Environmental Health Perspectives

Vol. 57, pp. 185-191, 1984

Acute and Subchronic Toxicity

of Ethylene Glycol Monobutyl Ether

by Tipton R. Tyler*

The available information on the acute and subchronic toxicity of ethylene glycol monobutyl ether is

reviewed. Data from animal studies have been examined from the standpoint of dose-response relationships

and the sensitivity of various animal species, including man, to the effects of this chemical. In view of

recent findings with other chemically related glycol ethers, particular attention has been given to possible

adverse effects on blood and testicular tissue. In evaluating the hazard that this chemical may pose to man,

consideration has been given to likely routes of exposure and its irritant properties. It is concluded that the

available information continues to support the current ACGIH TWA8-TLV of 25 ppm with a STEL of 75

ppm.

Introduction

Ethylene glycol monobutyl ether (EGBE) has been

studied extensively with respect to establishing exposure conditions at which adverse health effects are

unlikely to occur in humans. Information obtained in

these studies has defined the major organs and tissues

affected by EGBE, established differential response of

various laboratory animal species, and provides a clear

picture of dose-response relationships by various routes

of exposure. In this paper, the acute toxicity of EGBE

and the effects of repeated exposure by oral administration, inhalation of vapor and application to the

skin are reviewed. Recent interest in the toxicity of

monoalkyl glycol ethers has centered around effects on

blood forming tissues and the testes. Therefore, observations in some of the previous studies have been

reevaluated, paying particular attention to detecting

effects on these possible target tissues.

In attempting to assess the potential hazards of

EGBE to humans, the available toxicology information

clearly needs to be evaluated in terms of probable

routes of exposure. Therefore, emphasis has been

placed on studies conducted in laboratory animals by

dermal application and vapor inhalation. Although the

vapor pressure of EGBE (0.6 mm Hg) is lower relative

to that of ethylene glycol monomethyl (EGME) or

monoethyl (EGEE) ether (6 and 4 mm Hg, respectively),

inhalation remains one of the predominant routes of

exposure due to some of the major end uses, i.e.,

*Union Carbide Corporation, Corporate Applied Toxicology, P 0.

Box 8361, South Charleston, WV 25303.

coatings applications. Skin is also a potential significant

route of human exposure, through contact with various

cleaning solutions formulated with EGBE. Ingestion,

on the other hand, is an unlikely primary route of entry

for humans; exceptions include instances of accidental

poisoning or attempts at suicide. However, there appear

to be no reports of human ingestion of EGBE.

Acute Toxicity

The acute (single dose) lethal toxicity of EGBE has

been determined in a number of laboratory animal

species (Table 1). Rabbits appear to be the most

susceptible to the acute induced effects of this material

followed by mice, guinea pigs and rats (1). Carpenter et

al. (1) suggested that the wide intraspecies variation

reported for LD50 values in rats correlates with the

apparently greater susceptibility of older animals as

compared to younger animals, which are four to five

times more resistant to the effects of single oral EGBE

administration.

EGBE is readily absorbed across the skin as indicated by its lethal toxicity in dermal application studies.

Again, rabbits appear to be more susceptible to the

toxic effects of this chemical at a lower dosage level than

rats, when applied to the skin. Although quantitative

data are not available, it is relevant that Saparamedov

(5) submerged the tails of mice (up to two-thirds of their

lengths) into undiluted EGBE for 2-hr periods. No

death, adverse systemic effects or skin irritation was

reported.

The effects of a single inhalation exposure to EGBE

to different animal species are shown in Table 2. Again,
T. R. TYLER

Table 1. Acute toxicity and primary irritancy of EGBE.

Species

Single oral LD50, mg/kg

Rat 530 to 3000

1480

620

2680

Rabbit 320 to 370

Mouse 1230

1170 to 1700

1000 to 1600

Guinea pig 1200

Single percutaneou:

LD50, mL/kg

Rat

Rabbit

Primary irritation,

Rabbit

Mice

5

2.52 (4 hr)

0.45 to 2.00 (24 hr)

0.63 (24 hr)

0.11 (8 hr)

skin

Mild irritation

Mild irritation (grade 2 of 10)

Mild irritation

Primary irritation, eye

Rabbit Severe (grade 8 of 10)

Moderate (grade 4 of 10)

Reference

(1)

(2)

(3)

(4)

(1)

(1)

(3)

(5)

(1)

(7)

(1)

(4)

(6)

(3)

(4)

(5)

(4)

(8)

there is variability in the data, particularly with

respect to the response of rats. Substantially saturated vapor, which approaches a concentration of 1300

ppm (5), killed only one of six rats after an 8-hr

exposure, while a single exposure to a concentration of

375 ppm produced complete mortality in a group of

older animals. Again, this variability has been attributed to the greater susceptibility of older animals.

