November 2009
This document is a Final Agency/Inter agency Review draft. It has not been formally released by
the U.S. Environmental Protection Agency and should not at this stage be construed to represent
Agency position on this chemical. It is being circulated for review of its technical accuracy and
science policy implications.
0500
Ethylene glycol monobutyl ether (EGBE) (2-Butoxyethanol) (CASRN 111-76-2)
Human health assessment information on a chemical substance is included in IRIS only
after a comprehensive review of toxicity data by U.S. EPA health scientists from several
program offices, regional offices, and the Office of Research and Development. Sections I
(Health Hazard Assessments for Noncarcinogenic Effects) and II (Carcinogenicity Assessment
for Lifetime Exposure) present the positions that were reached during the review process.
Supporting information and explanations of the methods used to derive the values given in IRIS
are provided in the guidance documents located on the IRIS website at
http://www.epa.gov/iris/backgr-d.htm.
STATUS OF DATA FOR ETHYLENE GLYCOL MONOBUTYL ETHER (EGBE)
File First On-Line 12/30/1999
Category (section)
Chronic Oral RfD Assessment (I.A.)
Chronic Inhalation RfC Assessment (I.B.)
Carcinogenicity Assessment (II.)
Status
on-line
on-line
on-line
Last Revised
00/00/0000
00/00/0000
00/00/0000
I. HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
	I.A. REFERENCE DOSE (RfD) FOR CHRONIC ORAL EXPOSURE
Substance Name — Ethylene glycol monobutyl ether (EGBE)
CASRN-- 111-76-2
Section I. A. Last Revised — 00/00/0000
The RfD is an estimate (with uncertainty spanning perhaps an order of magnitude) of a
daily oral exposure to the human population (including sensitive subgroups) that is likely to be
without an appreciable risk of deleterious effects during a lifetime. The RfD is intended for use
in risk assessments for health effects known or assumed to be produced through a nonlinear
(presumed threshold) mode of action. It is expressed in units of mg/kg-day. Please refer to the
guidance documents at http://www.epa.gov/iris/backgr-d.htm for an elaboration of these
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concepts. Because RfDs can be derived for the noncarcinogenic health effects of substances that
are also carcinogens, it is essential to refer to other sources of information concerning the
carcinogenicity of this chemical substance. If the U.S. EPA has evaluated this substance for
potential human carcinogenicity, a summary of that evaluation will be contained in Section II of
this file.
The previous oral RfD for EGBE (posted on the IRIS database in 1999) was 0.5 mg/kg-
day, based on a National Toxicology Program (NTP, 1993) subchronic drinking water study in
rats and mice using changes in mean corpuscular volume as the critical effect. Cmax (peak blood
concentrations) for 2-butoxyacetic acid (BAA) in arterial blood of female rats following oral
exposure was estimated using the physiologically based pharmacokinetic (PBPK) model of
Corley et al. (1994) as modified by Corley et al. (1997). The benchmark dose (BMD)05 was
determined to be 64 |iM, using the 95% lower confidence limit of the dose-response curve
expressed in terms of the Cmax for BAA in blood. The PBPK model of Corley was used to
"back-calculate" " to a human equivalent dose (HED) of 5.1 mg/kg-day, assuming that rats and
humans receive their entire dose of EGBE from drinking water over a 12-hour period each day.
The RfD was calculated by applying a uncertainty factor (UF) of 10 for intrahuman variability to
the benchmark dose, 95% lower bound (BMDL) HED of 5.1 mg/kg-day.
I.A.1. CHRONIC ORAL RfD SUMMARY
Critical Effect	Point of Departure*	UF	Chronic RfD
Hemosiderin	BMDL(HED): 1.4 mg/kg-day 10	0.1 mg/kg-day
deposition in the (PBPK and BMDio)
liver
Chronic (rat and
mouse) inhalation
study
NTP 2000
*Conversion Factors and Assumptions — The database of oral studies for EGBE is more limited
than the database of inhalation studies. For this reason, a PBPK model for EGBE has been
applied to the inhalation data for derivation of an RfD. As with the animal-to-human
extrapolation used in the development of the reference concentration (RfC), the dose metric used
for animal-to-human and route-to-route (inhalation-to-oral) extrapolation for the derivation of the
RfD is the area under the curve (AUC) of BAA at 12 months in arterial blood. This dose metric
was used for dose-response modeling of chronic inhalation data to derive the point of departure
(POD) of 133 [j,mol-hour/L, expressed as a BMDL. The BMDL was then back-calculated using
the human PBPK model (Corley et al., 1997, 1994) to obtain an equivalent human oral drinking
water dose (BMDLhed) of 1.4 mg/kg-day. A simplifying assumption was used that the entire
dose of drinking water EGBE was consumed over a 12-hour period each day.
I.A.2. PRINCIPAL AND SUPPORTING STUDIES
NTP (National Toxicology Program). (2000) NTP technical report on the toxicology and
carcinogenesis studies of 2-butoxyethanol (CAS No. 111-76-2) in F344/N rats and B6C3Fi mice
(inhalation studies). Public Health Service, U.S. Department of Health and Human Services;
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NTP TR 484; NIH Publ. No. 00-3974. Available from the National Institute of Environmental
Health Sciences, Research Triangle Park, NC and online at
http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/tr484.pdf.
NTP (2000) completed a two-species, 2-year inhalation study on EGBE in both genders
of rats and mice. In this chronic study, animals were exposed to EGBE 6 hours/day, 5 days/week
at concentrations of 0, 31, 62.5, and 125 ppm (0, 150, 302, and 604 mg/m3) for groups of
50 F344/N rats and 0, 62.5, 125, and 250 ppm (0, 302, 604, and 1,208 mg/m3) for groups of
50 B6C3Fi mice. The researchers stated that the highest exposure was selected to produce a 10-
15% depression in hematologic indices. They reported that no effect on survival was observed in
rats, but survival was statistically significantly decreased in male mice exposed to 125 or
250 ppm, compared with chamber controls (54, 52, and 78% respectively). Although statistics
were not reported for mean body weights, the rats exposed to 31 and 62.5 ppm had similar mean
body weights to the control rats. Mean body weights of the exposed mice were generally less
than for controls, with females experiencing greater and earlier reductions. From week 17 to the
end of the study, the mean body weights of 125 ppm female rats were generally less than those
of controls. Non-neoplastic effects in rats included hyaline degeneration of the olfactory
epithelium in males (13/48, 21/49, 23/49, 40/50) and females (13/50, 18/48, 28/50, 40/49) and
Kupffer cell pigmentation in the livers of males (23/50, 30/50, 34/50, 42/50) and females (15/50,
19/50, 36/50, 47/50). The severity of the olfactory lesion was not affected by exposure. The
Kupffer cell pigmentation is a result of hemosiderin accumulation and is a recognized secondary
effect of the hemolytic activity of EGBE.
Non-neoplastic, statistically significant effects in mice included forestomach ulcers and
epithelial hyperplasia, hematopoietic cell proliferation and hemosiderin pigmentation in the
spleen, Kupffer cell pigmentation in the livers, and bone marrow hyperplasia (males only).
Hyaline degeneration of the olfactory epithelium (females only) was increased relative to
chamber controls but was not statistically significant. As in the rats, the Kupffer cell
pigmentation was considered a secondary effect of the hemolytic activity of EGBE. Bone
marrow hyperplasia, hematopoietic cell proliferation, and hemosiderin pigmentation in the
spleen were also attributed to the primary hemolytic effect; it was followed by regenerative
hyperplasia of the hematopoietic tissue. The forestomach lesions did not appear to be related to
the hemolytic effect of EGBE. Incidences of ulcer were significantly increased in all exposed
female groups, as well as males exposed to 125 ppm. Incidences of epithelial hyperplasia,
usually focal, were significantly increased in all exposed groups of males and females. The
hyperplasia was often associated with ulceration, particularly in the females, and consisted of
thickness of the stratified squamous epithelium and sometimes the keratinized layer of the
forestomach. Ulceration consisted of a defect in the forestomach wall that penetrated the full
thickness of the epithelium and frequently contained accumulations of inflammatory cells and
debris.
Using the same exposure levels described above, additional groups of rats (27/gender/
exposure group) and mice (30/gender/exposure group) in the 2-year study were examined at 3, 6,
and 12 months (8-10 animals/time point) for hematologic effects. Nine male and nine female
rats were exposed to 31 ppm EGBE, specifically to evaluate hematology at 3 months and to
receive a total evaluation at 6 months. Animals were continuously exposed, as described above,
until their sacrifice at 3, 6, or 12 months. As in the 14-week study, inhalation of EGBE by both
species resulted in the development of exposure-related hemolytic effects, inducing a responsive
anemia. In rats, the anemia was persistent and did not progress or ameliorate in severity from
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3 months to the final blood collection at 12 months. Statistically significant (p < 0.05) decreases
in automated and manual hematocrit (Hct) values, hemoglobin (Hb) concentrations, and red
blood cell (RBC) counts occurred at 3, 6, and 12 months in the 125 ppm female mice and the
250 ppm male and female mice. Statistically significant decreases in these same endpoints were
also observed in 62.5 ppm females at 6 months and in 125 ppm males at 6 and 12 months
(decreases in Hct were observed only at 3 and 6 months). Mean cell volume (MCV) was
increased in female mice at the highest duration (12 months) and exposure (250 ppm) levels.
