| ETHYLENE
GLYCOL MONO-N-BUTYL ETHER NOTE: To lower currently approved exposure limits...also use of 2-butoxyethanolOSHA seeks Comments * what did they find? why were they wanting more input? ETHYLENE
GLYCOL MONO-N-BUTYL ETHER http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~AAAGlaypx:1
Human Health Effects: Toxicity Summary: IDENTIFICATION: 2-Butoxyethanol
is a high production volume glycol ether. It is a colorless liquid that is
miscible in water and soluble in most organic solvents. 2-Butoxyethanol is used widely as a solvent in
surface coatings, such as spray lacquers, quick dry lacquers, enamels,
varnishes, varnish removers and latex paint. HUMAN EXPOSURE: Based on limited
data, ambient exposures in air are generally in the ug/cu m range. Industrial
exposure of the general population to this chemical is most likely from
inhalation and dermal absorption during the use of products containing 2-butoxyethanol.
Levels of airborne 2-butoxyethanol
in occupational settings are typically in the mg/cu m range. The results of in
vitro studies indicate that human red blood cells are not as sensitive to the
hemolytic effects of 2-butoxyethanol
and 2-butoxyacetic acid and also that red blood cells are more sensitive to
hemolysis by 2-butoxyacetic acid than to hemolysis by 2-butoxyethanol.
ANIMAL STUDIES: 2-Butoxyethanol
is readily absorbed following inhalation, oral or dermal exposure. The chemical
is metabolized via alcohol and aldehyde dehydrogenases, with the formation of
2-butoxyacetaldehyde and 2-butoxyacetic acid, the principal metabolite, although
other metabolic pathways have also been identified. This chemical has moderate
acute toxicity and it is irritating to the eyes and skin; it is not a skin
sensitizer. The principal effect exerted by 2-butoxyethanol
and its metabolite 2-butoxyacetic acid is hematotoxicity, with the rat being the
most sensitive species. In rats, adverse effects on the central nervous system,
kidneys and liver occur at higher exposure concentrations than do the hemolytic
effects. In animals, adverse effects on reproduction and development have not
been observed at less than toxic doses. Although the results of in vitro tests
for mutagenicity of 2-butoxyethanol
were inconsistent, the absence of structural alerts and the negative findings
from in vivo studies indicate that 2-butoxyethanol
is not mutagenic. Evidence for Carcinogenicity: WEIGHT-OF-EVIDENCE CHARACTERIZATION: No reliable human epidemiological
studies are available that address the potential carcinogenicity of EGBE. ...
NTP /the National Toxicology Program/ (1988) reported no evidence of
carcinogenic activity in male F344/N rats, and equivocal evidence of
carcinogenic activity in female F344/N rats on the basis of increased combined
incidences of benign and malignant pheochromocytoma (mainly benign) of the
adrenal medulla. They also reported some evidence of carcinogenic activity in
male B6C3F1 mice on the basis of increased incidences of hemangiosarcoma of the
liver, and some evidence of carcinoma (mainly papilloma). ... because of the
uncertain relevance of these tumor increases to humans, the fact that EGBE is
generally negative in genotoxic tests and the lack of human data to support the
findings in rodents, the human carcinogenic potential of EGBE, in accordance
with the recently proposed Guidelines for Carcinogen Risk Assessment (USEPA,
1996), cannot be determined at this time, but suggestive evidence exists from
rodent studies. Under existing EPA guidelines (USEPA, 1986), EGBE is judged to
be a possible human carcinogen, Group C. HUMAN CARCINOGENICITY DATA: There are
currently no human epidemiological studies addressing the potential
carcinogenicity of EGBE. Human Toxicity Excerpts: SYMPTOMATOLOGY: 1. Central nervous depression, although probably less
prominent than with ethylene glycol. 2. No hypocalcemic tetany or metabolic
acidosis with the possible exception of poisonings due to ethylene glycol
monomethyl ether. 3. Nausea, vomiting, and sometimes diarrhea. 4. Prominent
headache. Later abdominal and lumbar pain and costovertebral angle tenderness.
5. Transient polyuria & then oliguria, progressing to anuria. 6. Acute renal
failure ... 7. Less critical pathological lesions may appear in brain, lung,
liver, meninges and heart. 8. Observations in animals suggest the remote
possibility of pulmonary edema, intravascular hemolysis & bone marrow
depression, at least with some ether derivatives of ethylene and diethylene
glycols. ... /Ethylene glycol (Group B compounds)/ EXPOSURE ... TO HIGH CONCN ... OF ... VAPORS, PROBABLY IN RANGE OF 300-600
PPM FOR SEVERAL HR WOULD BE EXPECTED TO CAUSE RESP & EYE IRRITATION ... /CNS
DEPRESSION/, & DAMAGE TO KIDNEY & LIVER. FIRST SIGN OF ORGANIC ABNORMALITY ... RESULTING FROM EXCESSIVE EXPOSURE BY
ANY ROUTE LIKELY WOULD BE ABNORMAL BLOOD PICTURE CHARACTERIZED BY ERYTHROPENIA,
RETICULOCYTOSIS, GRANULOCYTOSIS, & LEUCOCYTOSIS. SOMEWHAT MORE INTENSE
EXPOSURE WOULD BE LIKELY TO CAUSE FRAGILITY OF ERYTHROCYTES & HEMATURIA. BONE MARROW DAMAGE. /FROM TABLE/ 2-Butoxyethanol penetrates
the skin readily, and toxic action from excessive skin exposure may be more
likely than from vapor inhalation. IT APPEARS THAT THIS CHEMICAL IS ONE OF THE FEW MATERIALS TO WHICH HUMAN IS
MORE RESISTANT THAN THE USUAL EXPERIMENTAL ANIMALS. THIS APPEARS TO BE DUE, IN
PART AT LEAST, TO THE FACT THAT HUMANS ARE MORE RESISTANT THAN ARE MOST LAB
ANIMALS TO THE HEMOLYTIC EFFECTS CAUSED BY THE MATERIAL ITSELF OR ITS
METABOLITE. ... REGARDED AS MOST TOXIC GLYCOL MONOALKYL ETHER USED AS SOLVENT ... . THE EFFECTS /OF ALKYL DERIV OF ETHYLENE GLYCOL/ ... UPON THE CNS INCLUDE
HEADACHE, DROWSINESS, WEAKNESS, SLURRED SPEECH, RECRUDESCENT STUTTERING,
STAGGERING GAIT, TREMOR, AND BLURRED VISION. CHANGES OF PERSONALITY ARE OFTEN
NOTED ... THESE CHANGES ARE SUCH THAT THE PATIENT, IN THE ABSENCE OF AN ACCURATE
OCCUPATIONAL HISTORY, MAY BE TREATED FOR SCHIZOPHRENIA OR NARCOLEPSY. IN ACUTE
POISONING WITH THE ETHYLENE GLYCOL MONOALKYL ETHERS, THERE IS ... RENAL INJURY:
ALBUMINURIA & HEMATURIA. /ETHYLENE GLYCOL MONOALKYL ETHERS/ A case of severe poisoning with ethylene glycol butyl ether after massive
ingestion is described. Deep coma, metabolic acidosis, hypokalemia
hemoglobinuria, oxaluria and a transitory rise in the serum creatinine level
were observed. The elimination of the various metabolites butoxyacetic acid and
oxalate was assessed in urine and a metabolic pattern for ethylene glycol butyl
ether is suggested. The effects of 2-butoxyethanol
and its metabolites, 2-butoxyacetaldehyde and butoxyacetic acid, on erythrocytes
from humans were investigated in vitro. ... Incubation of human blood with
butoxyacetic acid showed minimal swelling or hemolysis of erythrocytes with
minimal decline in blood ATP levels at butoxyacetic acid concentrations
several-fold higher than required to cause complete hemolysis of rat
erythrocytes. ... Human erythrocytes are comparatively insensitive to the
hemolytic effects of butoxyacetic acid in vitro. A case of acute poisoning with ethylene glycol butyl ether is reported in a
chronic alcoholic abuser. On admission the 53 yr old patient was comatose with
metabolic acidosis, shock and noncardiogenic pulmonary edema confirmed by
hemodynamic study. Following supportive treatment and hemodialysis the outcome
was favorable. ... In several, single, 8 hour exposures of humans at concentrations of 200 or
100 ppm, no objective effects were seen except for urinary excretion of
butoxyacetic acid. No increased osmotic fragility was observed in these short
term exposures. Subjectively, these concentrations were found to be
uncomfortable, and mild eye, nose, and throat irritation followed exposure. No clinical signs of adverse effects nor subjective complaints occurred among
seven male volunteers exposed at 20 ppm for 2 hours during light physical
exercise. Human Toxicity Values: The lethal oral dose /of ethylene glycols/ in humans is approximately 1.4
ml/kg, which would be equivalent to approximately 100 ml for a 70-kg person.
/Ethylene glycols/ Skin, Eye and Respiratory Irritations: Irritation of eyes, nose and throat ... Medical Surveillance: Consider the points of attack (liver, kidneys, lymphoid system, skin, blood,
eyes, respiratory system) in placement and periodic physical examinations. Probable Routes of Human Exposure: The most probable route of human exposure to ethylene glycol mono-n-butyl
ether is by inhalation, dermal contact and ingestion. Workplace exposures have
been documented(2-6). Drinking water supplies have been shown to contain
ethylene glycol mono-n-butyl ether(1). THERE IS ... HAZARD OTHER THAN VAPOR THAT MUST NOT BE OVERLOOKED WHEN
HANDLING THIS MATERIAL--THAT OF POSSIBLE ABSORPTION OF TOXIC QUANTITIES THROUGH
SKIN, BECAUSE OF LOW VAPOR PRESSURE ... @ ROOM TEMP, HAZARD FROM SKIN ABSORPTION
COULD WELL BE GREATER, OR CONTRIBUTE SUBSTANTIALLY TO OVER-ALL HAZARD. FROM INDUST POINT OF VIEW, ONLY ONE CASE OF POSSIBLE SYSTEMIC INJURY WAS THAT
OF MAN WHO WAS REPORTED ... AS HAVING HAD TWO ISOLATED ATTACKS OF HEMATURIA,
WITH 5 MO INTERVAL. ... HIS EXPOSURE ... INCL BUTYL CARBITOL AS WELL AS BUTYL
CELLOSOLVE. OCCUPATIONAL EXPOSURES TO BUTYL CELLOSOLVE, ETHANOL,
& XYLENE IN FILAMENT-DRAW DEPARTMENT OF ELECTRICAL RESISTOR MFR FACILITY DID
NOT POSE A HEALTH HAZARD. NIOSH (NOES Survey as of 3/28/89) has estimated that 1,680,764 workers are
potentially exposed to ethylene glycol mono-n-butyl ether in the USA(1).
According to the National Ambient Volatile Organic Compounds (VOCs) Database,
the median workplace atmospheric concn of ethylene glycol mono-n-butyl ether is
0.075 ppbV for 14 samples(3). Workers at paint stripping operations that used
stripping agents containing ethylene glycol mono-n-butyl ether were exposed to
it(2). Personal exposures to atmospheric ethylene glycol mono-n-butyl ether at a
specialty chemical production facility in June of 1981 ranged from undetected
levels to 0.1 ppm; indoor air concn within the facility were as high as 1.7
ppm(2). A national survey of workplaces in the Federal Republic of Germany
showed that workers were exposed to solvents containing ethylene glycol
mono-n-butyl ether with a 0.4% frequency of occurrence(1). A study initiated in 1983, which surveyed the workplace atmospheres of 336
businesses in Belgium, showed that ethylene glycol mono-n-butyl ether was
present in 25 of 94 air samples taken from sites that utilize printing pastes;
10 of 81 samples from where painting took place; 1 of 20 samples from automobile
repair shops; and 17 of 67 samples from sites where various materials such as
varnishes, sterilization agents and cleaners are employed(1). The geometric mean
concn of ethylene glycol mono-n-butyl ether in the air of printing shops was 4.1
mg/cu m with a range of 1.5 to 17.7 mg/cu m; 18.8 mg/cu m with a range of 3.4 to
93.6 mg/cu m for painting areas; 5.9 mg/cu m for car repair shops; and 8.5 mg/cu
m with a range of 0.2 to 1775 mg/cu m for various industries(1). Ethylene glycol mono-n-butyl ether was identified as a volatile emission from
used machine cutting oils in an automobile manufacturing facility in Japan(1).
Non-occupational exposures may occur among populations with contaminated
drinking water supplies(2). Because ethylene glycol mono-n-butyl ether is a
component of solvent based building materials such as silicone caulk(3), human
exposures may occur at construction sites and areas that have undergone
remodelling(SRC). Exposure of cleaning women and cleaners of cars to ethylene glycol
mono-n-butyl ether resulted in urine levels of <0.1-7.33 ppm (time-weighted
averages)(1). It was established that the predominant route of exposure to
ethylene glycol mono-n-butyl ether was through skin penetration(1). Ethylene
glycol mono-n-butyl ether was identified in air from automotive repair shops in
Sydney, Australia in 8 out of 70 samples at an average concentration of 2.0
mg/cu m(2). Emergency Medical Treatment: Emergency Medical Treatment:
Animal Toxicity Studies: Toxicity Summary: IDENTIFICATION: 2-Butoxyethanol
is a high production volume glycol ether. It is a colorless liquid that is
miscible in water and soluble in most organic solvents. 2-Butoxyethanol
is used widely as a solvent in surface coatings, such as spray lacquers, quick
dry lacquers, enamels, varnishes, varnish removers and latex paint. HUMAN
EXPOSURE: Based on limited data, ambient exposures in air are generally in the
ug/cu m range. Industrial exposure of the general population to this chemical is
most likely from inhalation and dermal absorption during the use of products
containing 2-butoxyethanol.
Levels of airborne 2-butoxyethanol
in occupational settings are typically in the mg/cu m range. The results of in
vitro studies indicate that human red blood cells are not as sensitive to the
hemolytic effects of 2-butoxyethanol
and 2-butoxyacetic acid and also that red blood cells are more sensitive to
hemolysis by 2-butoxyacetic acid than to hemolysis by 2-butoxyethanol.
ANIMAL STUDIES: 2-Butoxyethanol
is readily absorbed following inhalation, oral or dermal exposure. The chemical
is metabolized via alcohol and aldehyde dehydrogenases, with the formation of
2-butoxyacetaldehyde and 2-butoxyacetic acid, the principal metabolite, although
other metabolic pathways have also been identified. This chemical has moderate
acute toxicity and it is irritating to the eyes and skin; it is not a skin
sensitizer. The principal effect exerted by 2-butoxyethanol
and its metabolite 2-butoxyacetic acid is hematotoxicity, with the rat being the
most sensitive species. In rats, adverse effects on the central nervous system,
kidneys and liver occur at higher exposure concentrations than do the hemolytic
effects. In animals, adverse effects on reproduction and development have not
been observed at less than toxic doses. Although the results of in vitro tests
for mutagenicity of 2-butoxyethanol
were inconsistent, the absence of structural alerts and the negative findings
from in vivo studies indicate that 2-butoxyethanol
is not mutagenic. Evidence for Carcinogenicity: WEIGHT-OF-EVIDENCE CHARACTERIZATION: No reliable human epidemiological
studies are available that address the potential carcinogenicity of EGBE. ...
NTP /the National Toxicology Program/ (1988) reported no evidence of
carcinogenic activity in male F344/N rats, and equivocal evidence of
carcinogenic activity in female F344/N rats on the basis of increased combined
incidences of benign and malignant pheochromocytoma (mainly benign) of the
adrenal medulla. They also reported some evidence of carcinogenic activity in
male B6C3F1 mice on the basis of increased incidences of hemangiosarcoma of the
liver, and some evidence of carcinoma (mainly papilloma). ... because of the
uncertain relevance of these tumor increases to humans, the fact that EGBE is
generally negative in genotoxic tests and the lack of human data to support the
findings in rodents, the human carcinogenic potential of EGBE, in accordance
with the recently proposed Guidelines for Carcinogen Risk Assessment (USEPA,
1996), cannot be determined at this time, but suggestive evidence exists from
rodent studies. Under existing EPA guidelines (USEPA, 1986), EGBE is judged to
be a possible human carcinogen, Group C. HUMAN CARCINOGENICITY DATA: There are
currently no human epidemiological studies addressing the potential
carcinogenicity of EGBE. Non-Human Toxicity Excerpts: Tests of the liquid by dropping on rabbit eyes induces reddening and swelling
of the conjunctiva with slight clouding of the corneal epithelium. The degree of
injury judged 24 hours after the application of a single drop has been graded 4
on a scale of 1 to 10. Rabbit eyes in contact with the liquid for eight minutes
before irrigation with water have recovered completely in four days. ON EXCISED BEEF CORNEA ... /IT REDUCED/ ADHESION OF EPITHELIUM TO STROMA ...
. ... RATS OF DIFFERENT AGES /WERE EXPOSED/ TO VARIOUS CONCN OF VAPOR. ...
1-YR-OLD RATS WERE MORE SUSCEPTIBLE THAN YOUNG, ACTIVELY GROWING RATS. AT ...
375 PPM OLD ADULTS DIED AFTER 7 HR WHILE 6-WK-OLD RATS SURVIVED 8 HR AT 500 PPM. ... REPEATED INHALATION STUDIES ... AT HIGH CONCN, RATS EXHIBITED HEMORRHAGE
OF LUNG, CONGESTION OF VISCERA, LIVER INJURY, HEMOGLOBINURIA, & MARKED
ERYTHROCYTE FRAGILITY. FEMALES WERE MORE SENSITIVE THAN MALES. GUINEA PIGS ... AT HIGH CONCN, CONGESTION & CLOUDY SWELLING OF TUBULES OF
KIDNEYS ... BUT NO INCR IN FRAGILITY OF ERYTHROCYTES ... @ ANY CONCN STUDIED.
MICE WERE ... AS RESISTANT AS GUINEA PIGS, WITH EXCEPTION THAT THEIR
ERYTHROCYTES WERE AS FRAGILE AS THOSE OF RAT. ... RATS /WERE MAINTAINED/ ... ON DIETS CONTAINING 2.0, 0.5, 0.125, &
0.03% ... AT TOP LEVEL, GROWTH DEPRESSION & INCR KIDNEY & LIVER WEIGHTS
... AT 0.5% ... GROWTH DEPRESSION & INCR LIVER WT ... . ... 2 DOGS /WERE/ EXPOSED TO VAPOR CONCN OF 415 PPM 7 HR/DAY, 5 DAYS/WK, FOR
12 WK. ... THERE WAS INCR IN NUMBER OF CALCIUM OXALATE CRYSTALS IN URINE &
... RETENTION OF UREA IN BLOOD ... . DOGS EXPOSED TO HIGH CONCN SUFFERED CONGESTION OF KIDNEYS & LUNG, WT
LOSS, INCR FRAGILITY OF ERYTHROCYTES, NASAL & EYE INFECTIONS, APATHY,
ANOREXIA, NAUSEA, & ... CHANGES IN CIRCULATING BLOOD. LEUCOCYTES ... INCR.