A consideration of the data from these studies

indicates that EGBE presents a slight to moderate

acute hazard to man by single skin contact or by

swallowing. Results of acute inhalation studies indicate

EGBE to be of moderate toxicity. However, its relatively low vapor pressure and good warning properties,

discussed by Carpenter et al. (1), diminish the inhalation hazard when handled under most foreseeable

situations.

Primary Irritation

EGBE is only mildly irritating to rabbit skin when

applied and left uncovered for a 4-hr period. However,

more prolonged exposure to the undiluted chemical, as

encountered in 24-hr percutaneous toxicity studies,

can lead to moderate irritation characterized by erythema, edema and necrosis (4).

There is conflict with regard to reports on the effects

of EGBE on the eye. Early work by Carpenter and

Smyth (8) indicated that the chemical produced only

moderate irritation when 0.02 mL was instilled into the

conjunctival sac; the response was graded 4 out of a

possible maximum of 10. In a more recent study (4),

instillation of 0.005 mL into rabbit eyes produced severe

corneal injury with iritis. Moderate corneal injury was

observed when 0.5 mL of a 15% aqueous dilution was

Table 2. Effects of single vapor exposure of EGBE to

laboratory animals.

Exposure

level, ppm Response Reference

2400 8 hr: killed 8 of 8 rats (9)

Substantially Rats: LT50 = 9 hr (1)

saturated vapor Guinea pigs: LT50 = 7 hr (10)

( 4300)

800 8 hr: killed 3 of 6 rats (1)

4 hr: killed 0 of 6 rats

700 7 hr: LC50 for mice (11)

500 8 hr: killed 0 of 6 rats (1)

4 hr: killed 1 of 6 rats

375 7 hr: killed 11 of 13 (1)

and 23 of 23 older rats

instilled into the eye, and no injury was noted from a 5%

aqueous dilution. Based on these observations, the

material was graded 8 on the 10-point scale.

Repeated Oral Administration

Results of three studies in which EGBE was administered repeatedly by mouth to rats or mice are given in

Table 3. In an early rat study conducted by Carpenter

and Pozzani (12), decreased weight gain was noted at

dosage levels of 1500 or 300 mg/kg administered in feed

for 90 days. An increase in the relative liver and kidney

weight was reported at 1500 mg/kg, and in relative liver

weight at 300 mg/kg. The value of this study is limited

by a high mortality in all treatment and control groups,

probably caused by a high incidence of pneumonia. It is

of interest to note that when pooled urine from rats fed

EGBE at 1500 or 300 mg/kg for 3 or 6 days was analyzed

by a benzidine test, no hemoglobin was detected.

In a second study (13) decreased weight gain and

increased relative liver and kidney weights were reported at 950 mg/kg. In addition, testicular atrophy was

reported at 950 and 200 mg/kg. The sections of testes

from this study have been recently reviewed and confirm

a treatment-related degeneration and atrophy of the

seminiferous tubules. The lesion was present at 950 and

200 mg/kg, but not in those animals receiving EGBE at

40 or 8 mg/kg. The EGBE used in this study was

manufactured using boron trifluoride (BF3) as a catalyst,

a process which has not been used for the past 15 years.

EGBE so produced is known to contain a number of

impurities not found in current production material

(16); these include crown ethers, which have been

shown to produce testicular atrophy with degeneration

of the germinal epithelium (17), and fluoroethanol.

More recently, mice were given EGBE by gavage over

a 5-week period at dosages of 2000, 1000 and 500 mg/kg

(14,15). At 2000 mg/kg all the animals died. This finding

is consistent with the acute toxicity data presented in

Table 1, which indicates that the acute oral LD50 in mice

lies between 1000 and 1700 mg/kg. In the mice receiving

the test chemical at 1000 and 500 mg/kg, erythrocyte

counts were statistically significantly decreased, but

186
ACUTE AND SUBCHRONIC TOXICITY OF EGBE

Table 3. Effects of repeated peroral administration of EGBE in rats and mice.