Reticulocyte counts were increased significantly in the 125 ppm females at 3 and 6 months and
in the 125 ppm males at 6 months of exposure.
In the subchronic portion of the inhalation NTP (2000) study, F344 rats and B6C3Fi mice
(10/gender) were exposed to EGBE concentrations of 0, 31, 62.5, 125, 250, and 500 ppm (0, 150,
302, 604, 1,208, and 2,416 mg/m3) 6 hours/day, 5 days/week for 14 weeks. Hematologic and
hemosiderin staining results are indicative of the various degrees of hemolysis caused by
exposure to increasing concentrations of EGBE. Both rat genders exhibited clinical signs at the
three highest doses, consistent with the hemolytic effects of EGBE, including: (1) deficits in
RBCs as a result of lysis manifestation through the clear dose-related decrease in Hct, a finding
consistent with decreases noted for both RBC count and Hb concentrations; and (2) increases in
both reticulocytes and nucleated erythrocytes at higher doses, homeostatic responses that would
be anticipated to occur as the lysed blood cells are being replaced. Female rats may be
somewhat more sensitive: several statistically significant effects occurred at the 31 ppm level in
females, as opposed to a single parameter for males. In addition, the degree to which these
various measures are affected is somewhat greater in females than males, indicated as percent
control, particularly at the three highest concentrations. Hematologic evaluation showed mild-
to-moderate regenerative anemia at all concentrations in females and at the three highest
concentrations in males. Exposure-related trends were noted for reticulocyte count, RBC count,
MCV, Hb concentration, and Hct. Liver-to-body-weight ratios increased significantly in males
at the two highest concentrations and in females at the highest concentration. Histopathologic
effects at concentrations in excess of 62.5 ppm for male rats and 31 ppm for females consisted of
excessive splenic congestion in the form of extramedullary hematopoiesis, hemosiderin
accumulation in Kupffer cells, liver necrosis, centrilobular hepatocellular degeneration, renal
tubular degeneration, intracytoplasmic Hb and hemosiderin deposition, and bone marrow
hyperplasia. In addition, five moribund female rats were sacrificed from the highest
concentrations, and one from the 250 ppm group. The lowest-observed-adverse-effect level
(LOAEL) for hematological alterations was 31 ppm for female rats and 62.5 ppm for male rats.
The 31 ppm exposure level was considered a no-observed-adverse-effect level (NOAEL) for
male rats.
The mice exposed via the inhalation route exhibited clinical signs consistent with the
hemolytic effects of EGBE at the two highest concentrations for both genders. Hematologic
evaluation indicated a moderate regenerative anemia (marked by decreased RBC counts,
increased reticulocyte counts, and increased MCV) with an increase in platelets at the three
highest concentrations in both genders. Histopathological effects consisted of excessive
extramedullary splenic hematopoiesis, renal tubular degeneration, hemosiderin deposition in the
spleen and kidney and accumulation in Kupffer cells, and testicular degeneration. Forestomach
necrosis, ulceration, inflammation, and epithelial hyperplasia were observed at concentrations
>31 ppm for females and 62.5 ppm for males. In addition, four females and four males either
died or were sacrificed moribund at the highest concentration. The NOAEL for male and female
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mice was 31 ppm and the LOAEL in mice was 62.5 ppm, based on histopathological changes in
the forestomach.
I.A.3. UNCERTAINTY FACTORS
UF= 10
A factor of 10 was selected to account for the uncertainty associated with the variability of the
human response (UFH) to the effects of EGBE. Potentially susceptible subpopulations include
individuals with enhanced metabolism or decreased excretion of BAA and individuals whose
RBC membranes are more susceptible to the lysis caused by BAA, the precursor step to
developing hemosiderin staining in the liver. Human in vitro studies suggest that the elderly and
patients with fragile RBCs would not be more sensitive to the hemolytic effects of EGBE than
normal adults. Laboratory animal studies suggest that older animals are more sensitive than
neonates and that females are more sensitive than males. While developmental studies do not
reveal increased susceptibility in infants, none of the developmental studies examined fetal or
infant blood for signs of effects from prenatal exposure to EGBE. Additionally, human
responses to EGBE have not been observed under a broad range of exposure conditions (e.g.,
repeated or long-term exposures) and potentially sensitive subjects (e.g., individuals predisposed
to hemolytic anemia or infants).
A factor of 1 was selected to account for the uncertainty associated with interspecies variability
resulting from toxicodynamic and toxicokinetic differences between animals and humans (UFA).
Traditionally, these components (toxicodynamic and toxicokinetic) are individually represented
by partial UFs of 3 for a total UF of 10 in the absence of chemical-specific information; thus,
application of a full UF of 10 would depend on two areas of uncertainty (i.e., toxicokinetic and
toxicodynamic uncertainties). In this assessment, the toxicokinetic uncertainty is addressed by
the determination of an FLED, using a combination of measured internal blood levels in the test
animals and PBPK modeling. A value of 1 was selected for the toxicokinetic portion of the UFA.
Regarding toxicodynamics, in vivo (Carpenter et al., 1956) and in vitro (Udden, 2002; Udden
and Patton, 1994; Ghanayem and Sullivan, 1993) studies indicate that humans may be
significantly less sensitive than rats to the hematological effects of EGBE. A value of 1 was
selected for the toxicodynamic portion of the UFA.
A factor to account for extrapolation from subchronic to chronic exposure (UFS) was not needed
because the RfD was derived from a chronic inhalation study.
A factor for LOAEL to NOAEL (UFL) was not applied because the current approach is to
address this extrapolation as one of the considerations in selecting a benchmark response (BMR)
for BMD modeling. In this case, EPA concluded a 10% increase in hemosiderin staining,
indicating a precursor to an adverse effect, is appropriate for use in deriving the RfD under the
assumption that it represents a minimal biologically significant change.
A factor of 1 was selected to account for deficiencies in the database (UFD). While no chronic
oral studies or adequate human data are available for EGBE, PBPK models allow for deriving a
BMDL from the chronic inhalation study using measured internal dose metrics and then
extrapolating it back to an equivalent human oral dose. The database for inhalation exposure
includes chronic and subchronic studies in two species (rats and mice), and several reproductive
and developmental studies, including a two-generation reproductive toxicity study.
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I.A.4. ADDITIONAL STUDIES/COMMENTS
Carpenter et al. (1956) conducted three controlled inhalation studies. In the first study, a
group of two men and six rats were exposed simultaneously for 4 hours to an EGBE
concentration of 113 ppm in a 1,250 cubic foot room. Effects observed in humans included nasal
and ocular irritation, a metallic taste, and belching. Erythrocyte osmotic fragility did not change
for the men, yet rose appreciably for the rats. In a second study, a group of two men, one
woman, and three rats were exposed to 195 ppm EGBE for two 4-hour periods, separated by a
30-minute recess, in a 6.5 cubic foot room. There was no change in the subjects' blood pressure,
erythrocyte fragility, or pulse rate. They experienced nose and throat irritation, followed by
ocular irritation and disturbed taste; one subject reported a headache. In the rats, an increase in
erythrocyte fragility values was noted. In the third study, two men and two women were
exposed for 8 hours to a 100 ppm EGBE concentration. No changes in blood pressure,
erythrocyte fragility, or pulse rate were observed. Again, nasal and throat irritation followed by
ocular irritation and a disturbing metallic taste were experienced. Two subjects reported
headaches.
There are a number of case reports of acute ingestion of EGBE, consisting primarily of
accidental or intentional ingestion. Bauer et al. (1992) reported the effects of acute ingestion of
500 mL of window cleaner containing 9.1% EGBE and 2.5% ethanol by a 53-year-old alcoholic
male. He was comatose with metabolic acidosis, shock and noncardiogenic pulmonary edema
when brought to a hospital, approximately 10 hours after ingestion. He had increased heart rate,
decreased blood pressure, and transient polyuria and hypoxemia. Hypochromic anemia was
evident with an Hb concentration of 9.1 g/100 mL, a Hct of 25%, and thrombocytopenia. The
patient recovered and was discharged after 15 days.
Gijsenbergh et al. (1989) reported that a 23-year-old woman weighing 64 kg ingested
approximately 25-30 g of EGBE (-400-500 mg/kg) and ethanol (-4:1 ratio) as a window
cleaner in an apparent suicide attempt. She was comatose when admitted to the hospital,
exhibiting dilated pupils, obstructive respiration, and metabolic acidosis, including depression of
blood Hb concentration and hematuria. The presence of EGBE in the blood and dialysis fluid
was confirmed. Treatment consisted of supportive therapy, forced diuresis, bicarbonate
administration, and hemodialysis. Her Hb concentration fell from 11.9 g Hb/100 mL upon
admission to 8.9 g Hb/100 mL. She was discharged after 8 days.