WHEREAS ... HEMOGLOBIN ... DECR. ... INCR IN PLASMA FIBRINOGEN. MONKEYS EXPOSED TO 200 PPM SUFFERED MARKED REDUCTION IN NUMBER OF CIRCULATING
RED BLOOD CELLS & IN HEMOGLOBIN CONCN. ... FEMALE MONKEYS EXCRETED 309 MG OF
BUTOXYACETIC ACID OVER A 48-HR PERIOD AFTER RECEIVING THE 48-HR EXPOSURE. CHRONIC. LUNG ... SLIGHT TO MODERATE CONGESTION; SOMETIMES BRONCHOPNEUMONIA.
SPLEEN, CONGESTION & FOLLICULAR PHAGOCYTOSIS ... . ... BY INHALATION /MEDIAN LETHAL DOSE/, FOR RATS, 432 PPM 7 HR/DAY, 5 DAYS/WK
FOR 30 DAYS; FOR GUINEA PIGS, 494 PPM KILLED ONLY 2 OUT OF 10; FOR DOGS, 617 PPM
AFTER 13 1/2 HR EXPOSURES IN 2 DAYS. ACUTE. SLUGGISHNESS, ROUGH COAT,
PROSTRATION & ... /CNS DEPRESSION/ IN HIGH CONCN ... CORNEAL OR LENS
OPACITY. ACUTE. SLUGGISHNESS, ROUGH COAT, PROSTRATION & ... /SRP: CNS DEPRESSION/
IN ANIMALS DYING FROM ORAL DOSE ... IN MICE ... DYSPNEA WAS CONSTANT SIGN &
WITH HIGH CONCN ... CORNEAL OR LENS OPACITY. INHALATION (84 MG/CU M, 6 HR DAILY, 3 DAYS/WK, FOR 4 MO) CAUSED ADAPTATION IN
RATS & MICE, PROBABLY CONSISTING OF CHANGES OF ENZYME SYSTEMS OF
ERYTHROCYTES, PROTECTING HEMOGLOBIN & ERYTHROCYTE MEMBRANE FROM
PEROXIDATION. 3-HR, 6 DAYS/WK FAILED TO INDUCE ADAPTATION. HIGH DOSES OF ORALLY ADMIN ETHYLENE GLYCOL MONOALKYL ETHERS PRODUCED
TESTICULAR ATROPHY & LEUKOPENIA IN MICE. A DOSE RESPONSE RELATION WAS
OBSERVED. /ETHYLENE GLYCOL MONOALKYL ETHERS/ Fifty pregnant CD-1 mice were given 1,180 mg/kg/day of ethylene glycol
monobutyl ether in water by gavage on days 6-13 of gestation and allowed to
deliver. Ethylene glycol monobutyl ether caused 20% mortality in treated dams
but had no effect on the offspring of treated animals. The reproductive effects of ethylene glycol monomethyl ether and propylene
glycol monomethyl ether inhalation were investigated in rats. To determine the
effects on testis and hematology, male Wistar rats were exposed to 100 or 300
ppm ethylene glycol monomethyl ether or 200 or 600 ppm propylene glycol
monomethyl ether for 6 hr per day for 10 consecutive days in an inhalation
chamber. The teratogenic potential on the developing embryo was assessed by
exposing pregnant female rats to 100 or 300 ppm ethylene glycol monomethyl ether
and 200 or 600 ppm propylene glycol monomethyl ether for 6 hr per day on days 6
to 17 of gestation. Other studies investigated the teratogenic potential of
diethylene ethylene monomethyl ether in the postnatal development test, effect
on route of administration on teratogenic potential of ethylene glycol
monomethyl ether, effect of ethylene glycol monoisopropyl ether on the testis
and blood, effect of a single inhalation exposure to ethylene glycol monomethyl
ether, ethylene glycol monoisopropyl ether, ethylene glycol monomethyl ether,
and ethylene glycol monobutyl ether, and exposure of a single exposure to
ethylene glycol monomethyl ether on the testis of male rats. Ethylene glycol
monomethyl ether caused testicular atrophy at 300 ppm and showed teratogenic
potential at 100 ppm; propylene glycol monomethyl ether did not cause testicular
atrophy or affect embryonic development at 600 ppm by inhalation. Diethylene
glycol monomethyl ether showed no teratogenic potential when administered
subutaneously in rats up to 1,000 ul/kg, whereas ethylene glycol monomethyl
ether had effects at 40 ul/kg. Ethylene glycol monomethyl ether caused
testicular changes in rats after a single exposure to 600 ppm or more for 4 hr.
Ethylene glycol monoethyl ether caused a reduction in testicular weight
following a single exposure to saturated vapor of 17 mg/l for 3 hours; ethylene
glycol monoisopropyl ether at 15 mg/l and ethylene glycol monobutyl monobutyl
ether at 4 mg/l showed no effect on the testis. Previous NIOSH studies demonstrated the embryo- and fetotoxicity and
teratogenicity of ethylene glycol monoethyl ether applied to the shaved skin of
pregnant rats. In the present study ethylene glycol monoethyl ether acetate,
ethylene glycol monobutyl ether, and diethylene glycol monoethyl ether were
tested in the same experimental model, using distilled water as the negative
control and ethylene glycol monoethyl ether as a positive control. Water or
undiluted glycols were applied four times daily on days 7 to 16 gestation to the
shaved interscapular skin with automatic pipetter. Volumes of ethylene glycol
monoethyl ether (0.25 ml), ethylene glycol monoethyl ether acetate (0.35 ml),
and diethylene glycol monoethyl ether (0.35 ml) were approximately equimolar
(2.6 mmole per treatment). Ethylene glycol monobutyl ether at 0.35 ml four times
daily (approximately 2.7 mmole per treatment) killed 10 of 11 treated rats, and
was subsequently tested at 0.12 ml (0.9 mmole) per treatment. Ethylene glycol
monoethyl ether and ethylene glycol monoethyl ether acetate treated rats showed
a reduction in body weight relative to water controls that was associated with
completely resorbed litters and significantly fewer live fetuses per litter.
Visceral malformations and skeletal variations were significantly increased in
ethylene glycol monoethyl ether and ethylene glycol monoethyl ether acetate
groups over the negative control group. No embryotoxic, fetotoxic, or
teratogenic effects were detected in the ethylene glycol monobutyl ether or
diethylene glycol monoethyl ether treated litters. Mice were intubated during gestation and were evaluated for signs of
toxicity. In the teratology probe, uterine contents were examined at term. In
the postnatal study, offspring were examined and weighed through day 22
postpartum. Ethylene glycol monoethyl ether produced embryo lethality and
malformations, and decreased fetal weight at a dose level which was not
maternally toxic in the teratology probe. In the postnatal study, ethylene
glycol monoethyl ether decreased litter size and neonatal body weight; while
litter size continued to decrease beyond neonatal period, body weights of
surviving pups were not significantly different from control. Pups exposed
prenatally to ethylene glycol monoethyl ether developed kinked tail which was
not apparent in fetuses or neonates. Maternally toxic doses levels of ethylene
glycol monobutyl ether ethanol were associated with increased embryo lethality
in teratology probe studies. In postnatal studies, there were no significant
effects on pup growth or survival at maternally toxic dose levels. The
teratology probe measures resorption incidence which may be a more sensitive
index of prenatal death than number of live born. Neither fetal weight nor
neonatal weight reliably predict permanent alteration of growth. Structure activity studies with nine glycol alkyl ethers were conducted with
a cellular leukemia transplant model in male Fischer rats to measure the effects
on neoplastic progression in transplant recipients. Chemicals were given ad
libitum in the drinking water simultaneously with the transplants and continued
throughout the study. In all 20 million leukemic cells were injected sc into
syngeneic rats, which after 60 days resulted in a 10-fold increase in relative
spleen weights, a 100-fold increase in white blood cell counts, and a 50%
reduction in red blood cell indices and platelet counts. Ethylene glycol
monomethyl ether given at a dose of 2.5 mg/ml in the drinking water completely
eliminated all clinical, morphological, and histopathological evidence of
leukemia, whereas the same dose of ethylene glycol monoethyl ether reduced these
responses by about 50%. Seven of the glycol ethers were ineffective as
anti-leukemic agents, including ethylene glycol, the monopropyl, monobutyl, and
monophenyl ethylene glycol ethers, diethylene glycol, and the monomethyl and
monoethyl diethylene glycol ethers. Ethylene glycol monomethyl ether more than
double the latency period of leukemia expression and extended survival for at
least 21 days. A minimal effective dose for a 50% reduction in the leukemic
responses was 0.25 mg/ml ethylene glycol monomethyl ether in the drinking water
(15 mg/kg body weight), whereas a 10-fold higher dose of 2-ethylene glycol
monoethyl ether was required for equivalent antileukemic activity. In addition,
the in vitro exposure of a leukemic spleen mononuclear cell culture to ethylene
glycol monomethyl ether caused a dose- and time-dependent reduction in the
number of leukemia cells after a single exposure to 1-100 uM concentrations,
whereas the ethylene glycol monomethyl ether metabolite, 2-methoxyacetic acid,
was only half as effective. Studies were conducted on the percutaneous absorption, distribution,
excretion, and hemolytic activity of n-butoxyethanol.
Rats receiving a subcutaneous dose of (14)C-labeled n-butoxyethanol
excreted the radioactivity in the urine (79%), expired air (10%), and feces
(0.5%) within 72 hr. Of the organs analyzed, thymus and spleen showed elevated
specific radioactivities as compared with blood. A percutaneous application of
n-butoxyethanol on rats, under
nonocclusive conditions, showed 25-29% absorption within 48 hr. Peak blood
levels of n-butoxyethanol
occurred at 2 hr after application; butoxyacetic acid was found to be the major
metablite. Comparison of in vitro skin penetration data showed the following
absorption pattern of n-butoxyethanol:
hairless rat much greater than pig greater than human skin. Hemolysis and
associated hematological changes were noted in the rats which received single
dermal applications of 260-500 mg/kg of n-butoxyethanol.
In vitro, butoxy acetic acid showed markedly greater hemolytic ability on rat
erythrocytes than did n-butoxyethanol.
Human erythrocytes showed no hemolysis when incubated with n-butoxyethanol
or butoxy acetic acid at concentrations that are hemolytic to rat erythrocytes.
An intravenous dose of 62.5 mg/kg of n-butoxyethanol
does not result in hemolysis or hemoglobinuria in the rat. The rat may be an
animal model with increased susceptibility to the effects of n-butoxyethanol
compared with humans because of its rapid percutaneous absorptive ability and
its greater hemolytic sensitivity. 2-Butoxyethanol causes acute
hemolytic anemia in rats, and activation of 2-butoxyethanol
to butoxyacetic acid, presumably through the intermediate 2-butoxyacetaldehyde,
is a prerequisite for development of hematotoxicity. The effects of 2-butoxyethanol
and its metabolites, 2-butoxyacetaldehyde and butoxyacetic acid, on erythrocytes
from rats were investigated in vitro. At 20 mM, 2-butoxyethanol
caused hemolysis of rat erythrocytes accompanied by a decrease in hematocrit. In
contrast, incubation of 2-butoxyacetaldehyde or butoxyacetic acid with rat blood
caused time- and concentration-dependent swelling of red blood cells followed by
hemolysis; butoxyacetic acid was significantly more efficacious than
2-butoxyacetaldehyde. Addition of aldehyde dehydrogenase and its co-factors
potentiated the effect of 2-butoxyacetaldehyde on rat erythrocytes. Incubation
of rat blood with butoxyacetic acid or 2-butoxyacetaldehyde cused a time- and
concentration-dependent decrease in blood ATP concentration. The decrease in
blood ATP was greater with butoxyacetic acid than with 2-butoxycetaldehyde and
was not induced by 2-butoxyethanol.
Butoxyacetic acid caused no significant changes in the concentration of reduced
glutathione and glucose-6-phosphate dehydrogenase in rat erythrocytes. The
hemolytic effect of 2-butoxyethanol
can be attributed primarily to its metabolite butoxyacetic acid, and hemolysis
of rat erythrocytes by butoxyacetic acid or 2-butoxyacetaldehyde is preceded by
swelling and ATP depletion. Male rats were given ethylene glycol monomethyl ether or ethylne glycol
monobutyl ether per os for 4 consecutive days at doses of 100 or 500 mg/kg body
wt/day for ethylene glycol monobutyl ether, and 500 or 1000 mg/kg body wt/day
for ethylene glycol monobutyl ether. Animals were examined on days 1, 4, 8, and
22 after the final treatment. Both ethylene glycol monomethyl ether and ethylene
glycol monobutyl ether produced thymic atrophy and lymphocytopenia and, in the
case of ethylene glycol monobutyl ether, neutropenia also. Hemolytic anemia
induced by ethylene glycol monobutyl ether resulted in splenic extramedullary
hemopoiesis, hyperplasia of both spleen and bone marrow, and reticulocytosis.
Apart from residual slight increases in spleen weight, mean red cell volume, and
mean corpuscular hemoglobin at the end of the recovery period, other effects
were reversible. With ethylene glycol monomethyl ether, reduction in the numbers
of circulating red cells was only slight. Treatment with ethylene glycol
monomethyl ether also abolished splenic extramedullary hemopoiesis which
partially recovered on day 4, followed by a marked response on day 8, and return
to the control values on day 22. Femoral bone marrow was hemorrhagic 1 day after
treatment with ethylene glycol monomethyl ether which appeared to be associated
with sinus endothelial cell damage. By day 4 the histologic appearance of the
marrow was normal. Testicular atrophy was also produced in ethylene glycol
monomethyl ether-treated animals. Ethylene glycol monomethyl ether and ethylene
glycol monobutyl ether differ considerably in the spectrum of toxic changes
induced, and apart from testicular atrophy, these changes were largely
reversible within a short time of the end of treatment. Structurally related alkyl glycol ethers were examined for their ability to
block junction-mediated intercellular communication. Interruption of
intercellular communication was measured in vitro by an assay that depends on
the transfer of metabolites via gap junctions, ie, metablic cooperation. All
compounds tested ethylene glycol, ethylene glycol monomethyl ether, ethylene
glycol monoethyl ether, ethylene glycol monopropyl ether, and ethylene glycol
monobutyl ether were able to block metabolic cooperation in vitro. The potencies
of the compounds were inversely related to the length of the aliphatic chain,
the dose required for maximum blockage increasing as the aliphatic chain
shortened. Cytotoxicity, as measured by cell survival, was also related to the
structure of the compound, generally increasing with increased length of the
aliphatic chain. Timed-pregnant Fischer 344 rats and New Zealand White rabbits were exposed to
ethylene glycol monobutyl ether vapors by inhalation on gestational days 6
through 15 (rats) or 6 through 18 (rabbits) at concentrations of 0, 25, 50, 100
or 200 ppm. The animals were sacrificed on gestational day 21 (rats) or 29
(rabbits). In rats, exposure to 200 or 100 ppm resulted in maternal toxicity
(clinical signs, decreased body weight and weight gain, decreased absolute and
relative organ weights, decreased food and water consumption and evidence of
anemia), embryotoxicity (increased number of totally resorbed litters and
decreased number of viable implantations per litter) and fetotoxicity
(reductions in skeletal ossification). No increase in fetal malformations was
observed in any exposure group relative to controls. At 50 or 25 ppm, there was
no maternal, embryo or fetal toxicity (including malformations) in rats. In
rabbits, exposure to 200 ppm resulted in maternal toxicity (apparent
exposure-related increases in deaths and abortions, clinical signs, decreased
weight during exposure and reduced gravid uterine weight at sacrifice) and
embryotoxicity (reduced number of total and viable implantations per litter). No
treatment-related fetotoxicity was seen. No treatment-related increase in fetal
malformations or variations were seen at any exposure concentration tested.
There was no evidence of maternal, embryo, or fetal toxicity (including
malformations) at 100, 50 or 25 ppm in rabbits. Investigated the teratogenicity of five compounds. Each chemical was
vaporized and administered to pregnant rats in one to three concentrations for 7
hr/day on gestation days 7 to 15, and dams were sacrificed on day 20. At
concentrations which were apparently not maternally toxic, 2-methoxyethanol was
highly embryotoxic, producing complete resorptions at 200 ppm; increased
resorptions, reduced fetal weights and skeletal and cardiovascular defects
occured at both 100 and 50 ppm. 2-Ethoxyethyl acetate at 600 ppm induced
complete resorption of litters; 390 ppm reduced fetal weights and induced
skeletal and cardiovascular defects, but only a single defect was observed at
130 ppm. 2-Butoxyethanol
evidenced slight maternal toxicity at 200 ppm but produced no increase in
congenital defects at that concentration. Neither 2-(2-ethoxyethoxy)ethanol (100
ppm) nor 2-methylaminoethanol (150 ppm) was maternally toxic or embryotoxic.
Shorter alkyl chained glycol ethers produced greater embryotoxicity than those
having longer chains, and the ester produced effects equivalent to the ether. In F344 male rats, 2-butoxyethanol
causes severe acute hemolytic anemia resulting in significant increase in the
concentration of free plasma hemoglobin. Secondary to the hemolytic effects, 2-butoxyethanol
also caused hemoglobinuria as well as histopathologic changes in the liver and
kidney. The hemolytic effects of 2-butoxyethanol
were age dependent with older rats being more sensitive than younger rats. There
was a higher portion of the administered dose eliminated as carbon dioxide a
higher portion of the administered dose was excreted in the urine of young rats.
