GLYCOL ETHERS

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) Alkylene oxide adducts
2) Glycol alkyl ethers
3) Glycol ether
4) Polyalkylene oxide ethers
5) Poly oxy alkylene glycols
6) Poly oxy alkylene oxide ethers

1) Butyl Cellosolve(R)
2) CAS 111-76-2

1) Cellosolve(R)
2) CAS 110-80-5

1) Glycol ether DPM
2) Methyl Cellosolve(R)
3) CAS 109-86-4

1) IPE
2) Isopropyl Cellosolve(R)
3) Isopropyl glycol
4) CAS 109-59-1

1) 2-phenoxyethanol
2) EGPE
3) phenoxy-Dowanol
4) phenyl Cellosolve

1) Propylene glycol methyl ether acetate

Available Forms Sources

1) Glycol ethers are synthesized by reaction of ethylene oxide with an alcohol in the presence of a catalyst, or by direct alkylation of a selected glycol with an alkylating agent. These compounds are referred to as glycol ethers, ethers of ethylene glycol, or by their respective alkoxyalcohol designation or trade name (Browning & Curry, 1994).

1) Glycol ethers are miscible in both water and many organic solvents, which has led to their use as mutual solvents in oil-water mixtures (Browning & Curry, 1994). Glycol ethers are commonly used industrial solvents and are also used in household cleaning products. They are used in lacquers, varnish removers, leather treatment products, dyeing and printing of textiles, and anti-icing agents for aviation fuels (ACGIH, 1986).
2) Propylene glycol methyl ether acetate (PMA) is a colorless liquid with an ether-like odor. PMA is a low-viscosity solvent (The Dow Chemical Company, 2008).
3) Some common household products that may contain glycol ethers include the following (Browning & Curry, 1994):

1) Acrylic polymers
2) Automotive brake fluid
3) Automotive injector cleaner
4) Automobile wax
5) Carpet steam cleaners and shampoos
6) Degreasing agents
7) Fabric cleaners
8) Floor finishes
9) Floor waxes
10) Ink removers
11) Leather dyes
12) Shoe polishes and savers
13) Shoe shampoo
14) Stain removers
15) Surface cleaning solution and detergents
16) Metal cleaners
17) Reducing agents
18) Vinyl cleaners
19) Window cleaning solutions
20) Wood finishes and preps

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: This management reviews the general toxicology of ethylene glycol monoalkyl ethers. These compounds are referred to as glycol ethers (eg, ethylene glycol butyl ether (EGBE), ethylene glycol methyl ether (EGME), ethylene glycol ethyl ether (EGEE)), ethers of ethylene glycol, or by their respective alkoxyalcohol (eg, butoxyethanol, ethoxyethanol, methoxyethanol) designation. Glycol ethers are used and found in many solvent mixtures. These solvents are commonly used as cleaning products, automotive fluids, lacquers, varnish removers, leather treatment products, dyeing and printing of textiles, and anti-icing agents for aviation fuels.
B) TOXICOLOGY: Toxic effects are likely due to both the parent compound and metabolites, but the mechanisms of toxicity are unknown. Following excessive exposure, these agents may cause 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. Acidosis might occur secondary to metabolism via alcohol dehydrogenase to alkoxyacids.
C) EPIDEMIOLOGY: Acute poisoning is relatively rare but glycol ethers are used widely in industrial settings and chronic exposure may occur in many workers among certain industries. Life-threatening effects are rare, but have been reported following large, deliberate ingestion.
D) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Most inadvertent ingestions of household products containing glycol ethers are asymptomatic. With acute inhalational exposure, eye and upper respiratory tract irritation may occur. Other symptoms that may occur include CNS symptoms such as headache, drowsiness, lethargy, fatigue, dizziness, weakness, staggered gait, and tremor. In chronic inhalation exposures, there have been reports of gynecologic disorders (benign neoplasms, cervical erosions, menstrual disorders), decreased sperm counts, leukopenia, mild anemia or granulocytopenia, and kidney injury (hematuria, albuminuria). Direct eye contact exposure may cause immediate pain, corneal and conjunctival irritation, and tearing that usually clears after one day. Hypocalcemia and hypokalemia have also been observed.
2) SEVERE TOXICITY: In large and intentional exposures, CNS depression, metabolic acidosis, renal injury, hypotension, seizures, acute lung injury, mild elevations in liver enzymes, hemolytic anemia, thrombocytopenia, and disseminated intravascular coagulation have been reported. ARDS was reported in one case after ingestion of 500 mL of 9.1% EGBE. Severe hypotension and ventricular dysrhythmias are rare effects of large ingestions of EGBE. Hemorrhagic gastritis and fatty degeneration of the liver were seen in a case of fatal poisoning with methyl ether.