Gualtieri et al. (2003, 1995) reported a case of a suicide attempt with an industrial-
strength window cleaner. The 18-year-old male weighed 71 kg; he consumed between 360 and
480 mL of a concentrated glass cleaner that contained 22% EGBE, a dose equivalent to 1,131—
1,509 mg/kg. He was admitted to the hospital with no abnormalities other than epigastric
discomfort within 3 hours postingestion. Approximately 10 hours postadmission, the patient was
noticeably lethargic, weak, and hyperventilating, symptoms consistent with the onset of
metabolic acidosis. BAA was measured; the highest serum concentration found was
4.86 mmol/L, collected approximately 16 hours postingestion. The patient was transferred to a
tertiary care hospital where hemodialysis was initiated at approximately 24 hours postingestion.
Ethanol therapy was started 30 minutes later. Treatment also consisted of intravenousdoses of
100 mg thiamine and 50 mg folic acid every 12 hours and 50 mg pyridoxine every 6 hours.
Following 4 hours of dialysis, the patient was alert and remained hemodynamically stable. Ten
days after discharge, the patient was readmitted following a second ingestion of 480 mL of the
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same cleaner, an EGBE dose equivalent to 1,509 mg/kg. Treatment included ethanol therapy
and hemodialysis, and was initiated within a few hours of ingestion to control the metabolic
acidosis. Due to this early treatment, ethanol therapy had an impact on the disposition of EGBE
and BAA. As with the first episode, metabolic acidosis was manifest. This high-dose oral
ingestion was nearly 1.1-1.5 g EGBE/kg body weight. The highest serum BAA concentration
was 2.07 mmol/L, collected 22 hours postingestion. No evidence of hemolysis or renal
abnormalities was detected.
A 50-year-old woman ingested approximately 250-500 mL of a window cleaner
containing 12% EGBE, representing -30-60 mL, in an apparent suicide attempt (Rambourg-
Schepens et al., 1988). She was diagnosed with metabolic acidosis, hypokalemia, a rise in serum
creatinine level, and a marked increase in urinary excretion of oxalate crystals. Moderate
hemoglobinuria appeared on the third day postexposure, and a progressive erythropenia was
noted. In the absence of more complete hematologic details from this and other similar case
studies, it is not possible to determine whether these effects were due to hemolysis or other
factors related to the profound blood chemistry changes observed. The clinical status improved
gradually and the patient was discharged on the 10th day.
Burkhart and Donovan (1998) summarized the case of a 19-year-old male who ingested
20-30 ounces, or -590-885 mL, of a product that contained 25-35% EGBE (an exposure
equivalent to -177-265 mL, estimated at >3,000 mg/kg) along with 15-25%) propylene glycol,
5-10%o monoethanolamine, and l-3%> potassium hydroxide. On his arrival at the hospital
3.5 hours after ingestion, the patient was deeply comatose with severe hypotension. Hematuria
developed on the second day, with no evidence of renal or hepatic toxicity; however, pulmonary
toxicity consisting of severe aspiration pneumonia was present. The patient had a significant
recovery, despite severe neurologic deficits that were slow to resolve.
Osterhoudt (2002) reported on a 16-month-old girl who ingested an unknown amount of
cleaning solution containing EGBE (10—30%>), monoethanolamine (5-10%>), alkoxylated linear
alcohols (l-5%>), ethylenediaminetetraacetic acid (l-5%>), and potassium hydroxide (l-5%>).
Metabolic acidosis was manifest, and a single dose (15 mg/kg) of the aldehyde dehydrogenase
(ALDH) inhibitor fomepizole was administered. Within 2 hours, the metabolic acidosis was
completely resolved, and there was no evidence of alkaline mucosal injury, hepatic or renal
dysfunction, or hemolysis.
Dean and Krenzelok (1991) reported that 24 children, aged 7 months to 9 years, were
observed subsequent to oral ingestion of at least 5 mL of glass window cleaner containing EGBE
in the 0.5-9.9% range. Two children drank more than 15 mL and were treated by gastric lavage.
No symptoms of EGBE poisoning, such as metabolic acidosis, and no hemolysis were observed
in any of the children.
Raymond et al. (1998) reported on seven clerical workers who were evaluated 8 months
after they entered a file room where the supervisor believed that EGBE had been applied
overnight to strip the floor. Exact details of the product used were unknown, but based on
containers found and exposure symptoms of noted intense eye and respiratory irritation, marked
dyspnea, nausea, and faintness, the authors suggested that they were exposed to EGBE
concentrations of 200-300 ppm. Of major concern were skin spots—cherry angiomas—that
appeared between 4 and 22 weeks after exposure in six of the seven workers. All workers
continued to experience recurrent eye and tracheobronchial irritation; four had a dry cough.
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Workplace air sampling conducted by a certified industrial hygienist 1 week after the floor
stripping found no detectable EGBE, although traces (0.1-0.2 ppm) of formaldehyde were
identified. Five years after the exposure, four of the workers who could be contacted reported
that they continued to have outbreaks of new cherry angiomas. It should be noted that no other
studies linking EGBE exposure to outbreaks of cherry angiomas are available in the literature.
The authors included the observation that, since this report, they had seen three patients who they
believe were also exposed to EGBE vapor in an unrelated incident, and who did not develop any
skin spots. Cherry angiomas are the most common cutaneous vascular lesion; they are benign
and formed by a proliferation of dilated venules. The spots occur more frequently with
increasing age but can appear in younger individuals. There are reports in the literature of cherry
angiomas appearing following individual exposure to other chemicals, such as bromides (Cohen
et al., 2001), glutaraldehyde (Raymond et al., 1998), and sulfur mustard gas (Firooz et al., 1999).
A cross section of 31 male workers, aged 22-45, employed for 1-6 years, who were
exposed to low levels of EGBE in a beverage packing production plant were monitored by
Haufroid et al. (1997). The effect of external EGBE exposure and internal BAA levels on
erythrocyte lineage were investigated by monitoring: RBC count, Hb, Hct, MCV, mean
corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC),
haptoglobin (Hp), reticulocyte count, and osmotic resistance (OR), a measure of osmotic
fragility. Also studied were serum glutamic-oxaloacetic and glutamic-pyruvic transaminases and
renal creatinine and urinary retinol binding protein parameters. The average airborne
concentration of EGBE was 2.91 mg/m3, or 0.6 ppm (standard deviation [SD] of ±1.30 mg/m3 or
0.27 ppm). In addition, there was coexposure to methyl ethyl ketone. Single determinations of
BAA in postshift urine samples were used to assess exposure to low levels of EGBE. No
differences were observed for RBC counts, Hb, MCV, MCH, Hp, reticulocyte count, or OR
between exposed and control workers. The only statistically significant change observed in
exposed workers when compared with a matched control group (n = 21) was a 3.3% decrease in
Hct (p = 0.03) and a 2.1% increase in MCHC (p = 0.02). The implications of these small
erythroid effects are unclear. Both values are within their corresponding normal clinical ranges
and, given that no statistically significant changes were observed in other erythroid parameters,
they do not appear to be related to the more severe adverse effects observed in laboratory
animals. Furthermore, no correlation was found between any of the nine erythroid parameters
measured and the parameters of internal exposure. No significant differences were observed in
hepatic and renal biomarkers.
Several human studies investigated the dermal absorption of EGBE. Jakasa et al. (2004)
dermally exposed six male research subjects, ages 22-55, to 50%, 90%, or neat EGBE for 4
hours on the forearm over an area of 40 cm2. The dermal absorption of EGBE from aqueous
solutions was markedly higher than from neat EGBE. In Jones et al. (2003), four research
subjects were exposed via inhalation of 50 ppm EGBE for 2 hours on nine separate occasions,
with each occasion separated by 3 weeks, at varying temperatures and humidity levels. Results
show that "baseline" dermal contribution to total body absorption of EGBE vapor in
appropriately dressed workers was, on average, 11%. Higher temperature (30°C, mean 14%,
p = 0.03) and greater humidity (65% relative humidity, mean 13%,p = 0.1) both increased
dermal absorption. The wearing of whole-body overalls did not attenuate absorption (mean
10%). By combining several factors together in the industrial scenario, dermal absorption of
vapors was reported to be as high as 39% of the total absorbed dose.
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I.A.5. CONFIDENCE IN THE CHRONIC ORAL RfD
Study — High
Data Base — Medium to high
RfD — Medium to high
The overall confidence in the RfD is medium to high because theRfD has been calculated
using a route-to-route extrapolation from the PBPK/benchmark concentration (BMC) method
used to derive the RfC. This method accounts for pharmacokinetic differences between rats and
humans using a validated PBPK model (Corley et al., 1997, 1994). There is high confidence in
the NTP (2000) study because it was a chronic study, employed both male and female rats and
mice, had a wide range of exposure levels, and animals were observed twice daily. There is
medium-to-high confidence in the database, because data are available for a variety of animal
species, including humans. Confidence in the database is not high, because the potential for
effects in humans from repeat, long-term exposures has not been investigated.
