Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

1) Aethylenglykol-Mono-MethylAether (German)
2) Dowanol EM
3) Ether Monomethylique de L'Ethylene-Glycol (French)
4) Ethylene glycol monomethyl ether
5) Ethylene glycol n -methyl ether
6) EGM
7) EGME
8) Glycol monomethyl ether
9) Glycol Ether EM
10) Glycolmethyl ether
11) Glycolmethyl monomethyl ether
12) Jefersol EM
13) Methoxyhydroxyethane
14) Methyl cellosolve
15) Methyl glycol
16) Methyl oxitol
17) Methyl Ethoxol
18) Methyl Glycol (German)
19) Metil Cellosolve (Italian)
20) Metoksyetylowy Alkohol (Polish)
21) Monomethyl Ether of Ethylene Glycol
22) MECS
23) Poly-Solv EM
24) Prist
25) 2-methoxyethanol
26) 2-Methoxy-Aethanol (German)
27) 2-MetossietAnolo (Italian)
28) 2ME
29) CAS 109-86-4
30) ACETATE DE L'ETHER MONOMETHYLIQUE DE L'ETHYLENE-GLYCOL (FRENCH)
31) AETHYLENEGLYKOL-MONO-METHYLAETHER (GERMAN)
32) EGM (ETHYLENE GLYCOL METHYL ETHER)
33) ETHANOL, 2-METHYOXY-
34) ETHER MONOMETHYLIQUE DE L'ETHYLENE-GLUCOL (FRENCH)
35) METHYL GLYCOL (CAS 109-86-4)

1.2.1) MOLECULAR FORMULA
1) C3-H8-O2

Available Forms Sources

A)

1) Ethylene glycol monomethyl ether is a colorless liquid with a mild, agreeable odor (Lewis, 1997).

B)

1) It is used as solvent for low-viscosity cellulose acetate, natural resins, some synthetic resins and some alcohol-soluble dyes; in dyeing leather; sealing moisture-proof cellophane; in nail polishes, quick-drying varnishes as well as enamels and wood stains; in modified Karl Fischer reagent; as perfume fixative; as jet fuel de-icing additive; as an aerosol propellant, methylating agent, as well as catalyst and stabilizer in polymerization; in manufacture of photographic film; and, as one of the glycol ethers contained in positive photoresists used in the wafer fabrication process for semiconductor manufacturing (Budavari, 1996; Harbison, 1998; HSDB , 1999; Paustenbach, 1988; Lewis, 1997).
2) Used as solvent for nitracellulose and acetylcellulose, alcohol-soluble dyes, separating agent for side-chained paraffins from cycloparaffin, solvent for ink, solvent for cortisone, leather treating agent, antifreeze for aviation fuels and hydraulic fluids (El-Zein et al, 2002; ITI, 1988).
3) One of the glycol ethers contained in positive photoresists used in the wafer fabrication process for semiconductor manufacturing (Paustenbach, 1988). It is used in Asia and Europe in the semiconductor industry as a solvent for copper laminate circuit board manufacturing(El-Zein et al, 2002).
4) Also found in surface coats such as quick-drying varnishes, nail polishes, and wood stains and paints(El-Zein et al, 2002; HSDB , 1990).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Ethylene glycol monomethyl ether (EGME) is used as a solvent in the chemical synthesis of a variety of products and is widely used in manufacturing. It is also found in surface coats such as quick-drying varnishes, nail polishes, and wood stains and paints.
B) TOXICOLOGY: In overdose, EGME causes central nervous system, renal, and hematologic toxicity. It remains speculation that glycol ethers may undergo cleavage of the ether bond to produce ethylene glycol with subsequent metabolism to oxalate.
C) EPIDEMIOLOGY: Clinically significant exposure to EGME is uncommon. Severe toxicity is rare. Deaths have been reported.
D) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Eye and mucous membrane irritation may occur with inhalation exposure. Dermal irritation may occur with skin exposure. Headache, drowsiness, lethargy, fatigue, dizziness, and mild anemia or granulocytopenia may develop with relatively low level inhalation exposures.
2) SEVERE TOXICITY: ACUTE: Higher concentration inhalation exposures may cause ataxia, tremor, confusion, dysarthria, personality changes, and coma that generally and gradually resolve with cessation of exposure. Acute ingestions may cause agitation, confusion, CNS depression, coma (may be delayed with onset of 8 to 18 hours), metabolic acidosis, acute renal failure, proteinuria, hematuria, oxaluria, and hemorrhagic gastritis.

0.2.20)

A) A major concern for possible occupational reproductive hazards of EGME stems from the ability of glycol ethers to cause male reproductive effects in laboratory animals.

0.2.21)

A) At the time of this review, no studies were found on the possible carcinogenic activity of EGME in humans or experimental animals.

Laboratory Monitoring

A)

B)

C)

D)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Treatment is symptomatic and supportive.

B) MANAGEMENT OF SEVERE TOXICITY

1) Treatment is symptomatic and supportive. Treat severe acidosis (pH less than 7.1) with intravenous sodium bicarbonate. Begin with 1 to 2 mEq/kg in adults and 1 mEq/kg in children, repeat every 1 to 2 hours as required. Although ethanol and fomepizole are not approved for use in ethylene glycol methyl ether (EGME) poisoning, they may be effective in preventing formation of the acid metabolites and lessening toxicity.

C) DECONTAMINATION

1) PREHOSPITAL: Irrigate exposed eyes with large quantities of water. Remove contaminated clothing and wash exposed skin. There is no role for prehospital gastrointestinal decontamination following oral exposure. Remove patients with inhalational exposure to fresh air. Administer oxygen if respiratory irritation develops.
2) HOSPITAL: Irrigate exposed eyes with large quantities of water. Remove contaminated clothing and wash exposed skin. In patients with inhalational exposure, administer oxygen if respiratory irritation develops. ACTIVATED CHARCOAL: Given the potential for CNS depression placing the patient at increased risk of aspiration, activated charcoal is not recommended unless the airway is protected via endotracheal intubation. GASTRIC LAVAGE: As EGME-containing products are generally liquid, early nasogastric aspiration may be useful for very large, recent ingestions if the patient is alert or the airway is protected.

D) AIRWAY MANAGEMENT

1) Endotracheal intubation may be required if significant CNS depression occurs.