Dosage

Experimental concentration,

Species design mg/kg Significant effects Reference

Rats 5/sex/dosage group 1500 Decreased body weight gain; increased relative liver and (12)

EGBE in feed daily kidney weights

for 90 days 300 Increased relative liver weight

80 No observable effects

20 No observable effects

Rats 10/sex/dosage group 950 Decreased body weight gain; increased relative liver (13)

EGBE in feed daily and kidney weights; seminiferous tubule degeneration

for 91 to 93 days 200 Decreased weight gain in males, seminiferous tubule

degeneration

40 No observable effects

8 No observable effects

Mice 5 males/dosage group 2000 Complete mortality (14,15)

administered by 1000 1 of 5 with testicular atrophy, depressed erythrocyte count

gavage 5 days/week 500 Depressed erythrocyte count

for 5 weeks

there was no statistically significant effect on white

blood cell counts, or on body, testicular, liver or kidney

weights. In the 1000 mg/kg group one of five mice

demonstrated seminiferous tubular atrophy.

The data taken from these studies indicate that

repeated oral administration of EGBE will produce

adverse effects on the liver, kidney and erythrocytes. It

is not clear whether the chemical which is available by

current production processes is capable of producing

damage to testicular tissues when administered orally.

The available data concerning this effect is equivocal

with respect to sample purity and a lack of response by

other routes of administration. The lowest dosage at

which any adverse effect was noted was 200 mg/kg in

the rat (testicular effects) and 500 mg/kg in the mouse

(decreased RBC). The no-observable effect level in rats

was 80 mg/kg.

Repeated Inhalation Exposure

Results of repeated inhalation exposures conducted

in various laboratory animal species, along with observations from brief human exposures, are given in Table 4.

The predominant effects observed in rats include reduced body weight gain, hematological changes and

increased absolute and relative kidney and liver weights.

In some of the earliest work with this chemical, Werner

and co-workers identified the red blood cell as one of the

more sensitive indicators of toxicity (20). Using in vitro

methodology, these workers demonstrated that erythrocytes became extremely susceptible to osmotic hemolysis in the presence of low concentrations of the chemical.

This observation was confirmed by extensive in vivo

studies conducted by Carpenter and his co-workers (1),

who demonstrated erythrocyte fragility in the rat,

mouse and rabbit after exposure to EGBE, but could

not demonstrate the effect in the monkey, dog, guinea

pig or human. The lowest exposure level at which

erythrocyte fragility was detected in rats was 62 ppm,

while no effect was noted at 32 ppm. Erythrocyte

fragility, at least in mice, appeared to be transient

with the effect being noted immediately after a 7-hr

exposure, but with recovery during the 17-hr period

between exposures. Mice did not develop a tolerance,

since the effect of EGBE on the erythrocyte was as

great after the 89th exposure as it was after the first

exposure.

The hemolytic effect of EGBE appears to be responsible for the transient hemoglobinuria, or red discolored

urine, noted during the first few days of several of the

animal studies. In all studies where hemoglobinuria has

been noted, it seldom persisted beyond 3 to 5 days of

exposure. Increased liver and kidney weights have also

been noted at higher exposure levels. This effect

appears to be reversible with absolute or relative organ

weights returning to values similar to those in control

animals after a recovery period as short as 1 week. In no

case did exposure to EGBE vapor produce decreased

testicular weight. Histological examination was conducted on testes of rats exposed to concentrations as

high as 250 ppm for 30 exposures (12) and more recently

to 77 ppm for 90 days (19), and on the testes from guinea

pigs exposed at a concentration of 500 ppm for 30 days

(1), a dog exposed to 385 ppm and a monkey exposed to

100 ppm (21). In no case was there any evidence of

treatment-related testicular pathology.

