-EE y el 2-EEA eran algo menos potentes.  En la rata y en
el  conejo se han  observado efectos sobre  el  desarrollo
tras  la exposición a 2-EE a concentraciones de 368 mg por
m3    o más. Estos efectos  eran ligeros en las  ratas ex-
puestas a 184 mg de 2-EE/m3, pero  tanto en las ratas como
en  los conejos se pudo establecer un NENO bien definido a
37 mg/m3.

    Estos éteres glicólicos producen efectos hematológicos
en  los ratones, las ratas,  los conejos, los perros,  los
hamsters,  y los cobayos.  Esta  observación concuerda con
los  efectos  hematológicos  señalados en  algunos  de los
escasos  estudios efectuados en  trabajadores industriales
expuestos  repetidamente al 2-EE y/o al 2-ME. En los estu-
dios  de exposición repetida de animales se obtuvo un NENO
de 93 mg de 2-ME/m3   en los conejos y de 368 mg  de  2-EE
por m3   en las ratas y los conejos.  No se  han  obtenido
datos  que permitan evaluar cuantitativamente  los efectos
hematológicos que siguen a la exposición aguda.


1.  Evaluación de los riesgos para la salud humana

1.1  Exposición

    Muchas  personas  pueden estar  expuestas al 2-metoxi-
etanol  (2-ME), al 2-etoxietanol  (2-EE) y a  sus acetatos
(2-MEA  y  2-EEA)  en concentraciones  comparables  a  las
industriales  como  consecuencia  del empleo  de productos
comerciales  y de consumo.   En cambio, la  exposición por
los alimentos, el agua o el aire ambiente es probablemente
insignificante.   Esta impresión se basa únicamente en las
propiedades  físicas y químicas  de estos compuestos  y en
los indicios de que experimentan una rápida degradación en
el medio ambiente.

    Tanto  por inhalación como por absorción cutánea puede
producirse  una  exposición  profesional importante.   Las
escasas  determinaciones  de  las  concentraciones  en  la
atmósfera  de  los lugares  de  trabajo han  dado  valores
comprendidos entre menos de 0,1 mg/m3 y  más de 150 mg por
m3.   Sin embargo, las posibilidades de vigilancia son muy
limitadas  y cabe la posibilidad de que haya grandes vari-
aciones  entre diferentes industrias  e incluso dentro  de
una misma industria. Habida cuenta de las posibilidades de
absorción  cutánea,  la vigilancia  del  aire por  sí sola
puede  dar una subestimación  de la exposición  total.  La
vigilancia biológica es el mejor método para  calcular  la
absorción total. Entre los trabajos que entrañan una expo-
sición  considerable figuran, por ejemplo, los de pintura,
imprenta  y limpieza; ahora bien,  no hay que olvidar  que
estos compuestos se utilizan también en otras muchas acti-
vidades  profesionales en las  que la exposición  debe ser
motivo de inquietud.

1.2  Efectos en la salud

    Los  principales motivos de inquietud en el ser humano
son los efectos en el desarrollo, los efectos testiculares
y  los  vinculados  a la  toxicidad  hematológica.   Estos
efectos  han sido demostrados  por una multitud  de  datos
sólidos  obtenidos en  el animal  y por  algunos datos  de
origen  humano.  Todos ellos pueden estar causados por una
exposición  a corto o a  largo plazo.  En los  animales de
experimentación, la exposición muy repetida al 2-ME  y  al
2-EE  (más de 939 y 1450 mg/m3,   respectivamente) produce
efectos  tóxicos  neuroconductuales, hepáticos  y renales,
los  cuales se observan  también en casos  de intoxicación

