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MEMORANDUM

TO: Megan Carroll

Acting Division Director

Environmental Analysis Division

CC: Daniel Bushman, Ph.D.

Analytical Support Branch, Environmental Analysis Division

FROM: Jocelyn Hospital

Acting Branch Chief/Toxicologist 

Analytical Support Branch, Environmental Analysis Division

DATE: July 24, 2015

SUBJECT: Review of the Data in the 2010 Integrated Risk Information System (IRIS)

Toxicological Review of Ethylene Glycol Monobutyl Ether (EGBE)

EPA’s evaluation of the toxicity of ethylene glycol monobutyl ether (EGBE) included a review 

of the 2010 Integrated Risk Information System (IRIS) toxicological review of EGBE (U.S. EPA 

2010). EPA also reviewed the findings of studies published since publication of the IRIS 

toxicological review of EGBE, but EPA found no data relevant to include in this evaluation. 

Below is (1) a summary of the evidence of EGBE’s human health toxicity from the 2010 IRIS 

toxicological review of EGBE and (2) the conclusions reached regarding EGBE’s potential 

toxicity to humans under Section 313 of the Emergency Planning and Community Right-toKnow Act (EPCRA).

Summary of the 2010 IRIS Toxicological Review of EGBE:

1. Toxicokinetics. In humans, EGBE is absorbed and rapidly distributed following 

inhalation, ingestion, or dermal exposure (Kumagai et al. 1999; Johanson and Bohman 

1991; Corley et al. 1994; Corley et al. 1997). Several reviews have described the 

metabolism of EGBE in detail (Commonwealth of Australia, 1996; ECETOC, 1994; EU 

2006). The principal products from EGBE metabolism are butoxyacetic acid (BAA) (rats 

and humans) and the glutamine or glycine conjugate of BAA (humans only). Other 

metabolic products, such as the glucuronide conjugate of EGBE, ethylene glycol, 

butoxyacetaldehyde, and carbon dioxide are minor metabolites or are transitory in nature 

(e.g., butoxyacetaldehyde) and do not accumulate in blood, tissues, or excreta. Alcohol 

dehydrogenase and O-dealkylation by a cytochrome P450 dealkylase (CYP 2E1) are the 

two main pathways of EGBE metabolism observed in rats. BAA is excreted in the urine 

of both rats and humans, which suggests that the creation of BAA through the formation 

of butoxyacetaldehyde by alcohol dehydrogenase is applicable to rats and humans 

(Corley et al. 1997; Corley et al. 2005; Medinsky et al. 1990). The other proposed 

metabolic pathways, however, may only be applicable to rats since the metabolites of 

these pathways (i.e., ethylene glycol, EGBE glucuronide, and EGBE sulfate) have been 
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observed in the urine of rats (Bartnik et al. 1987; Ghanayem et al. 1987), but not in 

humans (Corley et al. 1997). In addition, Corley et al. (1997) confirmed the finding from

Rettenmeier et al. (1993) that approximately two-thirds of the BAA formed in humans is 

conjugated with glutamine and glycine. These pathways, however, have not been 

observed in the rat. Please refer to Figure 3-1 in the 2010 IRIS toxicological review of 

EGBE (U.S. EPA 2010) for the proposed metabolic scheme of EGBE in rats and humans.

Several experimental studies have measured the concentration of BAA in human serum 

and urine following exposure to EGBE. For humans the elimination kinetics of EGBE 

and BAA appear to be independent of the route of exposure, with an approximate halflife of around one hour for EGBE and an approximate half-life of BAA of 3 – 4 hours 

(Johanson 1986; Johanson and Johnsson 1991; Johanson et al. 1988). In a study of 31 

male workers exposed to 2.91 ± 1.30 mg/m3(0.59 ± 0.27 ppm) EGBE, Haufroid et al. 