E) ANTIDOTE

1) There is no specific antidote for the treatment of EGME exposure. Although ethanol and fomepizole are not approved for use in EGME poisoning, they may be effective in preventing formation of the acid metabolites and lessening toxicity. They should be considered for large ingestions in patients developing metabolic acidosis or renal insufficiency. ETHANOL VS FOMEPIZOLE: Fomepizole is easier to use clinically, requires less monitoring, and does not cause CNS depression or hypoglycemia. Ethanol requires continuous administration and frequent monitoring of serum ethanol and glucose levels, and may cause CNS depression and hypoglycemia (especially in children). The drug cost associated with ethanol use is generally much lower than with fomepizole; however, other costs associated with ethanol use (continuous intravenous infusion, hourly blood draws and ethanol levels, possibly greater use of hemodialysis) may make the costs more comparable.

a) ETHANOL: Ethanol is given to maintain a serum ethanol concentration of 100 to 150 mg/dL. This can be accomplished by using a 5% to 10% ethanol solution administered IV through a central line. Intravenous therapy dosing, which is preferred, is 0.8 g/kg as a loading dose (8 mL/kg of 10% ethanol) administered over 20 to 60 minutes as tolerated, followed by an infusion rate of 80 to 150 mg/kg/hr (for 10% ethanol, 0.8 to 1.3 mL/kg/hr for a nondrinker; 1.5 mL/kg/hr for a chronic alcoholic). During hemodialysis, either add ethanol to the dialysate to achieve 100 mg/dL concentration or increase the rate of infusion during dialysis (for 10% ethanol, 2.5 to 3.5 mL/kg/hr). Blood ethanol concentrations must be monitored hourly and the infusion adjusted accordingly.
b) FOMEPIZOLE: Fomepizole is administered as a 15 mg/kg loading dose, followed by four bolus doses of 10 mg/kg every 12 hours. If therapy is needed beyond this 48 hour period, the dose is then increased to 15 mg/kg every 12 hours for as long as necessary. Fomepizole is also effectively removed by hemodialysis; therefore, doses should be repeated following each round of hemodialysis.

F) ENHANCED ELIMINATION

1) Hemodialysis is indicated for severe acid-base and/or fluid-electrolyte abnormalities despite conventional therapy, or renal failure. It is unknown if EGME is removed by hemolysis.

G) PATIENT DISPOSITION

1) HOME CRITERIA: Asymptomatic patients with brief inhalational exposures may be observed at home.
2) OBSERVATION CRITERIA: All symptomatic patients, or patients who ingested more than a lick, sip, or taste should be sent to a medical facility for evaluation.
3) ADMISSION CRITERIA: Patients with worsening symptoms should be admitted to the hospital for further treatment and evaluation. Delayed onset of symptoms (8 to 18 hours) has been seen following ingestion. It is therefore recommended that patients suspected to have ingested a toxic amount be admitted and observed for at least 18 hours. Admission to ICU may be required based on the severity of symptoms.
4) CONSULT CRITERIA: Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom diagnosis is unclear. Consult a nephrologist for severe acidosis, renal issues, or potential hemodialysis. Consultation with a critical care physician may be needed in cases of severe toxicity.

H) PITFALLS

1) Discharging patient after only 6 hours of observation following a significant ingestion. Prolonged observation may be needed after ingestion of EGME due to delayed onset of symptoms.

I) TOXICOKINETICS

1) Delayed onset of symptoms (8 to 18 hours) has been seen following ingestion.

J) DIFFERENTIAL DIAGNOSIS

1) Consider exposure to other glycol ethers or toxic alcohols that may cause CNS depression and/or acidosis.

Range Of Toxicity

A)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

1) MILD TO MODERATE TOXICITY: Eye and mucous membrane irritation may occur with inhalation exposure. Dermal irritation may occur with skin exposure. Headache, drowsiness, lethargy, fatigue, dizziness, and mild anemia or granulocytopenia may develop with relatively low level inhalation exposures.
2) SEVERE TOXICITY: ACUTE: Higher concentration inhalation exposures may cause ataxia, tremor, confusion, dysarthria, personality changes, and coma that generally and gradually resolve with cessation of exposure. Acute ingestions may cause agitation, confusion, CNS depression, coma (may be delayed with onset of 8 to 18 hours), metabolic acidosis, acute renal failure, proteinuria, hematuria, oxaluria, and hemorrhagic gastritis.

Heent

3.4.3)

A) BLURRED VISION: Blurred vision may occur (Zavon, 1963; Donley, 1936).
B) CONJUNCTIVITIS: Mild temporary redness, conjunctival irritation, and slight corneal cloudiness was noted following application to rabbit eyes. One case of human ocular exposure is recorded, with complete recovery within 48 hours (McLaughlin, 1946).

Respiratory

3.6.2)

A) HYPERVENTILATION

1) Hyperventilation is a common feature of acute oral toxicity (Young & Woolner, 1946; Nitter-Hauge, 1970).

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM DEFICIT

1) CNS symptoms are more pronounced following acute exposure.
2) Ataxia and tremor may occur (Zavon, 1963; Ohi & Wegman, 1978).
3) Somnolence and lethargy have been noted (Zavon, 1963; Donley, 1936).
4) Headache and dysarthria have been reported (Zavon, 1963; Donley, 1936).
5) Personality changes have been reported (Zavon, 1963).
6) Coma may be noted (Zavon, 1963).
7) CASE REPORT: Two men who ingested 100 mL each of pure EGME developed progressive agitation and confusion 8 and 18 hours post ingestion (Nitter-Hauge, 1970). The duration of CNS toxicity was not described.

B) TOXIC ENCEPHALOPATHY

1) Cases of toxic encephalopathy have been reported from industrial exposures that may have been as low as 60 ppm. Symptoms were headache, drowsiness, lethargy, and weakness. Manifestations of central nervous system instability included ataxia, dysarthria, tremor, and somnolence. These effects usually were reversible (Hathaway et al, 1996).

C) CHRONIC POISONING

1) Chronic exposure to high levels may result in encephalopathy characterized by gradual onset of personality changes, lethargy, memory loss, headache, dizziness, and inability to grasp conversations (Donley, 1936; Parsons & Parson, 1983; Zavon, 1963).
2) Fatigue and lethargy was reported in a cross-sectional study of shirt factory workers exposed to 25 to 76 ppm EGME in conjunction with 70 to 215 ppm ethyl alcohol, 5 to 16 ppm methanol, 2 to 5 ppm ethyl acetate and 0.3 to 1 ppm petroleum naphtha (Greenburg et al, 1938).

a) Physical findings included tremor (especially of the hand) and hyperreflexia with clonus. Interpretation of these data is difficult since there was no control group, blinding of the examiners or well defined clinical criteria for reported signs and symptoms.

3) CNS effects have been reported to spontaneously resolve over a period of weeks following cessation of exposure (Donley, 1936; Parsons & Parson, 1983; Zavon, 1963).
4) A patient presented with progressive personality changes, decreased memory, tremor, ataxia, and drowsiness 2 months after frequent use of EGME as a cleaning solvent in a printing operation. Symptoms improved over a 3 week period after removal from the environment. Several weeks after returning to work, sleepiness, ataxia and tremor recurred (Cohn, 1984).

3.7.3)

A) ANIMAL STUDIES

1) PARALYSIS

a) In animals, hind-limb paresis, glial cell damage, and demyelination have been observed (Savolainen, 1980).

Gastrointestinal

3.8.2)

A) GASTRIC HEMORRHAGE

1) Hemorrhagic gastritis was reported following ingestion of 2-methoxyethanol (Young & Woolner, 1946).

Hepatic

3.9.2)

A) LIVER DAMAGE

1) WITH POISONING/EXPOSURE

a) Changes in liver histology were among the postmortem findings reported with 2ME ingestion (Young & Woolner, 1946).
b) LACK OF EFFECT: CHRONIC: A 6-month study was conducted to evaluate hepatic effects of exposure to 2-methoxy ethanol (2-ME). Measurement of ALT, AST, and GGT were not significantly different in workers directly exposed to 2-ME when compared with measurements taken from workers with indirect exposure to 2-ME. The authors concluded that 2-ME was not hepatotoxic (Loh et al, 2004).