I.A.6. EPA DOCUMENTATION AND REVIEW OF THE CHRONIC ORAL RfD
Source Document — U.S. EPA (2009) Toxicological review of ethylene glycol monobutyl ether.
This document was provided for review to EPA scientists, interagency reviewers from
other federal agencies and White House offices, and the public, and peer reviewed by
independent scientists external to EPA. A summary and EPA's disposition of the comments
received from the independent external peer reviewers and from the public is included in
Appendix A of the Toxicological Review of Ethylene Glycol Monobutyl Ether (U.S. EPA, 2009).
I.A.7. EPA CONTACTS
Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in
general, at (202) 566-1676 (phone), (202) 566-1749 (fax), or hotline.iris@epa.gov (email
address).
	I.B. REFERENCE CONCENTRATION (RfC) FOR CHRONIC INHALATION
EXPOSURE
Substance Name — Ethylene glycol monobutyl ether (EGBE)
CASRN — 111-76-2
Section I.B. Last Revised — 00/00/0000
The RfC is an estimate (with uncertainty spanning perhaps an order of magnitude) of a
continuous inhalation exposure to the human population (including sensitive subgroups) that is
likely to be without an appreciable risk of deleterious effects during a lifetime. The RfC
considers toxic effects for both the respiratory system (portal-of-entry) and for effects peripheral
to the respiratory system (extrarespiratory effects). The inhalation RfC (generally expressed in
units of mg/m3) is analogous to the oral RfD and is similarly intended for use in risk assessments
for health effects known or assumed to be produced through a nonlinear (presumed threshold)
mode of action.
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Inhalation RfCs are derived according to Methods for Derivation of Inhalation Reference
Concentrations and Application of Inhalation Dosimetry (U.S. EPA, 1994). Because RfCs can
also be derived for the noncarcinogenic health effects of substances that are carcinogens, it is
essential to refer to other sources of information concerning the carcinogenicity of this chemical
substance. If the U.S. EPA has evaluated this substance for potential human carcinogenicity, a
summary of that evaluation will be contained in Section II of this file.
The previous RfC for EGBE (posted on the IRIS database in 1999) was 13 mg/m3, based
on an NTP (1998) subchronic inhalation study in rats using changes in mean RBC count as the
critical effect. Cmax (peak blood concentrations) for BAA in arterial blood of female rats
following inhalation exposure was estimated using the PBPK model of Lee et al. (1998). The
BMD05 was calculated to be 225 |iM, using the 95% lower confidence limit of the dose-response
curve expressed in terms of the Cmax for BAA in blood. The PBPK model of Corley et al. (1997,
1994) was used to "back-calculate" to a human equivalent concentration (HEC) of 78 ppm
(380 mg/m3) assuming continuous exposure (24 hours/day). The RfC was calculated by
applying a UF of 30 (10 for intrahuman variability and 3 for extrapolation from a LOAEL) to the
benchmark concentration, 95% lower bound (BMCL) HEC of 380 mg/m3.
I.B.I. CHRONIC INHALATION RfC SUMMARY
Critical Effect	Point of Departure*	UF	Chronic RfC
Hemosiderin	BMCL(HEC): 16 mg/m3	10	1.6 mg/m3
deposition in the (PBPK and BMCLio)
liver
Chronic (rat and
mouse) inhalation
study
NTP 2000
*Conversion Factors and Assumptions — For the purposes of deriving an RfC for EGBE,
hemosiderin staining data were evaluated in male and female rats from the 2-year chronic study
by NTP (2000). A 10% extra risk was used as a BMR level for quantal data as this is at or near
the limit of sensitivity in most cancer bioassays and in some noncancer bioassays as well.
Because the hemosiderin staining endpoint was observed in control animals and a 10% increase
in incidence was within the observable range of the data, 10% extra risk was considered an
appropriate BMR and a BMCLio an appropriate POD for derivation of the RfC (U.S. EPA, 2000,
1995).
The AUC was selected as the appropriate dose metric due to the nature of the endpoint,
hemosiderin deposition. This endpoint increased in severity with increased duration (subchronic
to chronic) and is believed to be the result of the cumulative exposure to EGBE as opposed to a
peak event. A BMCLio of 133-[j,mol hour/L for hemosiderin staining in liver of male rats
chronically exposed to EGBE (NTP, 2000) was used as the POD to calculate the RfC. A human
PBPK model (Corley et al., 1997) was used to back-calculate to an HEC of 16 mg/m3 (3.4 ppm)
for the BMCLrec-
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I.B.2. PRINCIPAL AND SUPPORTING STUDIES
NTP (National Toxicology Program). (2000) NTP technical report on the toxicology and
carcinogenesis studies of 2-butoxyethanol (CAS No. 111-76-2) in F344/N rats and B6C3Fi mice
(inhalation studies). Public Health Service, U.S. Department of Health and Human Services;
NTP TR 484; NIH Publ. No. 00-3974. Available from the National Institute of Environmental
Health Sciences, Research Triangle Park, NC and online at
http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/tr484.pdf.
See Section 1.A.2 for a complete description.
I.B.3. UNCERTAINTY FACTORS
UF= 10
A factor of 10 was selected to account for the uncertainty associated with the variability of the
human response (UFH) to the effects of EGBE. Potentially susceptible subpopulations include
individuals with enhanced metabolism or decreased excretion of BAA and individuals whose
RBC membranes are more susceptible to the lysis caused by BAA, the precursor step to
developing hemosiderin staining in the liver. Human in vitro studies suggest that the elderly and
patients with fragile RBCs would not be more sensitive to the hemolytic effects of EGBE than
normal adults. Laboratory animal studies suggest that older animals are more sensitive than
neonates and that females are more sensitive than males. While developmental studies do not
reveal increased susceptibility in infants, none of the developmental studies examined fetal or
infant blood for signs of effects from prenatal exposure to EGBE. Additionally, human
responses to EGBE have not been observed under a broad range of exposure conditions (e.g.,
repeated or long-term exposures) and potentially sensitive subjects (e.g., individuals predisposed
to hemolytic anemia or infants).
A factor of 1 was selected to account for the uncertainty associated with interspecies variability
resulting from toxicodynamic and toxicokinetic differences between animals and humans (UFA).
Traditionally, these components (toxicodynamic and toxicokinetic) are individually represented
by partial UFs of 3 for a total UF of 10 in the absence of chemical-specific information; thus,
application of a full UF of 10 would depend on two areas of uncertainty (i.e., toxicokinetic and
toxicodynamic uncertainties). In this assessment, the toxicokinetic uncertainty is addressed by
the determination of an HEC, using a combination of measured internal blood levels in the test
animals and PBPK modeling. A value of 1 was selected for the toxicokinetic portion of the UFA.
Regarding toxicodynamics, in vivo (Carpenter et al., 1956) and in vitro (Udden, 2002; Udden
and Patton, 1994; Ghanayem and Sullivan, 1993) studies indicate that humans may be
significantly less sensitive than rats to the hematological effects of EGBE. A value of 1 was
selected for the toxicodynamic portion of the UFA.
A factor to account for extrapolation from subchronic to chronic exposure (UFS) was not needed
because the RfC was derived from a chronic inhalation study.
A factor to account for the extrapolation from a LOAEL to a NOAEL (UFL) was not applied
because the current approach is to address this extrapolation as one of the considerations in
selecting a benchmark response (BMR) for BMD modeling. In this case, EPA concluded a 10%
increase in hemosiderin staining, indicating a precursor to an adverse effect, is appropriate for
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use in deriving the RfC under the assumption that it represents a minimal biologically significant
change.
A factor of 1 was selected to account for deficiencies in the database (UFD). Chronic and
subchronic studies are available for two species (rats and mice), and several reproductive and
developmental studies, including a two-generation reproductive toxicity study. There are also
limited human studies available following short-term inhalation exposure.
I.B.4. ADDITIONAL STUDIES/COMMENTS
See Section l.A.4. for additional information.
I.B.5. CONFIDENCE IN THE CHRONIC INHALATION RfC
Study — High
Data Base — Medium to high
RfC — Medium to high
The overall confidence in the RfC is medium to high because the RfC was derived from
internal dose measures (PBPK method and combined PBPK/BMC method) which account for
pharmacokinetic differences between rats and humans using PBPK models (Corley et al., 2005,
1997; Lee et al., 1998) and actual measurements of internal blood concentrations in test animals
of interest were used (Dill et al., 1998). There is high confidence in the NTP (2000) study
because it was a chronic study, employed both male and female rats and mice, had a wide range
of exposure levels, and animals were observed twice daily. There is medium-to-high confidence
in the database, because data are available for a variety of animal species, including humans.
Confidence is not high, because the potential for effects in humans from repeat, long-term
exposures has not been investigated.