In rats, the lowest exposure concentration of EGBE

which produced any adverse effect was 62 ppm, where

erythrocyte fragility was increased. Exposure to 77

ppm produced transient decreases in weight gain and

erythrocyte count with complete recovery by the completion of the 90-day exposure period. The no observable effect level in rats was 32 ppm. No effects were

observed in guinea pigs exposed to 125 ppm, but

increased erythrocyte fragility was detected in mice

187
T. R. TYLER

Table 4. Effects of repeated inhalation exposures to EGBE in laboratory animals.

Dosage

Experimental concentration,

Species design mg/kg Significant effects Reference

Rats 23/exposure concentrations for 5 hr/day, 320 Decreased erythrocyte count and Hb (18)

5 days/week; groups killed at 1, 3,

or 5 weeks of exposure and at 1 week

post-exposure

Rats 15/sex/exposure concentration for 7

hr/day for 5 days/week for 30

exposures

Rats 4/sex/exposure concentration for 6

hr/day for 15 exposures

Rats 7 to 8/sex exposure concentration for 6

hr/day, 5 days/week for 9 exposures

over 11 days with one of two groups

exposed to 245 ppm killed at 14 days

post-exposure

Rats 16/sex/exposure concentration for 6

hr/day, 5 days/week with groups killed

at 5 and 13 weeks of exposure

Guinea pigs 10 males/exposure concentration for 7

hr/day, 5 days/week for 6 weeks

Guinea pigs 10 males/exposure concentration for 7

hr/day, 5 days/week for 6 weeks

Mice 70 males/exposure concentration for 7

hr/day, for 5 days/week, with groups

killed at 6, 12, and 18 weeks of

exposure and at 6 weeks post-exposure

Dogs 2 exposed 5 hr/day for 5 days/week for

12 weeks and killed 5 weeks postexposure

Humans 3 to 4 subjects exposed for two 4-hr

periods with 30 min rest period

between exposures

concentration; increased reticulocytes;

Recovery during post-exposure period

135 Decreased erythrocyte count and Hb

concentration; increased reticulocytes;

recovery during week 3-5 of exposure

250 Hemoglobinuria in both sexes after first

3 exposures; increased relative liver and

kidney weight

125 Increased relative liver and kidney weights

62 No observable effects

100 Increased erythocyte fragility

50 No observable effects

20 No observable effects

245 Decreased weight gain; hemoglobinuria; decreased

erythrocyte count and Hb concentration;

increased reticulocytes and nucleated RBC;

increased liver weight; substantial recovery of

erythroid values during 14 day recovery;

complete recovery of liver weight

86 Decreased body weight gain in females; decreased

erythrocyte count and Hb concentration;

increased reticulocytes and nucleated

erythrocyte count

20 No observable effects

77 Transient decrease in weight gain of females;

decrease in erythrocyte count in females at 6

weeks but not at 13 weeks of exposure

25 No observable effects

5 No observable effects

250 Increased kidney weight

125 No observable effects

62 No observable effects

500 Increased mortality; decreased body weight

375 Increased mortality; decreased body weight

gain; increased kidney weight

400 Increased erythrocyte fragility; hemoglobinuria

during first 3 exposures; increased liver weight

with recovery during post-exposure

200 Increased erythrocyte fragility; hemoglobinuria

during first 3 exposures; increased liver weight

after 6 weeks of exposure with recovery during

post-exposure

100 Increased erythrocyte fragility

415 Signs of respiratory and eye irritation; decreased

erythrocyte count and Hb concentration;

increased blood urea

200 Nose, throat and eye irritation with taste

disturbances; headache

100 Nose, throat and eye irritation with taste

disturbances; nausea

(12)

(9)

(19)

(19)

(12)

(1)

(1)

(20)

(1)

exposed to 100 ppm. Humans found both 200 ppm and

100 ppm intolerable due to irritancy.

Repeated Dermal Exposure

The results from two repeated skin application studies conducted with New Zealand rabbits are summarized in Table 5. In a 9-day study, EGBE was applied to

the clipped skin of the animals under an occlusive

dressing (22). Different doses were achieved by applying a constant volume of varying concentrations of

aqueous dilutions of the test material. Applications

were made for 5 consecutive days followed by a 2-day

recovery period and then four additional applications

188
ACUTE AND SUBCHRONIC TOXICITY OF EGBE

were made. The animals were killed 14 days after the

ninth application.

