2-Methoxyethanol (EGME)
Molecular Formula. C3H802
M=76.11
CAS No 109-86-4
RTECS No KL5775000
Abbreviations. ME, MAA (2-methoxyacetic acid).
Synonyms
and Trade Names.
Ethylene glycol, monomethyl ether; Methyl cellosolve; Methyl
glycol; Methyl oxitol; Monomethyl ethylene glycol ether;
Monomethyl glycol.
Properties.
Colorless,
transparent, volatile liquid with a mild non-residual odor.
Soluble in water and ethanol. Does not affect transparency and
color of water; does not form foam and film on the water
surface. Odor perception threshold is 14.3 mg/l or <0.09 mg/1.010
According to other data, organoleptic threshold is 100 mg/l.01
Applications.
ME has wide industrial
and consumer applications. It is used as a solvent in the
production of nitro- and acetyl cellulose, natural and
artificial resins. Used in the manufacture of protective epoxy
resin coatings for metals. A surfactant.
Acute Toxicity.
LD50 is found
to be 2.46 to 3.25 g/kg BW in male rats, 3.4 g/kg BW in female
rats, 0.89 to 1.425 g/kg BW in rabbits, and 0.95 g/kg BW in
guinea pigs.1,2 High doses caused anuria.
Death occurred in rabbits in 2 to 4 days after poisoning.
Observations in
man. ME affects
hematology parameters and CNS functions.
Repeated
Exposure. Gross
pathology examination in rats exposed to 100 or 150 mg/kg BW
for three weeks revealed reduced weights of the visceral
organs, normochromic, normocytic anemia, hemorrhagic changes in
the bone marrow and ovarian atrophy.3 Inflammatory
changes were observed in the bladder mucosa.4
Decrease in
liver weights was observed in Wistar rats administered 300 mg
ME/kg BW for 20 days. The activity of cytosolic ADH was
increased.5
In 2-week
studies, F344 rats and B6C3F, mice received ME in their
drinking water. Consumption values ranged from 100 to 400 mg/kg
BW (rats) and 200 to 1300 mg/kg BW (mice). There were no
effects on survival. Decrease in BW gain in rats was reported.
The treatment caused thymic and testicular atrophy in males of
both species.6
Short-term
Toxicity. In 13-week
studies, histology changes were observed in the testes, thymus,
and hematopoietic tissues. There was progressive anemia, effect
on the testes, spleen, and adrenal gland (in females only). The
NOAEL in rats was not reached, since testicular degeneration in
males and decreased thymus weights occurred at the lowest
concentration administered. The NOAEL for testicular
degeneration and increased hematopoiesis in the spleen was 2000
ppm in mice
Long-term
Toxicity. Chronic
exposure causes hemodynamic injuries and dystrophic changes in
the brain, liver, kidneys, myocardium, etc. ME produced
hematological disorders in both humans and experimental
animas.7 Medinsky et al. believe hematotoxic effects to be due
to the MAA metabolite of ME.8
Immunotoxicity.
ME has been shown
to be immunosuppressive in rats but not in mice, with oxidation
of ME to MAA being a prerequisite for immunosuppression. Oral
and dermal exposure to ME revealed the ability of the immune
system to mount an effective humoral immune response.15
MAA, the main
metabolite of ME, is shown to cause immunodepressive effect
when administered by gavage to young adult F344 rats. Thymic
involution is reported."
Repeated high
dose oral exposure to MAA does not suppress humoral immunity in
the mouse.9
Rats given doses
greater than 100 mg ME/kg BW displayed significant thymic
depression.10 Dose-related increase in natural
killer cells cytotoxic activities and decrease in specific
antibody production in rats were reported."
Mice, however,
appeared to be insensitive to the immunosuppressive effects of
ME and MAA, at the doses producing such effects in rats.12,13
House did not observe changes in the immunological functions or
host resistance in B6C3F1 female mice dosed by gavage 10 times
over 2 weeks with 25 to 100 mg ME or MAA per kg BW.14
Nevertheless, thymic involution was revealed at 50 to 100 mg/kg
BW doses.
F344 rats were
gavaged with 25 to 200 mg ME/kg BW in distilled water for 4
consecutive days. The treatment caused a reduction in thymus
weights at the doses of 50 to 200 mg/kg BW, while spleen
weights were reduced in rats that were dosed at 200 mg/kg BW.
The lymphoproliferative responses to phytohaemagglutinin,
pokeweed mitogen, and Salmonella typhimirium were
increased at the 200 mg/kg BW.
Reproductive
Toxicity. ME produces a
dose-related embryotoxic and teratogenic effect in mice,
hamsters and guinea pigs.
Embryotoxicity.
ME is metabolized to
the active compound MAA, which readily crosses the placenta and
impairs fetal development. Pregnant mice were exposed to 100,
150, or 200 mg ME/kg BW from gestation days 10 to 17. The
treatment caused a significant thymus atrophy and cellular
depletion in fetal mice. ME inhibited thymocyte maturation.
ME-induced immunodepression may result from targeting of
multiple hematopoietic compartments.'