    Estos  cuatro éteres glicólicos dan  valores muy simi-
lares  de  toxicidad testicular  y  de toxicidad  para  el
desarrollo  en todas las  especies estudiadas y  por todas
las vías de exposición que se han  ensayado  (inhalatoria,
dérmica  y oral).  En los  estudios sobre el mecanismo  de
acción se ha visto que la metabolización al  derivado  del
ácido  alcoxiacético constituye una etapa indispensable de
activación,  tanto en los efectos sobre el desarrollo como
en los testiculares. Dicho metabolismo se efectúa mediante
el  sistema de deshidrogenasa  alcohólica que es  común al
hombre y a los animales de laboratorio.   Los  metabolitos
tóxicos,  el ácido metoxiacético  (MAA) y el  ácido etoxi-
acético  (EAA), aparecen en la  orina de las personas  ex-
puestas a estos solventes. La coherencia de las respuestas
en las distintas especies de animales de laboratorio estu-
diadas, junto con la semejanza del metabolismo en  el  ser
humano, permiten concluir que el hombre está probablemente
expuesto  a los efectos testiculares y sobre el desarrollo
de  estos éteres glicólicos.  Los  datos disponibles sobre
la  excreción  de  ácidos  alcoxiacéticos  por  el  hombre
sugieren la existencia de una retención prolongada en com-
paración  con la que se observa en los animales de labora-
torio,  lo cual hace pensar  que las personas quizás  sean
más  sensibles  que  las especies  experimentales de mayor
sensibilidad. Un motivo de especial inquietud es la rápida
absorción  cutánea de estos  compuestos. Se han  observado
efectos  teratógenos y otros  efectos sobre el  desarrollo
tras  la  aplicación  de 2-ME,  2-EE  y  2-EEA en  la piel
intacta de la rata.

    En  la  rata, el  ratón y el  conejo se han  observado
alteraciones  testiculares  tras  la  exposición  a  estos
éteres glicólicos, tanto por inhalación como por vía oral.
Una  exposición aislada de la rata a la inhalación de 1944
mg de 2-ME/m3   o más durante 4 h y la exposición repetida
a  933 mg de 2-ME/m3   o más durante 13 semanas han provo-
cado  signos  histológicos evidentes  de alteración testi-
cular.  El NENO para la exposición aguda fue de 933  mg/m3
y  para la exposición repetida de 311 mg/m3.     El  ratón
parece  ser menos sensible, siendo el NENO para la exposi-
ción repetida de 933 mg/m3.   En cambio, el conejo resulta
más sensible, observándose en él alteraciones testiculares
marcadas  tras la exposición repetida  a 311 mg/m3   y  un
efecto marginal (uno en cinco conejos afectados)  a  93 mg
por m3. Efectos  análogos se han observado tras la exposi-
ción  oral de la rata  al 2-ME, con aparición  de lesiones
testiculares  tras la exposición breve (inclusive de dosis
única) a 100 mg/kg. En un estu-dio subagudo  (11 días)  el
NENO  fue  de  50 mg/kg.  El  2-EE  es algo  menos potente
respecto  a la toxicidad testicular  que el 2-ME; sólo  se
observaron  efectos con dosificaciones de 500 mg/kg o más,
siendo el NENO de 250 mg/kg.

    Los  datos obtenidos en las  personas profesionalmente
expuestas al 2-ME y al 2-EE coinciden con los de los estu-
dios  en animales e  indican que estos  éteres  glicólicos
pueden  producir  toxicidad  testicular en  el ser humano.
Los  estudios epidemiológicos de pequeños grupos de traba-
jadores expuestos al 2-EE en una empresa de  fundición  de
metales  y de pintores de embarcaciones expuestos tanto al
2-ME  como  al  2-EE muestran  indefectiblemente una mayor
incidencia de recuentos reducidos de espermatozoides.  Los
datos  sobre los niveles de  exposición, aunque limitados,
aportan  en cada caso pruebas de la exposición dérmica así
como de la exposición por inhalación.