(1997) reported average post shift urine BAA concentrations of 10.4 mg/g creatinine. In a 

study of 5 healthy male humans exposed to 20 ppm EGBE for 2 hours during light 

exercise, Johanson and Johnsson (1991) reported an average peak blood concentration of 

45 μM BAA (range of 30 to 60μM) 2 – 4 hours after exposure. The authors also reported 

a low renal clearance of BAA relative to the glomerular filtration rate, indicating binding 

of BAA to blood proteins. Laitinen (1998) measured BAA levels in 8 silkscreen printers 

exposed to a mixture of EGBE and 2-butoxyethylacetate. He reported a daily mean 8-

hour air concentration ranging from 0.1 to 0.6 ppm over a 5-day period. Urine samples 

from these workers contained an average of 75 mg BAA/g creatinine immediately after 

their shift and 58 mg BAA/g creatinine 14 – 16 hours post-exposure. Please refer to Table 

3-1 in the 2010 IRIS toxicological review of EGBE (U.S. EPA 2010) for a summary of 

species-specific toxicokinetic parameters.

Several physiologically based pharmacokinetic models for EGBE have been developed. 

Some older models have described the kinetics of EGBE for acute human exposure and 

exposure to rats via the ingestion, inhalation, and dermal routes (Johanson 1986; Shyr et 

al. 1993 based on data from Medinsky et al. 1990 and Sabourin et al. 1992; 1993). Newer 

models have extended upon the work of these previous models. Corley et al. (1994) 

described the kinetics of EGBE and BAA in both rats and humans. These authors later 

validated the human dermal exposure model (Corley 1997). Lee et al. (1998) modeled the 

kinetics of EGBE and BAA in mice and rats from an NTP 2-year inhalation bioassay 

(based on data from Dill et al. 1998). Species, gender, age, and exposure concentrationdependent differences in the kinetics of BAA were observed. Corley et al. (2005) built on 

the Lee et al. (1998) model by replacing some model assumptions with experimental data

(Note: the Corley et al. (2005) model, along with the Lee et al. (1998) rat and mouse 

model and Corley et al. (1997) human model were used by EPA to calculate internal 

doses of EGBE in the 2010 IRIS toxicological review of EGBE (U.S. EPA 2010)). 

2. Effects of Acute and Short-Term Exposure. Hematologic and other effects have been 

observed in several acute and short-term oral studies in animals. Ghanayem et al. (1987) 

reported a lowest-observed-adverse-effect level (LOAEL) of 32 mg/kg/day based on 

increased hemoglobin concentrations in the urine and associated hemolytic effects at 

higher doses for both young and adult F344 rats (number not specified) after a single 
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gavage dose of EGBE. Hemolysis and decreases in hemoglobin concentrations and red 

blood cell counts were also reported at 250 mg/kg/day, the only dose tested, in an acute 

oral toxicity study in male F344 rats (number not specified) (Ghanayem and Sullivan 

1993). Grant et al. (1985) reported a LOAEL of 500 mg/kg/day, the lowest dose tested, 

based on hemolytic anemia, reticulocytosis, and increased hematopoiesis in male F344 

rats (N = 24) after administering EGBE by gavage for 4 days. Ghanayem et al. (1992) 

observed similar effects after administering 125 mg/kg/day EGBE to male F344 rats (N =

6) for 12 days. These effects included: significant hemolysis, increased mean corpuscular 

volume, increased ATP concentration, increased reticulocyte counts, and increased 

relative spleen-to-body weight ratios. Gradual recovery, however, was observed over the 

course of treatment. 

Other studies have investigated the impact of EGBE on specific organs and cells. Ezov et 

al. (2002) exposed male and female F344 rats (N = 4) to daily doses of 250 mg/kg/day

EGBE. These authors reported significant morphological changes in red blood cells in 

both males and females, with disseminated thrombosis and infarction mainly observed in 

females consisting of necrosis in several organs. Renal tubular necrosis with hemoglobin

casts was observed in both males and females. Koshkaryev et al. (2003) found that EGBE 

exposure did not affect red blood cell aggregability, and its effect on deformability was 

inconclusive. EGBE did, however, enhance red blood cell adherence to endothelial cells. 