F344 rats were
treated on days 6 to 15 of gestation by dosed feed or gavage
(doses 12.5 to 100 mg/kg BW). This exposure caused only a small
decrease in maternal BW gain during treatment. Litter weights
and postnatal survival were decreased (100 mg/kg BW group);
percentage of resorption was increased in 50 and 100 mg/kg BW
dosed groups. The number of the live pups was decreased in 25
to 100 mg/kg BW dosed groups. 1'
Monkey were
dosed with up to 55 mg ME/kg BW on gestation days 20 to 45. All
pregnancies at the highest dose ended in death. One of the
fetuses at the highest dose had a missing digit on each
forelimb. The LOAEL was considered to be 12 mg/kg BW in this
study.18
Teratogenicity.
Time-mated CD-1 mice
were orally dosed on gestation day 11 with distilled water
(control) or ME at a dose of 304 mg/kg BW. There were no signs
of treatment-related maternal toxicity, and intrauterine
survival was unaffected by the treatments. There was no
treatment-related pattern of gross external malformations other
than paw defects. Paw defects were present in ME-treated
litters (68.5% of fetuses). Hindpaw defects predominated over
forepaw, and syndactyly was the most common malformation. The
incidences of oligodactyly and short digits were also
significantly increased. The similarity of malformations
produced by methyl-substituted glycol ethers is proposed to be
attributable to in vivo conversion to a common teratogen,
methoxyacetic acid.33
Bifurcated or
split cervical vertebrae were found in the offspring of female
mice treated on days 7 to 14 of gestation. The LOAEL of 31
mg/kg BW was established.19 The NOAEL for induction
of malformations after a single administration on gestation day
11 was 100 mg/kg BW.4
Gonadotoxicity.
ME causes
testicular atrophy, degenerative changes in the germinal
epithelium, pathological changes in the sperm head, and
infertility.20
Rats and guinea
pigs received a single oral dose of 200 mg/kg BW. The treatment
induced spermatocyte degeneration in 24 and 96 hours after
dosing, respectively.21
ME was found to
deplete the spermatocytes of rats and mice which were given a
single oral dose of 0.5 to 1.5 g/kg BW. This treatment produced
morphologic abnormalities in rat spermatozoa that had been
exposed as spermatocytes.22
In a 5-week
study, male mice were exposed to oral doses of 0.5 to 4.0 g/kg
BW. Male Dutch rabbits received the doses of 12.5, 25, 37.5, or
50 mg ME/kg BW in the drinking water for 12 weeks. The
treatment caused oligospermia in the highest dose groups. No
notable histopathology was found. A marked disruption in
spermatogenesis increased above 25 mg ME/kg BW. The NOAEL of
12.5 mg/kg BW was established in this study�
The NOAEL of 0.5
mg/kg BW for testicular atrophy was identified.24
The ineffective dose for lesions and degeneration in primary
spermatocytes and spermatids in male rats dosed for 11 days
appeared to be 0.05 g/kg BW.25
Mutagenicity.
In vivo
cytogenetics.
B6C3F1 mice received the doses of 35 to 2500 mg
ME/kg BW during acute and subchronic oral exposure. The
treatment did not cause induction of CA even after ME
administration in cytotoxic doses.26
ME is shown to
increase the rate of DLM in rats. It produced damage in mouse
sperm head morphology following inhalation exposure. Equivocal
results are observed in Dr. melanogaster (NTP-82).
In vitro
genotoxicity.
ME gave negative results in mutagenicity assays with
Salmonella typhymurium strains TA 98, TA 100, and
TA 102 either with or without S9 mix.27,28
At high concentrations, it induced SCE in Chinese hamster ovary
cells with and without S9 fraction. 6
Methoxyacetaldehyde, a metabolite of ME, was mutagenic in a
subline of Chinese hamster ovary cells.29 It
displayed mutagenic potency in Salmonella typhimurium
strain TA 97a with or without S9 mix at high
concentrations.28
Chemobiokinetics.
Observations in
man. MAA is found in the
urine of 7 male volunteers exposed to 5.0 ppm ME30
but it was not found in human urine in acute poisoning cases.
Animal studies.
ME is metabolized
via alcohol dehydrogenase to methoxyacetaldehyde
and via aldehyde dehydrogenase to MAA, which seems to be a
major oxidative metabolite. The urine appears to be a major
route of excretion.16'31
According to
Medinsky et al., ethylene glycol, a metabolite of ME, is a
result of dealkylation of the ether occurred prior to oxidation
to MAA. Ethylene glycol was excreted in urine,
representing approximately 21% of the dose administered.$
Biotransformation of ME has also been detected in testes from
Wistar rats and one strain of mice, but not in testes from
hamsters, guinea pigs, rabbits, dogs, cats, or humans. Testes
from all these species readily converted the aldehyde
metabolite of ME to MAA
ME is removed
mainly in the urine, it does not accumulate in the testes
Excretion also occurs via exhalation as CO2.
Less than 5.0% ME was exhaled unchanged.
Ethylene Glycol Monomethyl Ether (EGME)
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