Analysis of the urinary metabolites showed that the ratio of butoxyacetic acid
2-butoxyethanol glucuronide +
2-butoxyethanol
sulfate (previously thought to reflect an activation/detoxification index of 2-butoxyethanol)
was higher in old rats. The increase in the activation/detoxification index in
older rats is caused by decreased degradation of butoxyacetic acid to carbon
dioxide and by depressed urinary excretion of butoxyacetic acid in the urine of
older rats. 2-Butoxyethanol given orally
to mice for 5 weeks at a dose of 1000 mg/kg produced no change in absolute or
relative testis weights. Exposure of pregnant rats at 100 ppm or rabbits at 200 ppm during
organogenisis resulted in maternal toxicity and embryotoxicity, including a
decrease number of viable implantations per litter. Slight fetotoxicity in the
form of poorly ossified or unossified skeletal elements was also observed in
rats. Teratogenic effects were not observed in either species. ... ... Conclusions: Under the conditions of these 2 yr inhalation studies,
there was no evidence of carcinogenic activity of 2-butoxyethanol
in male F344/N rats exposed to 31.2, 62.5 or 125 ppm. There was equivocal
evidence of carcinogenic activity of 2-butoxyethanol
in female F344/N rats based on incr incidences of benign or malignant
pheochromocytoma (mainly benign) of the adrenal medulla. There was some evidence
of carcinogenic activity of 2-butoxyethanol
in male B6C3F1 mice based on incr incidences of hemangiosarcoma of the liver.
... There was some evidence of carcinogenic activity of 2-butoxyethanol
in female B6C3F1 mice based on incr incidences of forestomach squamous cell
papilloma or carcinoma (mainly papilloma). National Toxicology Program Studies: ... 2 Year Study in Rats: Groups of 50 male and 50 female F344/N rats were
exposed to 2-butoxyethanol by
inhalation at concn of 0, 31.2, 62.5 or 125 ppm 6 hr/day, 5 days per week for
104 weeks. ... 2 Year Study in Mice: Groups of 50 male and 50 female B6C3F1 mice
were exposed to 2-butoxyethanol
by inhalation at concn of 0, 62.5, 125 or 250 ppm 6 hr/day 5 days per week for
104 weeks. ... Conclusions: Under the conditions of these 2 yr inhalation
studies, there was no evidence of carcinogenic activity of 2-butoxyethanol
in male F344/N rats exposed to 31.2, 62.5 or 125 ppm. There was equivocal
evidence of carcinogenic activity of 2-butoxyethanol
in female F344/N rats based on incr incidences of benign or malignant
pheochromocytoma (mainly benign) of the adrenal medulla. There was some evidence
of carcinogenic activity of 2-butoxyethanol
in male B6C3F1 mice based on incr incidences of hemangiosarcoma of the liver.
... There was some evidence of carcinogenic activity of 2-butoxyethanol
in female B6C3F1 mice based on incr incidences of forestomach squamous cell
papilloma or carcinoma (mainly papilloma). Non-Human Toxicity Values: LD50 Rat oral 1.48 g/kg LD50 Mouse oral 1.2 g/kg LD50 Rabbit oral 0.32 g/kg LD50 Guinea pig oral 1.2 g/kg LD50 Rabbit dermal 400 mg/kg Ecotoxicity Values: LC50 Lepomis macrochirus 1490 ppm/96 hr. (Static bioassay in fresh water at
23 deg C, mild aeration applied after 24 hr). LC50 Menidia beryllina 1250 ppm/96 hr (static bioassay in synthetic seawater
at 23 deg C, mild aeration applied after 24 hr). LC50 Crangon crangon (brown shrimp) 800 mg/l/48 hr (range: 600-1000 mg/l).
/Conditions of bioassay not specified/ LC50 Poecilia reticulata (guppy) 983 ppm/7 day. /Conditions of bioassay not
specified/ TSCA Test Submissions: Teratogenicity was evaluated in mated Fischer 344 rats (30/group) exposed by
inhalation to ethylene glycol mono-butyl ether (EGBE) at nominal concentrations
(number of pregnant rats) of 0 (21), 100 (21), 200 (16) or 300 (24) ppm on
gestation days (GD) 6-15 for 6 hrs/day. The rats were sacrificed on GD 21. There
were significant differences observed between pregnant treated and control
animals in the following: decreased maternal body weight gain and decrease in
food consumption (all treated groups during exposure), increased food
consumption (200 and 300 ppm groups, post-exposure), decreased water consumption
(200 and 300 ppm, exposure period), decreased uterine and liver absolute weights
(300 ppm), increased non-viable implantations and percent pre-implantation loss
and decreased viable implantations and percent live implantations (300 ppm),
increased incidence of ventricular septal defect, and absent and severely
shortened innominate artery (300 ppm). There were no significant differences
observed between pregnant treated and control animals in the following:
post-exposure water consumption, weights of thymus and spleen, relative weights
of uterus and liver, numbers of corpora lutea, and total implantations. Teratogenicity was evaluated in pregnant Fischer 344 rats (36/group) exposed
by inhalation to ethylene glycol mono-butyl ether (EGBE) at nominal
concentrations of 0, 25, 50, 100 or 200 ppm on gestation days (GD) 6-15. The
rats were sacrificed on GD 21. There were significant differences observed
between treated and control animals in the following: increase in number of
totally resorbed litters (200 ppm group), increased incidence of clinical
observations including cold and pale extremities, abnormal tails, fur and
urogenital areas stained, urogenital wetness and encrustation, occult blood (200
ppm), periocular wetness and perinasal encrustation (100 and 200 ppm), decreased
body weight (200 ppm), decreased body weight gain (100 and 200 ppm, exposure
period, 200 ppm post-exposure period also), decreased food consumption (100 and
200 ppm, exposure period), increased water consumption (100 ppm, post-exposure),
decreased gravid uterine weight and increased relative and absolute spleen and
relative kidney weights (200 ppm), decreased red blood cell count and mean
corpuscular hemoglobin volume and increased mean corpuscular volume and
corpuscular hemoglobin level (100 and 200 ppm), increased hemoglobin and
hematocrit levels (200 ppm), decreased viable implants and percent live fetuses
and increased non-viable implants and embryonic resorptions (200 ppm), increased
number of litters with 1 or more cases of unossified skeletal elements (100 and
200 ppm) including anterior arch of the atlas and cervical centra, cervical
arches, sternebrae, and proximal phalanges (200 ppm), unossified cervical
centrum (100 ppm), and decreased incidence of bilobed cervical centrum 5 (100
and 200 ppm). There were no significant differences observed between treated and
control animals in the following: pregnancy rates, early deliveries, dead
fetuses, liver and thymus and absolute kidney weights, numbers of corpora lutea,
total implants, dead fetuses, pre-implantation loss, fetal sex ratio, mean
litter weight, external, visceral, skeletal or total malformations. Teratogenicity was evaluated in pregnant New Zealand white rabbits (24/group)
exposed by inhalation to ethylene glycol mono-butyl ether (EGBE) at nominal
concentrations of 0, 25, 50, 100 or 200 ppm on gestation days (GD) 6-18. The
rats were sacrificed on GD 29. There were significant differences observed
between treated and control animals in the following: decreased maternal body
weight (200 ppm group on GD 15), increased hemoglobin and hematocrit levels (100
ppm group), decreased gravid uterine weight (200 ppm), reduced number of total
implants and viable implants/litter (200 ppm), increased number of litters with
fusion of papillary muscles in left ventricle (100 ppm), and reduced
ossification of sternebra 6 and rudimentary rib (200 ppm). There were no
significant differences observed between treated and control animals in the
following: maternal mortality, number of spontaneous abortions, pregnancy rates,
maternal body weight gain, number of non-viable implants, pre-implantation
losses, percent live fetuses, sex ratio, fetal body weights/litter, and number
of fetuses or of litters with one or more affected fetuses with pooled external,
visceral, skeletal or total malformations. Acute oral toxicity was evaluated in 4 groups of 10 male albino rats (Wistar
strain) administered PolySolv EB (ethylene glycol mono-n-butyl ether) by gavage
at 0.67, 1.31, 2.56 and 5.0 g/kg dose levels. Mortality was observed within 14
days of dosing in 3 rats at the 1.31 g/kg dose level, 8 rats at the 2.56 g/kg
dose level and all rats at the 5.0 g/kg dose level. The LD50 was calculated to
be 1.59 g/kg with 95% confidence limits of 1.11 - 2.27 g/kg. Clinical
observations include piloerection and lethargy at the 1.31 and 2.56 g/kg dose
levels, flaccidity at the 2.56 g/kg dose level, and ataxia at the 5.0 g/kg dose
level. Gross necropsy revealed dark liver and kidney in 3, and enlarged kidney
in 4 rats at the 1.31 g/kg dose level; red intestine in 1 and blood in the
bladder in all rats at the 2.56 g/kg dose level; blood in the bladder in all
rats at the 5.0 g/kg dose level. Acute oral toxicity was evaluated using 5 groups of 5 Charles River COBS male
rats administered ethlyene glycol mono-n-butyl ether by gavage (dose levels not
reported). Mortality occurred within 14 days after dosing, but the LD50 value
was not reported. Clinical observations included inactivity, labored breathing,
rapid respiration, anorexia, slight to moderate weakness, tremors and
prostration. Gross necropsy of animals dying within 14 days of dosing revealed
bloody urine, and blood in the stomach and intestine. These conditions were not
observed in animals surviving through 14 days. Acute oral toxicity was evaluated using 5 groups of 5 Charles River COBS CD-1
male mice administered ethlyene glycol mono-n-butyl ether by gavage (dose levels
not reported). Mortality occurred within 14 days after dosing, but the LD50
value was not reported. Clinical observations included inactivity, labored
breathing, rapid respiration, anorexia, slight to moderate weakness, tremors and
prostration. Gross necropsy of animals dying within 14 days of dosing revealed
bloody urine and blood in the stomach and intestines. These conditions were not
observed in animals surviving through 14 days. Acute oral toxicity was evaluated using 5 groups of 5 Charles River COBS male
rats administered ethlyene glycol mono-n-butyl ether by gavage (dose levels not
reported). Mortality occurred within 14 days after dosing, but the LD50 value
was not reported. Clinical observations included inactivity, labored breathing,
rapid respiration, anorexia, slight to moderate weakness, tremors and
prostration. Gross necropsy of animals dying within 14 days of dosing revealed
bloody urine, and blood in the stomach and intestine. These conditions were not
observed in animals surviving through 14 days. Acute oral toxicity was evaluated using 5 groups of 5 Charles River COBS CD-1
male mice administered ethlyene glycol mono-n-butyl ether by gavage (dose levels
not reported). Mortality occurred within 14 days after dosing, but the LD50
value was not reported. Clinical observations included inactivity, labored
breathing, rapid respiration, anorexia, slight to moderate weakness, tremors and
prostration. Gross necropsy of animals dying within 14 days of dosing revealed
bloody urine and blood in the stomach and intestines. These conditions were not
observed in animals surviving through 14 days. Acute oral toxicity was evaluated in groups of male and female Sherman rats
(total number not reported) administered single doses of a 10% water dilution of
butyl Cellosolve (ethylene
glycol mono-n-butyl ether) by gavage (number of dose levels not reported).
Mortality was observed within 14 days of dosing. The oral LD50 value for males
was calculated (using Thompson's method) to be 2.9 g/kg, and for females, 2.3
g/kg. Clinical observations included sluggishness, rough coat, prostration and
narcosis. Gross necropsy revealed congested or hemorrhagic lungs, mottled liver,
congested kidneys and bloody urine. Acute oral toxicity was evaluated in groups of 5 rats (sex and strain not
reported) administered single doses (method of administration not reported) of
ethylene glycol n-butyl ester ether at dose levels of 0.252, 0.5, and 1.0 g/kg.
Mortality was observed within 4 days of dosing in 3 animals at 0.5 g/kg and 2 at
1.0 mg/kg; the LD50 was 0.47 g/kg. Clinical observations included drowsiness and
blood in the urine. Gross necropsy findings were not reported. Acute oral toxicity was evaluated in groups of 5 male Wistar rats
administered single doses of butyl oxide by oral gavage at dose levels of 1.25,
2.50, 5.0, and 10.0 ml/kg of body weight. Mortality was observed within 1 day of
dosing in 2 animals of the 2.50 ml/kg group, and in 5 rats of each of the 5.0
and 10.0 ml/kg groups; the LD50 was 2.68 ml/kg of body weight. Clinical
observations included bloody saliva, sluggishness, difficult breathing and an
unsteady gait. Gross necropsy revealed dark livers, stomach distention, red
kidneys and adrenals, and blood was found in the intestines. Acute oral toxicity was evaluated in 5 groups of 3 female CDF Fischer-344
rats receiving ethylene glycol mono-n-butyl ether by oral gavage at dose levels
of 130, 250, 300, 500, 1000, or 2000 mg/kg. Mortality was observed at the 2
highest dose levels. The oral LD50 ranged from 1000 and 2000 mg/kg. Clinical
observations included staining of perineal region, rough hair coat, lethargy,
rapid shallow breathing and palpebral closure. Gross necropsy findings were not
reported. Acute dermal toxicity was evaluated in 4 groups of 4 New Zealand white
rabbits (sex not reported) administered single doses of PolySolv EB (ethylene
glycol mono-n-butyl ether) on clipped and abraded skin at dose levels of 0.25,
0.5, 1.0 and 2.0 g/kg. Mortalities were observed winthin 14 days of dosing in
0/4 rabbits at dose level 0.25 g/kg, 1/4 rabbits at the 0.5 g/kg dose level, and
all animals at the two highest dose levels. The Litchfield and Wilcoxon LD50 was
calculated to be 0.58 g/kg with 95% confidence limits of 0.31 and 0.85 g/kg.
Clinical observations include blood in the urine, yellow cornea, flaccidity,
lacrimation and anorexia. Gross necropsy revealed blood in the bladder, as well
as discolored liver, kidney and intestines. Acute dermal toxicity was evaluated in rabbits (number, sex distribution and
strain not reported) administered single doses (dose levels not reported) of 2-butoxyethanol
by open application. The LD50 was 2.0 mL/kg (specific mortalities, clinical
observations and gross necropsy not reported). Acute dermal toxicity was evaluated in rabbits (sex and strain not reported)
receiving dermal applications of ethylene glycol mono-n-butyl ether at dose
levels of 0.2 g/kg (group of 10) or 0.252 g/kg (group of 4). Mortality was
observed within 2 to 7 days of dosing in 4 animals of the 0.252 g/kg group. No
mortalities were observed at the 0.2 g/kg dose level. A dermal LD50 was not
reported. Clinical observations included slight initial weight loss and slight
to moderate irritation of the skin at both dose levels. Gross necropsy results
were not reported. Acute dermal toxicity was evaluated in groups of 4 male New Zealand white
rabbits receiving single applications of butyl oxide to clipped intact skin of
the trunk at dose levels of 0.5 and 1.0 ml/kg body weight. Mortality was
observed within 1 to 2 days of dosing in 1 animal of the 0.5 ml/kg group and in
all animals exposed to 1.0 ml/kg body weight. The LD50 was 0.630 ml/kg body
weight (95% confidence limit = 0.386 to 1.03 ml/kg). Erythema and necrosis were
noted in the high dose groups. Gross necropsy revealed included blood in the
urine, orange-red colored lungs and livers, dark colored spleens, dark red
kidneys, orange colored peritoneal and intestines. An acute inhalation toxicity study was conducted with groups of male and
female albino Wistar rats (3/sex/group) receiving whole body exposure to the
vapors of ethylene glycol monobutyl ether in a dynamic air flow chamber. The
vapor was generated in a glass flask containing the test substance maintained at
20 +/- 1 degrees celsius. Maximum exposure was for 7 hours, but if deaths
occurred during either the exposure period or observation period, exposures were
repeated at shorter intervals. During the 7 hour exposure, no animals died, but
3 females and 1 male animals died between day 1 and day 3 of the 14 day
observation period. Therefore the test was repeated, and two additional test
were performed at exposure times of 1 and 3 hours. No deaths were reported for
the 1 hour group rats and only one 3 hour exposed female animal died on the day
1 of the observation period. Post exposure observations were lethargy (7 & 3
hour group rats), blood in urine (all exposures), piloerection (7 & 3 hour),
paleness of eyes and feet (all exposures) and necrosis at the ends of the tail
(7 hour). Seven hour group males appeared to recover by day 11; 3 hour males by
day 1 and females by days 6-8; and 1 hour males by day 1 and females by day 2.
The theoretical saturated concentration of ethylene glycol monobutyl ether at 20
degrees celsius was calculated to be 617ppm and the concentrations by weight
loss estimation were calculated to be 769, 771 and 828ppm for the 7, 3 and 1
hour exposure, respectively. Acute 7-hour inhalation toxicity of different industrial formulations of
ethylene glycol monobutyl ether (Dowanol EB, n-butyl
oxitol - USA (BO-USA), and n-butyl
oxitol - Europe (BO-Europe) was evaluated in 3 groups of 4 male
albino rabbits (strain not reported) exposed to the nominal concentration of 410
ppm. A fourth group served as negative control. A 1-week observation period
followed exposure. The number dead or moribund by group were 3, 1, and 4 in the Dowanol
EB, BO-USA, and BO-Europe groups, respectively. Clinical signs
reported were poor coordination and loss of equilibrium. Changes in body weight
and necropsy results were not reported. Acute 7-hour inhalation toxicity of different industrial formulations of
ethylene glycol monobutyl ether (Dowanol EB, n-butyl
oxitol - USA (BO-USA), and n-butyl
oxitol - Europe (BO-Europe) was evaluated in 3 groups of 2 male
beagle dogs exposed to the nominal concentration of 410 ppm. A fourth group
served as negative control. A 1-week observation period followed exposure. No
dogs died. The only clinical sign reported was salivation during exposure. No
body weight changes are mentioned. No animals were sacrificed for necropsy. Acute 7-hour inhalation toxicity of different industrial formulations of
ethylene glycol monobutyl ether (Dowanol EB, n-butyl
oxitol - USA (BO-USA), and n-butyl
oxitol - Europe (BO-Europe) was evaluated in 3 groups of 8 male
guinea pigs (strain not reported) exposed to 410 ppm (nominal). A fourth group
served as negative control. A 1-week observation period followed exposure. No
mortalities were observed. Clinical signs, changes in body weight, and necropsy
results are not reported. Acute toxicity was evaluated in groups of 4 female Sprague-Dawley rats
receiving a single intraperitoneal injection of n-butyl Oxidol or Dowanol
EB Glycol Ether (ethylene glycol monobutyl ether) at dose levels
of 200, 252, 316, or 398 mg/kg bw, then observed for two weeks. The LD50 was
252-317 mg/kg bw. All treated rats had bloody urine and nasal porphryin
secretion; those treated with the two higher doses of n-butyl Oxidol also
displayed tremors. Surviving rats gained weight throughout the recovery period.