Adherence was highest on day 2 (the first day examined) and decreased over time. Shabat 

et al. (2004) concluded that in EGBE-treated rats, interactions of several factors may 

generate a thrombotic crisis, such as the release of procoagulant factors from destroyed 

red blood cells. These authors also concluded that disturbed blood flow may result from 

alterations in the rheology of red blood cells, including self-aggregation, deformation, 

and adherence to the endothelium of the blood vessel wall. Redlich et al. (2004) observed 

necrosis in the dental pulp of incisors and molars and muscle-cell damage in the tongue 

in EGBE-treated rats. The observed effects were likely the result of ischemia in the blood 

vessels supplying these tissues, rather than a direct cytotoxic effect of EGBE. 

A few short-term studies in mice have also been conducted. Corley et al. (1999)

administered neat EGBE to male and female mice (N = 5) via gavage (no vehicle) for one 

week at doses of 100, 400, or 800 mg/kg/day. The dose in the 100 mg/kg/day group was 

increased to 1,200 mg/kg/day after 2 days. Severe hemolysis and mortality were seen, 

and the 2-week study was terminated after only four doses. Forestomach lesions 

consisting of focal areas of irritation and epithelial hyperplasia were seen at all exposure 

levels in this study. Poet et al. (2003) exposed male and female B6C3F1mice (N = 16) by 

gavage to 400, 800, or 1,200 mg/kg/day of EGBE for 2 days. High levels of mortality 

occurred, after which the doses were halved and then discontinued when survival did not 

improve. Epithelial hyperplasia and inflammation of the forestomach were observed in 

males and females at the higher doses. Mild epithelial hyperplasia was observed in males 

and females at the lower doses. Green et al. (2002) administered a single, daily gavage 

dose of either EGBE or BAA (0, 50, 150, or 500 mg/kg) to female B6C3F1 mice (N = 5) 

for 10 days. Mice were sacrificed 18 hours after the last dose to observe cell proliferation 

in the forestomach and glandular stomach. The authors reported a thickening of the 

keratinized layers or hyperkeratosis of the forestomach (statistics not reported), but a no-
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observed-adverse-effect level (NOAEL) of 500 mg/kg EGBE and 150 mg/kg BAA was 

reported. 

A few studies investigated the effect of EGBE on guinea pigs. Shepard (1994) 

administered a 2,000 mg/kg oral dose of EGBE to guinea pigs, which resulted in 

complete mortality of females and 60% mortality in males. A dose of 1,000 mg/kg 

resulted in a 20% mortality in both males and females. Clinical signs and gross necropsy 

indicated toxicity was due to irritation of the stomach. No evidence of hemolytic toxicity 

was reported. Gingell et al. (1998) investigated the acute oral and inhalation toxicity of 

EGBE in guinea pigs. They administrated 2,000 mg/kg of EGBE by gavage to 5 male and 

female guinea pigs, resulting in excessive mortality in both genders. The authors then 

administered lower doses of 500 or 1,000 mg/kg. The acute oral median lethal dose was 

determined to be 1,414 mg/kg for both genders. No evidence of hematologic effects were 

reported. In the acute inhalation study, the median lethal concentration for a 1-hour 

exposure for guinea pigs was > 633 ppm in males and > 691 ppm in females, as no 

effects were reported after exposure to 633 ppm or 691 ppm of EGBE, respectively. 

Additionally, rats and rabbits exhibit varying degrees of hematotoxicity following dermal 

application of EGBE (Bartnik et al. 1987; Tyler 1984). EGBE has also been found to be 

an ocular irritant when instilled in rabbits (Jacobs and Martens 1989; Kennah et al. 1989).

A few in vitro studies have investigated EGBE’s potential hemolytic effects in human red 

blood cells after acute exposures. Bartnik et al. (1987) reported no hemolysis of human 

red blood cells exposed for three hours to BAA levels up to 15 millimolar (mM). 