    En  la rata,  el ratón,  el conejo  y el  mono se  han
observado  efectos  tóxicos  sobre el  desarrollo  tras la
exposición a estos éteres glicólicos por vía dérmica, oral
o  inhalatoria.  Con 12  aplicaciones diarias de  2-ME sin
diluir en la piel rasurada de ratas  gestantes  (oclusión:
6  h) se obtuvo un  efecto letal, mientras que  10 aplica-
ciones  abiertas de 2-EE (1,0 ml/día) o 2-EEA (1,4 ml/día)
se  mostraron teratógenas pero  no tóxicas para  la madre.
Doce  aplicaciones cerradas de 2-ME al 10% en suero salino
resultaron  tóxicas para el desarrollo (en este estudio el
NENO fue del 3% para el 2-ME. No se han encontrado niveles
sin  efecto aparente tras la  administración oral repetida
de  2-ME a las hembras preñadas. El nivel de efecto obser-
vado mínimo (NEOM) en la administración oral de  2-ME  fue
de 31,25 mg/kg por día en el caso de los ratones, de 25 mg
por  kg  por  día en el de las ratas y de 0,16 mmol/kg por
día en el de los monos.  Sólo se han hecho experimentos de
dosis única con el 2-ME en los ratones, con  el  resultado
de  que el 11° día de la gestación (que es el día más sen-
sible)  el NENO era de  100 mg/kg y el  NEOM de 175 mg/kg.
Tanto  el 2-EE como  el 2-EEA se  han evaluado en  ratas y
conejos por inhalación.  A las ratas se las expuso al 2-EE
en  dos estudios, en los que se obtuvieron efectos terató-
genos (743 mg/m3 durante  7 h/día los días 1-19 de la ges-
tación)  o efectos fetotóxicos  (184 y 920 mg/m3 durante 6 h
por  día los días  6-15 de la  gestación). En este  último
estudio,  el NENO fue de  37 mg/m3.   También los  conejos
expuestos  al 2-EE presentaron efectos teratógenos (589 mg
por  m3   durante 7 h/día los días 1-18 de la gestación) o
efectos  fetotóxicos (644 mg/m3   durante 6 h/día los días
6-18  de la gestación).  En el último estudio, el NENO fue
de  184 mg/m3.   En los conejos expuestos al 2-EEA durante
6 h/día  los días 6-18 de la gestación se obtuvieron efec-
tos teratógenos a 2160 mg/m3   en un estudio y  a  1620 mg
por m3   en otro. En ambos estudios se observó fetotoxici-
dad a 540 mg/m3   y en uno y otro el nivel  de  exposición
mínimo  (135 y 270 mg/m3,   respectivamente) coincidía con
el  NENO. Las ratas expuestas al 2-EEA por inhalación dur-
ante  6 h/día los días 6-15 de la gestación presentaron el
mismo  tipo de expuesta: efectos teratógenos a 1620 mg por
m3,    fetotoxicidad a 1080 mg/m3   y ausencia de todo ef-
ecto a 270 mg/m3.

    Así,  pues, se ha  observado toxicidad para  el desar-
rollo en todas las especies (ratones, ratas y conejos) ex-
puestas al 2-ME a 156 mg/m3   o más. Para las  tres  espe-
cies,  el NENO fue  de 31 mg/m3.    En ratas  expuestas  in
 utero a  78 mg/m3   se han  observado alteraciones conduc-
tuales  y  neuroquímicas,  no habiéndose  señalado  ningún

    El  2-EE y el 2-EEA han resultado algo menos potentes.
En la rata y el conejo, todas las exposiciones al  2-EE  a
368 mg/m3   o más fueron seguidas de efectos sobre el des-
arrollo. En las ratas expuestas a 184 mg de 2-EE/m3 estos ef-
ectos eran leves, pero 37 mg/m3 constituía un NENO patente.
En el caso del 2-EEA,  el NENO era de 170 mg/m3 tanto en
la rata como en el conejo.

    Tanto en los animales como en los casos  de  envenena-
miento  humano se han observado efectos hematológicos tras
la  exposición a una dosis aguda única.  La exposición por
inhalación repetida de la especie más sensible, el conejo,
al  2-ME durante 13 semanas  y a razón de  cinco veces por
semana dio un NEI de 93 mg/m3.   También las dosis repeti-
das  de  2-ME  provocan  toxicidad  hematológica  en   los
ratones,  conejos, perros, hámsters y cobayos.  El 2-EE es
menos  potente que el 2-ME  como causa de efectos  hemato-
lógicos.  El NENO correspondiente a estos efectos  fue  de
368  mg/m3   en las ratas  y los conejos expuestos  a 2-EE
durante  13 semanas  a razón  de cinco  veces  por  semana
durante 6 h/día.  También en los perros y los  ratones  se
han  registrado  efectos hematológicos  tras la exposición
repetida  a  concentraciones  más elevadas  de  2-EE.   La
exposición  a los  ésteres acéticos  del 2-EE  y del  2-ME
quizá  provoque efectos análogos  a los mismos  niveles de
exposición,  pero los datos disponibles sobre exposición y
efectos  hematológicos  de  esos compuestos  son demasiado
escasos  para determinar en qué condiciones una exposición
humana aislada tendrá efectos hematológicos.