0.2.4)

A) Eye irritation is generally slight, but may be severe with the propyl ether.

0.2.20)

A) Teratogenic effects have been observed at maternally non-toxic doses for the methyl ether and ethyl ether of ethylene glycol.

Laboratory Monitoring

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. Fluid resuscitation and hemodialysis may be needed for severe acid-base abnormality. 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. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Alcohol dehydrogenase inhibition with ethanol or fomepizole has been used, however, its effectiveness is unclear. There are reports of progression of acidosis following fomepizole treatment. Hemodialysis for severe and persistent symptoms has shown to improve clinical and metabolic status.

C) DECONTAMINATION

1) PREHOSPITAL: Gastrointestinal decontamination is not indicated due to rapid absorption and the risk of CNS depression and aspiration after large ingestion. Irrigate exposed eyes after ocular exposure. Remove contaminated clothing and wash exposed skin. Remove patients with inhalational exposure to fresh air. Administer oxygen if respiratory irritation develops.
2) HOSPITAL: Irrigate exposed eyes after ocular exposure. Remove contaminated clothing and wash exposed skin. In patients with inhalational exposure, administer oxygen if respiratory irritation develops. ACTIVATED CHARCOAL: Not routinely recommended. The risk of aspiration is high and activated charcoal likely does not bind these substances well. GASTRIC ASPIRATION: As these products are generally liquid, early nasogastric aspiration may be useful for very large, very 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 glycol ethers exposure. Although fomepizole and ethanol are not approved for use in glycol ether 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. FOMEPIZOLE VS ETHANOL: 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) 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.
b) 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.

F) ENHANCED ELIMINATION

1) There is no clinical experience; however, hemodialysis is indicated for severe acid-base and/or fluid-electrolyte abnormalities despite conventional therapy, or renal failure. It is unknown if glycol ethers are removed by hemolysis.

G) PATIENT DISPOSITION

1) HOME CRITERIA: Asymptomatic, inadvertent ingestions (taste or sip of a household product) , dermal or inhalation exposures may be managed at home.
2) OBSERVATION CRITERIA: All symptomatic patients, or those with large or intentional ingestions should be referred to a healthcare facility for evaluation. Patients with significant ingestions should be observed for at least 24 hours. Delayed symptom onset of 8 to 18 hours has been seen following ingestion of some glycol ethers. Symptomatic patients with less significant exposures may be sent home if their symptoms are clearly improving and discharge is clinically indicated.
3) ADMISSION CRITERIA: 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.
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) Failure to recognize co-ingestions, or ingestion of another toxic alcohol. Failure to recognize progression and worsening of symptoms. Discharging patient after only 6 hours of observation following a significant ingestion. Delayed symptom onset of 8 to 18 hours has been seen following ingestion of some glycol ethers.