3.9.3)

A) ANIMAL STUDIES

1) ENZYME ABNORMALITY

a) RAT studies have shown alcohol dehydrogenase activity increased with the increment of dose of ethylene glycol methyl ether (Kawamoto et al, 1990).
b) Rats exposed to ethylene glycol monomethyl ether by gavage had increased serum GGT concentrations and induction of hepatic microsomal GGT activity, but depressed renal GGT activity (Kawamoto et al, 1992).

Genitourinary

3.10.2)

A) RENAL FAILURE SYNDROME

1) ALBUMINURIA and HEMATURIA usually without oxaluria, are frequent findings following acute exposure. Renal failure and oxaluria (up to 1000 mg oxalate/day) were reported in 1 of 2 individuals who ingested approximately 100 mL of ethylene glycol monomethyl ether (Nitter-Hauge, 1970).
2) Proteinuria and mild elevations in serum creatinine have been reported following acute ingestion (Nitter-Hauge, 1970) Rambourg-Schepens, 1988).
3) Marked renal tubular degeneration and "toxic changes" have been reported at autopsy in a fatal case of EGME ingestion (Young & Woolner, 1946).
4) It remains speculation that glycol ethers may undergo cleavage of the ether bond to produce ethylene glycol, with subsequent metabolism to oxalate.

B) ABNORMAL URINE

1) Elevated urinary oxalate levels and the presence of urinary oxalate crystals were reported in a patient who ingested EGME (Nitter-Hauge, 1970). Other patients with severe toxicity form glycol ether ingestion have developed oxaluria or urinary oxalate crystal formation (Nitter-Hauge, 1970; Young & Woolner, 1946).

C) DISORDER OF TESTIS

1) In a cross sectional study workers exposed to EGME (TWA 8.5 ppm or less) were found to have decreased testicular width as compared with unexposed workers, but there were no differences in testicular length, hormonal profile, or sperm counts. Potential biases and confounding variables include exposure to a variety of chemicals, older age of the exposed workers compared to the unexposed group, and interobserver bias (Cook et al, 1982).

3.10.3)

A) ANIMAL STUDIES

1) TESTIS DISORDER

a) Following a 13-week exposure to 100 and 300 ppm of EGME, male rats and rabbits had reduced body weight gain, testicular weights, and platelet counts (Miller et al, 1983a).
b) Decreased testicular weight, disordered spermatogenesis, and tubular atrophy were seen in the testis of rats exposed for 4 hours to at least 1250 ppm of EGME (Samuels et al, 1984).
c) Treatment of rats with 2ME administered at various doses for 7 consecutive days caused a dose-related decline in sperm count, a reduction in weights of testis and epididymis, an increase in the number of sperm with abnormal morphology, and a reduction in fertility (Feuston et al, 1989).

2) URINE ABNORMAL

a) Oxaluria has not been demonstrated in animal models of glycol ether exposure (Wiley et al, 1938; Truhaut et al, 1979).

Acid-Base

3.11.2)

A) ACIDOSIS

1) Metabolic acidosis has been documented after large ingestions (Nitter-Hauge, 1970; Young & Woolner, 1946).
2) Acidosis may be severe but resolves within 24 hours with supportive care (Nitter-Hauge, 1970).

Hematologic

3.13.2)

A) ANEMIA

1) WITH POISONING/EXPOSURE

a) Human studies revealed that male workers exposed to ethylene glycol monomethyl ether had significantly higher levels of anemia and decreased red blood counts than unexposed workers (El-Zein et al, 2002).

B) MACROCYTIC ANEMIA

1) Macrocytic anemia has been reported following chronic exposure to vapors. A predominance of immature leukocytes has been observed with less intense and more prolonged exposures, which resolves on cessation of exposure. The degree of anemia is variable with red cell counts of 2.9 to 4.0 million reported (Zavon, 1963; Cohen, 1984).

a) Prolonged exposure to lower concentrations primarily produced evidence of depression of erythrocyte formation. Below 20 ppm, no effects were noted (Hathaway et al, 1996).

C) APLASTIC ANEMIA

1) Aplastic anemia has been reported (Parsons & Parson, 1983).

D) PANCYTOPENIA

1) Bone marrow injury and pancytopenia have been described in workers with dermal and inhalation exposure (average air concentration 8 parts per million) (Ohi & Wegman, 1978).
2) In a cross-sectional study that did not assure correct temporal relationships, the following hematologic effects were observed among shipyard painters ascertained of exposure to ethylene glycol ethers (Welch & Cullen, 1988):

a) 10% of the painters were anemic and 5% were granulocytopenic whereas none of the controls (shipyard employees not involved in painting) were affected (p=0.04). However, the mean hemoglobin levels did not differ between the painters and the controls (15.43 g/dL +/- 1.09 SD versus 15.67 g/dL +/- 0.84 SD, p=0.14).
b) 3.4% of the painters had total polymorphonuclear leukocyte counts below 1,800 cells/microliter whereas none of the controls had such low levels. The mean values of the PMNs did not differ between the two groups. Linear regression showed no correlation between the total PMN count and exposure in years.
c) The mean platelet counts did not differ significantly between the two groups and there was no correlation between platelet count and the index of exposure.

E) HYPOPLASTIC ANEMIA

1) Chronic exposure to high levels of EGME may result in bone marrow toxicity that includes anemia and granulocytopenia.
2) There are several reports of erythropenia and granulocytopenias in workers with prominent signs of CNS toxicity, presumably due to excessive exposure to EGME in the workplace (Donley, 1936; Parsons & Parson, 1983; Zavon, 1963).
3) Workers chronically exposed to 25 to 76 ppm EGME, 70 to 215 ppm ethanol and lesser amounts of methanol, ethyl acetate and petroleum naphtha had an increase in immature neutrophilic granulocytes despite normal total WBC. Some workers had RBC counts less than 4.4 million/mm3 (Greenburg et al, 1938).
4) A previously healthy 32-year-old man with a 9 month history of respiratory and dermal exposure to EGME (TWA 18 to 57.8 ppm) and propylene glycol monomethyl ether (TWA 4.2 to 12.8 ppm) developed macrocytic anemia, and mild leukopenia accompanied by apathy, increased fatigue, and increased hourly sleep. The abnormal hematologic parameters returned to normal after removing the patient from exposure (Cohn, 1984).
5) No study convincingly demonstrates hematologic toxicity resulting from chronic, low level exposure to ethylene glycol ethers in the occupational setting.

3.13.3)

A) ANIMAL STUDIES

1) ANEMIA

a) Exposure of experimental animals to glycol ethers results in hemolysis with hemoglobinuria, decreased WBC counts and hypocellular bone marrow (Kalf et al, 1987). Metabolism of the glycol ether to the acetate form by alcohol and aldehyde dehydrogenase is necessary to produce the hemolytic effect.
b) Human RBCs have been shown to be much less susceptible to the hemolytic effects compared to rat, dog and rabbit RBCs (Carpenter et al, 1956).

Dermatologic

3.14.2)

A) SKIN IRRITATION

1) Irritation to skin and mucous membranes may be noted (EPA, 1982; Clayton & Clayton, 1994).