The authors concluded that both types of ethylene glycol monobutyl ether have
similar toxicity when injected intraperitoneally in rats. The effects of ethylene glycol butyl ether (EGBE) at concentration of 0.05,
0.1, 0.25, 0.4, and 0.5% on in vitro human erythrocyte fragility was evaluated
employing 0.68% sodium chloride and 37 degrees C incubation. Hemolytic activity
was reported to be 1.5, 20.5 and 70.9% at EGBE concentrations of 0.25, 0.4 and
0.5% respectively. This activity was compared to the hemolysis activity of rat,
rabbit and dog erythrocytes under the same conditions. Rat hemolytic activity
was reported to be 2.5, 51.5 and 62.0% and rabbit activity was 2.8, 83.7, and
72.0% at EGBE concentrations of 0.25, 0.4 and 0.5% respectively. Dog hemolytic
activity was 46.8, 36.2, 41.2 and 62.3% at EGBE concentrations of 0.05, 0.1,
0.4, and 0.5% respectively. Subchronic toxicity was evaluated in groups of 10 male Charles River COBS
albino rats receiving once daily oral gavage doses of undiluted ethylene glycol
monobutyl ether at dose levels of 222, 443, or 885 mg/kg body weight/day, 5 days
a week for 6 weeks. Mortality was observed in 2 high dose group rats and 1
middle dose group rat during the treatment period. Clinical observations
included lethargy, and red discolored urine. A dose dependent decrease in body
weight gain observed throughout the treatment period was only statistically
significant (ANOVA, p < 0.05) at the high dose level. Effects on
hematological parameters included a dose dependent decrease in hemoglobin
concentration, red blood cell count, and mean corpuscular hemoglobin
concentrations (MCHC); hemoglobin concentrations and red blood cell counts were
reduced (p < 0.05) at all doses, while MCHC was lower (p < 0.05) than
control at the middle and high dose levels. Mean corpuscular volume (MCV) and
mean corpuscular hemoglobin (MCH) showed a dose-dependent increase which was
significant (p < 0.05) at all levels for MCH and at the middle and high dose
levels for MCV. Slight but significant (p < 0.05) increases were seen in
serum glutamic pyruvic transaminase in the high dose group, and alkaline
phosphatase was significantly increased in the middle and high dose groups.
Relative liver weights were increased (p < 0.05) at all dose levels, while
relative weights of the kidneys, heart, brain and spleen were increased in the
middle and high dose groups. Gross necropsy examination revealed darkened,
enlarged spleens in the middle and high dose groups. Treatment related
histopathology included hepatocytomegaly (in the high dose group); focal
hemosiderin in livers (high and mid groups); and hyalin droplet degeneration,
splenic congestion, minor hemosiderin accumulation in the proximal convoluted
tubules of the kidney, hyperkeratosis and acanthosis in the stomach (in all
groups). Subchronic oral toxicity was evaluated in 4 groups of 10 male rats (strain
not reported) administered ethylene glycol monobutyl ether by gavage at dose
levels of 0, 222, 443 and 885 mg/kg/day for 5 days/week over 6 weeks.
Mortalities included 2 rats at the 885 mg/kg/day dose level and 1 rat at the 443
mg/kg/day level. Clinical observations included lethargy at the 443 and 885
mg/kg/day treatment levels, as well as rough coat and piloerection at the 885
mg/kg/day dose level. A dose-related weight reduction was observed, but reduced
food consumption was significant (statistical test and significance level not
reported) only at the 885 mg/kg/day dose level. Dose-related decreases in red
blood cell count and in hemoglobin concentration were observed. Elevated liver
weights, increased serum alkaline phosphatase concentration (443, 885 mg/kg/day)
and increased serum glutamic pyruvic transaminase concentration (885 mg/kg/day)
were observed. Serum glucose was reduced in rats at the 885 mg/kg/day treatment
level. Gross necropsy revealed enlarged dark spleens at the 443 and 885
mg/kg/day treatment levels. Histopathological evaluation revealed
hepatocytomegally and focal hemosiderin in the liver at the two highest dose
levels, as well as hemosiderin in the kidney, splenic congestion, and
hyperkeratosis and acanthosis in the stomach at all dose levels. Urinalysis was
not reported. Subchronic oral toxicity was evaluated in 3 groups of 10 male albino Charles
River rats administered diethylene glycol monomethyl ether by gavage at dose
levels equivalent to 1/2, 1/4 and 1/8 of the acute LD50 (actual dose levels not
reported) 5 days/week for 6 weeks. An additional group of 10 untreated rats was
used as a negative control. Compound-related mortality was not observed. The
only clinical sign of toxicity was bloody urine and blood around the nares in
one rat at the highest dose level. Significant (p < 0.05) weight loss was
observed only in rats at the highest treatment level. No treatment-related
hematological or clinical biochemistry effects were reported. Reduction in
relative testis weight was observed in rats at the highest dose level. Gross
necropsy revealed no abnormalities in treated rats, but histopathologic
examination revealed testicular atrophy. Subchronic toxicity was evaluated in groups of 10 male albino rats (CR, COBS,
CD, BR) given doses of ethylene glycol mono-n-butyl ether equivalent to 0, 1/2,
1/4 or 1/8 of the acute oral LD50 for the test compound in rats (more specific
information regarding doses was not reported), by oral gavage, 5 days/week for
six weeks. No effect was noted on mortality. Food consumption and body weights
were reduced only in rats from the high-dose group. Dose-related effects were
seen on hematological parameters, but not serum chemistry. Relative spleen
weights increased in rats from the mid- and high-dose groups, liver weights
increased in rats from the high-dose group and smaller than normal thymuses were
observed in two rats from the high-dose group. Rats given mid- or high-dose
levels had bloody urine, lethargy, unkempt hair coats, piloerection, rales,
slight weakness and inactivity. Diffuse hemorrhage of the thymus was observed in
one high-dose rat. Rats given the test compound (response to specific dose
levels was not reported) had hepatocytomegally, anisokaryosis, and lack of
cytoplasmic basophilia in livers, and congestion and extramedullary
hematopoiesis in spleens. Subchronic toxicity was evaluated in groups of 10 male albino rats (CR, COBS,
CD, BR) given doses of ethylene glycol mono-n-butyl ether equivalent to 0, 1/2,
1/4 or 1/8 of the acute oral LD50 for the test compound in rats (more specific
information regarding doses was not reported), by oral gavage, 5 days/week for
six weeks. No effect was noted on mortality. Food consumption and body weights
were reduced only in rats from the high-dose group. Mean hemoglobin
concentration and total erythrocyte count were reduced, and mean corpuscular
hemoglobin was increased, in rats from all treatment groups. Rats from the mid-
and high-dose groups had increased in mean corpuscular volume and decreased mean
corpuscular hemoglobin concentration. Treatment did not alter serum chemistry.
Relative spleen weights increased in rats from the mid- and high-dose groups,
and liver weights increased and smaller than normal thymuses were observed in
rats from the high-dose group. Rats given mid- or high-dose levels had bloody
urine, lethargy, unkempt hair coats, piloerection, rales, slight weakness and
inactivity. Diffuse hemorrhage of the thymus was observed in one high-dose
animal. Rats given the test compound (response to specific dose levels was not
reported) had hepatocytomegally, anisokaryosis, and lack of cytoplasmic
basophilia in livers, and congestion and extramedullary hematopoiesis in
spleens. Subchronic dermal toxicity was evaluated in groups of 20 New Zealand White
rabbits (10 male and 10 female) receiving occluded applications of ethylene
glycol monobutyl ether at doses of 10, 50 or 150 mg/kg body weight, 5 days/week
for 13 weeks. Mortality was observed in 1 low dose group female, 1 mid dose and
1 high dose group male during the treatment period. Clinical observations
included red feces, red liquid material on cage lining, anorexia, congestion,
nasal discharge, and emaciation. Slight to moderate erythema and edema, along
with scaling and flaking were observed at the treatment site. Treatment related
changes in food consumption, body weights, or organ to body weight ratios were
not observed at any dose level. Additionally, the test article did not induce
changes in hematology, or in serum chemistry parameters. Treatment related
pathological effects were not observed on gross or microscopic examination of
the adrenals, aorta bone, brain, epidymis, esophagus, eyes, gall bladder, heart,
intestines, kidneys, liver, lung, lymph node, mammary gland, ovaries, pancreas,
parathyroids, pituitary, prostate, sciatic nerve, seminal vesicles, skeletal
muscle, spleen, stomach, submandibular salivary gland, testes, thyroids, thymus,
tongue, trachea, urinary bladder, uterus, or vagina. Subchronic toxicity was evaluated in 3 female and 3 male New Zealand White
rabbits exposed to unoccluded doses of diethylene glycol butyl ether as a 1.5%
solution in distilled water at a level of 2.0 mg/kg/day for 28 days. There were
no mortalities. Clinical observations included slight dermal reaction. Necropsy
revealed compound-related abberations in none of the treated animals. Subchronic dermal toxicity was evaluated in 5 groups of 10 New Zealand White
rabbits (1:1 sex ratio/group) exposed dermally under occlusive patches to 2-butoxyethanol
at nominal dose levels of 0, 0.02, 0.1, 0.2, and 0.4 ml/kg for 6 hours/day, on 9
of 11 consecutive days. Residual test compound was removed with absorbant
material, but not washed off, after each exposure. Animals were sacrificed after
a 14-day observation period. No treatment-related mortality or ophthalmologic
effects were observed. Dose-related progressive erythema, edema, and necrosis
were observed at the site of application. Both hemoglobinuria and proteinuria
were observed at the 2 highest dose levels, and both were reversible after
cessation of dosing. Both reduced red blood cell count and a decrease over time
of urinary hemoglobin were observed in the highest dose group. No
treatment-related changes were observed in clinical chemistry, body weight,
organ weight, or histopathologic data. A gross thickening of the skin at the
site of treatment was observed. Subchronic dermal toxicity was evaluated in 4 groups of 20 New Zealand White
rabbits (1:1 sex ratio per group) dermally exposed to 0, 10, 50, and 150 mg/kg,
respectively. Rabbits were dosed under an occlusive dressing for 6 hours/day, 5
days/week, over a 90-day period. It was not reported whether the site of
application was washed after each 6-hour dosing. No treatment-related changes in
mortality, clinical signs, food consumption rate, body weight, hematological
parameters, serum chemistry, organ weights, gross pathological parameters, or
histopathological parameters were observed. Subchronic dermal toxicity was evaluated in groups of 5 male and 5 female New
Zealand White rabbits receiving daily dermal (occluded) applications of 1 ml/day
of 0, 5, 25, 50, or 100% concentrations of butyl
CELLOSOLVE for a total of 9 applications over an 11-day period.
There were no treatment-related mortalities. Clinical observations included
dermal irritation (necrosis, edema, and erythema). Females in the 100%
(undiluted) butyl CELLOSOLVE group
displayed significantly reduced (p < 0.05) body weights. Hematological
examination revealed significant (p < 0.05) reductions in the mean
erythrocyte counts, hemoglobin, and mean corpuscular hemoglobin concentrations
and increased mean corpuscular hemoglobin in females administered the undiluted
material. Urinalysis revealed hemoglobin in the urine (males at 100%), increased
urinary protein levels (males and females at 100%), and the presence of blood
(females at 50 and 100%). Clinical biochemical anlaysis was not reported. Gross
necropsy findings included thickening of the skin of males at 100%. There were
no treatment-related organ/body weight changes. Histopathological examination of
the kidneys revealed interstitial nephritis and tubular changes in rabbits
exposed to the undiluted material. Subchronic inhalation toxicity was evaluated in 4 groups of Fischer 344 rats
exposed by inhalation to ethylene glycol monomethyl ether (butyl
CELLOSOLVE) at air concentrations of 0 ppm (15 female, 16 male),
20 ppm (8 female, 8 male), 86 ppm (8 female, 8 male), and 245 ppm (15 female, 16
male), respectively, for 6 hours/day for 9 days. Rats were sacrificed either
shortly after the final exposure or after a 14-day observation period. No
mortalities were observed. Audible respiration, nasal discharge, and red-stained
urine were seen in the highest exposure group. Transient body weight gain
decreases occurred in the 2 highest exposure groups. Increases were observed in
the 245 ppm group in mean corpuscular volume, nucleated red cells, reticulocytes
and lymphocytes (males only), and decreases were seen in erythrocyte count,
hemoglobin, and mean corpuscular hemoglobin concentration. Groups exposed to 86
ppm showed an increase in mean corpuscular volume and a decrease in hemoglobin.
After the 14-day observation period, only the leukocyte count recovered to
control levels. The mean liver/body weight ratio was elevated in females and
males of the 2 highest and in the highest exposure groups, respectively. The
incidence of gross lesions was not treatment-related. Evaluations of treatment
effects on urinalysis, clinical chemistry, and histopathology were not reported. Subchronic inhalation toxicity was evaluated in 4 groups of 32 Fischer 344
rats (1:1 sex ratio per group) exposed by inhalation to ethylene glycol
monomethyl ether (butyl CELLOSOLVE) at
air concentrations of 0, 5, 25, and 77 ppm for 6 hours/day, 5 days/week over 13
weeks. An interim sacrifice of 6 rats of each sex was executed after 30
exposures. No treatment-related effects were observed in male rats at any
exposure level, with respect to mortality, clinical signs (via the Irwin Screen
Test), mean body weight, food consumption rate, clinical chemistry, urinalysis,
hematology, gross necropsy, and histopathology. Females in the highest exposure
group exhibited a transitory depression of weight gain in the first weeks of
exposure, as well as minimal reductions in red blood cell count, hemoglobin, and
hematocrit. No other treatment-related effects were observed in the females. Hemolysis was evaluated in vitro with human erythrocytes (suspended in
veronal buffered isotonic saline) exposed to ethylene glycol butyl ether (EGBE)
for 1 hour. The percent hemolysis for 0.1, 0.25, 0.4, or 0.5% EGBE was 0, 1.5,
20.5, and 70.9%, respectively. Hemolysis was evaluated in vitro with rat erythrocytes (suspended in veronal
buffered isotonic saline) exposed to ethylene glycol butyl ether (EGBE) for 1
hour. The percent hemolysis for 0.1, 0.25, 0.3, 0.4, and 0.5% EGBE was 0, 2.5,
0, 51.5, and 62%, respectively. Hemolysis was evaluated in vitro with dog erythrocytes (suspended in veronal
buffered isotonic saline) exposed to ethylene glycol butyl ether (EGBE) for 1
hour. The percent hemolysis for 0.05, 0.1, 0.4, and 0.5% EGBE was 46.8, 36.2,
41.2, and 62.3%, respectively. Hemolysis was evaluated in vitro with rabbit erythrocytes (suspended in
veronal buffered isotonic saline) exposed to ethylene glycol butyl ether (EGBE)
for 1 hour. The percent hemolysis for 0.1, 0.25, 0.4, or 0.5% EGBE was 0, 2.8,
83.7, and 72.0%, respectively. In an absorption study, the permeability of human abdominal skin to 2-butoxyethanol
was measured in vitro using Franz-type glass diffusion cells. Epidermal layers
from human skin were exposed for 8 hours to a solution containing radiolabeled
test compound in the donor chamber and the appearance of radioactivity was
measured in the receptor chamber. Damage to skin was calculated by comparing the
water absorption rates of skin before and after exposure to the test compound.
The rate of absorption of the test compound across human skin was 0.20
mg/cm2/hr. Exposure to the test chemical did not alter the permeability of skin
to water. In an absorption study, the permeability of human abdominal skin to 2-butoxyethanol
was measured in vitro using Franz-type glass diffusion cells. Epidermal layers
from human skin were exposed for 8 hours to a solution containing radiolabeled
test compound in the donor chamber and the appearance of radioactivity was
measured in the receptor chamber. Damage to skin was calculated by comparing the
water absorption rates of skin before and after exposure to the test compound.
The rate of absorption of the test compound across human skin was 0.20
mg/cm2/hr. Exposure to the test chemical did not alter the permeability of skin
to water. Metabolism of Dowanol EB (ethylene
glycol mono-n-butyl ether) was evaluated in vitro with an equine liver alcohol
dehydrogenase assay obtained from the Sigma Chemical Company. The Vmax, Km, and
Vmax/Km were 4.06, 1.18X10E-3, and 3.50, respectively. The authors concluded
that alcohol dehydrogenase has a high affinity for the test compound, indicating
that the test compound is probably metabolized to a significant extent by this
enzyme in vivo. Ethylene glycol monobutyl ether (CAS# 111-76-2) was studied for reproductive
effects in 50 CD-1 mice when administered by oral gavage for 8 days at 1180
mg/kg/day on gestation days 7 through 14. Observations continued through day 3
postpartum. The dose was selected based on the results of a preliminary maximum
tolerated dose test on groups of 10 nonpregnant, female CD-1 mice using doses of
295, 590, 1180, 2365, and 4275 mg/kg administered by oral gavage for 8 days. A
water (vehicle) control group was used. The test group included 11 deaths, of
which 5 were of pregnant mice, 7 resorbed pregnancies and 24 live births.
Chi-square testing showed significant difference (p<0.01) from the control in
the reproductive index (number of females bearing viable litters per number
ofpregnant females). ANOVA testing indicated that a trend toward decreased
maternal weight and maternal weight changes were not significant and there were
no significant changes in litter sizes and litter weight changes between day 1
and day 3 postpartum. Ethylene glycol monobutyl ether (CAS# 111-76-2) was studied for reproductive
effects in 50 CD-1 mice when administered by oral gavage for 8 days at 1180
mg/kg/day on gestation days 7 through 14. Observations continued through day 3
postpartum. The dose was selected based on the results of a preliminary maximum
tolerated dose test on groups of 10 nonpregnant, female CD-1 mice using doses of
295, 590, 1180, 2365, and 4275 mg/kg/day administered by oral gavage for 8 days.
A water (vehicle) control group was used. The test group included 11 deaths of
which 5 were of pregnant mice, 7 resorbed pregnancies and 24 live births.