I) TOXICOKINETICS

1) Glycol ethers are rapidly absorbed orally, and can be absorbed vial prolonged dermal and inhalational exposures. Distribution is rapid and extensive. Many of the glycol monoalkyl ethers have been shown to be oxidized by alcohol dehydrogenase in the liver to their respective alkoxyacetic acid. The major metabolites appear to be the acid derivatives and glycine conjugates. Butoxyacetic acid, methoxyacetic acid, ethoxyacetic acid, and isopropoxyacetic acid, are the major metabolites of the butyl ether, methyl ether, ethyl ether, and isopropyl ether, respectively. There is no direct evidence that glycol ethers undergo cleavage of the ether bond to produce ethylene glycol, with subsequent metabolism to oxalate. The elimination half-life of butoxyacetic acid in 5 volunteers exposed to 20 ppm of 2-butoxyethanol ranged from 1.7 to 9.6 hours. Urinary ethoxyacetic acid was detected in urine within the first hour of human inhalations, with continuing increases until 3 to 4 hours post exposure, when a subsequent exponential decline in urinary ethoxyacetic acid occurred, with an elimination half life of 21 to 24 hours.

J) DIFFERENTIAL DIAGNOSIS

1) Consider exposures to other toxic alcohols or glycols: methanol, ethylene glycol, diethylene glycol, isopropanol, and ethanol.

0.4.3)

A) Move patient from toxic environment to fresh air. Monitor for respiratory distress and administer oxygen as needed. Treat bronchospasms with inhaled beta-2-agonists.

0.4.4)

A) Remove contact lenses and irrigate exposed eyes with normal saline or water for at least 15 minutes. If symptoms continue after irrigation, an ophthalmologic examination is indicated.

0.4.5)

A) OVERVIEW

1) Remove contaminated clothing and wash exposed areas thoroughly with soap and water.

Range Of Toxicity

Clinical Effects

Hematologic

3.13.2)

A) ANEMIA

1) Anemia has been described in shipyard painters exposed via inhalation or dermal routes to ethylene glycol ethers (Welch & Cullen, 1988).

B) HEMOLYTIC ANEMIA

1) WITH POISONING/EXPOSURE

a) CASE REPORTS (EGBE): Hemolytic anemia and secondary hemoglobinuria was observed in two patients after ingestions of the butyl ether (Rambourg- Schepens et al, 1988; (Gijsenbergh et al, 1989).

C) APLASTIC ANEMIA

1) EGME: Aplastic anemia has been reported following chronic workplace exposure to the methyl ether (Cullen et al, 1983).

D) LEUKOPENIA

1) An industrial hygiene survey was conducted to identify exposure to ethylene glycol monoethyl ether acetate (EGEEA) of two groups of shipyard painters, a low exposure group (n = 30) and a high exposure group (n = 27). Mean white blood cell counts were significantly lower in the high risk group along with an increase in leukopenia (Kim et al, 1999).
2) Granulocytopenia has been described in shipyard painters exposed via inhalation or dermal routes to ethylene glycol ethers (Welch & Cullen, 1988).

E) MACROCYTIC ANEMIA

1) EGME: Macrocytic anemia has been described following chronic workplace exposure, via inhalation or dermal routes to the methyl ether (Ohi & Wegman, 1978; Cohen, 1984).

F) DISSEMINATED INTRAVASCULAR COAGULATION

1) WITH POISONING/EXPOSURE

a) EGBE: Disseminated intravascular coagulation (DIC) was a reported complication in a fatality due to EGBE ingestion (Litovitz et al, 1990).

G) THROMBOCYTOPENIC DISORDER

1) WITH POISONING/EXPOSURE

a) EGBE: Thrombocytopenia and non-hemolytic hypochromic anemia were noted in one case of massive overdose (Bauer et al, 1992a).

H) LYMPHOCYTOSIS

1) EGME: Mild depression of the white blood cell count with a relative lymphocytosis and macrocytosis were reported in three women who were chronically exposed to ethylene glycol monomethyl ether and acetone (Larese et al, 1992).

3.13.3)

A) ANIMAL STUDIES

1) ANEMIA HEMOLYTIC

a) SUMMARY: Experimental animals, with acute glycol ether exposures, develop hemolysis with hemoglobinuria, decreased WBC count, and hypocellular bone marrow (Browning & Curry, 1994).