Immunologic

3.19.2)

A) DISORDER OF IMMUNE FUNCTION

1) IMMUNOSUPPRESSIVE: 2-Methoxyethanol and its principal active metabolite, 2-methoxyacetic acid, has been shown to be immunosuppressive in rat studies (Smialowicz et al, 1992).

Reproductive

3.20.1)

A) A major concern for possible occupational reproductive hazards of EGME stems from the ability of glycol ethers to cause male reproductive effects in laboratory animals.

3.20.2)

A) CONGENITAL ANOMALY

1) ETHYLENE GLYCOL MONOMETHYL ETHER - A study was conducted on offspring born to females employed in manufacturing using ethylene glycol monomethyl ether (EGME) during a 7 year period. Forty-one offspring, including 6 offspring exposed in utero were evaluated clinically and developmentally for physical and dysmorphic characteristics and by cytogenic analysis.

a) All 6 of the offspring exposed in utero had dysmorphic features and various degrees of mental retardation. Other abnormalities included mid-face retrusion, short webbed neck, wide base of nose, and prognathism (6 of 6). High arched palate (4 of 6), macroglossia (3 of 6), deformed toes (2 of 6) and asymmetrical lower limbs (1 of 6) were also seen. In the remaining 35 offspring not exposed in utero, 29 exhibited no abnormalities. The remaining offspring exhibited minor anomalies (webbed fingers, cryptorchidism and small organs) and high arched palate, macroglossia and mental retardation to a much milder degree than those exposed in utero (El-Zein et al, 2002).

2) A syndrome of facial and musculoskeletal malformations and mental retardation was reported in offspring of women who's factory work involved dipping their hands in a solution mainly consisting of ethylene glycol monomethyl ether and ethylene glycol. The women developed fatigue, vertigo, nausea and vomiting after exposure. The offspring had facial malformations and musculoskeletal malformations of the spine, hands and feet; about half of the affected children also had eye and ear defects (Johanson, 2000).

B) ANIMAL STUDIES

1) SKELETAL MALFORMATION

a) Increased fetal skeletal variations and reduced maternal weight gain were reported in pregnant ICR mice treated with intragastric intubation of EGME given at a dose of more than 125 mg/kg or 31 mg/kg/day (Nagano, 1981).
b) 2-methoxyethanol induced cardiovascular and skeletal defects in rabbits upon inhalational exposure (Nelson et al, 1982).
c) Exposure of mice to 50 ppm of EGME for 6 hours/day from days 6 to 15 of gestation caused increased reports of skeletal variations with delayed ossification (Hanley et al, 1982a) 1982b).
d) Embryonic death and fetal abnormalities among rodents were seen at concentrations less than the OSHA permissible exposure limits and less than that needed to produce abnormal blood effects (NIOSH, 1983).
e) Exposure to 50 parts per million in pregnant rabbits resulted in an increased incidence of malformations. No effects on fetal development were seen with any species exposed to 10 parts per million or less (Hanley et al, 1984).
f) Single oral doses of 175 mg/kg EGME given to pregnant mice produced digit malformations which were absent at a dose of 100 mg/kg but maximal when given at 350 mg/kg. Exencephaly also occurred whenever EGME administration was in the earlier stages of pregnancy (Horton et al, 1985).
g) Administration of 50 to 100 mg/kg by gavage to pregnant rats resulted in visceral abnormalities; the higher dose caused all fetuses to be resorbed. In these doses maternal toxicity was negligible (Toraason et al, 1986).

2) HEART MALFORMATION

a) ECG changes were observed beyond the fetal/neonatal period when rats were gavaged on gestation days 7 to 13 with 50 or 75 mg/kg EGME (Toraason & Breitenstein, 1988).
b) Heart weights were unaffected but heart/body weight ratios were increased when rats were 8 weeks old.
c) There was increased QRS interval in 3- and 6-week-old rats and increased T-wave in 6-week-old rats.
d) 36% of the 3-week-old litters and 54% of the 6-week-old ones had intraventricular conduction delays which were not associated with microscopic heart abnormalities.
e) In rats, it induced abnormalities of the heart and blood vessels in the offspring (Toraason, 1985).

3) EMBRYOTOXICITY

a) Concentrations above 0.025% 2ME (approximately 73/mg/kg/day given in a liquid diet) produced total embryomortality among rats while cardiovascular malformations and increased errors in the Cincinnati maze were noted among survivors given lower doses (Nelson et al, 1989).
b) Developmental effects of EGME such as growth retardation and skeletal anomalies have been demonstrated after oral subchronic dosing studies (31.25 milligrams/kilogram/day) in dams (EPA, 1984).
c) Subchronic inhalation of EGME at concentrations as low as 50 ppm has resulted in decreased litter size, skeletal defects, growth retardation and malformation in rodents (EPA, 1984).
d) EGME is the most potent glycol ether for inducing birth defects and male sterility in laboratory animals. EGME was teratogenic in mice (Nagano, 1981), in rats exposed to 100 ppm (Doe, 1984), and in rabbits exposed to 50 ppm (Nelson, 1984).
e) In mice, it reduced fetal weight, increased post-implantation losses, and caused birth defects of the central nervous system (CNS), paws, and spine (Horton et al, 1985).
f) EGME also caused birth defects in rats when applied dermally (Miller, 1982), and smaller litter size and poor survival were also found in rats exposed by the dermal route (Wickramaratne, 1986). Behavioral and neurochemical differences were seen in the offspring of rats given doses of only 25 ppm (Nelson, 1984).
g) The selectivity and dose-response of EGME for inducing birth defects was studied in the rat. Maximum incidence of embryolethality was from dosing EGME on gestational day 10. External defects in live fetuses were highest when EGME was administered on day 13, and those involving viscera on day 11. Malformations did not occur at 100 mg/kg when given on day 13 (Sleet et al, 1996).

4) TESTIS DISORDER

a) Unilateral testicular hypoplasia and hemorrhage in the male fetuses of pregnant mice were reported with EGME at 50 ppm (Johnson, 1984).

3.20.3)

A) HUMANS

1) Working in fabrication rooms in the silicon based semiconductor industry was associated with a 45% excess risk for spontaneous abortion in a nationwide study on 14 companies. Stratification of exposure revealed a strong dose-dependent link with exposure to photoresist and developer solvents, which contain mainly ethylene glycol ethers (Schenker et al, 1995; Swan et al, 1995).

B) ANIMAL STUDIES

1) BLOOD DYSCRASIA

a) Exposure of mice to 50 ppm of EGME for 6 hours/day from days 6 to 15 of gestation caused:
b) Minimal decrease in maternal weight gain and insignificant but concentration-related changes in the white blood cell count and platelet counts (Hanley et al, 1982a) 1982b).
c) Decreased number of fetuses per litter and increased number of resorbed implantation sites (Hanley et al, 1982a) 1982b).

2) EMBRYOTOXICITY

a) Embryonic death and fetal abnormalities among rodents were seen at concentrations less than the OSHA permissible exposure limits and less than that needed to produce abnormal blood effects (NIOSH, 1983).
b) The embryotoxic effects of 2ME were studied in macaques (Macaca fascicularis) who received the chemical daily by gavage throughout the organogenetic phase of pregnancy (days 20 to 45) (Scott et al, 1989).