Significant findings included decreased rate of body

weight gain in the female rabbits dosed with undiluted

material. These animals also exhibited a decreased

erythrocyte count, hemoglobin (Hb) concentration,

mean corpuscular Hb concentration and an increase in

the mean corpuscular Hb. Hemoglobinuria was noted in

male and female rabbits treated with undiluted EGBE

and in females treated with 50% aqueous dilution.

Erythema and edema were noted at the site of application of the test material in all animals dosed with the

undiluted chemical. Necrosis also developed in these

animals by the sixth study day. In those receiving the

50% aqueous dilution, erythema and edma were also

present with necrosis developing in one of five males

and four of five females. Only mild indications of skin

irritation were reported in the lower two dosage level

groups in which 25%, or 5% aqueous dilutions of EGBE

were applied. There were no differences in the weight

gain of male animals at any dosage level. In addition,

there were no differences in the absolute or relative

weights of organs between the treated male or female

rabbits at any dosage level and the controls. Of note was

one female rabbit treated with undiluted EGBE killed

in extremis on the fifth treatment day. The moribund

condition of this animal could not be attributed to

EGBE application.

Based on the results of the 9-day study, a 13-week

(subehronic) study was conducted under sponsorship of

the Chemical Manufacturers Association. Dosage levels

were 150, 50 and 10 mg/kg body weight (23). In order to

ensure a relatively constant surface area coverage of

test material, aqueous dilutions were prepared which

would allow approximately 1 mL of solution to supply

the appropriate quantity of EGBE, i.e., 42.8% 14.3% or

2.8%. The diluted test material was applied under a

poly (vinylidene chloride) wrap to the clipped skin of

10 rabbits of each sex for each dosage group. Applications were made 6 hr/day for 5 days/week. The animals

remained unrestrained both during and after exposure.

No EGBE-induced changes were noted with respect

to clinical observations, skin irritation, body weight,

body weight changes, food consumption, hematology

values, red blood cell fragility, differential white blood

cell counts, serum chemistry, organ weights, final body

weights or relative organ weights. The only microscopic

pathological changes noted in animals of all groups,

including the control, were related to subelinical parasitic or bacterial infections. Four animals were either

found dead or killed in extremis during the study for

causes unrelated to treatment. These included: one

male from the high dose group found dead on study day

92 from encephalitozoonosis; one female in this group

killed on study day 32 after suffering a broken back; a

male rabbit in the 50 mg/kg group found dead on study

day 15, attributed to a gastric ulcer; and finally, a female

in the 10 mg/kg dosage group found dead due to

pasteurellosis on study day 96.

In summary, the two studies show that adverse

systemic effects from dermal application of EGBE to

rabbits would appear to be dependent both on the

concentration applied and the dosage level employed.

The lowest level at which effects were noted was 180

mg/kg applied as a 50% aqueous dilution, where hemoglobinuria was noted in female rabbits. The highest

no-observable level for systemic effects was 150 mg/kg

applied as a 43% solution. Indeed, at this dosage level

no increased incidence of skin irritation was noted.

Discussion

Over a number of years, extensive animal testing of

EGBE has provided information which may be used to

evaluate the potential for adverse effects in exposed

humans. The most sensitive index of toxicity is the

effect on the red blood cell, although liver and kidney

are also implicated as target organs. EGBE would

Table 5. Effects of repeated application of EGBE to the skin of rabbits.

Experimental

design

5/sex/dosage concentration treated with 1 mL of

100%, 50% 25% or 5% solutions of EGBE under

an occlusive dressing 5 days/week for 6 hr/day

for 9 applications over 11 days; 14 day

observation period after final application

10/sex/dosage level treated with 1 mL of 43%,

14% or 3% solutions of EGBE under an

occlusive dressing; 5 days/week, 6 hr/day for

13 weeks

Dosage

concentration,

mg/kg

360

(undiluted)

180

(50%)

90

(25%)

18

(5%)

150

(43%)

50

(14%)

10

(3%)

Significant effects

Decreased body weight gain and erythropoietic

values in females; hemoglobinuria in males and

females; erythema, edema and necrosis at site

of application; recovery at end of 14-day

observation period

Hemoglobinuria in females; erythema, edema and

necrosis at site of application

Mild skin irritation

Mild skin irritation

No observable systemic effects

No observable effects

No observable effects

Reference

(22)