    Se  han  observado  niveles de  exposición  industrial
próximos o idénticos al NENO de efectos  hematológicos  en
animales  expuestos a dosis repetidas  de 2-ME o de  2-EE.
Este  hecho, junto con la mayor sensibilidad que probable-
mente tienen las personas y la acumulación  previsible  de
metabolitos  en la sangre humana, hace pensar que tanto la
exposición  industrial como la de  los consumidores pueden
tener  efectos hematológicos.  Esto ha sido confirmado por
la observación de efectos de este tipo en algunos  de  los
escasos  estudios realizados sobre  trabajadores industri-
ales  expuestos repetidamente al 2-EE,  al 2-ME o a  ambos
compuestos a la vez.

2.  Evaluación de los efectos sobre el medio ambiente

    La  exposición  ambiental  a estos  éteres  glicólicos
puede producirse como consecuencia de su paso directo a la
atmósfera  cuando  se  utilizan como  solventes volátiles.
También  pueden ser causa de exposición ambiental los ver-
tidos  en el suelo y el agua a consecuencia de escapes ac-
cidentales. La acumulación en el suelo y en las aguas sup-
erficiales  sólo podría producirse en ausencia de degrada-
ción.   Sin embargo, estos  éteres glicólicos se  degradan
rápidamente a causa de procesos químicos y biológicos, por
lo que no es probable que se acumulen. Tanto el 2-MEA como
el  2-EEA pueden hidrolizarse fácilmente  y, por consigui-
ente,  biodegradarse en condiciones aerobias.   En cambio,
la  contaminación de acuíferos  y suelos anaerobios  sigue
planteando un problema potencial, aunque es de esperar que
no pase de ser una situación transitoria y, por ende, poco

    Tanto  el 2-ME como el  2-EE se muestran poco  tóxicos
con  los  microorganismos  y las  especies acuáticas.  Los
acetatos de éteres glicólicos, en cambio, tienen una toxi-
cidad  aguda mucho mayor. No se dispone de datos para cal-
cular  las posibilidades de  efectos adversos en  especies
del medio ambiente a causa de la exposición prolongada.


1.  Protección de la salud

1.  Hay  que identificar otros solventes menos tóxicos que
puedan  sustituir al 2-metoxietanol, al  2-etoxietanol y a
sus  ésteres, especialmente en los productos destinados al
consumo.   También es particularme importante  evaluar los
efectos  de otros éteres etilenglicólicos,  ya que algunos
pueden tener efectos análogos a los de los  cuatro  éteres
glicólicos que aquí se evalúan.

2.  Habida  cuenta  de  los conocidos  efectos  tóxicos de
estos  éteres  glicólicos, las  autoridades deben ocuparse
seriamente  de  establecer  estrategias  apropiadas   para
informar  a los usuarios de  esos productos acerca de  los
riesgos  que entrañan, especialmente los resultantes de la
exposición dérmica.

3.  En  vista de los nuevos  datos toxicológicos y de  las
posibilidades  de  absorción  dérmica importante  de estos
éteres  glicólicos, habrá que reconsiderar  los límites de
exposición profesional fijados por los países a fin de que
la  dosis diaria total  que reciben los  trabajadores  por
todas  las  vías de  administración  no plantee  un riesgo
indebido para la salud.