1) Chronic exposures in experimental animals have resulted in bone marrow findings characterized by erythroid and myeloid hypoplasia with damage to endothelial cells of the marrow sinuses.

b) EGBE: Hemolytic anemia and secondary hemoglobinuria has been observed in animals exposed to the butyl ether (Carpenter et al, 1956).
c) RABBITS (EGPE): The phenyl ether (EGPE) produced a dose-related intravascular hemolytic anemia in rabbits given oral doses of 100 to 1000 mg/kg/day. A subsequent in vitro investigation showed erythrocyte lysis at concentrations of 10 mg/mL; hemolysis was only associated with the intact ether; exposure to the acid metabolite did not cause lysis (Breslin et al, 1991).

Dermatologic

3.14.3)

A) ANIMAL STUDIES

1) IRRITATION

a) Occluded 4 hour dermal application of ethylene glycol monohexyl ether to rabbits resulted in mild to moderate erythema, mild to marked edema, necrosis, and desquamation. Signs of systemic intoxication (salivation, ataxia, coma) were present, and the oral and percutaneous LD50s were similar (Ballantyne & Myers, 1987).

2) PERCUTANEOUS ABSORPTION

a) Percutaneous absorption may occur. An in vitro study using isolated human abdominal epidermis demonstrated variable skin permeability depending on the individual glycol ether tested. Four of the glycol ethers tested (2-methoxyethanol, 2-ethoxyethanol, 1-methoxypropan-2-ol, and 2-(2-ethoxyethoxy)ethanol) damaged the skin and compromised the barrier (Dugard et al, 1984).

Reproductive

3.20.1)

A) Teratogenic effects have been observed at maternally non-toxic doses for the methyl ether and ethyl ether of ethylene glycol.

3.20.2)

A) CONGENITAL ANOMALY

1) Teratogenic effects have been observed at maternally non-toxic doses for the methyl ether and ethyl ether of ethylene glycol. Testicular changes were seen in male animals (NIOSH, 1983). Conversely, higher molecular weight homologs, such as the butyl or propyl ether, have produced only minor fetotoxicity at maternally toxic doses only (Tyl et al, 1984; Krasavage & Katz, 1985).
2) A male infant born to a woman exposed to ethylene glycol monomethyl ether acetate had perineal hypospadia, micropenis and a bifid scrotum (Bolt & Golka, 1990). The second child born to this woman also had penile hypospadia and a bifid scrotum.
3) Exposure by gavage to doses of ethylene glycol diethyl ether that did not produce maternal toxicity produced reduced fetal body weight, exencephaly and fused ribs in mice and short tail, small spleen, fused sternebrae and fused rib cage in rabbits (George et al, 1992).
4) In mice, exposure to ethylene glycol monomethyl ether by gavage produced thymic atrophy and cellular depletion in offspring (Holladay et al, 1994).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS111-76-2 (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) IARC Classification

a) Listed as: 2-Butoxyethanol
b) Carcinogen Rating: 3

1) The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.

B) 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

C) IARC Carcinogenicity Ratings for CAS110-80-5 (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

D) IARC Carcinogenicity Ratings for CAS109-59-1 (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

Summary Of Exposure

Heent

3.4.1)

A) Eye irritation is generally slight, but may be severe with the propyl ether.

3.4.3)

A) BUTOXYETHANOL: Drops applied to rabbit eyes have produced redness, conjunctivitis, and slight corneal clouding, with complete recovery in 4 days (Grant, 1986). Exposure to vapors has caused mild eye irritation (Carpenter et al, 1956).
B) ETHOXYETHANOL: Drops applied to rabbit eyes produced slight reversible injury (Grant, 1986).
C) METHOXYETHANOL: Drops applied to rabbit eyes produced slight irritation, redness, and conjunctivitis (Grant, 1986). In a case of human exposure, recovery was complete in 48 hours.
D) PROPOXYETHANOL: Drops applied to rabbit eyes produced strong irritation, redness, conjunctivitis, purulent discharge, and long-lasting corneal clouding (Grant, 1986).
E) HETHOXYETHANOL: Drops (0.005 mL) applied to rabbit eyes produced mild conjunctival hyperemia, with moderate to severe chemosis and iritis, which resolved in 2 to 3 days.