Chi-square testing showed significant difference (p<0.01) from the control in
the reproductive index (number of females bearing viable litters per number of
pregnant females). ANOVA testing indicated that a trend toward decreased
maternal weight and maternal weight changes were not significant and there were
no significant changes in litter sizes and litter weight changes between day 1
and day 3 postpartum. A one-generation reproductive toxicity study was conducted with groups of 25
male and 25 female Charles River COBS CD rats administered diethylene glycol
butyl ether (DGBE) in deionized water by gavage at a level of 250, 500 or 1000
mg/kg/day. Three groups of males were dosed 60 days prior to mating through to
sacrifice and 3 groups of females were dosed 14 days prior to mating, continuing
until sacrifice or weaning. Control animals received the vehicle only at a level
of 5 ml/kg/day. Treated animals were mated with untreated counterparts and about
one-half of the females in each group underwent uterine examinations on
gestation day 13. Observations of the treated F0 animals and their offspring
included the following: mortality observed in 2 low-dose females, 1 mid-dose
male and female and 3 high-dose males and females; excess salivation in
high-dose females; reduced body weights in high- dose males; reduction in mean
pup body weight during latter stages of lactation in the offspring of high-dose
females; and reduction in the mean numbers of uterine implants in high-dose
females and females paired with high-dose males. Teratogenicity was evaluated in groups of 6 pregnant CD-1 mice administered
ethylene glycol monobutyl ether by oral gavage at doses of 0, 350, 600, 1000,
1500, and 2000 mg/kg on days 8-14 of gestation. Surviving animals were
sacrificed on gestation day 18. Maternal mortality was observed in 3 mice at
1500 mg/kg and in all 6 at 2000 mg/kg. Significant reductions in maternal body
weights were observed at 1000 and 2000 mg/kg. Clinical signs of maternal
toxicity included green-brown or red-brown staining of papers beneath the cages
of animals at treatment levels 600 mg/kg and above, while at 1500 and 2000
mg/kg, animals exhibited vaginal discharge, lethargy, abnormal breathing, and
the inability of several animals to right themselves. Gross necropsy revealed
distention and enlargement of gall bladders (350, 600, 1000 and 1500 mg/kg),
enlargement of the spleen (350, 1500 and 2000 mg/kg), and distention of the
stomach and intestinal tract (1500 & 2000 mg/kg). Significant changes
between dose groups and controls were observed for total resorptions (increased
at 1000 and 1500 mg/kg), resorptions/implantation (increased at 1500 mg/kg), and
live fetuses/implantation (decreased at 1500 mg/kg). A dose-related increase in
resorptions and dead fetuses and decrease in live fetuses was observed. Cleft
palates were observed in 4/43 fetuses at 1000 mg/kg and in 1/25 at 1500 mg/kg. Reproductive toxicity was evaluated in groups of 10 pregnant Charles River CD
female mice receiving an oral gavage dose of ethylene glycol mono-n-butyl ether
at 10 ml/kg body weight on gestation days 7 through 14. Maternal mortality was
approximatedly 8% in the test group. Clinical observations and gross necropsy
results were not reported. There was a significant reduction (p<0.05) in the
number of live pups per litter, reduced survival, and reduced birth weight among
offspring of treated dams. Teratogenicity was evaluated in mated Fischer 344 rats (30/group) exposed by
inhalation to ethylene glycol mono-butyl ether (EGBE) at nominal concentrations
(number of pregnant rats) of 0 (21), 100 (21), 200 (16) or 300 (24) ppm on
gestation days (GD) 6-15 for 6 hrs/day. The rats were sacrificed on GD 21. There
were significant differences observed between pregnant treated and control
animals in the following: decreased maternal body weight gain and decrease in
food consumption (all treated groups during exposure), increased food
consumption (200 and 300 ppm groups, post-exposure), decreased water consumption
(200 and 300 ppm, exposure period), decreased uterine and liver absolute weights
(300 ppm), increased non-viable implantations and percent pre-implantation loss
and decreased viable implantations and percent live implantations (300 ppm),
increased incidence of ventricular septal defect, and absent and severely
shortened innominate artery (300 ppm). There were no significant differences
observed between pregnant treated and control animals in the following:
post-exposure water consumption, weights of thymus and spleen, relative weights
of uterus and liver, numbers of corpora lutea, and total implantations. Teratogenicity was evaluated in pregnant Fischer 344 rats (36/group) exposed
by inhalation to ethylene glycol mono-butyl ether (EGBE) at nominal
concentrations of 0, 25, 50, 100 or 200 ppm on gestation days (GD) 6-15. The
rats were sacrificed on GD 21. There were significant differences observed
between treated and control animals in the following: increase in number of
totally resorbed litters (200 ppm group), increased incidence of clinical
observations including cold and pale extremities, abnormal tails, fur and
urogenital areas stained, urogenital wetness and encrustation, occult blood (200
ppm), periocular wetness and perinasal encrustation (100 and 200 ppm), decreased
body weight (200 ppm), decreased body weight gain (100 and 200 ppm, exposure
period, 200 ppm post-exposure period also), decreased food consumption (100 and
200 ppm, exposure period), increased water consumption (100 ppm, post-exposure),
decreased gravid uterine weight and increased relative and absolute spleen and
relative kidney weights (200 ppm), decreased red blood cell count and mean
corpuscular hemoglobin volume and increased mean corpuscular volume and
corpuscular hemoglobin level (100 and 200 ppm), increased hemoglobin and
hematocrit levels (200 ppm), decreased viable implants and percent live fetuses
and increased non-viable implants and embryonic resorptions (200 ppm), increased
number of litters with 1 or more cases of unossified skeletal elements (100 and
200 ppm) including anterior arch of the atlas and cervical centra, cervical
arches, sternebrae, and proximal phalanges (200 ppm), unossified cervical
centrum (100 ppm), and decreased incidence of bilobed cervical centrum 5 (100
and 200 ppm). There were no significant differences observed between treated and
control animals in the following: pregnancy rates, early deliveries, dead
fetuses, liver and thymus and absolute kidney weights, numbers of corpora lutea,
total implants, dead fetuses, pre-implantation loss, fetal sex ratio, mean
litter weight, external, visceral, skeletal or total malformations. Teratogenicity was evaluated in pregnant New Zealand white rabbits (24/group)
exposed by inhalation to ethylene glycol mono-butyl ether (EGBE) at nominal
concentrations of 0, 25, 50, 100 or 200 ppm on gestation days (GD) 6-18. The
rats were sacrificed on GD 29. There were significant differences observed
between treated and control animals in the following: decreased maternal body
weight (200 ppm group on GD 15), increased hemoglobin and hematocrit levels (100
ppm group), decreased gravid uterine weight (200 ppm), reduced number of total
implants and viable implants/litter (200 ppm), increased number of litters with
fusion of papillary muscles in left ventricle (100 ppm), and reduced
ossification of sternebra 6 and rudimentary rib (200 ppm). There were no
significant differences observed between treated and control animals in the
following: maternal mortality, number of spontaneous abortions, pregnancy rates,
maternal body weight gain, number of non-viable implants, pre-implantation
losses, percent live fetuses, sex ratio, fetal body weights/litter, and number
of fetuses or of litters with one or more affected fetuses with pooled external,
visceral, skeletal or total malformations. An inhalation toxicity study was conducted with groups of 36 mated female
F-344 rats exposed to ethylene glycol mono-n-butyl ether at target
concentrations (analytical concentrations) of 25 (25), 50 (50), 100 (98), 200
(201), ppm on gestation days (GD) 6-15 for 6 hrs/day. The animals were
sacrificed on GD 21. Mortality was not observed. Clinical observations included
hematuria, urogenital discharge, red urogenital wetness and encrustations, pale
and cold extremities, and necrosis of the tail tip. Maternal toxicity was
evident in the high-exposure group by significant changes (p<0.001) in body
weight, body weight gain, gravid uterine weight, and food and water consumption.
Absolute and relative spleen weights and relative kidney weights were also
increased relative to controls in this group. Toxicity related hematologic
observations included significant reductions in erythrocyte count, significant
increases in hemoglobin and hematocrit, significant enlargement of red blood
cells, increase in hemoglobin per cell, and significant reduction in mean
corpuscular hemoglobin concentration. Evidence of maternal toxicity in the 100
ppm dose group included significant changes in the following: weight gain, food
consumption, size of red blood cells, and mean corpuscular hemoglobin
concentration. Embryotoxicity was indicated in the 200 ppm dose group by a
significant increase in number of totally resorbed litters (p<0.01), a
significant decrease in number of viable implantations per litter (p<0.001)
and a significant decrease in percent of live fetuses (p<0.01). A reduction
in skeletal ossification was also observed in these groups. There were no
statistically significant increases in the incidence of external, visceral,
skeletal, or total malformations in any treatment group relative to controls. An inhalation toxicity was conducted with groups 24 pregnant New Zealand
white rabbits of exposed to ethylene glycol mono-n-butyl ether at target
concentrations, (analytical concentration) of 25 (25), 50 (50), 100 (98), 200
(201), ppm on gestation days (GD) 6-18 for 6 hrs/day. The animals were
sacrificed on GD 29. Mortality was observed in 4 dams in the high-exposure
group; however, a significant difference from controls was not observed.
Clinical observations included periocular wetness, perinasal wetness and
discharge, red fluid on tray, and stained fur. Significantly decreased
(p<0.05) maternal body weight, and gravid uterine weight, and increased
number of abortions (4) were observed in the high dose group. A significant
reduction (p<0.05) in the number of total implants and viable implants per
litter were observed at the high-exposure level. There were no significant
effects on the number of non-viable implants, preimplantation loss, percent live
fetuses, sex ratio, or fetal body weight per litter. A significant increase
(p<0.05, Fisher's Exact Test) was observed in unossified sternebra 6 and in
the rudimentary rib lumbar 1, bilateraly. No statistically significant increases
in the incidence of malformations was observed in any treatment group relative
to controls. Teratogenicity was evaluated in groups of 36 pregnant Fischer 344 rats
exposed to ethylene glycol monobutyl ether vapors at concentrations of 0, 25,
50, 100, and 200 ppm for 6 hours/day on days 6-15 of gestation. Maternal
mortality was not observed and all rats were sacrificed on gestation day 21.
Clinical signs of maternal toxicity at 100 and 200 ppm included red straining
and wetness of the fur, fluid on trays beneath cages, periocular wetness, and
perinasal encrustation. Additional clinical observations at 200 ppm included
cold and pale extremities, discoloration and ulceration of the tail tip, and
absence of the tail tip. A significant (p<0.001, Bonferroni t-test) reduction
in maternal body weights was observed at 200 ppm, as was the rate of food
consumption at 100 and 200 ppm. Hematologic findings included significantly
(p<0.001) reduced hemoglobin and hematocrit values at 200 ppm and red blood
cell counts at 100 and 200 ppm. Gross necropsy of dams revealed a significant
(p<0.001) reduction in relative spleen weights. Examination of the uteri
revealed significant (p<0.01) reductions in the numbers of viable implants
and resorptions and the percent of live fetuses at 200 ppm. The numbers of
corpora lutea, total implants and preimplantation losses and the sex ration were
not effected by the material at any concentration. There were no significant
differences between control and exposure groups with respect to the incidence of
external, visceral, skeletal, or total fetal malformations. Teratogenicity was evaluated in groups of 24 pregnant New Zeland white
rabbits exposed to ethylene glycol monobutyl ether vapors at concentrations of
0, 25, 50, 100, and 200 ppm for 6 hours/day on days 6-18 of gestation. Maternal
mortality was observed in 4 rabbits at 200 ppm; all surviving rabbits were
sacrificed on gestation day 29 and the uteri examined. Clinical signs of
maternal toxicity at 100 and 200 ppm included periocular wetness and red fluid
on the trays beneath the cages. Additional clinical observations at 200 ppm
included staining of the fur and perinasal wetness and discharge. There were no
differences between control and treatment groups with respect to maternal body
weights, hematological findings, the number of non-viable implants,
preimplantation losses, percent live fetuses, sex ratios, or fetal weights.
Significant (p<0.05) reductions in uterine weights and the number of total
and viable implants/litter were observed at 200 ppm. The incidence of external,
visceral, skeletal, and total fetal malformations at all exposure levels was not
significantly different from that of the control group. Developmental toxicity was evaluated in groups of 36 female Fischer 344 rats
receiving whole-body exposure to ethylene glycol monobutyl ether at vapor
concentrations of 0, 25, 50, 100, or 200 ppm, for 6 hours/day, on gestation days
6-15, followed by fetal examination on gestation day 21. Maternal toxicity was
observed at the two highest dose levels, including clinical signs, reduced body
weight gain, food consumption, and gravid uterine weight, and increased relative
spleen and kidney weight. The compound was embryotoxic (increased incidence of
resorptions) and fetotoxic (reduced skeletal ossification) at the two highest
dose levels, but the incidence of fetal malformations was unchanged at all dose
levels. The NOEL was estimated at 50 ppm. Developmental toxicity was evaluated in groups of 24 female New Zealand white
rabbits receiving whole-body exposure to ethylene glycol monobutyl ether at
vapor concentrations of 0, 25, 50, 100, or 200 ppm, for 6 hours/day, on
gestation days 6-18, followed by fetal examination on gestation day 29. Maternal
toxicity was observed at the highest dose level, including clinical signs,
reduced body weight gain and gravid uterine weight, and increased incidence of
mortality and abortion. The compound was embryotoxic (reduced number of viable
fetuses) at the highest dose level, but no treatment-related effects were noted
with respect to fetotoxicity or fetal malformations. The NOEL was estimated at
100 ppm. Developmental toxicity was evaluated in groups of pregnant rabbits exposed to
ethylene glycol monoethyl ether acetate at vapor concentrations of 0, 25, 100,
and 400 ppm. Maternal body weight gain and food consumption decreased in the
high-dose group. Decreased body weight and retarded skeletal ossification were
observed in fetuses from the mid- and high-dose groups; the high dose was also
embryotoxic (increased resorptions) and teratogenic (major malformations of the
vertebral column). The document summarized this study, and no further
information was available regarding experimental methods or results. Developmental toxicity was evaluated in groups of pregnant rats (strain and
number per group not reported) exposed to ethylene glycol monobutyl ether at
vapor concentrations of 0, 100, 200, or 300 ppm. Maternal toxicity was observed
at all dose levels and some fetal effects were noted (not specified). The
document summarized this study, and no further information was available
regarding experimental methods or results. Ethylene glycol monobutyl ether (CAS# 111-76-2) was evaluated for
developmental toxicity. It was administered in 24 pregnant New Zealand white
rabbits exposed to 0, 25, 50, 100 or 200 ppm of the test material on days 6-18
of gestation. Maternal weight gains were not significantly altered by treatment.
At 200 ppm maternal toxicity was observed, including apparent exposure-related
increases in deaths and abortions, clinical signs (periocular wetness, perinasal
wetness and discharge), decreased weight during gestation day 15 (p < 0.05)
and reduced gravid uterine weight (p < 0.05) at sacrifice. Embryotoxicity was
exhibited by a reduced number of total and viable implantations (p < 0.05)
per litter. No treatment-related fetotoxicity was observed. No treatment-related
increases in fetal malformations or variations were seen at any exposure level.
At 200 ppm ethylene glycol monobutyl ether exhibited maternal and embryo
toxicity, but no fetotoxicity or teratogenicity. Ethylene glycol monobutyl ether (CAS# 111-76-2) was evaluated for
developmental toxicity. It was administered in 24 pregnant New Zealand white
rabbits at exposure levels of 0, 25, 50, 100 or 200 ppm of the test material on
days 6-18 of gestation. Maternal weight gains were not significantly altered by
treatment. At 200 ppm maternal toxicity was observed, including apparent
exposure-related increases in deaths and abortions, clinical signs (periocular
wetness, perinasal wetness and discharge), decreased weight during gestation day
15 (p < 0.05) and reduced gravid uterine weight (p < 0.05) at sacrifice.
Embryotoxicity was exhibited by a reduced number of total and viable
implantations (p < 0.05) per litter. No treatment-related fetotoxicity was
observed. No treatment-related increases in fetal malformations or variations
were seen at any exposure level. At 200 ppm ethylene glycol monobutyl ether
exhibited maternal and embryo toxicity, but no fetotoxicity or teratogenicity. Ethylene glycol monobutyl ether (CAS# 111-76-2) was evaluated for
developmental toxicity. It was administerd in 36 pregnant Fischer 344 rats per
group exposed to 0, 25, 50, 100, or 200 ppm of ethylene glycol monobutyl ether
on days 6-15 of gestation. Maternal toxicity was expressed as significant
reductions in body weight (p < 0.001) at 200 ppm, weight gain (p < 0.05)
during exposure at 100 and 200 ppm, food consumption (p < 0.001) at 100 and
200 ppm, and the presence of hematuria. Embryofetal toxicity included increased
numbers of resorbed litters (p < 0.01), decreased numbers of viable implants
(p < 0.001), decreased percent of live fetuses (p < 0.01) and delayed
ossification (p < 0.05). No statistically significant increases in the
incidence of external, visceral, skeletal, or total malformations were observed.
At 25 ppm or less there was no maternal, embryo or fetal toxicity. Inhalation
exposure to 100 ppm or above of ethylene glycol monobutyl ether caused maternal
toxicity, embryotoxicity, and fetotoxicity, but no teratogenicity. Ethylene glycol monobutyl ether (CAS# 111-76-2) was evaluated for
developmental toxicity. It was administered in 24 pregnant New Zealand white
rabbits exposed to 0, 25, 50, 100 or 200 ppm of ethylene glycol monobutyl ether
on days 6-18 of gestation. Maternal weight gains were not significantly altered
by treatment. At 200 ppm maternal toxicity was observed, including apparent
exposure-related increases in deaths and abortions, clinical signs (periocular
wetness, perinasal wetness and discharge), decreased weight during gestation day
15 (p < 0.05) and reduced gravid uterine weight (p < 0.05) at sacrifice.
Embryotoxicity was exhibited by a reduced number of total and viable
implantations (p < 0.05) per litter. No treatment related fetotoxicity,
increases in fetal malformations, or variations were seen at any exposure level.
At 200 ppm ethylene glycol monobutyl ether exhibited maternal and embryo
toxicity, but no fetotoxicity or teratogenicity. The ability of 2-butoxyethanol
to induce mutations at the gene locus coding for hypoxanthine-guanine
phosphoribosyl transferase in Chinese hamster ovary cells (CHO/HGPRT Assay) was
evaluated in both the presence and absence of added metabolic activation by
Aroclor-induced rat liver S9 fraction. Based on preliminary toxicity tests,
nonactivated cultures were treated with 0.0625, 0.125, 0.25, 0.5 or 1.0% butyl
cellosolve (v/v) and produced a range of 138.6 to 95.6 relative
growth. S9-activated cultures treated with 0.03125, 0.0625, 0.125, 0.25, or 0.5%
produced a range of 137 to 84.7% relative growth. None of the culture produced
mutant frequencies significantly greater than the solvent control. The frequency of sister chromatid exchange (SCE) was determined in Chinese
hamster ovary cells exposed in vitro to butyl
cellosolve with and without metabolic activation provided by
Aroclor-induced rat liver S9 fraction. The test article was administered at
concentrations of 0.00780, 0.01560, 0.03125, 0.625, 0.125, and 0.25% butyl
cellosolve (v/v) both in the presence and absence of metabolic
activation. A statistically significant (p < 0.05) increase in SCE's/cell and
SCE's/chromosome was not observed in any of the cultures at any concentration. The effects of 2-butoxyethanol
were examined in the rat hepatocyte primary culture/DNA repair assay. Based on
preliminary toxicity tests, 2-butoxyethanol
was tested at concentrations of 0.0001, 0.001, 0.003, 0.01, 0.03, and 0.1% v/v.
