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 fromanimal studies havebeenexamined fromthe standpointofdose-responserelationships and the sensitivity of various animal species, including man, to the effects of this chemical. In view of recent findings with otherchemically related glycol ethers, particularattention has beengiven topossible adverse effects onbloodandtesticulartissue. Inevaluatingthehazardthatthis chemical mayposetoman, consideration hasbeengiventolikelyroutes ofexposure andits irritantproperties. It isconcludedthatthe 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 ofdose-response 

### relationships byvarious 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 (6and4 mmHg, 

### 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 

### withvarious 

### cleaning solutions 

### formulated with 

### EGBE. Ingestion,

onthe other

### hand, is an

### unlikelyprimaryroute ofentry 

### for 

### humans; exceptions include instances of 

### accidental 

### poisoningor

### attempts at suicide. 

### However, thereappear 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 ofthismaterial 

### followed

### bymice, 

### guineapigs 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 indi

### cated

### byits

### lethaltoxicityin

### dermal 

### applicationstudies. 

### Again, 

### rabbits appear to 

### be more 

### susceptible to 

### the toxic

### effects ofthis 

### chemical ata

### lower

### dosagelevelthan rats, 

### when 

### applied to 

### the skin. 

### Although quantitative data are not 

### available, it is 

### relevant that 

### Saparamedov (5) 

### submergedthe tailsofmice 

### (upto

### two-thirds oftheir 

### 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 andgoodwarningproperties, 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 conflictwith

### 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 irritationwhen 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), instillationof0.005 mL intorabbit eyesproduced 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