1) Larger amounts (0.1 mL) produced moderate to severe conjunctivitis, which was still present 21 days later in some animals. Mild iritis resolved within 7 days. Moderate corneal injury cleared within 7 to 21 days (Ballantyne & Myers, 1987).

Cardiovascular

3.5.2)

A) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Hypotension and ventricular arrhythmias have been reported with exposures to glycol ethers (Marsh et al, 1986; Litovitz et al, 1990).
b) Large ingestions have been reported to result in severe systolic hypotension requiring vasoactive amines and intravenous fluids (Burkhart & Donovan, 1998; McKinney et al, 2000; Gijsenbergh et al, 1989; Bauer et al, 1992).
c) CASE REPORT (EGBE): Severe hypotension, requiring dopamine infusion for 7 hours, was reported after oral ingestion of an unknown quantity of butylglycol in a suicide attempt in a 23-year-old woman (Gijsenbergh et al, 1989).
d) CASE REPORT: Hypotension developed in a 53-year-old man who ingested 500 mL of a solution containing 9.1% ethylene glycol butyl ether and 2.5% ethanol (Bauer et al, 1992).

B) HYPERTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Nitter-Hauge (1970) reported two cases of hypertension that occurred following toxic ingestions of glycol ethers (Nitter-Hauge, 1970a).
b) Hypertension (164/100, initially) which worsened and required antihypertensive therapy was reported following ingestion of brake oil containing a mixture of glycols in 1 of 3 cases (Sharma & Jain, 2002).

C) VENTRICULAR TACHYCARDIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT (EGBE): Ventricular tachycardia and hypotension were reported complications prior to death from cardiac arrest in an 87-year-old woman who ingested an unknown amount of 6.5% EGBE (Litovitz et al, 1990).

Respiratory

3.6.2)

A) HYPERVENTILATION

1) WITH POISONING/EXPOSURE

a) CASE REPORTS (EGME): Hyperventilation developed in 3 patients who acutely overdosed on methoxyethanol (Young & Woolner, 1946; Nitter-Hauge, 1970).

B) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) CASE REPORT (EGBE): ARDS was reported after ingestion of 45.5 mL of EGBE by a 53-year-old man; he recovered after initiation of PEEP and supportive care (Bauer et al, 1992a).

Neurologic

3.7.2)

A) TOXIC ENCEPHALOPATHY

1) WITH POISONING/EXPOSURE

a) SUMMARY: Acute encephalopathy is typical in serious cases of acute human glycol ether poisoning, and is characterized by agitation, confusion or coma. There is also a potential for delayed onset of CNS toxicity 8 to 18 hours following acute ingestions (Mroz et al, 1996; Browning & Curry, 1994).

1) Chronic exposures are characterized predominantly by neurological symptoms, including gradual onset of personality changes, lethargy, memory loss, headache, dizziness, and comprehension problems. Symptoms appear to resolve spontaneously over several weeks following discontinuation of exposure.