None of the tested concentrations caused a significant increase in unscheduled
DNA synthesis over the solvent (DMSO) control. The ability of 2-butoxyethanol
to induce mutations at the gene locus coding for hypoxanthine-guanine
phosphoribosyl transferase in Chinese hamster ovary cells (CHO/HGPRT Assay) was
evaluated in both the presence and absence of added metabolic activation by
Aroclor-induced rat liver S9 fraction. Based on preliminary toxicity tests,
nonactivated cultures were treated with 0.0625, 0.125, 0.25, 0.5 or 1.0% butyl
cellosolve (v/v) and produced a range of 138.6 to 95.6 relative
growth. S9-activated cultures treated with 0.03125, 0.0625, 0.125, 0.25, or 0.5%
produced a range of 137 to 84.7% relative growth. None of the culture produced
mutant frequencies significantly greater than the solvent control. The effects of 2-butoxyethanol
were examined in the rat hepatocyte primary culture/DNA repair assay. Based on
preliminary toxicity tests, 2-butoxyethanol
was tested at concentrations of 0.0001, 0.001, 0.003, 0.01, 0.03, and 0.1% v/v.
None of the tested concentrations caused a significant increase in unscheduled
DNA synthesis over the solvent (DMSO) control. The frequency of sister chromatid exchange (SCE) was determined in Chinese
hamster ovary cells exposed in vitro to butyl
cellosolve with and without metabolic activation provided by
Aroclor-induced rat liver S9 fraction. The test article was administered at
concentrations of 0.00780, 0.01560, 0.03125, 0.625, 0.125, and 0.25% butyl
cellosolve (v/v) both in the presence and absence of metabolic
activation. A statistically significant (p < 0.05) increase in SCE's/cell and
SCE's/chromosome was not observed in any of the cultures at any concentration. [Bushy Run Research Center; Butyl Cellosolve In Vitro Mutagenesis Studies: 3-Test Battery with Attachments, Cover Sheets and Letter Dated 06/06/89. (1980). EPA Document No. 86-890000946, Fiche No. OTS0520384} In an in vitro sister chromatid exchange assay, chinese hamster ovary cells (CHO-K1-BH4-D1) were exposed to 0.0, 0.0156, 0.03125, 0.0625, 0.125, 0.25% ethylene glycol mono-n-butyl ether, with or without an S-9 metabolic activating system from Arochlor 1254 induced rat liver. Doses were selected based on low cytotoxicity to CHO cells in a preliminary study. No treatment-related effects were seen, either in the presence or absence of a metabolic activating system. [Bushy Run Research Center; Butyl Cellosolve In Vitro Mutagenesis Studies: 3-Test Battery with Attachments, Cover Sheets and Letter Dated 06/06/89. (1980). EPA Document No. 86-890000946, Fiche No. OTS0520384} The ability of butyl cellosolve to induce specific mutations at the gene locus coding for hypoxanthine-guanine phosphoribosyl transferase in Chinese hamster ovary cells (CHO/HGPRT Assay) was evaluated in presence and absence of metabolic activation from Aroclor-induced rat liver S9 fraction. Based on preliminary toxicity tests, non-S9 activated cultures were treated with 0.0625, 0.125, 0.25, 0.5, or 1.0% v/v, and the S9 activated cultures were treated with 0.03125, 0.0625, 0.125, 0.25, or 0.5% v/v. None of the cultures had mutant frequencies significantly greater than the solvent (H2O) control. In an in vitro DNA repair assay, hepatocytes from Hilltop-Wistar albino rats
were exposed for 2 hours to 0.0001, 0.001, 0.003, 0.01, 0.03, and 0.1% ethyl
glycol mono-n-butyl ether, dissolved in DMSO. No metabolic activating system was
used. The concentrations used were non-cytotoxic to rat hepatocytes. The level
of unscheduled DNA synthesis was determined by measuring the incorporation of
3H-thymidine into cell nuclei DNA or into precipitated DNA, using a liquid
scintillation counter. Statistically significant increases in the level of
unscheduled DNA synthesis were observed at the two lowest dose-levels, but not
at the four highest dose-levels. The mutagenicity of butyl cellosolve (ethylene
glycol mono-n-butyl ether) was evaluated in Salmonella tester strains TA98,
TA100, TA1535, TA1537, and TA1538 (Ames Test), both in the presence and absence
of added metabolic activation by Aroclor-induced rat liver S9 fraction. Based on
the results of preliminary bacterial toxicity testing, the material was tested
for mutagenicity at concentrations of 0, 2000, 4000, 6000, 8000, 10000, and
15000 ug/plate using the direct plate incorporation method. Butyl
cellosolve did not cause a reproducible positive response in any
of the bacterial tester strains, either in the presence or absence of added
metabolic activation. Metabolism/Pharmacokinetics: Metabolism/Metabolites: ... METABOLIZED, @ LEAST IN PART, TO BUTOXYACETIC ACID ... . Seventeen persons who were exposed to glycolethers in a varnish production
plant, were examined according to their external and internal solvent exposure.
The workers in the production plant (n= 12) were exposed to average
concentrations of ethoxyethanol, ethoxyethyl acetate, butoxyethanol,
1-methoxypropanol-2, 2-methoxypropyl-1-acetate and xylene of 2.8; 2.7; 1.1; 7.0;
2.8 and 1.7 ppm. Internal exposure was estimated by measuring butoxyethanol
in blood as well as ethoxyacetic acid and butoxyacetic acid in urine samples. As
expected, the highest values were found in the varnish production. The average
post shift concentrations of butoxyethanol,
ethoxyacetic acid and butoxyacetic acid were 121.3 ug/l; 167.8 and 10.5 mg/l.
The relatively high concentrations of ethoxyacetic acid and butoxyacetic acid in
pre-shift samples can be explained by the long half-lives of these metabolites.
Most of the glycolethers were taken up through the skin. The authors think that
a future tolerable limit value for the concentration of ethoxyacetic acid in
urine should be in the order of 100 to 200 mg/l. The elimination kinetics of 2-butoxyethanol
(ethylene glycol monobutyl ether) were studied in the once-through isolated
perfused rat liver system in the presence and absence of ethanol. Dose-dependent
Michaelis-Menten kinetics in the elimination of ethylene glycol monobutyl ether
were observed. The apparent Michaelis constant range from 0.32 to 0.70 mM while
the maximum elimination rate ranged from 0.63 to 1.4 umol/min/g liver. In the
presence of 17.1 mM ethanol (0.1%) the extraction ratio of ethylene glycol
monobutyl ether decreased from 0.44 to 0.11. Ethylene glycol monobutyl ether is
mainly metabolized via oxidation by alcohol dehydrogenase in the rat liver. For the glycol ethers 2-methoxyethanol, 2-ethoxyethanol, and 2-butoxyethanol,
the effect of alkyl group length on disposition of these three glycol ethers was
studied in male F344/N rats allowed access for 24 hr to
2-butoxy(U-(14)C)ethanol, 2-ethoxy (U-(14)C)ethanol, or
2-methoxy(U-(14)C)ethanol in drinking water at three doses (180 to 2590 ppm),
resulting in absorbed doses ranging from 100 to 1450 umols/kg body weight. The
majority of the (14)C was excreted in urine or exhaled as carbon dioxide. Less
than 5% of the dose was exhaled as unmetabolized glycol ether. Distinct
differences in the metabolism of the glycol ethers as a function of alkyl chain
length were noted. For 2-butoxyethanol
50-60% of the dose was eliminated in the urine as butoxyacetic acid and 8-10% as
carbon dioxide; for 2-ethoxyethanol 25-40% was eliminated as ethoxyacetic acid
and 20% as carbon dioxide; for 2-methoxyethanol 34% was eliminated as
methoxyacetic acid and 10-30% as carbon dioxide. Ethylene glycol, a previously
unreported metabolite of these glycol ethers, was excreted in urine,
representing approximately 10, 18, and 21% of the dose for 2-butoxyethanol,
2-ethoxyethanol, and 2-methoxyethanol, respectively. Thus, for longer alkyl
chain lengths, a smaller fraction of the administered glycol ether was
metabolized to ethylene glycol and carbon dioxide. Formation of ethylene glycol
suggests that dealkylation of the glycol ethers occurs prior to oxidation to
alkoxyacetic acid and, as such, represents an alternate pathway in the
metabolism of these compounds that does not involve formation of the toxic acid
metabolite. Ethylene glycol monobutyl ether was rapidly absorbed in male rats after
gavage administration, metabolized, and eliminated. Tissue distribution of
ethylene glycol monobutyl ether revealed that ethylene glycol monobutyl ether is
distributed to all tissues with the highest levels (detected 48 hr after dosing)
detected in the forestomach followed by the liver, kidney, spleen, and the
glandular stomach. However, the increase in the tissue concn in rats treated
with 500 mg/kg (as compared to that in rats treated with 125 mg/kg ethylene
glycol monobutyl ether) was not proportional to the increase in ethylene glycol
monobutyl ether dose. The major route of ethylene glycol monobutyl ether
elimination was in the urine, followed by (14)CO2 exhalation. The portion of the
ethylene glycol monobutyl ether dose eliminated in urine or as (14)CO2 was
significantly higher in rats treated with 125 mg/kg than in the rats treated
with 500 mg/kg. This indicates that saturation of ethylene glycol monobutyl
ether-metabolizing enzymes occurs at the high dose. A small portion (8%) of the
administered dose (500 mg/kg) was excreted in the bile in 8 hr after dosing. The
major urinary metabolite, butoxyacetic acid, accounted for >75% of the
radioactivity excreted in the urine. The 2nd major metabolite in urine was the
glucuronide conjugate of ethylene glycol monobutyl ether. In the bile, the major
biliary metabolite was BEG followed by butoxyacetic acid. A small quantity of
the radioactivity excreted in the urine of rats treated with the low dose of
ethylene glycol monobutyl ether was the sulfate conjugate of ethylene glycol
monobutyl ether; however, no BES was detected in the urine of rats treated with
the high dose of ethylene glycol monobutyl ether. The following metabolic
pathways of ethylene glycol monobutyl ether are identified: oxidation of
ethylene glycol monobutyl ether to butoxyacetic acid, conjugation of ethylene
glycol monobutyl ether with uridine diphosphate glucuronic acid, and conjugation
of ethylene glycol monobutyl ether with the sulfate. Absorption, Distribution & Excretion: ... ABSORBED VIA SKIN, LUNG, OR GASTROINTESTINAL TRACT. ... BUTOXYACETIC ACID ... IS EXCRETED IN URINE OF MOST ANIMAL SPECIES &
OF HUMAN BEINGS. ANIMAL TESTS ALSO INDICATE THAT ETHYLENE GLYCOL BUTYL ETHER IS
EXCRETED VIA THE LUNG. THEY FOUND 55 MG OF BUTOXYACETIC ACID IN 16 HR URINE SAMPLES OF DOGS EXPOSED
TO 385 PPM. ... 100 & 42 MG IN 24-HR URINE SAMPLES FROM 2 DOGS EXPOSED TO
200 PPM OF VAPOR & 100 & 94 MG IN SIMILAR URINE SAMPLES FROM 2 DOGS
EXPOSED TO 100 PPM. ONE OF TWO MONKEYS EXPOSED TO 100 PPM EXCRETED 30 MG ... IN
48-HR PERIOD ... . HUMAN BEINGS EXPOSED 8 HR TO 195 PPM EXCRETED ANYWHERE FROM 6-300 MG
BUTOXYACETIC ACID IN 24 HR PERIOD. ... ONCE ABSORBED INTO BODY, ESTERS ARE SAPONIFIED & SYSTEMIC EFFECT IS
QUITE TYPICAL OF PARENT GLYCOL OR GLYCOL ETHER. /ETHER-ESTERS OF GLYCOLS/ The percutaneous absorption of 2-butoxyethanol
(Butyl cellosolve) was
investigated in 5 men. The presence of butoxyethanol
in blood and of butoxyacetic acid in urine confirmed that butoxyethanol
enters the systemic circulation in man in vivo during dermal exposure.
Calculated percutaneous uptake rates ranged from 7 to 96 nmol/min/sq cm. Persons
exposing large portions of their skin to butoxyethanol
are at risk of absorbing acutely toxic doses. The absorption across isolated human abdominal epidermis was measured in
vitro. Epidermal membranes were set up in glass diffusion cells.
2-Methoxyethanol was most readily absorbed (mean steady rate 2.82 mg/sq cm/hr)
was also apparent for 1-methoxypropan-2-ol. There was a trend of reducing
absorption rate with increasing molecular weight or reducing volatility for
monoethylene glycol ethers (2-methoxyethanol, 2.82 mg/sq cm/hr; 2-ethoxyethanol,
0.796 mg/sq cm/hr; 2-butoxyethanol,
0.198 mg/sq cm/hr) and also within the diethylene glycol series:
2-(2-methoxyethoxy) ethanol, (0.206 mg/sq cm/hr); 2-(2-ethoxyethoxy) ethanol,
(0.125 mg/sq cm/hr) and 2-(2-butoxyethoxy) ethanol, (0.035 mg/sq cm/hr). The
rate of absorption of 2-ethoxyethyl acetate was similar to that of the parent
alcohol, 2-ethoxyethanol. Absorption rates of diethylene glycol ethers were
slower than their corresponding monoethylene glycol equivalents. Acute exposure to 2-butoxyethanol
causes dose- and age-dependent hemolytic anemia in rats. Butoxyacetic acid is
the proximate hemolytic agent and inhibition of alcohol or aldehyde
dehydrogenases protected rats against 2-butoxyethanol
induced hemolytic anemia. The kinetics of (14)C-2-butoxyethanol
metabolism and clearance were studied in control adult (3-4 months old) and old
(12-13 months old) male F344 and in adult male F344 rats treated with pyrazole,
cyanamide or probenecid. The area under the curve, maximum plasma concentration
and systemic clearance of 2-butoxyethanol
were dose-dependent. In contrast, there was no effect of dose on half-life
(T1/2) or volume of distribution of 2-butoxyethanol.
There was no age effect on T1/2, volume of distribution, or systemic clearance
of 2-butoxyethanol. However,
maximum plasma concentration and area under the curve of 2-butoxyethanol
increased as a function of age. Inhibition of 2-butoxyethanol
metabolism by pretreatment of rats with pyrazole or cyanamide resulted in an
increase in the T1/2 and area under the curve of 2-butoxyethanol,
whereas it caused a decrease in the systemic clearance. Furthermore, pyrazole
had no effect, whereas cyanamide had decreased volume of distribution of 2-butoxyethanol. Mechanism of Action: ... Ethylene glycol monobutyl ether, and to a greater extent its metabolite,
butoxyacetic acid, both increase the osmotic fragility of the erythrocyte. This
action appears to be greatest in the rat, mouse, and rabbit and distinctly less
in the guinea pig, dog, rhesus monkey, and human. Pharmacology: Environmental Fate & Exposure: Environmental Fate/Exposure Summary: Ethylene glycol mono-n-butyl ether's production and use as a synthetic
intermediate and as a solvent in a variety of applications may result in its
release to the environment through various waste streams. If released to soil,
ethylene glycol mono-n-butyl ether is expected to have high mobility based on as
estimated Koc of 67. Volatilization of ethylene glycol mono-n-butyl ether is not
expected to be important from moist soil surfaces but may be important from dry
soil surfaces based on an estimated Henry's Law constant of 2X10-8 atm-cu m/mol
and a measured vapor pressure of 0.88 mm Hg, respectively. Alcohols and ethers
are generally resistant to hydrolysis. Such functional groups do not absorb UV
light at environmentally significant wavelengths (>290 nm) and are commonly
used as solvents for obtaining UV spectra. Therefore, direct photolysis will not
be an important process. According to several biodegradation tests, aerobic
degradation of ethylene glycol mono-n-butyl ether should occur rapidly in soil
and water. If released to water, ethylene glycol mono-n-butyl ether is not
expected to adsorb to suspended solids and sediment given its estimated Koc
value. Ethylene glycol mono-n-butyl ether is expected to be essentially
non-volatile from water surfaces because of its Henry's Law constant. An
estimated BCF value of 2.5 suggests that bioconcentration of ethylene glycol
mono-n-butyl ether will be low in aquatic organisms. If released to the
atmosphere, ethylene glycol mono-n-butyl ether will exist as a vapor based on
its vapor pressure. Vapor-phase ethylene glycol mono-n-butyl ether is degraded
in the atmosphere by reaction with photochemically produced hydroxyl radicals
with an estimated half-life of about 20 hours. Particulate-phase ethylene glycol
mono-n-butyl ether may be physically removed from the air by wet deposition. The
predominant route of exposure to ethylene glycol mono-n-butyl ether is through
dermal adsorption; other routes of exposure include ingestion and inhalation of
this compound, particularly from household products. (SRC) Probable Routes of Human Exposure: The most probable route of human exposure to ethylene glycol mono-n-butyl
ether is by inhalation, dermal contact and ingestion. Workplace exposures have
been documented(2-6). Drinking water supplies have been shown to contain
ethylene glycol mono-n-butyl ether(1). THERE IS ... HAZARD OTHER THAN VAPOR THAT MUST NOT BE OVERLOOKED WHEN
HANDLING THIS MATERIAL--THAT OF POSSIBLE ABSORPTION OF TOXIC QUANTITIES THROUGH
SKIN, BECAUSE OF LOW VAPOR PRESSURE ... @ ROOM TEMP, HAZARD FROM SKIN ABSORPTION
COULD WELL BE GREATER, OR CONTRIBUTE SUBSTANTIALLY TO OVER-ALL HAZARD. FROM INDUST POINT OF VIEW, ONLY ONE CASE OF POSSIBLE SYSTEMIC INJURY WAS THAT
OF MAN WHO WAS REPORTED ... AS HAVING HAD TWO ISOLATED ATTACKS OF HEMATURIA,
WITH 5 MO INTERVAL. ... HIS EXPOSURE ... INCL BUTYL CARBITOL AS WELL AS BUTYL
CELLOSOLVE. OCCUPATIONAL EXPOSURES TO BUTYL CELLOSOLVE, ETHANOL,
& XYLENE IN FILAMENT-DRAW DEPARTMENT OF ELECTRICAL RESISTOR MFR FACILITY DID
NOT POSE A HEALTH HAZARD. NIOSH (NOES Survey as of 3/28/89) has estimated that 1,680,764 workers are
potentially exposed to ethylene glycol mono-n-butyl ether in the USA(1).