1) At 0.47 mmole/kg, all eight pregnancies ended in death of the embryo with one embryo missing a digit on each forelimb.
2) Fewer embryonic deaths were reported at doses of 0.32 mmol/kg and 0.16 mmol/kg.
3) Maternal toxicity was evident in all treated pregnancies but was most severe in the high-dosage primates.
4) The metabolite, 2-methoxyacetic acid, had a half-life of 20 hours resulting in its accumulation in maternal serum after repeated daily dosing.

3) IMMUNE SYSTEM DISORDER

a) Maternal exposure to EGME on days 10 to 17 indicate effects on immune maturation and altered ratios of lymphocyte subtypes (Holladay et al, 1994).

4) LACK OF EFFECT

a) Single oral doses of 175 mg/kg EGME given to pregnant mice produced no apparent maternal toxicity (Horton et al, 1985).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS109-86-4 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

3.21.2)

A) At the time of this review, no studies were found on the possible carcinogenic activity of EGME in humans or experimental animals.

Genotoxicity

A)

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs and mental status.
B) Monitor CBC, serum electrolytes, renal function, urinalysis, and ABG's in symptomatic patients.
C) Serum ethanol, methanol, and ethylene glycol concentrations are theoretically useful in assessing concurrent ingestions or metabolites of EGME.
D) It remains speculation that glycol ethers may undergo cleavage of the ether bond to produce ethylene glycol, with subsequent metabolism to oxalate. However, elevated urinary oxalate concentrations and urinary oxalate crystals have been reported after human overdose. EGME increases the serum osmolality, but the utility of the osmolar gap for the diagnosis of EGME is unknown.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Monitor serum electrolytes in symptomatic cases or after a significant ingestion.
2) Serum ethanol, methanol, and ethylene glycol concentrations are theoretically useful in assessing concurrent ingestions or metabolites of EGME.
3) It remains speculation that glycol ethers may undergo cleavage of the ether bond to produce ethylene glycol, with subsequent metabolism to oxalate. However, elevated urinary oxalate concentrations and urinary oxalate crystals have been reported after human overdose. EGME increases the serum osmolality, but the utility of the osmolar gap for the diagnosis of EGME is unknown.
4) Obtain testing as indicated to monitor renal function.

B) SPECIFIC AGENT

1) EGME levels and those of its metabolites are not readily available laboratory tests and are not clinically useful in the management of acute poisoning.

4.1.3)

A) URINALYSIS

1) Obtain urinalysis in symptomatic cases (look for oxalate crystals and hemoglobin).

B) SPECIFIC AGENT

1) Urinary concentration of the acetic acid metabolites of glycol ethers may be useful indicators of workplace exposure to glycol ethers and their acetates. Urinary concentrations of these metabolites correlate with respiratory and dermal absorption.

4.1.4)

A) OTHER

1) MONITORING

a) The presence of abnormal bone marrow aspirates in asymptomatic occupationally exposed lithographers who had normal peripheral blood pictures is suggestive that CBC's alone may not be adequate monitoring screening for chronic exposure (Cullen et al, 1983).

Methods

A)

1) Using gas chromatography and alkylation with pentafluorobenzylbromide, alkoxyacetic acid concentrations in the range of 0.1 to 200 mg/L could be determined with an average imprecision of plus/minus 3.5% (Groeseneken et al, 1989).
2) Shih et al (2001) described a gas chromatographic-mass spectrometric assay for simultaneous determination of ethylene glycol monomethyl ether and its metabolite 2-methyoxyacetic acid in human blood (Shih et al, 2001).

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Delayed onset of symptoms (8 to 18 hours) has been seen following ingestion (Nitter-Hauge, 1970a). It is therefore recommended that patients suspected to have ingested a toxic amount be admitted and observed for at least 18 hours.
B) Patients with worsening symptoms should be admitted to the hospital for further treatment and evaluation. Admission to ICU may be required based on the severity of symptoms. Criteria for discharge includes clearly improving symptoms in patients who are clinically stable.

6.3.1.2) HOME CRITERIA/ORAL

A) Asymptomatic patients with brief inhalational exposures may be observed at home.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom diagnosis is unclear. Consult a nephrologist for severe acidosis, renal issues, or potential hemodialysis. Consultation with a critical care physician may be needed in cases of severe toxicity.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) All symptomatic patients, or patients who ingested more than a lick, sip, or taste should be sent to a medical facility for evaluation.

Monitoring

A)

B)

C)

D)

Oral Exposure

6.5.1)

A) PREHOSPITAL: Irrigate exposed eyes with large quantities of water. Remove contaminated clothing and wash exposed skin. There is no role for prehospital gastrointestinal decontamination following oral exposure. Remove patients with inhalational exposure to fresh air. Administer oxygen if respiratory irritation develops.

6.5.2)

A) ACTIVATED CHARCOAL

1) Given the potential for CNS depression placing the patient at increased risk of aspiration, activated charcoal is not recommended unless the airway is protected via endotracheal intubation.

B) NASOGASTRIC TUBE

1) As EGME-containing products are generally liquid, early nasogastric aspiration may be useful for very large, recent ingestions if the patient is alert or the airway is protected.

6.5.3)

A) MONITORING OF PATIENT

1) Monitor vital signs and mental status.
2) Monitor CBC, serum electrolytes, renal function, urinalysis, and ABG's in symptomatic patients.
3) Serum ethanol, methanol, and ethylene glycol concentrations are theoretically useful in assessing concurrent ingestions or metabolites of EGME.
4) It remains speculation that glycol ethers may undergo cleavage of the ether bond to produce ethylene glycol, with subsequent metabolism to oxalate. However, elevated urinary oxalate concentrations and urinary oxalate crystals have been reported after human overdose. EGME increases the serum osmolality, but the utility of the osmolar gap for the diagnosis of EGME is unknown.

B) ACUTE LUNG INJURY

1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

C) ACIDOSIS

1) METABOLIC ACIDOSIS: Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate, 1 to 2 mEq/kg is a reasonable starting dose(Kraut & Madias, 2010). Monitor serum electrolytes and arterial or venous blood gases to guide further therapy.

D) FOMEPIZOLE

1) Fomepizole (4-MP) is not FDA approved for glycol ether poisoning and there are no published reports describing its use in humans with glycol ether poisoning. Theoretically, it should be as useful as ethanol. Fomepizole is a specific antagonist of alcohol dehydrogenase, and has been demonstrated to be highly effective in the treatment of ethylene glycol poisoning (Battistella, 2002; Druteika et al, 2002; Sivilotti et al, 2000; Borron et al, 1999; Brent et al, 1999).
2) DOSE

a) An initial loading dose of 15 mg/kg is intravenously infused over 30 minutes followed by doses of 10 mg/kg/every 12 hours for 4 doses, then 15 mg/kg every 12 hours until ethylene glycol concentrations are below 20 mg/dL (Prod Info ANTIZOL(R) IV injection, 2006).
b) HEMODIALYSIS: The frequency of dosing should be increased during dialysis. If dialysis is begun 6 hours or more since the last fomepizole dose the next scheduled dose should be administered. Dosing during dialysis should be increased to every 4 hours (Prod Info ANTIZOL(R) IV injection, 2006).