Hemolysis was observed in rat red blood cells, however, at BAA levels as low as 1.25 

mM. Udden (2000) incubated human red blood cells with up to 2.0 mM BBA for four 

hours, and the authors observed none of the morphological changes observed in rat red 

blood cells at the same concentration. Udden (2002) reported a significant change in 

human red blood cell deformability at exposure to 7.5 and 10 mM BAA for 4 hours, 

whereas deformability in rat red blood cells was significantly increased at 0.05 mM 

BAA. Mean cellular volume in human blood samples was significantly increased at 10 

mM BAA while mean cellular volume in rats was significantly increased at 0.05mM

BAA.

There are a number of case reports of acute ingestion of EGBE with little or no 

hematologic effects observed (Bauer et al. 1992; Gijsenbergh et al. 1989; Gualtieri et al. 

1995; 2003; Rambourgh-Schepens et al. 1988; Burkhart and Donovan 1998; Osterhoudt 

2002; Dean and Krenzelok 1991). Some other observed effects were likely not directly 

related to hemolysis; however, the cause of the effects cannot be explained based on the 

limited data available. Also, hemodialysis was employed to remove un-metabolized 

EGBE in many of the cases.

One experimental study in humans (Carpenter et al. 1956), observed no effects on red 

blood cell fragility after exposure of two males and one female to up to 195 ppm EGBE 

for 8 hours. 
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3. Carcinogenicity. Under the Guidelines for Carcinogen Risk Assessment (U.S. EPA 

2005), there is suggestive evidence of EGBE’s carcinogenic potential. In a 2-year chronic 

bioassay, NTP (2000) exposed male and female F344 rats to 31, 62.5, or 125 ppm EGBE 

(150, 302, 604 mg/m3). This study also exposed male and female B6C3F1 mice to 62.5, 

125, or 250 ppm EGBE (302, 604, 1208 mg/m3). The authors concluded that there was no 

evidence of carcinogenic activity in male F344 rats and equivocal evidence of 

carcinogenic activity in female F344 rats based on increased combined incidences of 

benign (mainly) and malignant pheochromocytoma of the adrenal medulla at 125 ppm

(approximately 113 mg/kg/day using the species-specific chronic reference values for 

inhalation rate and body weight from U.S. EPA 19881). However, given the marginal 

dose response, lack of tumor evidence in any other organ, and difficulty in distinguishing 

pheochromocytomas from nonneoplastic adrenal medullary hyperplasia, this tumor could 

not be given significant weight in assessment of EGBE’s potential carcinogenicity. The 

NTP (2000) study also concluded that there was some evidence of carcinogenic activity 

in male B6C3F1 mice based on increased incidences of hemangiosarcoma of the liver at 

250 ppm and an increase in the incidence of hepatocellular carcinoma at 125 and 250 

ppm (approximately 182 and 363 mg/kg/day, respectively, using the species-specific 

chronic reference values for inhalation rate and body weight from U.S. EPA 1988). There 

was also some evidence of carcinogenic activity in female B6C3F1 mice based on an 

increased incidence of forestomach squamous cell papilloma (mainly) or carcinoma at 

250 ppm (approximately 365 mg/kg/day using the species-specific chronic reference

values for inhalation rate and body weight from U.S. EPA 1988). 

4. Mutagenicity. EGBE has been tested for its potential for genotoxicity both in vitro and 

in vivo. Available data do not suggest that EGBE is mutagenic or clastogenic (Zeiger et 

al. 1992; Gollapudi et al. 1996; Chiewchanwit and Au 1995; Klaunig and Kamendulis 

2005; NTP 1996; Keith et al. 1996). While two studies reported weak genotoxicity 

responses in vitro at toxic doses (Elias et al. 1996; Hoflack et al. 1995), these findings are 

questionable in light of the limited published information provided in the studies. 