	I.B.6. EPA DOCUMENTATION AND REVIEW OF THE CHRONIC INHALATION
RfC
Source Document — U.S. EPA (2009) Toxicological review of ethylene glycol monobutyl ether.
This document was provided for review to EPA scientists, interagency reviewers from
other federal agencies and White House offices, and the public, and peer reviewed by
independent scientists external to EPA. A summary and EPA's disposition of the comments
received from the independent external peer reviewers and from the public is included in
Appendix A of the Toxicological Review of Ethylene Glycol Monobutyl Ether (U.S. EPA, 2009).
I.B.7. EPA CONTACTS
Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in
general, at (202) 566-1676 (phone), (202) 566-1749 (fax), or hotline.iris@epa.gov (email
address).
II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
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Substance Name — Ethylene glycol monobutyl ether (EGBE)
CASRN — 111-76-2
Section II. Last Revised — 00/00/0000
This section provides information on three aspects of the carcinogenic assessment for the
substance in question: the weight-of-evidence judgment of the likelihood that the substance is a
human carcinogen, and quantitative estimates of risk from oral and inhalation exposure. Users
are referred to Section I of this file for information on long-term toxic effects other than
carcinogenicity.
The rationale and methods used to develop the carcinogenicity information in IRIS are
described in the Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a) and the
Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens
(U.S. EPA, 2005b). The quantitative risk estimates are derived from the application of a low-
dose extrapolation procedure, and are presented in two ways to better facilitate their use. First,
route-specific risk values are presented. The "oral slope factor" is a plausible upper bound on
the estimate of risk per mg/kg-day of oral exposure. Similarly, a "unit risk" is a plausible upper
bound on the estimate of risk per unit of concentration, either per [j,g/L drinking water (see
Section II.B. 1.) or per (j,g/m3 air breathed (see Section II.C. 1.). Second, the estimated
concentration of the chemical substance in drinking water or air when associated with cancer
risks of 1 in 10,000, 1 in 100,000, or 1 in 1,000,000 is also provided.
This assessment revises the current carcinogenicity assessment of 1999 in which the
human carcinogen potential could not be determined at that time
	II.A. EVIDENCE FOR HUMAN CARCINOGENICITY
II.A.1. WEIGHT-OF-EVIDENCE CHARACTERIZATION
Under the Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a), EGBE is
deemed "not likely to be carcinogenic to humans" at environmental concentrations at or below
the RfD and RfC, based on laboratory animal evidence, mode-of-action information, and limited
human study information. The available data indicate that carcinogenic effects from EGBE are
not likely to occur in humans in the absence of the critical noncancer effects, including hepatic
hemosiderin staining and irritant effects at the portal of entry, and are not likely to be
carcinogenic to humans exposed at levels at or below the RfC and RfD values established in this
assessment. Carpenter et al. (1956) reported that no changes in erythrocyte osmotic fragility
were found in human subjects exposed to up to 195 ppm (942 mg/m3; -600 times the RfC) for
two 4-hour periods separated by a 30-minute break. At oral doses of 400-500 mg/kg with a one-
time bolus dose, hematuria has been noted in two human case reports. This dose is 3,000-3,500
times the RfD and would need to be sustained for a significant period of time to produce
hemosiderin deposition. This is unlikely to occur because the primary response of humans to
high oral doses of EGBE, as shown in the case studies, is metabolic acidosis, which, if not
treated, can lead to shock and eventually death. No information is available on the carcinogenic
effects of EGBE via the oral or inhalation route in humans. A 2-year inhalation bioassay with
mice and rats (NTP, 2000) reported tumors of the liver in male mice, forestomach tumors in
female mice, and tumors of the adrenal medulla in female rats. Non-neoplastic effects in rats
included hyaline degeneration of the olfactory epithelium and Kupffer cell pigmentation. Non-
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neoplastic effects in mice included forestomach ulcers and epithelial hyperplasia, hematopoietic
cell proliferation, Kupffer cell pigmentation, hyaline degeneration of the olfactory epithelium
(females only), and bone marrow hyperplasia (males only).
EGBE has been tested in conventional genotoxicity tests for its potential to induce gene
mutations in vitro and for cytogenicity in both in vitro and in vivo assays. The available data do
not support a mutagenic or clastogenic mechanism for EGBE. Two laboratories (Elias et al.,
1996; Hoflack et al., 1995) reported weak genotoxicity responses in vitro at high treatment
concentrations, but results were not replicated in five other labs reporting negative results.
The hypothesized MOA for the tumors observed following EGBE treatment involves exposure to
high doses for prolonged periods of time. The weight of evidence indicates that EGBE is not
likely to be carcinogenic to humans at expected environmental concentrations.
II.A.2. HUMAN CARCINOGENICITY DATA
There are currently no human studies addressing the potential carcinogenicity of EGBE.
II.A.3. ANIMAL CARCINOGENICITY DATA
NTP (2000) conducted a 2-year inhalation study on EGBE in both genders of F344/N rats
and B6C3Fi mice. Rats (50/gender/group) were exposed to concentrations of 0, 31, 62.5, and
125 ppm (0, 150, 302, and 604 mg/m3) and mice (50/gender/group) were exposed to
concentrations of 0, 62.5, 125, and 250 pm (0, 302, 604, and 1,208 mg/m3). The NTP report
stated that the highest exposure was selected to produce a 10-15% depression in hematologic
indices and survival was significantly decreased in male mice at 125 and 250 ppm (54.0 and
53.1%, respectively). While the NTP researchers report that no effect on survival was observed
in rats, the female rats appeared to show a trend toward decreased survival that may have been
attributable to the hematological effects. Mean body weights of rats exposed to 31 and 62.5 ppm
were similar to those of control animals. Mean body weights of the exposed mice were generally
less than for controls, with females experiencing greater and earlier reductions. From week 17 to
the end of the study, the mean body weights of 125 ppm female rats were generally less than
those of controls.
At the end of the 2-year chronic bioassay (NTP, 2000), neoplastic effects were observed
in female rats and in male and female mice. In female rats, the combined incidence of benign
and/or malignant pheochromocytoma of the adrenal medulla was 3/50, 4/50, 1/49, and 8/49. The
incidence in the high-dose group (16%) did not represent a statistically significant increase over
the chamber control group (6%), but it exceeded the historical control (6.4 ± 3.5%; range 2-
13%>) for this effect.
The low survival rate in male mice exposed to 125 and 250 ppm EGBE may have been
due to carcinogenic effects in the liver. A high rate of hepatocellular carcinomas was found in
these exposure groups (10/50 [control], 11/50, 16/50, 21/50); the increase at the high-exposure
level was statistically significant (p < 0.01). However, when hepatocellular adenomas and
carcinomas were combined, no significant increase was observed in any exposure group. The
incidence of hemangiosarcomas in males exposed to 250 ppm (8%>) was also significantly
increased (p = 0.046) relative to chamber controls (0/50, 1/50, 2/49, 4/49) and exceeded the
range of historical controls (14/968; 1.5 ± 1.5%; range 0-4%). No significant increases in
benign or malignant hepatocellular tumors or hemangiosarcomas were noted in the female mice,
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and the incidence of hepatocellular adenomas actually decreased significantly (p < 0.05) in
relation to the control chamber group (16/50, 8/50, 7/49, 8/49). It should be noted that in light of
the high survival rate of the exposed female mice relative to controls (29/50, 31/50, 33/50,
36/50), the high exposure of 250 ppm may not have provided the maximum tolerated dose.
Forestomach squamous cell papillomas and carcinomas, combined, were significantly
increased (trend test = 0.003) in female mice relative to the chamber control group (0/50, 1/50,
2/50, 6/50). The incidence of these tumor types (12%) at the highest exposure level was also
statistically significant and exceeded the range for the occurrence of these tumors in historical
controls (0.9 ± 1.1%; range 0-3%). The first incidence of these tumors appeared in the group
exposed to 250 ppm at 582 days, as compared to 731 days at 62.5 and 125 ppm, indicating a
decreased latency period in the highest exposure group. While the incidence of these types of
forestomach tumors was not significantly increased over controls in male mice (1/50, 1/50, 2/50,
2/50), the incidence of squamous cell papillomas (4%) in the two highest exposure groups
exceeded the range for historical controls (0.5 ± 0.9%; range 0-2%). The increased incidence of
forestomach neoplasms in males, as in females, occurred in groups with ulceration and
hyperplasia.
The NTP (2000) study concluded that there was no evidence showing carcinogenic
activity in male F344/N rats and equivocal evidence of carcinogenic activity in female F344/N
rats, based on increased combined incidences of benign (mainly) and malignant pheochromo-
cytoma of the adrenal medulla. The researchers reported some evidence of carcinogenic activity
in male B6C3Fi mice based on increased incidences of hemangiosarcoma of the liver and an
increase in the incidence of hepatocellular carcinoma, as well as some evidence of carcinogenic
activity in female B6C3Fi mice based on increased incidence of forestomach squamous cell
papilloma (mainly) or carcinoma.