b) EGME: Ataxia, tremor, somnolence, lethargy, headache, dysarthria, blurred vision, coma, and personality changes have been reported after industrial inhalation exposure to the methyl ether (Zavon, 1963; (Donley, 1936a; Ohi & Wegman, 1978).
c) EGME: Oral ingestion of the methyl ether has resulted in confusion, disorientation, agitation, motor restlessness, and coma (Nitter-Hauge, 1970; Young & Woolner, 1946).
d) EGBE: Oral ingestion of the butyl ether has resulted in coma. Onset of coma ranged from 1 to 12 hours after ingestion (Rambourg-Schepens et al, 1988a; Gijsenbergh et al, 1989; Litovitz et al, 1990; Bauer et al, 1992a).
e) 2-PHENOXYETHANOL: Percutaneous exposure to about 500 mL/day resulted in complaints of headache, lightheadedness, slurred speech, euphoria, grogginess, a "drunk" sensation, and diminished strength and sensation in exposed hands and fingers in workers at a fish hatchery. After prolonged exposure over 1 to 2 years, cognitive impairment was documented with neuropsychologic testing (Morton, 1990).
f) TIGME and TEGME: Following the intentional ingestion of brake fluid, containing trimethylene glycol monomethyl ether (TIGME) and tetramethyl glycol monomethyl ether (TEGME), a 37-year-old male presented 2 days later with acidosis, acute renal failure, detectable serum levels of methanol (9.2 mg/dL) and ethylene glycol (22 mg/dL), and calcium dihydrate crystals in his urine. Four days post-ingestion he developed severe brain stem abnormalities resulting in respiratory arrest and eventual death (Mroz et al, 1996). The authors suggest the delayed onset of symptoms is due to slow metabolism of the parent compounds. One week after ingestion serum methanol was 6.2 mg/dL and ethylene glycol was 8.2 mg/dL.

Gastrointestinal

3.8.2)

A) GASTRIC HEMORRHAGE

1) WITH POISONING/EXPOSURE

a) EGME: Hemorrhagic gastritis developed in a case of fatal poisoning with the methyl ether (Young & Woolner, 1946).

B) ULCER OF ESOPHAGUS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Oral and esophageal burns were reported after an intentional ingestion of 150 mL of DOT 3 brake fluid in a 30-year-old male. Vomiting occurred immediately after the ingestion. Superficial ulcerations over the uvula and posterior oropharynx were noted. Several diffuse, superficial erosions were visible throughout the esophagus when viewed with esophagoscopy. The patient was discharged the following day (Williams et al, 1998).

Hepatic

3.9.2)

A) DISEASE OF LIVER

1) WITH POISONING/EXPOSURE

a) EGME: Fatty degeneration of the liver was noted on autopsy after a fatal poisoning with the methyl ether (Young & Woolner, 1946).

B) HEPATIC NECROSIS

1) WITH POISONING/EXPOSURE

a) Hepatic centrilobular necrosis presenting with slight jaundice and enlarged firm liver may occur following large ingestions of glycol ethers (Geiling & Cannon, 1938; Young & Woolner, 1946a; Drut et al, 1994).

3.9.3)

A) ANIMAL STUDIES

1) HEPATIC NECROSIS

a) Hepatic necrosis in animals is thought to be secondary to hemolytic effects (Ghanayem et al, 1987).

Genitourinary

3.10.2)

A) CRUSH SYNDROME

1) WITH POISONING/EXPOSURE

a) SUMMARY: Renal tubular degeneration and necrosis may occur following acute glycol ether exposures. Acute human ingestions have resulted in proteinuria and elevations of serum creatinine (Browning & Curry, 1994).
b) EGME: Acute tubular necrosis with proteinuria has been seen following oral ingestion of the methyl ether (Young & Woolner, 1946), and butyl ether (Litovitz et al, 1990).

B) ABNORMAL URINE

1) WITH POISONING/EXPOSURE

a) EGME: Oxalate crystals were seen in the urine in one patient ingesting the methyl ether (Young & Woolner, 1946; Nitter-Hauge, 1970), and following ingestion of the butyl ether in one patient (Rambourg-Schepens et al, 1988a).
b) EGBE: No oxaluria was noted in a case of butyl ether overdose (Gijsenbergh et al, 1989).
c) Oxalate crystals may or may not be present in the urine following poisoning with glycol ethers (Young & Woolner, 1946a; Nitter-Hauge, 1970a; Rambourg-Schepens et al, 1988; Gijsenbergh et al, 1989).
d) TIGME and TEGME: Calcium dihydrate crystals were noted in the urine 2 in an adult who presented with acute renal failure 2 days after ingestion of brake fluid containing trimethylene glycol monomethyl ether and tetramethyl glycol monomethyl ether (Mroz et al, 1996).