1) If the last fomepizole dose was administered one to three hours before completion of dialysis, half of the next scheduled dose should be administered at the completion of dialysis. If the last fomepizole dose was administered more than 3 hours before completion of hemodialysis, the next scheduled dose should be administered when dialysis is completed.

3) INDICATIONS

a) Anion gap metabolic acidosis associated with a history of ethylene glycol methyl ether ingestion.
b) Any symptomatic patient with a history of ethylene glycol methyl ether ingestion.
c) A good history of substantial ethylene glycol methyl ether ingestion.
d) Keep in mind that EGME serum levels are not routinely available, and interpretation is difficult since a toxic range has not been established. Thus, the endpoint of therapy will often be arbitrary.

E) ETHANOL

1) EFFICACY

a) The role of ethanol therapy in preventing toxicity of methoxyethanol is uncertain. No human studies evaluating efficacy in poisoned patients are available.

2) INDICATIONS

a) Anion gap metabolic acidosis associated with a history of ethylene glycol methyl ether ingestion.
b) Any symptomatic patient with a history of ethylene glycol methyl ether ingestion.
c) A good history of substantial ethylene glycol methyl ether ingestion.
d) Keep in mind that EGME serum levels are not routinely available, and interpretation is difficult since a toxic range has not been established. Thus, the endpoint of ethanol therapy will often be arbitrary.

3) ETHANOL THERAPY

a) CONCENTRATIONS AVAILABLE (V/V)

1) In the United States, 5% or 10% (V/V) ethanol in 5% dextrose for intravenous infusion is no longer available commercially (Howland, 2011). Ethanol 10% (V/V) contains approximately 0.08 gram ethanol/mL.
2) ABSOLUTE ETHANOL or dehydrated ethanol, USP contains no less than 99.5% volume/volume or 99.2% weight/weight of ethanol with a specific gravity of not more than 0.7964 at 15.56 degrees C. Absolute ethanol is hygroscopic (absorbs water from the atmosphere) and when exposed to air may be less than 99.5% ethanol by volume (S Sweetman , 2002).

b) PREPARATION OF 10% V/V ETHANOL IN A 5% DEXTROSE SOLUTION

1) A 10% (V/V) solution can be prepared by the following method (Howland, 2011):

a) If available, use sterile ethanol USP (absolute ethanol). Add 55 mL of the absolute ethanol to 500 mL of 5% dextrose in water for infusion. This yields a total volume of 555 mL. This produces an approximate solution of 10% ethanol in 5% dextrose for intravenous infusion (Howland, 2011).

4) PRECAUTIONS

a) HYPOGLYCEMIA

1) Hypoglycemia may occur, especially in children. Monitor blood glucose frequently (Howland, 2011; Barceloux et al, 2002).

b) CONCURRENT ETHANOL

1) If the patient concurrently has ingested ethanol, then the ethanol loading dose must be modified so that the blood ethanol level does not exceed 100 to 150 mg/dL (Barceloux et al, 2002).

c) DISULFIRAM

1) Fomepizole is preferred as an alcohol dehydrogenase inhibitor in patients taking disulfiram. If fomepizole is not available, ethanol therapy should be initiated in those patients with signs or symptoms of severe poisoning (acidemia, toxic blood level) despite a history of recent disulfiram (Antabuse(R)) ingestion.
2) The risk of not treating these patients is excessive, especially if hemodialysis is not immediately available.
3) Administer the ethanol cautiously with special attention to the severity of the "Antabuse reaction" (flushing, sweating, severe hypotension, and cardiac dysrhythmias).
4) Be prepared to treat hypotension with fluids and pressor agents (norepinephrine or dopamine). Monitor ECG and vital signs carefully. Hemodialysis should be performed as soon as adequate vital signs are established, and every effort should be made to obtain fomepizole.

5) LOADING DOSE

a) INTRAVENOUS LOADING DOSE

1) Ethanol is given to maintain a patient’s serum ethanol concentration at 100 to 150 mg/dL. This can be accomplished by using a 5% or 10% ethanol solution administered intravenously through a central line (10% ethanol is generally preferred due to the large volumes required for 5%). Intravenous therapy dosing, which is preferred, is 0.8 g/kg as a loading dose (8 mL/kg of 10% ethanol) administered over 20 to 60 minutes as tolerated. Begin the maintenance infusion as soon as the loading dose is infused (Howland, 2011).

b) ORAL LOADING DOSE

1) Oral ethanol may be used as a temporizing measure until intravenous ethanol or fomepizole can be obtained, but it is more difficult to achieve the desired stable ethanol concentrations. The loading dose is 0.8 g/kg (4 mL/kg) of 20% (40 proof) ethanol diluted in juice administered orally or via a nasogastric tube(Howland, 2011).

6) MAINTENANCE DOSE

a) MAINTENANCE DOSE

1) Maintain a serum ethanol concentration of 100 to 150 mg/dL. Intravenous administration is preferred, but oral ethanol may be used if intravenous is unavailable(Howland, 2011; Barceloux et al, 2002).

INTRAVENOUS ADMINISTRATION OF 10% ETHANOL
Non-drinker to moderate drinker	80 to 130 mg/kg/hr (0.8 to 1.3 mL/kg/hr)
Chronic drinker	150 mg/kg/hr (1.5 mL/kg/hr)
ORAL ADMINISTRATION OF 20% (40 proof) ETHANOL*
Non-drinker to moderate drinker	80 to 130 mg/kg/hr (0.4 to 0.7 mL/kg/hr) orally or via nasogastric tube
Chronic drinker	150 mg/kg/hr (0.8 mL/kg/hr) orally or via nasogastric tube
*Diluted in juice

b) MAINTENANCE DOSE/ETHANOL DIALYSATE

1) During hemodialysis maintenance doses of ethanol should be increased in accordance with the recommendation given below, or ethanol should be added to the dialysate to achieve a concentration of 100 milligrams/deciliter (Pappas & Silverman, 1982).

c) MAINTENANCE DOSE/ETHANOL-FREE DIALYSATE

1) Maintain a serum ethanol concentration of 100 to 150 mg/dL(Howland, 2011; Barceloux et al, 2002):

INTRAVENOUS ADMINISTRATION OF 10% ETHANOL - 250 to 350 mg/kg/hr (2.5 to 3.5 mL/kg/hr)
ORAL ADMINISTRATION OF 20% (40 proof) ETHANOL* - 250 to 350 mg/kg/hr (1.3 to 1.8 mL/kg/hr) orally or via nasogastric tube
*Diluted in juice

2) Variations in blood flow rate and the ethanol extraction efficiency of the dialyzer will affect the dialysance(McCoy et al, 1979).
3) If the ethanol dialysance ((CL)D) is calculated, the infusion rate during dialysis (Kod) can be individually adjusted using the following expression (McCoy et al, 1979):

Kod = Vmax x   Cp   + (CL)D x Cp
             -------
             Km + Cp
where Cp = desired blood ethanol level
*  Vmax = 175 mg/kg/hr in chronic ethanol drinkers 
*  Vmax = 75 mg/kg/hr in non-chronic drinkers
*  Km = 13.8 mg/dL

7) PEDIATRIC DOSE

a) There is very little information on ethanol dosing in the pediatric patient (Barceloux et al, 2002). The loading dose and maintenance infusion should be the same as for an adult non-drinker. Loading dose is 0.8 g/kg (8 mL/kg) of 10% ethanol infused over 1 hour, maintenance dose is 80 mg/kg/hr (0.8 mL/kg/hr) of 10% ethanol (Howland, 2011).
b) Blood ethanol concentration should be initially monitored hourly and the infusion rate should be adjusted to obtain an ethanol concentration of 100 to 150 mg/dL (Howland, 2011; Barceloux et al, 2002).