With respect to the pheochromocytomas reported in female rats, while the data showed a
positive trend (p = 0.044) and the high-dose tumor frequencies (16%) were above the upper
range of historical controls (13%), the tumor incidence data were not statistically significant.
Further, the NTP (2000) report noted that pheochromocytomas can be difficult to distinguish
from non-neoplastic adrenal medullary hyperplasia. The presence of mild-to-moderate
compression of the adjacent tissue is a primary criterion used to distinguish pheochromocytomas
from medullary hyperplasia; most tumors observed were small and not substantially larger than
the more severe grades of adrenal medullary hyperplasia. Interpretation of these tumors should
be done cautiously. Given the marginal dose response, lack of tumor evidence in any other organ
system of the rats, and reported difficulties in distinguishing pheochromocytomas from non-
neoplastic adrenal medullary hyperplasia, this tumor type was not given significant weight in the
qualitative or quantitative assessment of EGBE cancer potential.
II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Although weakly genotoxic responses have been obtained in two laboratories (Elias et al.,
1996; Hoflack et al., 1995), EGBE is not expected to be mutagenic or clastogenic based on the
available data. The NTP reported negative responses for mutagenicity when EGBE was tested in
Salmonella typhimurium strains TA97, TA98, TA100, TA1535, and TA1537 at up to
10 mg/plate with and without metabolic activation (Zeiger et al., 1992). However, Hoflack et al.
(1995) reported that at 38 (amol/plate (4.5 mg/plate), EGBE induced a weak mutagenic response
in salmonella tester strain TA97a in the absence of S9 mix (Hoflack et al., 1995). The work of
Hoflack and colleagues was repeated by Gollapudi et al. (1996), and EGBE was found to be
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negative in these tester strains when evaluated at 0.5, 1.0, 2.5, 5.0, 8.5, and 10 mg/plate in the
presence and absence of Aroclor-induced rat liver S9 mix. Thus, the weak positive result
reported in salmonella TA97a by Hoflack et al. (1995) is unconfirmed. A plausible explanation
put forth by Gollapudi et al. (1996) is that, given the sensitivity of the Ames test, perhaps the
weak positive result reported by Hoflack et al. (1995) is attributed to an impurity in their test
material.
Elias et al. (1996) reported that EGBE did not induce chromosomal aberrations in
Chinese hamster V79 fibroblast cells but that EGBE, at treatment concentrations of >8.5 mM,
weakly induced sister chromatid exchanges (SCEs) and micronuclei (MN) and potentiated the
clastogenicity induced by methyl methanesulfonate. Elias et al. (1996) also reported that EGBE
weakly induced aneuploidy (numerical chromosomal anomalies) in V79 cells; however, this
response was found at very high concentrations (16.8 mM EGBE).
When tested at doses nearing toxicity, EGBE and its metabolite butoxyacetaldehyde
(BAL) were not mutagenic in an in vitro gene mutation assay using Chinese hamster ovary
(CHO) cells (CHO-AS52) (Chiewchanwit and Au, 1995). In contrast, Elias et al. (1996)
reported that both EGBE and BAL weakly induced gene mutations in Chinese hamster V79 cells
only at high treatment concentrations (>7.5 mg/mL). It should be noted that Chiewchanwit and
Au (1995) reported high cytotoxicity at 38.1 mM EGBE (4.5 mg/mL). The gene mutation data
presented by Elias et al. (1996) is in graphic form only with mean values and no SDs presented.
The presence or absence of cytotoxicity was not reported. BAL was also tested for induction of
deoxyribonucleic acid (DNA) damage in the mouse endothelial cell line, SVEC4-10, using the
comet assay. BAL failed to produce a statistically significant increase in DNA strand breaks at
any of the concentrations or time points examined (Klaunig and Kamendulis, 2005, 2004; Reed
et al., 2003). Other lines of evidence indicate that direct interaction of BAL with the DNA
molecules does not play a significant role in the carcinogenic activity of EGBE. First, BAL
causes cytotoxicity at levels associated with chromosome effects, and cytotoxicity itself can have
effects that result in chromosome damage, such as reduction in the repair of SCEs. Second,
acetaldehyde is recognized as "weakly mutagenic" and structural comparisons of the aldehyde
metabolites of glycol ethers shows that longer-chain aldehydes such as BAL are less mutagenic
(Chiewchanwit and Au, 1995). Third, if BAL were a stable mutagenic metabolite in any of the in
vitro assays exposed to EGBE, one would expect them to give positive results; however, the
results were generally negative. Elias et al. (1996) suggested that the V79 cells possess neither
ALDH nor alcohol dehydrogenase. The relevance of these studies, or of any systems that lack
these enzymes, is of limited value in elucidating the MOA of toxicity in biological systems that
possess these enzymes. BAA has been found negative for reverse mutations in S. typhimurium
his" with and without metabolic activation (Hoflack et al., 1995). Concentrations of up to
8 (amol/plate were tested, and dose was limited by toxicity. BAA (up to 10 mM) was also found
negative for induction of DNA damage in SVEC4-10 mouse endothelial cells (Klaunig and
Kamendulis, 2005) and in an SCE assay in V79 cells (Elias et al., 1996). BAA was weakly
positive for aneuploidy in V79 cells at 0.38 mM and positive for MN induction in the same cell
line at 10 mM, as reported by Elias et al. (1996). As noted above, the data means are presented
in graphic form without SDs and cannot be critically evaluated; no cytotoxicity data are reported.
EGBE did not increase the incidence of MN in the bone marrow cells of male mice or
rats (NTP, 1996). Animals were given three intraperitoneal injections of EGBE 24 hours apart
and sacrificed 24 hours after the last injection; rats were dosed at 0, 7, 14, 28, 56, 112.5, 225, or
450 mg/kg and mice were dosed at 0, 17, 34, 69, 137.5, 275, or 550 mg/kg (NTP, 1996). There
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was high mortality (2/5 mice survived) in mice injected with 1,000 mg/kg doses of EGBE. Keith
et al. (1996) treated Sprague-Dawley rats and transgenic FVB/N mice carrying the v-Ha-ras
oncogene with a single oral dose of 120 mg/kg EGBE; there was no increase in DNA adducts in
the brain, liver, kidney, testes, or spleen of the rats, and no changes in DNA methylation patterns
in either species.
	II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL
EXPOSURE
No reliable human epidemiological studies or chronic oral animal studies are available
that address the potential carcinogenicity of EGBE. However, the NTP (2000) performed a 2-
year inhalation bioassay with rats and mice and found no evidence of carcinogenic activity in
male F344/N rats and equivocal evidence of carcinogenic activity in female F344/N rats, based
on increased combined incidences of benign and malignant pheochromocytoma (mainly benign)
of the adrenal medulla. The researchers reported some evidence of carcinogenic activity in male
B6C3Fi mice, based on an increased incidence of hemangiosarcoma of the liver and an increase
in the incidence of hepatocellular carcinoma that may have been exposure related. They also
reported some evidence of carcinogenic activity in female B6C3Fi mice, based on an increased
incidence of forestomach squamous cell papilloma or carcinoma (mainly papilloma).
The MO As presented for the animal tumors indicate that both high doses and sustained
periods of exposure are necessary for the carcinogenic response. The available human
exposure/response information indicates that these conditions are unlikely to occur because the
primary response of humans to high oral doses of EGBE, as shown in the case studies, is
metabolic acidosis, which, if not treated, can lead to shock and eventually death. Further, based
on simulations from PBPK modeling, the maximum blood concentrations of BAA that could be
produced in humans following exposure to a saturated atmosphere of EGBE would be below
those needed to produce hemolysis (Corley et al., 2005a).
The available data indicate that carcinogenic effects from EGBE are not likely to occur in
humans in the absence of the critical noncancer effects, including hepatic hemosiderin staining
and irritant effects at the portal of entry, and are not likely to be carcinogenic to humans exposed
at levels at or below the RfD values established in this assessment. Based on its physical-
chemical properties, toxicokinetic and dynamic factors, and MOA information, under existing
EPA guidelines (U.S. EPA, 2005a), EGBE is judged not likely to be carcinogenic to humans at
expected environmental concentrations.
Following the U.S. EPA (2005a) Guidelines for Carcinogen Risk Assessment, a nonlinear
approach to dose-response assessment is taken for agents, such as EGBE, for which the most
plausible mode of action at low doses is consistent with nonlinearity. The RfD of 0.1 mg/kg-day
derived in Section 5.2 of the Toxicol ogical Review represents the outcome of nonlinear
assessment based on hemolytic effects (i.e., hemosiderin deposition) associated with oral and
exposure to EGBE. Doses (or concentrations) of EGBE below the RfD would not be expected to
produce hemolytic effects (i.e., hemosiderin depostition) and is therefore not expected to produce
any increase in cancer risk.
