| 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 aft |