5. Reproductive and Developmental Toxicity. The reproductive and developmental 

toxicity of EGBE has been investigated in a number of oral and inhalation studies in rats, 

mice, and rabbits. In a two-generation reproductive toxicity study, fertility was reduced in 

mice at very high maternally toxic doses (>1,000 mg/kg) (Heindel et al. 1990), but no 

other significant reproductive effects were reported in any study (Nagano et al. 1979; 

1984; Dodd et al. 1983; Doe 1984; Grant et al. 1985; Foster et al. 1987; Exon et al. 1991; 

NTP 1993; 2000). Maternal toxicity related to the hematologic effects of EGBE and 

relatively minor developmental effects have been reported in developmental studies 

(Nelson et al. 1984; Tyl et al. 1984; Hardin et al. 1984; Wier et al. 1987). No teratogenic 

 

1Approximate mg/kg/day = (dose in mg/m3 * species-specific inhalation rate)/(species-specific body weight) * 

(duration of exposure)

Example conversion of chronic inhalation by F344 female rats at 604 mg/m3, 6 hours/day and 5 days/week:

(604 mg/m3 * 0.24 m3/day)/(0.229 kg) * (0.178) = 113 mg/kg/day
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effects were noted in any of the studies. As such, EGBE is not reasonably anticipated to 

be a reproductive or developmental toxicant at moderately low to low doses.

6. Neurotoxicity. There is no evidence of neurotoxicity in any animal studies of EGBE. 

One case study patient demonstrated neurologic deficits after ingesting a product with a 

high dose of EGBE and other chemicals (Burkhart and Donovan 1998). Given the general 

limitations of case studies and the presence of other chemicals, however, EPA cannot

draw conclusions about EGBE’s potential neurotoxicity from this particular study.

7. Other Chronic Toxicity. Hematologic effects and liver toxicity have been observed at 

low doses of EGBE in several animal studies.

NTP (1993) conducted a 13-week study in F344 rats and B6C3F1 mice in which groups 

of 10 animals/gender/species received EGBE in drinking water at doses of 0, 750, 1,500, 

3,000, 4,500, and 6,000 ppm. The corresponding doses in mg/kg/day, based on measured 

drinking water consumption were: 0, 69, 129, 281, 367, or 452 mg/kg/day in male rats; 0, 

82, 151, 304, 363, or 470 mg/kg/day in female rats; 0, 118, 223, 553, 676, or 694 

mg/kg/day in male mice; and 0, 185, 370, 676, 861, or 1,306 mg/kg/day in female mice. 

Indications of mild to moderate anemia were observed in both genders. Statistically 

significant hematologic effects in female rats included reduced red blood cell counts and 

hemoglobin concentrations at ≥ 82 mg/kg/day and increased reticulocytes, decreased 

platelets, and increased bone marrow cellularity at 304 mg/kg/day. Liver effects

including cytoplasmic alterations, hepatocellular degeneration, and pigmentation were 

reported in the mid- and high-dose groups (≥ 129 mg/kg/day for males and ≥ 

151mg/kg/day for females; statistics not reported). Additionally, cytoplasmic alterations 

of liver hepatocytes, were observed in the lowest-dose groups (69 mg/kg/day for males

and 82 mg/kg/day for females). The lack of cytoplasmic granularity of the hepatocytes 

indicates that this response was not due to enzyme induction (Greaves 2000). NTP (1993) 

identified a LOAEL for rats of 750 ppm (approximately 58.6 mg/kg/day calculated using 

water consumption rates and body weights measured during the last week of exposure 

and, therefore, slightly different from those reported by the study authors (U.S. EPA 

2010)) based on decreased red blood cell count and hemoglobin in female rats. A 

NOAEL was not identified.

A reduction in body weight gain at ≥ 3,000 ppm was observed in male and female mice. 

An increase in relative kidney weight was also observed at all doses in female mice.