According to the National Ambient Volatile Organic Compounds (VOCs) Database,
the median workplace atmospheric concn of ethylene glycol mono-n-butyl ether is
0.075 ppbV for 14 samples(3). Workers at paint stripping operations that used
stripping agents containing ethylene glycol mono-n-butyl ether were exposed to
it(2). Personal exposures to atmospheric ethylene glycol mono-n-butyl ether at a
specialty chemical production facility in June of 1981 ranged from undetected
levels to 0.1 ppm; indoor air concn within the facility were as high as 1.7
ppm(2). A national survey of workplaces in the Federal Republic of Germany
showed that workers were exposed to solvents containing ethylene glycol
mono-n-butyl ether with a 0.4% frequency of occurrence(1). A study initiated in 1983, which surveyed the workplace atmospheres of 336
businesses in Belgium, showed that ethylene glycol mono-n-butyl ether was
present in 25 of 94 air samples taken from sites that utilize printing pastes;
10 of 81 samples from where painting took place; 1 of 20 samples from automobile
repair shops; and 17 of 67 samples from sites where various materials such as
varnishes, sterilization agents and cleaners are employed(1). The geometric mean
concn of ethylene glycol mono-n-butyl ether in the air of printing shops was 4.1
mg/cu m with a range of 1.5 to 17.7 mg/cu m; 18.8 mg/cu m with a range of 3.4 to
93.6 mg/cu m for painting areas; 5.9 mg/cu m for car repair shops; and 8.5 mg/cu
m with a range of 0.2 to 1775 mg/cu m for various industries(1). Ethylene glycol mono-n-butyl ether was identified as a volatile emission from
used machine cutting oils in an automobile manufacturing facility in Japan(1).
Non-occupational exposures may occur among populations with contaminated
drinking water supplies(2). Because ethylene glycol mono-n-butyl ether is a
component of solvent based building materials such as silicone caulk(3), human
exposures may occur at construction sites and areas that have undergone
remodelling(SRC). Exposure of cleaning women and cleaners of cars to ethylene glycol
mono-n-butyl ether resulted in urine levels of <0.1-7.33 ppm (time-weighted
averages)(1). It was established that the predominant route of exposure to
ethylene glycol mono-n-butyl ether was through skin penetration(1). Ethylene
glycol mono-n-butyl ether was identified in air from automotive repair shops in
Sydney, Australia in 8 out of 70 samples at an average concentration of 2.0
mg/cu m(2). Artificial Pollution Sources: Ethylene glycol mono-n-butyl ether was listed as a volatile organic emission
of silicone caulk(4). Ethylene glycol mono-n-butyl ether is also released to the
environment via leachate from municipal landfills and hazardous waste site(1-3). Ethylene glycol mono-n-butyl ether's production and use in hydraulic
fluids(1), as coupling agent for many water-based coatings(2), to make acetate
esters as well as phthalate and stearate plasticizers(2), as a coupling agent to
stabilize immiscible ingredients in metal cleaners, textile lubricants, cutting
oils, and liquid household products(2), as a solvent for nitrocellulose resins,
spray lacquers, quick-drying lacquers, varnishes, enamels, dry-cleaning
compounds, varnish removers, textile, mutual solvent for "soluble"
mineral oils to hold soap in solution and to improve the emulsifying
properties(3), vinyl and acrylic paints(4), in aqueous cleaners to solubilize
organic surfactants(4), and as a solvent in cosmetics(5) may result in its
release to the environment through various waste streams(SRC). Environmental Fate: TERRESTRIAL FATE: Based on a recommended classification scheme(1), an
estimated Koc value of 67(SRC), determined from an experimental log Kow(2) and a
recommended regression-derived equation(3), indicates that ethylene glycol
mono-n-butyl ether is expected to have high mobility in soil(SRC).
Volatilization of ethylene glycol mono-n-butyl ether is not expected to be
important from moist soil surfaces(SRC) given an estimated Henry's Law constant
of 2X10-8 atm-cu m/mole(SRC), using a recommended regression equation(4).
Volatilization may be important from dry soil surfaces(SRC) based on an
experimental vapor pressure of 0.88 mm Hg(5). Alcohols and ethers are generally
resistant to hydrolysis(6). They do not absorb UV light at environmentally
significant wavelengths (>290 nm) and are commonly used as solvents for
obtaining UV spectra(3). Therefore, direct photolysis will not be an important
process. According to several biodegradation tests, aerobic degradation of
ethylene glycol mono-n-butyl ether should occur rapidly in soil(5,7-12). AQUATIC FATE: Based on a recommended classification scheme(1), an estimated
Koc value of 67(SRC), determined from an experimental log Kow(2) and a
recommended regression-derived equation(1), indicates that ethylene glycol
mono-n-butyl ether is not expected to adsorb to suspended solids and
sediment(SRC) in the water. Ethylene glycol mono-n-butyl ether is expected to be
essentially non-volatile from water surfaces based on an estimated Henry's Law
constant of 2X10-8 atm-cu m/mole(SRC), developed using a fragment constant
estimation method(3). An estimated BCF value of 2.5(1,SRC), from an experimental
log Kow(2), suggests that ethylene glycol mono-n-butyl ether bioconcentration in
aquatic organisms will be low(SRC), according to a recommended classification
scheme(4). Alcohols and ethers are generally resistant to hydrolysis(5). They do
not absorb UV light at environmentally significant wavelengths (>290 nm) and
are commonly used as solvents for obtaining UV spectra(1). Therefore, direct
photolysis will not be an important process. According to several BOD
biodegradation tests, aerobic degradation of ethylene glycol mono-n-butyl ether
should occur rapidly in water(6-12). ATMOSPHERIC FATE: According to a model of gas/particle partitioning of
semivolatile organic compounds in the atmosphere(1), ethylene glycol
mono-n-butyl ether, which has an experimental vapor pressure of 0.88 mm Hg at 25
deg C(2,SRC), will exist as a vapor in the ambient atmosphere. Vapor-phase
ethylene glycol mono-n-butyl ether is degraded in the atmosphere by reaction
with photochemically produced hydroxyl radicals(SRC); the half-life for this
reaction in air is estimated to be about 20 hours(3,SRC). Particulate-phase
ethylene glycol mono-n-butyl ether may be physically removed from the air by wet
deposition(SRC). Environmental Biodegradation: A number of aerobic biological screening studies, which utilized settled
waste water, sewage, or activated sludge for inocula, indicate that ethylene
glycol mono-n-butyl ether should biodegrade rapidly in the environment(1-4).
Five and ten-day Theoretical BOD values were 73% (with acclimation)(1) and
74%(2). The maximum Theoretical BOD reported was 88% for 20 days(2). A two-week biodegradation study using 30 mg/l sludge and an ethylene glycol
mono-n-butyl ether concentration of 100 mg/l gave a theoretical BOD of 96%(1).
The theoretical BODs for ethylene glycol mono-n-butyl ether after 5, 10, and 20
days have been determined to be 5, 57, and 72%(2). Biooxidation of ethylene
glycol mono-n-butyl ether using a 20 day BOD test and a 28 day OECD test
resulted in 88 and 75% degradation(3). Environmental Abiotic Degradation: The rate constant for the vapor-phase reaction of ethylene glycol
mono-n-butyl ether with photochemically produced hydroxyl radicals has been
experimentally determined to be 1.86x10-11 cu cm/molecule-sec at 25 deg C(1).
This corresponds to an atmospheric half-life of about 20 hours at an atmospheric
concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). Alcohols and ethers
are generally resistant to hydrolysis(2). They do not absorb UV light at
environmentally significant wavelengths (>290 nm) and are commonly used as
solvents for obtaining UV spectra(3). Therefore, ethylene glycol mono-n-butyl
ether should not undergo hydrolysis or direct photolysis in the
environment(SRC). Environmental Bioconcentration: An estimated BCF value of 2.5 was calculated for ethylene glycol mono-n-butyl
ether(SRC), using an experimental log Kow of 0.83(1) and a recommended
regression-derived equation(2). According to a recommended classification
scheme(3), this BCF value suggests that bioconcentration in aquatic organisms is
low(SRC). Soil Adsorption/Mobility: The Koc of ethylene glycol mono-n-butyl ether is estimated as approximately
67(SRC), using an experimental log Kow of 0.83(1) and a regression-derived
equation(2,SRC). According to a recommended classification scheme(3), this
estimated Koc value suggests that ethylene glycol mono-n-butyl ether should have
high mobility in soil(SRC). Volatilization from Water/Soil: The Henry's Law constant for ethylene glycol mono-n-butyl ether is estimated
as 2X10-8 atm-cu m/mole(SRC) using a fragment constant estimation method(1).
This value indicates that ethylene glycol mono-n-butyl ether will be essentially
nonvolatile from water surfaces(2,SRC). Ethylene glycol mono-n-butyl ether's
Henry's Law constant(1,SRC) indicate that volatilization from moist soil
surfaces is not expected(SRC). The potential for volatilization of this compound
from dry soil surfaces may exist(SRC) based on the measured vapor pressure of
0.88 mm Hg(3). Environmental Water Concentrations: DRINKING WATER: Ethylene glycol mono-n-butyl ether was listed as a
contaminant found in drinking water for a survey of US cities including Pomona,
Escondido, Lake Tahoe and Orange Co, CA and Dallas, Washington, DC, Cincinnati,
Philadelphia, Miami, New Orleans, Ottumwa, IA, and Seattle(1). GROUNDWATER: Ethylene glycol mono-n-butyl ether was detected at a concn of 23
ug/l in 1 of 7 groundwater samples collected near "The Valley of
Drums", KY(1). A ground water sample from an aquifer underlying a municipal
landfill in Norman, OK contained ethylene glycol mono-n-butyl ether(2,3).
Ethylene glycol mono-n-butyl ether was qualitatively identified in ground water
in Milan, Italy near a paint factory where several underground tanks of solvents
were located(4). SURFACE WATER: In April 1980, ethylene glycol mono-n-butyl ether was detected
in Hayashida River water (the Matsubara area in Tatsuno City, Hyogo Prefecture)
at concn of 1310 and 5680 ppb(1). Ethylene glycol mono-n-butyl ether was
identified in the Rhine River at Lobith at a concentration of 0.036 ug/l(2). Effluent Concentrations: Ethylene glycol mono-n-butyl ether was identified in 1 and 4 neutral
fractions of 33 industrial wastewater effluents at concn of <10 and <100
ug/l, respectively(4). Because ethylene glycol mono-n-butyl ether was detected
in groundwater receiving municipal landfill leachate, it may be present in other
landfill leachates(2,3). Ethylene glycol mono-n-butyl ether was listed as a
volatile organic emission of silicone caulk(4). Ethylene glycol mono-n-butyl
ether was detected in the emissions of waste incineration plants at 0.23 ug/cu
m(5). Atmospheric Concentrations: INDOOR: According to the National Ambient Volatile Organic Compounds (VOCs)
Database, the average daily indoor atmospheric concn of ethylene glycol
mono-n-butyl ether is 0.214 ppbv for 14 samples(1). Ethylene glycol mono-n-butyl
ether was detected at a concn of 8 ug/cu m in 1 of 6 samples of indoor air from
14 homes of northern Italy(2). Ethylene glycol mono-n-butyl ether was been
identified in air from occupational buildings at concentrations of 1.8, 3.4,
3.9, 6.7, 8.5, 16, and 34 ug/cu m, in building exhaust at 6.0 and 13 ug/cu m,
and in an elevator shaft at 19 ug/cu m(3). Food Survey Values: Ethylene glycol mono-n-butyl ether has been qualitatively identified in the
volatile fraction of raw beef(1,2). Other Environmental Concentrations: Ethylene glycol mono-n-butyl ether was contained in organic solvents with a
frequency of occurrence of 0.4%(1). A paint stripping formulation was comprised
of 35% ethylene glycol mono-n-butyl ether(2). Ethylene glycol mono-n-butyl ether
was not detected in a machine cutting fluid prior to its use; however, the used
fluid contained ethylene glycol mono-n-butyl ether at a concn of 0.060 ug/g(3). Ethylene glycol mono-n-butyl ether was qualitatively detected in the
headspace of liquid wax for marble, ceramic, linoleum, plastic, and varnished
wood floors(1). Ethylene glycol mono-n-butyl ether was found in printer's inks
used for serigraphy on paper and paper boards at concentrations of 0.1 and 0.4
wt%(2). Ethylene glycol mono-n-butyl ether has been identified as a major
component of latex caulk(3). Ethylene glycol mono-n-butyl ether has been
identified in a variety of household products including paints, primers and
varnishes; all purpose cleaners; window and glass cleaners; engine degreasers;
rug and upholstery cleaners; and metal cleaners and polishes(4). Environmental Standards & Regulations: FIFRA Requirements: Ethylene glycol monobutyl ether is exempted from the requirement of a
tolerance when used in accordance with good agricultural practice as inert (or
occasionally active) ingredients in pesticide formulations applied to growing
crops only. TSCA Requirements: Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety
Data Reporting Rule. The section 8(d) model rule requires manufacturers,
importers, and processors of listed chemical substances and mixtures to submit
to EPA copies and lists of unpublished health and safety studies. Ethylene
glycol mono-n-butyl ether is included on this list. Atmospheric Standards: This action promulgates standards of performance for equipment leaks of
Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing
Industry (SOCMI). The intended effect of these standards is to require all newly
constructed, modified, and reconstructed SOCMI process units to use the best
demonstrated system of continuous emission reduction for equipment leaks of VOC,
considering costs, non air quality health and environmental impact and energy
requirements. Ethylene glycol monobutyl ether is produced, as an intermediate or
final product, by process units covered under this subpart. FDA Requirements: Ethylene glycol monobutyl ether is an indirect food additive for use only as
a component of adhesives. Allowable Tolerances: Ethylene glycol monobutyl ether is exempted from the requirement of a
tolerance when used in accordance with good agricultural practice as inert (or
occasionally active) ingredients in pesticide formulations applied to growing
crops only. Chemical/Physical Properties: Molecular Formula: C6-H14-O2 Molecular Weight: 118.20 Color/Form: ...Colorless liquid. Odor: ... Mild, ether-like odor. Slight, rancid odor. Weak, pleasant odor. Boiling Point: 171-172 DEG C Melting Point: -70 deg C Critical Temperature & Pressure: CRITICAL TEMP: 694 DEG F= 368 DEG C= 641 DEG K; CRITICAL PRESSURE: 470 PSIA=
32 ATM= 3.2 MEGANEWTONS/SQUARE M Density/Specific Gravity: SP GR: 0.9012 @ 20 DEG C/4 DEG C Heat of Combustion: -13,890 BTU/LB= -7720 CAL/G= -323X10+5 JOULES/KG Heat of Vaporization: 157 BTU/LB= 87.1 CAL/G= 3.65X10+5 JOULES/KG Octanol/Water Partition Coefficient: log Kow= 0.83 Solubilities: SOL IN MOST ORG SOLVENTS, IN MINERAL OIL Mixes in all proportions with acetone, benzene, carbon tetrachloride, ethyl
ether, n-heptane and water; miscible in all proportions with many ketones,
ethers, alcohols, aromatic paraffin and halogenated hydrocarbons. water solubility = 1X10+6 mg/l Spectral Properties: SADTLER REF NUMBER: 2292 (IR, PRISM); 10979 (IR, GRATING) Index of refraction: 1.4198 @ 20 deg C/D Intense mass spectral peaks: 57 m/z (100%), 45 m/z (38%), 41 m/z (31%), 87
m/z (16%) IR: 1052 (Coblentz Society Spectral Collection) NMR: 4023 (Sadtler Research Laboratories Spectral Collection) Surface Tension: Surface tension: 27.4 mN/m (=dyn/cm) @ 25 deg C. Vapor Density: 4.1 (Air= 1) Vapor Pressure: Vapor pressure = 0.88 mm Hg at 25 deg C Viscosity: At 25 deg C= 2.83 centistokes Other Chemical/Physical Properties: Acidity (as acetic acid), % by wt (max) 0.01. Blush resistance (@ 27 Deg C 96% rh; Coefficient of expension: 0.00092 cu cm hydroxyl radical rate constant = 1.86X10-11 cu-cm/molc sec Chemical Safety & Handling: DOT Emergency Guidelines: Health: Highly toxic, may be fatal if inhaled, swallowed or absorbed through
skin. Contact with molten substance may cause severe burns to skin and eyes.
Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire
may produce irritating, corrosive and/or toxic gases. Runoff from fire control
or dilution water may be corrosive and/or toxic and cause pollution. Fire or explosion: Combustible material: may burn but does not ignite
readily. Containers may explode when heated. Runoff may pollute waterways.
Substance may be transported in a molten form. Public safety: CALL Emergency Response Telephone Number on Shipping Paper
first. If Shipping Paper not available or no answer, refer to appropriate
telephone number listed on the inside back cover. Isolate spill or leak area
immediately for at least 25 to 50 meters (80 to 160 feet) in all directions.
Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Protective clothing: Wear positive pressure self-contained breathing
apparatus (SCBA). Wear chemical protective clothing which is specifically
recommended by the manufacturer. Structural firefighters' protective clothing is
recommended for fire situations ONLY; it is not effective in spill situations. Evacuation: Spill: See the Table of Initial Isolation and Protective Action
Distances for highlighted substances. For non-highlighted substances, increase,
in the downwind direction, as necessary, the isolation distance shown under
"PUBLIC SAFETY". Fire: If tank, rail car or tank truck is involved in
a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider
initial evacuation for 800 meters (1/2 mile) in all directions. Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Water
spray, fog or regular foam. Move containers from fire area if you can do it
without risk. Dike fire control water for later disposal; do not scatter the
material. Do not use straight streams. Fire involving tanks or car/trailer
loads: Fight fire from maximum distance or use unmanned hose holders or monitor
nozzles. Do not get water inside containers. Cool containers with flooding
quantities of water until well after fire is out. Withdraw immediately in case
of rising sound from venting safety devices or discoloration of tank. ALWAYS
stay away from the ends of tanks. For massive fire, use unmanned hose holders or
monitor nozzles; if this is impossible, withdraw from area and let fire burn. Spill or leak: Do not touch damaged containers or spilled material unless
wearing appropriate protective clothing. Stop leak if you can do it without
risk. Prevent entry into waterways, sewers, basements or confined areas. Cover
with plastic sheet to prevent spreading . Absorb or cover with dry earth, sand
or other non-combustible material and transfer to containers. DO NOT GET WATER
INSIDE CONTAINERS. First aid: Move victim to fresh air. Call emergency medical care. Apply
artificial respiration if victim is not breathing. Do not use mouth-to-mouth
method if victim ingested or inhaled the substance; induce artificial
respiration with the aid of a pocket mask equipped with a one-way valve or other
proper respiratory medical device. Administer oxygen if breathing is difficult.