### instilledintothe eye, andno injury

### wasnoted froma 5% aqueous 

### dilution. Based on 

### these observations, the 

### material was 

### graded 8 on 

### the 10-point scale. 

## Repeated 

## Oral Administration

Results 

### ofthree studies in

### which

### EGBE was 

### administered 

### repeatedly

### bymouth 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/kgadministered in feed 

### for 90 

### days. An 

### increase in 

### the relative liver

### and

### kidney weightwas

### reportedat 1500

### mg/kg, andin

### relative liver 

### weight at 300 

### mg/kg. The 

### value ofthis 

### study is 

### limited 

### bya

### highmortality in

### all treatment 

### and control groups, 

### probablycausedbya

### high incidence of

### pneumonia. It is 

### ofinterest to note 

### thatwhen

### pooledurine 

### fromrats 

### fed 

### EGBE at 1500 or300

### mg/kgfor3 or6

### dayswas

### 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 re

### portedat 950

### mg/kg. In

### addition, 

### testicularatrophywas 

### reported at 950 

### and 200 

### mg/kg. The sections of testes 

### fromthis study

### havebeen

### recently

### reviewedandconfirm

a 

### treatment-related 

### degeneration and 

### atrophy of the seminiferous 

### tubules. The lesionwas present at 950 

### and 200

### mg/kg, but not inthose 

### animals 

### receiving EGBE at 40 or 8 

### mg/kg. The 

### EGBE used in 

### this 

### study was 

### manufactured

### usingborontrifluoride 

### (BF3) asa

### catalyst,

a

### process

### whichhas not

### beenused

### forthepast 15years. 

### 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 

### atrophywith 

### degeneration of the 

### germinal epithelium (17), and 

### fluoroethanol. More

### recently, micewere

### given EGBE 

### bygavage over
a 

### 5-week

### period at

### dosages of

### 2000, 1000 

### and 500

### mg/kg (14,15). At 2000

### mg/kgall the animals 

### died. This 

### finding is consistent with the acute 

### toxicity data 

### presented in Table 1, 

### whichindicates thatthe acute 

### oral 

### LD50 in

### mice liesbetween 1000 and 1700

### mg/kg. In

### themice

### receiving the test 

### chemical at 1000 

### and 500 

### mg/kg, 

### erythrocyte counts were 

### statistically significantly 

### decreased, but 186ACUTE 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, kidneyand

### 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 withrespect to 

### sample purity and a lack 

### ofresponse 

### 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 invarious

### laboratoryanimal

### species, alongwithobservations from

### briefhuman exposures, are 

### given in

### Table 4. 

### The predominant effects observed in rats include reduced 

### body weight gain, 

### hematological changes and increased

### absoluteandrelative

### kidneyandliver

### weights. In some ofthe earliestworkwith

### this 

### chemical, Werner and co-workers 

### identifiedthered

### bloodcell as one 

### ofthe

more 

### sensitive indicators of

### toxicity (20). 

### Using invitro 

### methodology, theseworkers

### demonstratedthat

### erythrocytes became 

### extremely susceptible to 

### osmotic

### hemolysisinthepresence oflow

### concentrations ofthe 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

### hemolyticeffect ofEGBE appears toberesponsible for the transient 

### hemoglobinuria, or red discolored 

### urine, noted during the 

### first few days 

### of several of the animal studies. In

### all studies 

### where hemoglobinuriahas been 

### noted, it seldom persisted beyond 3 to 5 days of exposure. 

### Increased liver and kidneyweights have 

### also been noted at 

### higher exposure levels. This effect appears tobe 

### reversible with 

### absolute orrelative organ 

### weights returning to values 

### similar to those in control animals

### afterarecovery

### periodas 

### short as 1 

### week. Inno case did exposure to 

### EGBE vapor produce decreased 

### testicular 

### weight. Histological examination was conducted on testes of rats 

### exposed to concentrations as 

### highas 250ppm

### for30 exposures (12) andmore recently to 77ppm

### for90 

### days (19), 

### andon

### thetestes fromguinea 

### pigs exposed at a concentration of 500 ppm for 30 days 

### (1), a

### dog exposed to 385 ppm

### and amonkey 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 com

### pletion of 

### the 90-day exposure period. The no observ

### able 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 187T. 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 Decreasedweightgain; 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 bodyweight 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 188ACUTE 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 

### themean

### corpuscularHb. Hemoglobinuriawasnotedin 

### male 

### and female rabbits treated with undiluted EGBE 

### and in 

### females treated with 50% aqueous 

### dilution. Erythema and edemawere noted at the site ofapplica

### tion 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 

### inwhich 25%, or 5% aqueous dilutions ofEGBE
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 atany

### dosage levelandthe controls. Ofnotewas 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) studywas 

### conducted under sponsorship of the 

### Chemical Manufacturers 

### Association. Dosage levels

were 150, 50 

### and 10

### mg/kgbodyweight (23). In

### orderto
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 quantityofEGBE, 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 remainedunrestrainedboth

### duringandafter 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 orrelative organ

### weights. The onlymicroscopic 

### 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 fromthe

### highdose group 

### found

### dead on 

### studyday 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/kggroup 

### found dead on 

### study 

### day 15, 

### attributed toa

### gastric

### ulcer; and

### finally, afemale 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 hemo

### globinuria 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 ofyears, 

### extensive animal 

### testing of 

### EGBE has 

### provided information whichmay

### 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 ofEGBE 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) 189190 T. R. TYLER



### appear to have a 

### specific effect on 

### the 

### erythrocyte membrane, 

### causingthe 

### cell to

### become more 

### fragile and have an

### increased susceptibilityto

### osmotichemolysis. It is likely 

### that in 

### exposed animals this 

### increased cellular fragility leads to 

### intravascular hemolysis which is re

### sponsible 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, andthat aftera 

### 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 kidneydamage 

### reported in some 

### EGBE 

### animal toxicity studies 

### (24). Increased liver 

### and kidney

### weight, 

### particularlywhen 

### 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 

### arisingfrom

### ingestionof

### EGBE (12), this

### result is 

### considered suspect for

### severalreasons. 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 inthe aqueous 

### dilutions 

### employed in

### the tests. 

### This suggests 

### thatwatermay

### influencethe

### abilityofthe chemical to pass 

### through the 

### skin barrier. 

### However, it has 

### beennotedthat no

### discernible 

### liquidremains on

### the skinat the end ofa 6 hr

### exposure. 

### Therefore, additional studies may

### be 

### required to 

### clarify the effect ofaqueous 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 inrats, 

### and 500

### mg/kgfor 5

### weeks inmicewhere

a 

### decrease in 

### erythrocyte count was 

### noted. The 

### significance ofthe testicular effect is uncertainbecause 

### of the 

### possibility that 

### impurities were 

### present in 

### the test 

### sample which are known to 

### produce germinal 

### epithelial celldamage. A

### no-observable effect 

### level of80 

### mg/kgwas obtained inratswhichreceivedthe 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 tran

### sient decrease in 

### erythrocyte count. An 

### exposure con

### centration 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. Adosage 

### concentra

### tion of 180 

### mg/kg applied as a 50% aqueous 

### dilution to the 

### skinoffemale

### rabbits fornine

### applications

### produced hemoglobinuria. No observable 

### systemic effects were 

### notedwhen 150mg/kgwas appliedtothe skinofrabbits 

### 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 

### andto

### effects on

### the erythrocyte. The

### dog, guinea pig, 

### monkey andman are resistant to the effects ofthis 

### 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) of25ppmanda

### short-termexposure limit 

### of 75 

### ppm.
The author would like to express his sincere appreciation to Dr. Robert H. Garman for the microscopic evaluation of testicular tissuereviewedfromsomeoftheolderstudiesandtoDr. BryanBallantyne for his continued encouragement and editorial review of the manuscript.

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