4.  En  los animales se observan efectos de dosis única en
niveles  de  exposición  bastante altos.   Con  objeto  de
reducir  los riesgos para la salud, se recomienda utilizar
con  prudencia estos compuestos  (prestando atención a  la
higiene  personal, los dispositivos apropiados  de protec-
ción  y la ventilación  adecuada).  Los datos  disponibles
indican que puede ser necesario aumentar la  protección  a
fin  de evitar efectos  en el desarrollo,  así como en  la
sangre y los testículos como resultando de  la  exposición

2.  Investigaciones necesarias

1.  En  vista de la  intervención del ácido  metoxiacético
(MAA)  y etoxiacético (EAA) (que son los principales meta-
bolitos identificados del 2-ME, del 2-EE y de sus ésteres)
en  la  toxicidad  para el  sistema reproductor masculino,
habrá que investigar su mecanismo de acción.  Si  de  ello
se deduce que el MAA y el EAA no son los principales agen-
tes  responsables, habrá que tratar de identificar éstos y
de aclarar su mecanismo de acción.

2.  Estos cuatro éteres glicólicos tienen a la vez efectos
hematológicos y efectos sobre el sitema reproductor mascu-
lino  (reducción  del  recuento de  espermatozoides).  Los
datos  disponibles, aunque limitados, parecen  indicar que
ambos efectos se hacen evidentes a niveles de dosificación

análogos.   Habrá que investigar el mecanismo de acción en
ambos  sistemas  orgánicos  y examinar  paralelamente  los
efectos  hematológicos y los recuentos  de espermatozoides
con  el fin de determinar si las alteraciones de la sangre
proporcionan  signos de alarma con repecto a otros efectos
de estos compuestos.

3.  La  vigilancia del  aire no  basta por  sí  sola  para
garantizar una exposición de poca intensidad.  La vigilan-
cia  biológica puede contribuir a detectar defectos de las
medidas  de protección.  De  momento no se  ha establecido
claramente  la  relación  existente entre  los indicadores
biológicos  de exposición, la  absorción corporal total  y
los efectos observados en la salud.  Habrá  que  proseguir
las  investigaciones a fin de adquirir una base para apli-
car  la  vigilancia biológica  a  la determinación  de  la
seguridad en las exposiciones.

4.  Hay  que proyectar estudios epidemiológicos y/o traba-
jos específicos de vigilancia sanitaria en poblaciones muy
expuestas a estos éteres glicólicos a fin de  estimar  las
relaciones  exposición-efecto con miras a determinar expo-
siciones  seguras, siempre que se pueda evaluar adecuada y
suficientemente la exposición total mediante la vigilancia
ambiental y biológica.

5.  Habrá  que investigar la posibilidad de que estos com-
puestos  ejerzan efectos sobre las gónadas femeninas medi-
ante  estudios  de reproducción  multigeneracional en ani-

6.  Los  datos disponibles indican que el ser humano puede
metabolizar  estos éteres glicólicos hasta  los correspon-
dientes ácidos alcoxiacéticos en mayor medida que la rata,
y  que  la vida  media de la  excreción urinaria de  estos
metabolitos  tóxicos  es aproximadamente  cuatro veces más
prolongada  en las personas  que en las  ratas.  Por  otra
parte,  éstas conjugan una mayor cantidad de los metaboli-
tos ácidos, cosa que no hacen las personas. Estas diferen-
cias  podrían explicar la sensibilidad relativamente elev-
ada del ser humano a estos éteres glicólicos. Un conocimi-
ento  detallado del metabolismo y de la cinética de excre-
ción  mejoraría nuestra capacidad para predecir cuáles son
los niveles de exposición seguros.

7.  Los resultados obtenidos en estudios a corto plazo (13
semanas)   indican efectos en diversos sistemas orgánicos.
En cambio, no se han hecho estudios de suficiente duración
que  permitan evaluar la reversibilidad  de tales efectos.
Por  consiguiente, convendría que se emprendieran estudios
de interrupción en los que los animales de experimentación
estuvieran  expuestos a estos  éteres glicólicos al  menos
durante  13 semanas, seguidas  de un periodo  apropiado de
recuperación.   Cabría evaluar así  importantes parámetros
fisiológicos  con miras a determinar si esos efectos son o
no transitorios.

    See Also:
       Toxicological Abbreviations