Remove and isolate contaminated clothing and shoes. In case of contact with
substance, immediately flush skin or eyes with running water for at least 20
minutes. For minor skin contact, avoid spreading material on unaffected skin.
Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin
contact) to substance may be delayed. Ensure that medical personnel are aware of
the material(s) involved, and take precautions to protect themselves. Skin, Eye and Respiratory Irritations: Irritation of eyes, nose and throat ... Fire Potential: ... Keep away from heat and open flame. NFPA Hazard Classification: Health: 2. 2= Materials that, on intense or continued (but not chronic)
exposure, could cause temporary incapacitation or possible residual injury,
including those requiring the use of respiratory protective equipment that has
an independent air supply. These materials are hazardous to health, but areas
may be entered freely if personnel are provided with full-face mask
self-contained breathing apparatus that provides complete eye protection. Flammability: 2. 2= Includes materials that must be moderately heated before
ignition will occur and includes Class II and IIIA combustible liquids and and
solids and semi-solids that readily give off ignitible vapors. Water spray may
be used to extinguish fires in these materials because the materials can be
cooled below their flash points. Reactivity: 0. 0= Includes materials that are normally stable, even under
fire exposure conditions, and that do not react with water. Normal fire fighting
procedures may be used. Flammable Limits: Lower: 1.1% @ 93 deg C; Upper: 12.7% @ 135 deg C Flash Point: 143 DEG F (62 DEG C) (CLOSED CUP) Flash point = 69.4 deg C (open cup) and 60.0 deg C (closed cup) Autoignition Temperature: 238 deg C Fire Fighting Procedures: CARBON DIOXIDE OR DRY CHEMICAL FOR SMALL FIRES; ALCOHOL-TYPE FOAM FOR LARGE
FIRES. If material on fire or involved in fire: Do not extinguish fire unless flow
can be stopped or safely confined. Use water in flooding quantities as fog. Cool
all affected containers with flooding quantities of water. Apply water from as
far a distance as possible. Use foam, dry chemical, or carbon dioxide. Keep
run-off water out of sewers and water sources. Hazardous Reactivities & Incompatibilities: Incompatibilities: Strong oxidizers, strong caustics. Strong oxidizers, strong caustics. Immediately Dangerous to Life or Health: 700 ppm Protective Equipment & Clothing: AIR PACK OR ORGANIC CANISTER RESPIRATOR, RUBBER GLOVES; GOGGLES; CLOTHING TO
PREVENT BODY CONTACT WITH LIQ Wear appropriate clothing to prevent repeated or prolonged skin contact. Wear
eye protection to prevent any reasonable probability of eye contact. Employees
should wash immediately when skin is wet or contaminated. Remove nonimpervious
clothing immediately if wet or contaminated. Provide emergency showers. Wear appropriate personal protective clothing to prevent skin contact. Wear appropriate eye protection to prevent eye contact. Facilities for quickly drenching the body should be provided within the
immediate work area for emergency use where there is a possibility of exposure.
[Note: It is intended that these facilities provide a sufficient quantity or
flow of water to quickly remove the substance from any body areas likely to be
exposed. The actual determination of what constitutes an adequate quick drench
facility depends on the specific circumstances. In certain instances, a deluge
shower should be readily available, whereas in others, the availability of water
from a sink or hose could be considered adequate.] Recommendations for respirator selection. Max concn for use: 50 ppm.
Respirator Class(es): Any chemical cartridge respirator with organic vapor
cartridge(s). May require eye protection. Any supplied-air respirator. May
require eye protection. Recommendations for respirator selection. Max concn for use: 125 ppm.
Respirator Class(es): Any supplied-air respirator operated in a continuous flow
mode. May require eye protection. Any powered, air-purifying respirator with
organic vapor cartridge(s). May require eye protection. Recommendations for respirator selection. Max concn for use: 250 ppm.
Respirator Class(es): Any chemical cartridge respirator with a full facepiece
and organic vapor cartridge(s). Any air-purifying, full-facepiece respirator
(gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any
powered, air-purifying respirator with a tight-fitting facepiece and organic
vapor cartridge(s). May require eye protection. Any self-contained breathing
apparatus with a full facepiece. Any supplied-air respirator with a full
facepiece. Recommendations for respirator selection. Max concn for use: 700 ppm.
Respirator Class(es): Any supplied-air respirator that has a full facepiece and
is operated in a pressure-demand or other positive-pressure mode. Recommendations for respirator selection. Condition: Emergency or planned
entry into unknown concn or IDLH conditions: Respirator Class(es): Any
self-contained breathing apparatus that has a full facepiece and is operated in
a pressure-demand or other positive pressure mode. Any supplied-air respirator
that has a full facepiece and is operated in pressure-demand or other positive
pressure mode in combination with an auxiliary self-contained breathing
apparatus operated in pressure-demand or other positive pressure mode. Recommendations for respirator selection. Condition: Escape from suddenly
occurring respiratory hazards: Respirator Class(es): Any air-purifying,
full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted
organic vapor canister. Any appropriate escape-type, self-contained breathing
apparatus. Preventive Measures: Contact lenses should not be worn when working with this chemical. SRP: The scientific literature for the use of contact lenses in industry is
conflicting. The benefit or detrimental effects of wearing contact lenses depend
not only upon the substance, but also on factors including the form of the
substance, characteristics and duration of the exposure, the uses of other eye
protection equipment, and the hygiene of the lenses. However, there may be
individual substances whose irritating or corrosive properties are such that the
wearing of contact lenses would be harmful to the eye. In those specific cases,
contact lenses should not be worn. In any event, the usual eye protection
equipment should be worn even when contact lenses are in place. SRP: Contaminated protective clothing should be segregated in such a manner
so that there is no direct personal contact by personnel who handle, dispose, or
clean the clothing. Quality assurance to ascertain the completeness of the
cleaning procedures should be implemented before the decontaminated protective
clothing is returned for reuse by the workers. Contaminated clothing should not
be taken home at end of shift, but should remain at employee's place of work for
cleaning. The worker should immediately wash the skin when it becomes contaminated. Work clothing that becomes wet or significantly contaminated should be
removed and replaced. If material not on fire and not involved in fire: Keep sparks, flames, and
other sources of ignition away. Keep material out of water sources and sewers.
Build dikes to contain flow as necessary. Attempt to stop leak if without undue
personnel hazard. Personnel protection: Avoid breathing vapors. Keep upwind. ... Do not handle
broken packages unless wearing appropriate personal protective equipment. Wash
away any material which may have contacted the body with copious amounts of
water or soap and water. Shipment Methods and Regulations: No person may /transport,/ offer or accept a hazardous material for
transportation in commerce unless that person is registered in conformance ...
and the hazardous material is properly classed, described, packaged, marked,
labeled, and in condition for shipment as required or authorized by ... /the
hazardous materials regulations (49 CFR 171-177)./ The International Maritime Dangerous Goods Code lays down basic principles
for transporting hazardous chemicals. Detailed recommendations for individual
substances and a number of recommendations for good practice are included in the
classes dealing with such substances. A general index of technical names has
also been compiled. This index should always be consulted when attempting to
locate the appropriate procedures to be used when shipping any substance or
article. Cleanup Methods: 1. VENTILATE AREA OF SPILL OR LEAK. 2. FOR SMALL QUANTITIES, ABSORB ON PAPER
TOWELS. EVAPORATE IN SAFE PLACE (SUCH AS FUME HOOD). ALLOW SUFFICIENT TIME FOR
EVAPORATING VAPORS TO COMPLETELY CLEAR HOOD DUCTWORK. BURN PAPER IN SUITABLE
LOCATION AWAY FROM COMBUSTIBLE MATERIALS. 2. LARGE QUANTITIES CAN BE COLLECTED
& ATOMIZED IN SUITABLE COMBUSTION CHAMBER. WASTE DISPOSAL: 1. BY ABSORBING
IT IN VERMICULITE, DRY SAND, EARTH OR SIMILAR MATERIAL & DISPOSING IN
SECURED SANITARY LANDFILL. 2. BY ATOMIZING IN SUITABLE COMBUSTION CHAMBER. IN SIMULATED WASTE GAS CONTAINING 1000 PPM ETHYLENE BUTYL MONOBUTYL ETHER WAS
ABSORBED BY SPINDLE OIL 88 CONTAINING CALCIUM NAPHTHANATE, A NONIONIC
SURFACTANT, AN ANTIOXIDANT & A STABILIZER. ACTIVATED SLUDGE DECOMPOSED ORGANIC SOLVENT CONTAINED IN ABSORBING LIQ OF
WASTE GAS FROM PAINTING BOOTHS. ETHYLENE GLYCOL MONOBUTYL ETHER WAS DECOMPOSED
BY ACCLIMATED SLUDGE. Disposal Methods: SRP: At the time of review, criteria for land treatment or burial (sanitary
landfill) disposal practices are subject to significant revision. Prior to
implementing land disposal of waste residue (including waste sludge), consult
with environmental regulatory agencies for guidance on acceptable disposal
practices. n-Butoxy ethanol should be atomized into an incinerator, and combustion may
be improved by mixing with a more flammable solvent. The following wastewater treatment technologies have been investigated for
Ethylene glycol monobutyl ether: Concentration process: Activated carbon. Occupational Exposure Standards: OSHA Standards: Permissible Exposure Limit: Table Z-1 8-hr Time-Weighted Avg: 50 ppm (240
mg/cu m). Skin Designation. Vacated 1989 OSHA PEL TWA 25 ppm (120 mg/cu m), skin designation, is still
enforced in some states. Threshold Limit Values: 8 hr Time Weighted Avg (TWA) 25 ppm, skin Excursion Limit Recommendation: Excursions in worker exposure levels may
exceed three times the TLV-TWA for no more than a total of 30 min during a work
day and under no circumstances should they exceed five times the TLV-TWA,
provided that the TLV-TWA is not exceeded. Notice of Intended Change (first notice appeared in 1998 edition): The ACGIH
has listed chemicals for which either a limit has been proposed for the first
time, for which a change in the "Adopted" listing has been proposed,
or for which retention on the Notice of Intended Changes has been proposed. The
proposed limits should be considered trial limits that will remain in the
listing for a period of at least one year. If, after one year no evidence comes
to light that questions the appropriateness of the values herein, the values
will be reconsidered for the "Adopted" list. Time Weighted Avg (TWA):
20 ppm. NIOSH Recommendations: NIOSH recommends reducing exposure to lowest feasible concn & preventing
contact with the skin. /Glycol ether/ Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 5 ppm (24 mg/cu m).
Skin. Immediately Dangerous to Life or Health: 700 ppm Manufacturing/Use Information: Major Uses: IN HYDRAULIC FLUIDS The preferred coupling agent for many water-based coatings. Used to make acetate esters as well as phthalate and stearate plasticizers. A coupling agent to stabilize immiscible ingredients in metal cleaners,
textile lubricants, cutting oils and liquid household products. Solvent for nitrocellulose resins, spray lacquers, quick-drying lacquers
varnishes, enamels, drycleaning cmpd, varnish removers, textile (preventing
spotting in printing or dyeing), mutual solvent for "soluble" mineral
oils to hold soap in solution and to improve the emulsifying properties. Crude oil/water coupling solvent (oil-well work-overs); solvent (surface
coatings, adhesives, organosol production). In vinyl and acrylic paints as well as lacquers and varnishes. Also in
aqueous cleaners to solubilize organic surfactants. As a solvent in cosmetics. Manufacturers: Dow Chemical USA, Hq, 2020 Dow Center, Midland, MI 48674, (517) 636-1000;
Production site: Main St, Midland, MI 48667 Eastman Chemical Co, Hq, PO Box 511, Kingsport, TN 37662; Texas Eastman
Division; Production site: Longview, TX 75607 Occidental Petroleum Corporation, Hq, 10889 Wilshire Blvd, Suite 1500, Los
Angeles, CA 90024, (213) 879-1700; Petrochemicals, Occidental Tower, 5005 LBJ
Freeway, PO Box 809050 (75380), Dallas, TX 75244 (214) 404-3800. Ethylene oxide
and Derivatives Division; Production site: Bayport, TX 77000 Shell Chemical Co, Hq, One Shell Plaza, PO Box 2463, Houston, TX 77252-2463,
(713) 241-6161; Production site: Geismar, LA 70734 Union Carbide Corporation, Hq, Old Ridgebury Road, Danbury, CT 06817, (203)
794-2000; Solvents and Intermediates; Production site: Seadrift, TX 77983 Methods of Manufacturing: (1) BY REACTION OF ETHYLENE OXIDE WITH SUITABLE ALCOHOL, WITH VARIOUS
CATALYSTS. (2) BY REACTING ETHYLENE CHLOROHYDRIN OR ETHYLENE GLYCOL WITH SODIUM
HYDROXIDE & DIALKYL SULFIDE. General Manufacturing Information: OTHER EFFECTIVE FOG REDUCING MIXT TESTED INCL HEXADECANOL WITH OCTADECANOL
& ETHYLENE MONOBUTYL ETHER. Ethylene Glycol Monobutyl Ether is now /1983/ the largest volume glycol ether
produced. Formulations/Preparations: GRADE: TECHNICAL Consumption Patterns: 41% AS SOLVENT FOR PROTECTIVE COATINGS; 18% AS SOLVENT FOR METAL CLEANERS AND
LIQUID HOUSEHOLD CLEANERS; 9% FOR SYNTHESIS OF 2-BUTOXYETHYL ACETATE; 1% FOR
SYNTHESIS OF DI(2-BUTOXYETHYL) PHTHALATE; 31% FOR OTHER SOLVENT USES (1972) Intermediates, 20%; Coatings solvent, 65%; Miscellaneous solvents, 15% (1983) U. S. Production: (1972) 6.05X10+10 GRAMS (1975) 5.93X10+10 GRAMS (1984) 1.23X10+11 g U. S. Imports: (1972) NEGLIGIBLE (1984) 4.02x10+7 g U. S. Exports: (1972) 4.01X10+9 GRAMS (1975) 5.45X10+9 GRAMS (1984) 3.24X10+10 g Laboratory Methods: Analytic Laboratory Methods: NIOSH Method 1403. Analyte: Alcohols. Matrix: Air. Procedure: Gas
chromatography, flame ionization detection. For 2-butoxyethanol,
this method has an estimated detection limit of 0.01 to 0.02 mg/10 liters. The
overall precision/RSD is 0.060 and the recovery is 92%. Applicability: This
method may be used to determine two or more analytes simultaneously by varying
GC conditions (eg, temperature). Interferences: High humidity reduces sampling
capacity. Less volatile compounds may displace more volatile compounds on the
charcoal. DETERMINED IN WASTE WATER BY GAS CHROMATOGRAPHY-MASS SPECTROMETRY. Gas chromatography is likely to be the analytical method for final analysis.
Infrared absorption is sometimes used. /Glycol ethers/ Sampling Procedures: In instances where materials are very soluble in water, samples of air can be
taken effectively by scrubbing through water. /Glycol ethers/ Special References: Special Reports: Jaraczewska W et al; Toxicology of butyl glycol; Med Pr 30 (5) 353 (1979). A review on the toxicity of butyl ethylene glycol, especially its CNS depressant effect & action inducing parenchymatous organ lesions. USEPA; Health effects assessment for glycol ethers pp 90 (1984) EPA/540/1-86/052 Johanson G; Aspects of biological monitoring of exposure to glycol ethers; Toxicol Lett 43 (1-3): 5-21 (1988) Miller RR; Metabolism and Disposition of Glycol Ethers; Drug Metab Rev 18 (1): 1-22 (1987). Tyler TR, Acute and subchronic toxicity of ethylene glycol monobutyl ether, Environ Health Perspect, 185-91 (1984). DHHS/NTP; NTP Technical Report on Toxicity Studies of Ethylene Glycol Ethers 2-Methoxyethanol, 2-Ethoxyethanol, 2-Butoxyethanol Administered in Drinking Water to F344/N Rats and B6C3F1 Mice. Toxicity Rpt Series No. 26 NIH Publication No. 93-3349 (1993) Toxicology & Carcinogenesis Studies of 2-Butoxyethanol in F344/N Rats and B6C3F1 Mice p.6 Technical Report Series No. 484 (2000) NIH Publication No. 00-3974 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 Synonyms and Identifiers: Synonyms: A13-0993 BUCS BUTOKSYETYLOWY ALKOHOL (POLISH) 2-BUTOSSI-ETANOLO (ITALIAN) 2-BUTOXY-AETHANOL (GERMAN) Butoxyethanol BETA-BUTOXYETHANOL N-BUTOXYETHANOL 2-BUTOXYETHANOL 2-BUTOXY-1-ETHANOL BUTYL CELLOSOLVE BUTYL CELLU-SOL Butylcelosolv (Czech) O-BUTYL ETHYLENE GLYCOL BUTYL GLYCOL BUTYLGLYCOL (FRENCH, GERMAN) BUTYL OXITOL Caswell No 121 CHIMEC NR DOWANOL EB Ektasolve EB EPA Pesticide Chemical Code 011501 Eter monobutilico del etilenglicol (Spanish) ETHANOL, 2-BUTOXY- Ether monobutylique de L'ethyleneglycol (French) ETHYLENE GLYCOL BUTYL ETHER ETHYLENE GLYCOL N-BUTYL ETHER Ethylene glycol monobutyl ether GAFCOL EB GLYCOL BUTYL ETHER GLYCOL MONOBUTYL ETHER MONOBUTYL ETHER OF ETHYLENE GLYCOL Monobutyl ethylene glycol ether MONOBUTYL GLYCOL ETHER 3-Oxa-1-heptanol POLY-SOLV EB Formulations/Preparations: GRADE: TECHNICAL Shipping Name/ Number DOT/UN/NA/IMO: UN 2369; Ethylene glycol monobutyl ether IMO 6.1; Ethylene glycol monobutyl ether RTECS Number: NIOSH/KJ8575000 Administrative Information: Hazardous Substances Databank Number: 538 Last Revision Date: 20020306 Last Review Date: Reviewed by SRP on 9/19/1996 Update History: Field Update on 03/06/2002, 1 field added/edited/deleted. Record Length: 218008
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