Body weight reductions followed decreased water consumption. No histopathologic 

changes were noted at any dose level, however, relative kidney weights showed a 

statistically significant increase at 750 and 1,500 ppm in the absence of reduction in body 

weight gain. NTP (1993) identified a LOAEL for mice of 3,000 ppm (approximately 553 

– 676 mg/kg/day calculated using water consumption rates and body weights measured 

during the last week of exposure and, therefore, slightly different from those reported by 

the study authors (U.S. EPA 2010)) based on reduced body weight and body weight gain.
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Dodd et al. (1983) conducted a 90-day subchronic inhalation study using F344 rats 

(16/gender/group) exposed to EGBE for 6 hours/day, 5 days/week at concentrations of 0, 

5, 25, and 77 ppm. After 6 weeks, the 77 ppm female rats had statistically significant 

decreases in red blood cell counts (13%) and hemoglobin concentrations, accompanied 

by an 11% increase in mean corpuscular hemoglobin. The authors reported a LOAEL of 

77 ppm (approximately 70 – 75 mg/kg/day using the species-specific subchronic 

reference values for inhalation rate and body weight from U.S. EPA 1988) based on 

decreases in red blood cell count and hemoglobin concentrations, accompanied by an 

increase in mean corpuscular hemoglobin in both genders. 

NTP (2000) conducted a subchronic study in F344 rats and B6C3F1 mice (10/gender).

Rats and mice 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. 

NTP (2000) identified a LOAEL of 31 ppm (approximately 30 mg/kg/day using the 

species-specific subchronic reference values for inhalation rate and body weight from 

U.S. EPA 1988) in female rats based on decreases in hematocrit, hemoglobin, and red 

blood cell count and a LOAEL of 62.5 ppm (approximately 57 mg/kg/day using the 

species-specific subchronic reference values for inhalation rate and body weight from 

U.S. EPA 1988) in male rats based on a decrease in red blood cell count. Histopathologic 

effects were observed in male and female rats. Effects reported in female rats included 

liver necrosis at 250 ppm and centrilobular degeneration and renal tubular degeneration at 

500 ppm (approximately 243 and 486 mg/kg/day, respectively, using the species-specific 

subchronic reference values for inhalation rate and body weight from U.S. EPA 1988). 

Other effects reported in both genders included: excessive splenic congestion in the form 

of extramedullary hematopoiesis (at 250 ppm in male rats and 125 ppm in female rats; 

approximately 227 and 121 mg/kg/day, respectively, using the species-specific 

subchronic reference values for inhalation rate and body weight from U.S. EPA 1988)), 

hemosiderin accumulation in Kupffer cells (at 125 ppm in male rats and 62.5 ppm in 

female rats; approximately 113 and 61 mg/kg/day, respectively, using the species-specific 

subchronic reference values for inhalation rate and body weight from U.S. EPA 1988)), 

intracytoplasmic hemoglobin (at 125 ppm in male rats and 31 ppm in female rats; 

approximately 113 and 30 mg/kg/day, respectively, using the species-specific subchronic 

reference values for inhalation rate and body weight from U.S. EPA 1988)), hemosiderin 

deposition (at 125 ppm in male rats and 62.5 ppm in female rats; approximately 113 and 

61 mg/kg/day, respectively, using the species-specific subchronic reference values for 

inhalation rate and body weight from U.S. EPA 1988)), and bone marrow hyperplasia (at 

250 ppm in male rats and 62.5 ppm in female rats; approximately 227 and 61 mg/kg/day, 

respectively, using the species-specific subchronic reference values for inhalation rate 

and body weight from U.S. EPA 1988)). For mice, the authors identified a LOAEL of 

62.5 ppm (approximately 87 – 90 mg/kg/day for male and female, respectively, using the 

species-specific subchronic reference values for inhalation rate and body weight from 

U.S. EPA 1988) based on histopathological changes in the forestomach (including: 

necrosis, ulceration, inflammation, and epithelial hyperplasia) in both males and females. 