C) DECREASED FERTILITY

1) EGME & EGEE: Oligospermia and azoospermia were detected in shipyard painters exposed to 2-ethoxyethanol and 2-methoxyethanol (Welch & Cullen, 1988; Welch et al, 1991).
2) A case-control study found a significant association between a diagnosis of impaired fertility and the detection of ethoxyacetic acid (EAA), a metabolite of ethylene glycol ether, in the urine. A dose response relation was found in an excess of azoospermia in the EAA positive subgroup of cases (Veulemans et al, 1993).
3) Paul & Kurtz (1994) suggest that material safety data sheets for ethylene glycol ethers grossly under-report the occurrence of effects on the male reproductive system, a target organ of these agents.

D) LESION OF CERVIX

1) GYNECOLOGIC DISORDERS: Female enamel workers exposed to ethylene glycol monomethyl ether and other solvents had 2.5 to 9.4 times as many GYNECOLOGIC DISORDERS (benign neoplasms, cervical erosions, and menstrual disorders) than comparison groups (Syrovadko & Malsheva, 1977).

Genotoxicity

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) Metabolic acidosis is a universal finding in cases of large acute ingestions of glycol ethers. Even though severe at times, the acidosis generally resolves within the first 24 hours with supportive care (Mroz et al, 1996; Browning & Curry, 1994).
b) Metabolic acidosis has been described after large ingestions (250 to 500 milliliters of solutions containing 6.5% to 22% EGBE) (Rambourg-Schepens et al, 1988; Gijsenbergh et al, 1989; Litovitz et al, 1990; Bauer et al, 1992; Gualtieri et al, 2003; McKinney et al, 2000).
c) CASE REPORT: McKinney et al (2000) described a case of rapid onset and persistent hyperchloremic metabolic acidosis, hypotension, and CNS depression following a massive ingestion of EGBE, treated with ethanol therapy (no dialysis) for 48 hours. The patient recovered with no apparent sequelae. The authors suggested that acidosis may not be a reliable indicator for the use of hemodialysis (McKinney et al, 2000).
d) CASE REPORTS (EGME & EGBE): Metabolic acidosis with a elevated anion gap was noted in 2 adults who ingested 100 mL each of the methyl ether (Nitter-Hauge, 1970), and in two patients who ingested 30 to 60 mL of the butyl ether (Rambourg-Schepens et al, 1988a; Gijsenbergh et al, 1989). Another adult, who ingested about 150 mL of brake fluid which contains glycol ethers, developed mild acidosis with a calculated anion gap of 14, which resolved with intravenous hydration (Williams et al, 1998).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs and mental status.
B) Monitor CBC, serum electrolytes, liver enzymes, renal function, urinalysis, and urine output in symptomatic patients or after a significant ingestion.
C) Monitor arterial blood gases for worsening metabolic acidosis.
D) Serum ethanol, methanol, and ethylene glycol concentrations are theoretically useful in assessing concurrent ingestions or metabolites of glycol ethers.
E) 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.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Obtain serum electrolytes (including calcium and potassium) and renal function tests in patients who are symptomatic or who have a history of ingestion.
2) Serum ethanol, methanol, and ethylene glycol concentrations are theoretically useful in assessing concurrent ingestions or metabolites of glycol ethers.
3) SERUM OSMOLALITY: Unlike ethylene glycol, which produces a linear increase in serum osmolality with increasing serum ethylene glycol concentrations, the butyl ether did not affect osmolality measurements in an in vitro study (Lund et al, 1983).

a) Browning & Curry (1992) found a linear increase in plasma osmolality with increasing plasma concentration, but the change in osmolality may be too small to be clinically useful at concentrations expected in cases of acute poisonings (Browning & Curry, 1992).

B) HEMATOLOGIC

1) Obtain CBC in all patients who are symptomatic or have a history of ingestion to rule out hemolysis.