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_II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM
INHALATION EXPOSURE
No reliable human epidemiological studies are available that address the potential
carcinogenicity of EGBE. The NTP (2000) performed a 2-year inhalation bioassay with rats and
mice and found no evidence of carcinogenic activity in male F344/N rats and equivocal evidence
of carcinogenic activity in female F344/N rats, based on increased combined incidences of
benign and malignant pheochromocytoma (mainly benign) of the adrenal medulla. The
researchers reported some evidence of carcinogenic activity in male B6C3Fi mice, based on an
increased incidence of hemangiosarcoma of the liver and an increase in the incidence of
hepatocellular carcinoma that may have been exposure related. They also reported some
evidence of carcinogenic activity in female B6C3Fi mice, based on an increased incidence of
forestomach squamous cell papilloma or carcinoma (mainly papilloma).
The MO As presented for the animal tumors indicate that both high doses and sustained
periods of exposure are necessary for the carcinogenic response. The available human
exposure/response information indicates that these conditions are unlikely to occur because the
primary response of humans to high oral doses of EGBE, as shown in the case studies, is
metabolic acidosis, which, if not treated, can lead to shock and eventually death. Further, based
on simulations from PBPK modeling, the maximum blood concentrations of BAA that could be
produced in humans following exposure to a saturated atmosphere of EGBE would be below
those needed to produce hemolysis (Corley et al., 2005a).
The available data indicate that carcinogenic effects from EGBE are not likely to occur in
humans in the absence of the critical noncancer effects, including hepatic hemosiderin staining
and irritant effects at the portal of entry, and are not likely to be carcinogenic to humans exposed
at levels at or below the RfC values established in this assessment. Based on its physical-
chemical properties, toxicokinetic and dynamic factors, and MOA information, under existing
EPA guidelines (U.S. EPA, 2005a), EGBE is judged not likely to be carcinogenic to humans at
expected environmental concentrations.
Following the U.S. EPA (2005a) Guidelines for Carcinogen Risk Assessment, a nonlinear
approach to dose-response assessment is taken for agents, such as EGBE, for which the most
plausible mode of action at low doses is consistent with nonlinearity. The RfC of 1.6 mg/m3
derived in Section 5.1 of the Toxicol ogical Review represents the outcome of a nonlinear
assessment based on hemolytic effects (i.e., hemosiderin deposition) associated with inhalation
exposures to EGBE. Doses (or concentrations) of EGBE below the RfC would not be expected
to produce hemolytic effects (i.e., hemosiderin depostition) and is therefore not expected to
produce any increase in cancer risk.
II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY
ASSESSMENT)
II.D.1. EPA DOCUMENTATION
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Source Document — U.S. EPA (2009) Toxicological review of ethylene glycol monobutyl ether.
This document has been provided for review to EPA scientists, interagency reviewers
from other federal agencies and White House offices, and the public, and peer reviewed by
independent scientists external to EPA. A summary and EPA's disposition of the comments
received from the independent external peer reviewers and from the public is included in
Appendix A of the Toxicological Review of Ethylene glycol monobutyl ether (U.S. EPA, 2009).
II.D.2. EPA REVIEW
II.D.3. EPA CONTACTS
Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in
general, at (202) 566-1676 (phone), (202) 566-1749 (fax), or hotline.iris@epa.gov (email
address).
III.	[reserved]
IV.	[reserved]
V.	[reserved]
VI. BIBLIOGRAPHY
Ethylene glycol monobutyl ether (EGBE)
CASRN — 111-76-2
Section VI. Last Revised — 00/00/0000
	VI.A. ORAL RfD REFERENCES
Bauer, P; Weber, M; Mur, JM; et al. (1992) Transient non-cardiogenic pulmonary edema
following massive ingestion of ethylene glycol butyl ether. Intensive Care Med 18:250-251.
Burkhart, KK; Donovan, JW. (1998) Hemodialysis following butoxyethanol ingestion. Clin
Toxicol 36:723-725.
Carpenter, CP; Pozzani, UC; Wiel, CS; et al. (1956) The toxicity of butyl cellosolve solvent.
AMAArchlnd Health 14:114-131.
Cohen, AD; Cagnano, E; Vardy, DA. (2001) Cherry angiomas associated with exposure to
bromides. Dermatology 202(l):52-53.
Corley, RA; Bormett, GA; Ghanayem, BI. (1994) Physiologically-based pharmacokinetics of
2-butoxyethanol and its major metabolite, 2-butoxyacetic acid, in rats and humans. Toxicol Appl
Pharmacol 129:61-79.
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Corley, RA; Markham, DA; Banks, C; et al. (1997) Physiologically-based pharmacokinetics and
the dermal absorption of 2-butoxyethanol vapors by humans. Toxicol Appl Pharmacol 39:120-
130.
Dean, BS; Krenzelok, EP. (1991) Critical evaluation of pediatric ethylene glycol monobutyl
ether poisonings. Vet Hum Toxicol 33:362.
Firooz, A; Komeili, A; Dowlati, Y. (1999) Eruptive melanocytic nevi and cherry angiomas
secondary to exposure to sulfur mustard gas. J Am Acad Dermatol 40(4):646-647.
Ghanayem, BI; Sullivan, CA. (1993) Assessment of the hemolytic activity of 2-butoxyethanol
and its major metabolite, butoxyacetic acid, in various mammals including humans. Hum Exp
Toxicol 12:305-311.
Gijsenbergh, FP; Jenco, M; Veulemans, H; et al. (1989) Acute butylglycol intoxication: a case
report. Hum Toxicol 8:243-245.
Gualtieri, JF; Harris, CR; Corley, RA; et al. (1995) Multiple 2-butoxyethanol intoxications in the
same patient: clinical findings, pharmacokinetics, and therapy. J Toxicol Clin Toxicol
33(5):550—551.
Gualtieri, JF; DeBoer, L; Harris, CR; et al. (2003) Repeated ingestion of 2-butoxyethanol: case
report and literature review. J Toxicol Clin Toxicol 41:57-62.
Haufroid, V; Thirion, F; Mertens, P; et al. (1997) Biological monitoring of workers exposed to
low levels of 2-butoxyethanol. Int Arch Occup Environ Health 70:232-236.
Jakasa, I; Mohammadi, N; Kruse, J; et al. (2004) Percutaneous absorption of neat and aqueous
solutions of 2-butoxyethanol in volunteers. Int Arch Occup Environ Health 77:79-84.
Jones, K; Cocker, J; Dodd, LJ; et al. (2003) Factors affecting the extent of dermal absorption of
solvent vapors: a human volunteer study. Ann Occup Hyg 47:145-150.
NTP (National Toxicology Program). (2000) NTP technical report on the toxicology and
carcinogenesis studies of 2-butoxyethanol (CAS No. 111-76-2) in F344/N rats and B6C3F1 mice
(inhalation studies). Public Health Service, U.S. Department of Health and Human Services;
NTP TR 484; NIH Publ. No. 00-3974. Available from the National Institute of Environmental
Health Sciences, Research Triangle Park, NC and online at
http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/tr484.pdf (accessed September 21, 2009).
Osterhoudt, KC. (2002) Fomepizole therapy for pediatric butoxyethanol intoxication. J Toxicol
Clin Toxicol 40:929-930.
Rambourg-Schepens, MO; Buffet, M; Bertault, R; et al. (1988) Severe ethylene glycol butyl
ether poisoning. Kinetics and metabolic pattern. Hum Toxicol 7:187-189.
Raymond, LW; Williford, LS; Burke, WA. (1998). Eruptive cherry angiomas and irritant
symptoms after one acute exposure to the glycol ether solvent 2-butoxyethanol. J Occup
Environ Med 40:1059-1064.
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U.S. EPA (Environmental Protection Agency). (2009) Toxicological review of ethylene glycol
monobutyl ether. Washington, DC: National Center for Environmental Assessment.
Udden, MM. (2002) In vitro sub-hemolytic effects of butoxyethanol acid on human and rat
erythrocytes. Toxicol Sci 69:258-264.
Udden, MM; Patton, CS. (1994) Hemolysis and decreased deformability of erythrocytes exposed
to butoxyacetic acid, a metabolite of 2-butoxyethanol. I. Sensitivity in rats and resistance in
normal humans. J Appl Toxicol 14:91-96.
	VI.B. INHALATION RfC REFERENCES
Carpenter, CP; Pozzani, UC; Wiel, CS; et al. (1956) The toxicity of butyl cellosolve solvent.
AMAArchlnd Health 14:114-131.
Corley, RA; Bormett, GA; Ghanayem, BI. (1994) Physiologically based pharmacokinetics of 2
butoxyethanol and its major metabolite, 2 butoxyacetic acid, in rats and humans. Toxicol Appl
Pharmacol 129:61-79.
Corley, RA; Markham, DA; Banks, C; et al. (1997) Physiologically-based pharmacokinetics and
the dermal absorption of 2-butoxyethanol vapors by humans. Toxicol Appl Pharmacol 39:120-
130.
Corley, RA; Grant, DM; Farris, E; et al. (2005) Determination of age and gender differences in
biochemical processes affecting the disposition of 2-butoxyethanol and its metabolites in mice
and rats to improve PBPK modeling. Toxicol Lett 156:127-161.