Signs consistent with the hemolytic effects of EGBE (including: decreased red blood cell 

counts, increased reticulocyte counts, and increased mean corpuscular volume) were also 

observed at 250 and 500 ppm (approximately 350 – 361 mg/kg/day and 699 – 721
8

mg/kg/day in males and females, respectively, using the species-specific subchronic 

reference values for inhalation rate and body weight from U.S. EPA 1988) in male and 

female mice.

NTP (2000) also completed a 2-year inhalation study of EGBE in both F344 rats and 

B6C3F1 mice. In this study, animals were exposed to EGBE for 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 B6C3F1 mice. The authors identified a LOAEL of 31 ppm

(approximately 28 mg/kg/day using the species-specific chronic reference values for 

inhalation rate and body weight from U.S. EPA 1988) in rats based on decreases in 

hematocrit, hemoglobin, and red blood cell count in female rats in a satellite group 

observed at 3 and 6 months. The authors identified 62.5 ppm (approximately 91 

mg/kg/day using the species-specific chronic reference values for inhalation rate and 

body weight from U.S. EPA 1988) as the LOAEL for mice based on hemosiderin 

deposition. 

One long-term occupational study of EGBE was identified in the literature. Haufroid et 

al. (1997) reported a small decrease in hematocrit and increase in mean corpuscular 

hemoglobin in a cross sectional study of 31 workers exposed to an average concentration 

of 0.6 ppm EGBE over 1 to 6 years. The biological significance of these findings, 

however, is unclear as they were within normal clinical ranges and no other measured 

parameters were affected by EGBE exposure.

Conclusions Regarding Human Hazard Potential

There is evidence to indicate that the human red blood cell response to EGBE exposure is less 

than that of rodents, however, this conclusion is based on a relatively small number of in vitro

and short-term human exposure studies with supporting evidence from pharmacokinetic models

(Bartnik et al. 1987; Udden 2000; 2002; Carpenter et al. 1956; Corley et al. 1994; 1997). Little is 

known of the long-term or repeated exposure responses in humans to EGBE. 

In 2010, EPA concluded in the IRIS toxicological review of EGBE that human red blood cells do 

appear capable of responding similarly to the causative EGBE metabolites, albeit at much higher 

exposures (U.S. EPA 2010). The IRIS toxicological review of EGBE employed an interspecies 

uncertainty factor of 1 to derive the reference values for EGBE in part because there was not a 

preponderance of toxicodynamic data in both animals and humans describing why humans are 

less sensitive than rats to the hematologic effects in question (U.S. EPA 2010). Also, EPA 

calculated a human equivalent concentration LOAEL (LOAELHEC) for hematologic effects of 

271 mg/m3(approximately 77 mg/kg/day, assuming constant exposure, an inhalation rate of 20 

m3/day, and a 70 kg human) using pharmacokinetic model estimates (Corley 1994; 1997) of the 

human internal dose equivalent of the toxic metabolite BAA to that estimated for female rats 

exposed to 31 ppm EGBE in the NTP (2000) study (U.S. EPA 2010). In its assessment of EGBE, 

the European Union carried out a slightly different calculation based on the same underlying data 
9

and reported a similar, but slightly higher, human equivalent LOAEL of 474 mg/m3

(approximately 135 mg/kg/day) (E.U. 2006).

Additionally, multiple animal studies by the NTP reported liver toxicity (e.g., cytoplasmic 

alterations of liver hepatocytes at 750 ppm (approximately 69 mg/kg/day) in male rats and 750 

ppm (82 mg/kg/day) in female rats (NTP 1993) and liver necrosis at 250 ppm (approximately 

243 mg/kg/day) in female rats (NTP 2000)) to which humans do not demonstrate decreased 

sensitivity. These findings provide further evidence of EGBE’s potential toxicity to humans at 

moderately low to low doses.

Therefore, the available evidence is sufficient to conclude that EGBE can be reasonably 

anticipated to demonstrate moderately high to high chronic toxicity in humans based on the 

EPCRA Section 313 listing criteria.

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