1) Monitor blood glucose and mental status frequently during therapy (Howland, 2011). Ethanol-induced hypoglycemia is more common in children (Barceloux et al, 2002) and children may develop more significant CNS depression.

8) MONITORING PARAMETERS

a) ETHANOL CONCENTRATION

1) Blood ethanol concentrations should be determined every 1 to 2 hours until concentrations are maintained within the therapeutic range (100 - 150 mg/dL). Thereafter concentrations should be monitored every 2 to 4 hours. Any change in infusion rate will require monitoring every 1 to 2 hours until the therapeutic range is reached and maintained (Barceloux et al, 2002).

b) ADDITIONAL MONITORING

1) Monitor serum electrolytes and blood glucose, monitor for CNS depression (Howland, 2011).

9) DURATION OF THERAPY

a) SERUM CONCENTRATIONS AVAILABLE: Ethanol therapy should be continued until the following criteria are met:

1) Glycol ether blood concentration, measured by a reliable technique, is no longer detectable.
2) Glycol ether-induced acidosis (pH, blood gases), clinical findings (CNS, hyperventilation), electrolyte abnormalities (calcium, potassium), and osmolal gap have resolved.
3) Glycol ether serum concentrations are not routinely available and a toxic range has not been established.

b) NO SERUM CONCENTRATIONS AVAILABLE: There is no data to guide the decision to terminate therapy. Treat until the patient's clinical findings resolve. Observe closely for recurrent toxicity after ethanol is discontinued.

1) If the clinical findings have not resolved, it may indicate the continued presence of glycol ether, metabolites, or both or some other etiology.

c) Metabolite concentrations have not been studied in blood (Rambourg-Schepens et al, 1988; Groeseneken et al, 1986b).
d) Serum osmolality may not be indicative of exposure (Lund et al, 1983).

10) MONITORING OF PATIENT

a) ETHANOL/ETHYLENE GLYCOL METHYL ETHER INGESTION: Patients who have concurrently ingested ethanol and ethylene glycol methyl ether may have a normal acid-base profile and urinalysis. Consider implementing the ethanol treatment regimen in these patients. Determine blood ETOH level before beginning ETOH therapy and modify loading dose accordingly.
b) ETHANOL DOSING: (Concurrent ingested ethanol)

1) To modify the loading dose for the patients who have concurrently ingested ethanol use the following equation to calculate the loading dose:

1) LD = {100 mg/dL - existing ethanol plasma concentration(mg/dL)} x (apparent Vd)

2) Note the loading dose obtained by this method is the amount of pure ethanol in milligrams/kilogram. It must be converted for intravenous and oral use to milliliters/kilogram. This can be accomplished by using the relationship:

1) LD(mL/kg) = LD(mg/kg) / {(specific gravity of ethanol) x (concentration as a fraction)}

3) Ten percent (V/V) ethanol for intravenous infusion:

1) LD(mL/kg) = LD(mg/kg) / {790 mg/mL x (10/100)}

4) 95 percent (V/V) ethanol for oral use:

1) LD(mL/kg) = LD(mg/kg) / {790 mg/mL x (95/100)}

5) Calculation of loading dose assumes instantaneous absorption.

Inhalation Exposure

6.7.1)

A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

6.8.1)

A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

6.9.1)

A) DERMAL DECONTAMINATION

1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

A)

1) Hemodialysis is indicated for severe acid-base and/or fluid-electrolyte abnormalities despite conventional therapy, or renal failure. It is unknown if EGME is removed by hemolysis.

Abstracts

Case Reports

A)

1) INHALATION: Donley (1936) described a case of "toxic encephalopathy" suffered by a female dipping shirt collars in a solution containing EGME, isopropanol, and cellulose acetate. She presented with headache, drowsiness, generalized weakness, irregular and unequal pupils, disorientation, and psychopathic symptoms (Donley, 1936a).
2) INHALATION: Two men employed in the manufacture of "permanently starched collars" inhaled vapors of EGME and developed weakness, sleepiness, headache, gastrointestinal upset, nocturia, weight loss, burning of eyes, and a complete change of personality from one of sharp intelligence to stupidity and lethargy. Both had macrocytic anemia and both recovered completely (Parsons & Parson, 1983).

a) Greenburg et al (1938) examined these two men (Case Report B) and 17 other workers employed in the same factory where 33% EGME was used. All workers had macrocytic anemia, general immaturity of leukocytes, abnormal reflexes and tremors, and complaints of excessive fatigue (Greenburg et al, 1938).

3) INHALATION: Zavon (1963) reported five cases of illness in workers exposed to levels ranging from 61 to 3960 ppm. Four of them had central nervous system depression and one case had cerebral atrophy manifested by ataxia, positive Romberg test, slurred speech, and tremors. All had anemia and one had a hypocellular bone marrow with reduced erythroid elements (Zavon, 1963).
4) ORAL: When a 44-year-old man ingested about 8 ounces of 2ME (total dose of 3 g/kg) and an unknown amount of ethanol, coma and death occurred within 5 hours. Autopsy revealed hemorrhagic gastritis, renal tubular degeneration, early necrosis of the pancreas, fatty degeneration of the liver, and brain edema. Urine contained no methanol (Young & Woolner, 1946).
5) ORAL: Two cases were reported of accidental ingestion of about 100 mL each of methoxymethanol (Nitter-Hauge, 1970).

a) In a 41-year-old man, confusion, agitation, disorientation, and motor restlessness began 8 hours postingestion. 20 hours postingestion, hyperventilation, renal dysfunction, metabolic acidosis (pH=7.18) with a high anion gap, and oxalate crystals in the urine were found. No methanol or methoxyethanol was found in urine. The patient recovered gradually.
b) In a 23-year-old man, muscle weakness and confusion developed 18 hours postingestion. On admission hyperventilation, proteinuria, and metabolic acidosis with a high anion gap was found, with no oxalate crystals in the urine.

6) DERMAL: Ohi and Wegman (1978) reported 2 cases of encephalopathy from EGME following dermal uptake when it was used as a substitute in a mandrel cleaning operation (Ohi & Wegman, 1978).

a) Confusion, disorientation, lethargy, anorexia, marked anemia, and bone marrow damage were present in both cases.
b) Tremors, agitation, weight loss, blurred vision, fever, headache, and bed wetting were observed in one or the other but not in both.
c) The 2-methoxyethanol vapor concentration averaged only 8 ppm thereby inferring cutaneous exposure.