(23)

189
190 T. R. TYLER

appear to have a specific effect on the erythrocyte

membrane, causing the cell to become more fragile and

have an increased susceptibility to osmotic hemolysis. It

is likely that in exposed animals this increased cellular

fragility leads to intravascular hemolysis which is responsible for the hemaglobinuria noted in several animal studies. Urine discoloration noted in these studies

was transient in nature. Carpenter et al. (1) suggested

that it was only the older erythrocytes which were

susceptible to the effects of EGBE, and that after a loss

of these cells due to lysis during initial exposures, a

younger and less susceptible cell population would be

established. It is possible that the early hemoglobinuria may have played a role in the pathogenesis of the

kidney damage reported in some EGBE animal toxicity

studies (24).

Increased liver and kidney weight, particularly when

expressed as a percentage of body weight, has been the

only other organ finding in laboratory animals exposed

to EGBE.

Although there has been one report of testicular

damage arising from ingestion of EGBE (12), this result

is considered suspect for several reasons. First, the test

chemical may have contained impurities known to produce testicular damage. Second, in a further and more

detailed gavage study no statistically significant decrease in testicular weight or increased incidence of

germinal epithelial cell damage was obtained (15).

Third, testicular effects have not been seen in laboratory animals administered EGBE by other routes i.e.,

inhalation or dermal exposure. Although there is no

analytical data on the test material, it is likely that the

effects produced in testes were the result of impurities

found in EGBE manufactured by a process which is no

longer in use.

The acute percutaneous toxicity of EGBE indicates

that it is readily absorbed across the skin. The dosage

levels at which adverse effects are observed, however,

appear to be influenced by the concentration of the

chemical in the aqueous dilutions employed in the tests.

This suggests that water may influence the ability of the

chemical to pass through the skin barrier. However, it

has been noted that no discernible liquid remains on the

skin at the end of a 6 hr exposure. Therefore, additional

studies may be required to clarify the effect of aqueous

dilution on the skin permeability of EGBE and other

glycol ethers.

Conclusions

EGBE has been tested for its potential to produce

adverse effects in laboratory animals by ingestion,

vapor inhalation and skin penetration. The lowest

dosage level at which effects were noted by ingestion

was 200 mg/kg for 90 days, which produced testicular

effects in rats, and 500 mg/kg for 5 weeks in mice where

a decrease in erythrocyte count was noted. The

significance of the testicular effect is uncertain because

of the possibility that impurities were present in the

test sample which are known to produce germinal

epithelial cell damage. A no-observable effect level of 80

mg/kg was obtained in rats which received the EGBE in

feed for 90 days. The lowest vapor exposure concentration at which effects were noted was 62 ppm (RBC

fragility). Female rats exposed to 77 ppm for 13 weeks

exhibited transient decreased weight gain and a transient decrease in erythrocyte count. An exposure concentration of 100 ppm produced increased erythrocyte

fragility in mice. The no-observable effect level in rats

exposed for 13 weeks was 25 ppm and in guinea pigs

exposed for 6 weeks was 125 ppm. A dosage concentration of 180 mg/kg applied as a 50% aqueous dilution to

the skin of female rabbits for nine applications produced

hemoglobinuria. No observable systemic effects were

noted when 150 mg/kg was applied to the skin of rabbits

for 13 weeks.

Although the rabbit appears to be the most sensitive

species with regard to the acutely induced effects of

EGBE, the rat is more susceptible to repeated exposures and to effects on the erythrocyte. The dog, guinea

pig, monkey and man are resistant to the effects of this

chemical on the erythrocyte. Vapor concentrations of

200 and 100 ppm produce nasal, respiratory and eye

irritations of approximately the same degree. It is

unlikely that humans would tolerate exposure levels of

100 ppm for prolonged periods of time.

The available information on the acute and repeated

exposure toxicity of EGBE to laboratory animals and

man accords with the current ACGIH Threshold Limit

Value (TWA8) of 25 ppm and a short-term exposure limit

of 75 ppm.

The author would like to express his sincere appreciation to

Dr. Robert H. Garman for the microscopic evaluation of testicular

tissue reviewed from some of the older studies and to Dr. Bryan Ballantyne for his continued encouragement and editorial review of the

manuscript.

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