Dill, JA; Lee, KM; Bates, DJ; et al. (1998) Toxicokinetics of inhaled 2-butoxyethanol and its
major metabolite, 2-butoxyacetic acid, in F344 rats and B6C3F1 mice. Toxicol Appl Pharmacol
153:227-242
Ghanayem, BI; Sullivan, CA. (1993) Assessment of the hemolytic activity of 2-butoxyethanol
and its major metabolite, butoxyacetic acid, in various mammals including humans. Hum Exp
Toxicol 12:305-311.
Lee, KM; Dill, JA; Chou, BJ; et al. (1998) Physiologically based pharmacokinetic model for
chronic inhalation of 2-butoxyethanol. Toxicol Appl Pharmacol 153:211-226.
NTP (National Toxicology Program). (2000) NTP technical report on the toxicology and
carcinogenesis studies of 2-butoxyethanol (CAS No. 111-76-2) in F344/N rats and B6C3F1 mice
(inhalation studies). Public Health Service, U.S. Department of Health and Human Services;
NTP TR 484; NIH Publ. No. 00-3974. Available from the National Institute of Environmental
Health Sciences, Research Triangle Park, NC and online at
http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/tr484.pdf (accessed September 21, 2009).
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U.S. EPA. (Environmental Protection Agency). (1994) Methods for derivation of inhalation
reference concentrations and application of inhalation dosimetry. Office of Research and
Development, Washington, DC; EPA/600/8-90/066F. Available from the National Technical
Information Service, Springfield, VA; PB2000-500023, and http://www.epa.gov/iris/backgr-
d.htm (accessed September 21, 2009).
U.S. EPA (Environmental Protection Agency). (1995) Use of the benchmark dose approach in
health risk assessment. Risk Assessment Forum, Washington, DC; EPA/630/R-94/007. Available
from the National Technical Information Service, Springfield, VA, PB95-213765, and online at
http://cfpub.epa.gov/ncea/raf/raf_pubtitles.cfm?detype=document&excCol=archive (accessed
September 21, 2009).
U.S. EPA (Environmental Protection Agency). (2000) Benchmark dose technical guidance
document [external review draft]. Risk Assessment Forum, Washington, DC; EPA/630/R-
00/001. Available online at http://cfpub.epa.gov/ncea/cfm/
nceapublication.cfm?ActType=PublicationTopics&detype=DOCUMENT&subject=BENCHMA
RK+DOSE&subjtype=TITLE&excCol=Archive (accessed September 21, 2009).
U.S. EPA (Environmental Protection Agency). (2009) Toxicological review of ethylene glycol
monobutyl ether. Washington, DC: National Center for Environmental Assessment.
Udden, MM. (2002) In vitro sub-hemolytic effects of butoxyethanol acid on human and rat
erythrocytes. Toxicol Sci 69:258-264.
Udden, MM; Patton, CS. (1994) Hemolysis and decreased deformability of erythrocytes exposed
to butoxyacetic acid, a metabolite of 2-butoxyethanol. I. Sensitivity in rats and resistance in
normal humans. J Appl Toxicol 14:91-96.
VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Carpenter, CP; Pozzani, UC; Wiel, CS; et al. (1956) The toxicity of butyl cellosolve solvent.
AMAArchlnd Health 14:114-131.
Chiewchanwit T; Au, WW. (1995) Mutagenicity and cytotoxicity of 2-butoxyethanol and its
metabolite, 2-butoxyacetaldehyde, in Chinese hamster ovary (CHO-AS52) cells. Mutat Res
334:341-346.
Corley, RA; Grant, DM; Farris, E; et al. (2005) Determination of age and gender differences in
biochemical processes affecting the disposition of 2-butoxyethanol and its metabolites in mice
and rats to improve PBPK modeling. Toxicol Lett 156:127-161.
Elias, Z; Daniere, MC; Marande, AM; et al. (1996) Genotoxic and/or epigenetic effects of some
glycol ethers: results of different short-term tests. Occup Hyg 2:187-212.
Elliott, BM; Ashby, J. (1997) Review of the genotoxicity of 2-butoxyethanol. Mutat Res
387:89-96.
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Gollapudi, BB; Barber, ED; Lawlor, TE; et al. (1996) Re-examination of the mutagenicity of
ethylene glycol monobutyl ether to Salmonella tester strain TA97a. Mutat Res 370:61-64.
Hoflack, JC; Lambolez, L; Elias, Z; et al. (1995) Mutagenicity of ethylene glycol ethers and of
their metabolites in Salmonella typhimurium his-. Mutat Res 341:281-287.
Keith, G; Coulais, A; Edorh, A; et al. (1996) Ethylene glycol monobutyl ether has neither
epigenetic nor genotoxic effects in acute treated rats and in sub-chronic v-Ha-ras transgenic
mice. Occup Hyg 2:237-249.
Klaunig, JE; Kamendulis, LM. (2004) Effect of 2-butoxyacetaldehyde on the induction of DNA
damage (comet) in rodent endothelial cells. Final report to Ethylene Glycol Ethers Panel,
American Chemistry Council, Arlington, VA; January 14, 2004.
Klaunig, JE; Kamendulis, LM. (2005) Mode of action of butoxyethanol induced mouse liver
hemangiosarcomas and hepatocellular carcinomas. Toxicol Lett 156:107-115.
NTP (National Toxicology Program). (1996) Toxicology and carcinogenesis studies of
acetonitrile (CAS No. 75-05-8) in F344/N rats and B6C3F1 mice (inhalation studies). Public
Health Service, U.S. Department of Health and Human Services; NTP TR 447. Available from
the National Institute of Environmental Health Sciences, Research Triangle Park, NC and online
at http://ehp.niehs.nih.gov/ntp/docs/400-4xx-doc.html (accessed September 21, 2009).
NTP (National Toxicology Program). (2000) NTP technical report on the toxicology and
carcinogenesis studies of 2-butoxyethanol (CAS No. 111-76-2) in F344/N rats and B6C3F1 mice
(inhalation studies). Public Health Service, U.S. Department of Health and Human Services;
NTP TR 484; NIH Publ. No. 00-3974. Available from the National Institute of Environmental
Health Sciences, Research Triangle Park, NC and online at
http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/tr484.pdf (accessed September 21, 2009).
Reed, JM; Kamendulis, LM; Klaunig, JE. (2003) Examination of DNA damage in endothelial
cells following treatment with 2-butoxyethanol using the single cell gel electrophoresis (Comet)
assay. Toxicologist 72(S1):206.
U.S. EPA (Environmental Protection Agency). (2005a) Guidelines for carcinogen risk
assessment. Federal Register 70(66): 17765-18717. Available online at
http://www.epa.gov/cancerguidelines (accessed September 21, 2009).
U.S. EPA (Environmental Protection Agency). (2005b) Supplemental guidance for assessing
susceptibility from early-life exposure to carcinogens. Risk Assessment Forum, Washington,
DC; EPA/630/R-03/003F. Available online at http://www.epa.gov/cancerguidelines (accessed
September 21, 2009).
U.S. EPA (Environmental Protection Agency). (2009) Toxicological review of ethylene glycol
monobutyl ether. Washington, DC: National Center for Environmental Assessment.
Zeiger, E; Anderson, B; Haworth, S; et al (1992) Salmonella in mutagenicity tests. V. Results
form the testing of 311 chemicals. Environ Mol Mutagen 19(Suppl 21):2—141.
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VII. REVISION HISTORY
Ethylene glycol monobutyl ether (EGBE)
CASRN — 111-76-2
File First On-Line — 00/00/0000
Date
Section
Description
04/01/1997 III, IV., Drinking Water Health Advisories, EPA Regulatory Actions, and
V.
12/30/1999 I...VI
12/03/2002 I.A.6.,
IB. 6.,
II.D.2.
02/09/2004 I., II.
Supplementary Data were removed from IRIS on or before April 1997.
IRIS users were directed to the appropriate EPA Program Offices for this
information.
RfD, RfC, and carcinogenicity assessment first on line
Screening-Level Literature Review Findings message has been added.
This chemical is being reassessed under the IRIS Program.
_VIII. SYNONYMS
Ethylene glycol monobutyl ether (EGBE)
CASRN-- 111-76-2
Section VII. Last Revised — 00/00/0000
Bucs, Butoxyethanol, N-Butoxyethanol, 2-Butoxyethanol, 2-Butoxy-l-Ethanol, Butyl
Cellosolve, O-Butyl Ethylene Glycol, Butyl Glycol, Butyl Oxitol, Dowanol EB, Ektasolve
EB, Ethylene Glycol N-Butyl, Gafcol EB, Glycol Butyl Ether, Glycol Ether EB, Glycol Ether
EB Acetate, Glycol Monobutyl Ether, Jeffersol EB, Monobutyl Ether Of Ethylene Glycol,
Monobutyl Glycol Ether, 3-Oxa-l-Heptanol, Poly-SolvEB
10/02/2009
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