7) OTHER: INHALATION/DERMAL: Cohen (1984) has observed that inhalation exposures of about 35 ppm of EGME coupled with dermal uptake in the microfilm industry can produce adverse but asymptomatic effects on the hematopoietic system and subjective CNS complaints (Cohen, 1984).

Range Of Toxicity

Summary

A)

Minimum Lethal Exposure

A)

1) A 44-year-old man who was reported to ingest about 8 ounces of ethylene glycol methyl ether in combination with ethanol died; autopsy revealed hemorrhagic gastritis, renal tubule degeneration, and fatty liver degeneration (Young & Woolner, 1946).

B)

1) In mice, the mean lethal vapor concentration (7-hour exposure) was found to be 1480 ppm (Gosselin et al, 1984).
2) In massive doses, EGME has a narcotic action but at lower dosage levels, deaths are delayed and are accompanied by lung edema, slight liver injury, and marked kidney injury (Clayton & Clayton, 1994).

Maximum Tolerated Exposure

A)

B)

1) INHALATION

a) Several clinical reports showed that glycol ethers could cause depression of the central nervous system and hematopoietic effects especially with chronic exposure to 25 to 76 ppm (Donley, 1936; Parsons & Parson, 1983; Greenburg, 1937; Greenburg, 1937).
b) Exposure to a TWA of 18.2 to 57.8 parts per million resulted in CNS toxicity and macrocytic anemia in a 32 year old man chronically exposed by skin and inhalation routes for 9 months (Cohen, 1984).
c) Paustenbach (1988) contends that human exposure to airborne concentrations less than 25 parts per million for 8 hours each day would not be expected to produce acute adverse effects (Paustenbach, 1988).
d) The bulk of data on reproductive toxicology of EGME confirms a no-adverse-effect-level (NOEL) of 10 parts per million for rats, rabbits, and mice (Paustenbach, 1988).

2) DERMAL

a) EGME is not appreciably irritating to the skin and is low in toxicity by this route (HSDB , 1999).
b) In toxic amounts, the signs of intoxication resulting from absorption through the skin are essentially the same as those resulting from other routes of administration (Clayton & Clayton, 1994).
c) EGME applied percutaneously (with occlusion) at doses of 1000 mg/kg/day for 5 days/week for 4 weeks caused significant decreases in rat RBC, Hb, MCV, WBC, bone marrow cellularity, pachytene spermatocytes, and spermatids (Fairhurst et al, 1989).

3) ORAL

a) Renal failure has occurred with ingestion of 100 mL of ethylene glycol monomethyl ether in adults (Nitter-Hauge, 1970).
b) The no-effect level for testis weight in mice was 125 mg/kg/day given 5 days/week for 5 weeks (Nagano et al, 1979).

Workplace Standards

A)

1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.

a) Adopted Value

1) 2-Methoxyethanol (EGME)

a) TLV:

1) TLV-TWA: 0.1 ppm
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: Not Listed
2) Codes: Skin
3) Definitions:

a) Skin: This refers to the potential significant contribution to the overall exposure by the cutaneous route, including mucous membranes and the eyes, either by contact with vapors or, of likely greater significance, by direct skin contact with the substance. It should be noted that although some materials are capable of causing irritation, dermatitis, and sensitization in workers, these properties are not considered relevant when assigning a skin notation. Rather, data from acute dermal studies and repeated dose dermal studies in animals or humans, along with the ability of the chemical to be absorbed, are integrated in the decision-making toward assignment of the skin designation. Use of the skin designation provides an alert that air sampling would not be sufficient by itself in quantifying exposure from the substance and that measures to prevent significant cutaneous absorption may be warranted. Please see "Definitions and Notations" (in TLV booklet) for full definition.

c) TLV Basis - Critical Effect(s): Hematologic eff; repro eff
d) Molecular Weight: 76.09

1) For gases and vapors, to convert the TLV from ppm to mg/m(3):

a) [(TLV in ppm)(gram molecular weight of substance)]/24.45

2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:

a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance

e) Additional information:

B) NIOSH REL and IDLH Values for CAS109-86-4 (National Institute for Occupational Safety and Health, 2007):

1) Listed as: Methyl Cellosolve(R)
2) REL:

a) TWA: 0.1 ppm (0.3 mg/m(3))
b) STEL:
c) Ceiling:
d) Carcinogen Listing: (Not Listed) Not Listed
e) Skin Designation: [skin]

1) Indicates the potential for dermal absorption; skin exposure should be prevented as necessary through the use of good work practices and gloves, coveralls, goggles, and other appropriate equipment.

f) Note(s):

3) IDLH:

a) IDLH: 200 ppm
b) Note(s): Not Listed

C) Carcinogenicity Ratings for CAS109-86-4 :

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed ; Listed as: 2-Methoxyethanol (EGME)
2) EPA (U.S. Environmental Protection Agency, 2011): Not Assessed under the IRIS program. ; Listed as: 2-Methoxyethanol
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Methyl Cellosolve(R)
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

D) OSHA PEL Values for CAS109-86-4 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Listed as: 2-Methoxyethanol (Methyl cellosolve)
2) Table Z-1 for 2-Methoxyethanol (Methyl cellosolve):

a) 8-hour TWA:

1) ppm: 25

a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.

2) mg/m3: 80

a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.

3) Ceiling Value:
4) Skin Designation: Yes
5) Notation(s): Not Listed

Toxicity Information

7.7.1)

A) References: (Lewis, 1996; RTECS, 1999

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 2147 mg/kg

2) LD50- (ORAL)MOUSE:

a) 2560 mg/kg

3) LD50- (INTRAPERITONEAL)RAT:

a) 2500 mg/kg

4) LD50- (ORAL)RAT:

a) 2370 mg/kg
b) 2460 mg/kg

5) TCLo- (INHALATION)HUMAN:

a) 25 ppm -- CNS

6) TCLo- (INHALATION)RAT:

a) Female, 25 ppm for 7H -- 7-13D post, REP

Pharmacology Toxicology

Toxicologic Mechanism

A)

B)

1) The fact that formate, acetate, glycine, glucose, serine, and sarcosine can eliminate digit malformations resulting from treatment with 2ME support the theory that methoxyacetic acid may interfere with the availability of one-carbon units for incorporation into purine and pyrimidine bases.
2) With alterations in the availability of these base precursors, DNA and/or RNA synthesis are affected thus influencing normal cellular proliferation and differentiation in the developing embryo.

C)

1) EGME is possibly teratogenic by itself.
2) Another enzyme system might be able to oxidize EGME to its teratogenic metabolite, methoxyacetic acid.

Physicochemical

Physical Characteristics

A)

B)

Ph

1) No information found at the time of this review.

Molecular Weight

A)

Animal Toxicology

References

General Bibliography

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ETHYLENE GLYCOL METHYL ETHER

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Heent

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Acid-Base

Hematologic

Dermatologic

Immunologic

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Inhalation Exposure

Eye Exposure

Dermal Exposure

Enhanced Elimination

Case Reports

Summary

Minimum Lethal Exposure

Maximum Tolerated Exposure

Workplace Standards

Toxicity Information

Toxicologic Mechanism

Physical Characteristics

Ph

Molecular Weight

General Bibliography