C) ACID/BASE

1) Monitor arterial blood gases for worsening metabolic acidosis.

4.1.3)

A) URINARY LEVELS

1) The major metabolites of the ethyl and methyl ether, ethoxyacetic acid and methoxyacetic acid, respectively, are detectable in the urine by gas chromatography and may be useful in monitoring workplace exposure (Groeseneken et al, 1986).

B) URINALYSIS

1) Perform urinalysis (look for oxalate crystals and hemoglobin) on patients with a history of exposure or who are symptomatic.

4.1.4)

A) OTHER

1) MONITORING

a) The presence of abnormal bone marrow aspirates in asymptomatic occupationally exposed lithographers to the methyl ether 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

1) AIR SAMPLING: Use of the OSHA-recommended method for air sampling of glycol ethers was found to produce falsely elevated concentrations in the presence of organic solvents, such as isobutanol. Analytical interference can be minimized by performing GC/MS or modifying the OSHA method to separate solvent interferance by using different capillary columns for elution (Piacitelli et al, 1990).
2) The major metabolites of the ethyl and methyl ether, ethoxyacetic acid and methoxyacetic acid, respectively, are detectable in the urine by gas chromatography and may be useful in monitoring workplace exposure (Groeseneken et al, 1986).

1) BIOLOGICAL MONITORING: Because glycol ethers are relatively nonvolatile and easily penetrate skin, traditional air sampling may not provide an accurate assessment of total exposure. Biomonitoring techniques may permit more complete assessment of workplace exposure, especially at low concentrations (Piacitelli et al, 1990).

Treatment

Monitoring

Oral Exposure

6.5.1)

A) PREHOSPITAL: Gastrointestinal decontamination is not indicated due to rapid absorption and the risk of CNS depression and aspiration after large ingestion. Irrigate exposed eyes after ocular exposure. Remove contaminated clothing and wash exposed skin. Remove patients with inhalational exposure to fresh air. Administer oxygen if respiratory irritation develops.

6.5.2)

A) SUMMARY

1) ACTIVATED CHARCOAL: Not routinely recommended. The risk of aspiration is high and activated charcoal likely does not bind these substances well. GASTRIC ASPIRATION: As these products are generally liquid, early nasogastric aspiration may be useful for very large, very recent ingestions if the patient is alert or the airway is protected.

6.5.3)

A) SUPPORT

1) MANAGEMENT OF MILD TO MODERATE TOXICITY

a) Treatment is symptomatic and supportive.

2) MANAGEMENT OF SEVERE TOXICITY

a) Treatment is symptomatic and supportive. Fluid resuscitation and hemodialysis may be needed for severe acid-base abnormality. 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. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Alcohol dehydrogenase inhibition with ethanol or fomepizole has been used, however, its effectiveness is unclear. There are reports of progression of acidosis following fomepizole treatment. Hemodialysis for severe and persistent symptoms has shown to improve clinical and metabolic status.

B) MONITORING OF PATIENT

1) Monitor vital signs and mental status.
2) Monitor CBC, serum electrolytes, liver enzymes, renal function, urinalysis, and urine output in symptomatic patients or after a significant ingestion.
3) Monitor arterial blood gases for worsening metabolic acidosis.
4) Serum ethanol, methanol, and ethylene glycol concentrations are theoretically useful in assessing concurrent ingestions or metabolites of glycol ethers.
5) 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.
6) The major metabolites of the ethyl and methyl ether, ethoxyacetic acid and methoxyacetic acid, respectively, are detectable in the urine by gas chromatography and may be useful in monitoring workplace exposure (Groeseneken et al, 1986).

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) 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).

E) FOMEPIZOLE

1) SUMMARY - Fomepizole (Antizole(TM); 4-Methylpyrazole; 4-MP), a specific antagonist of alcohol dehydrogenase, 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). Fomepizole has not been approved for use in children.
2) AVAILABILITY

a) Fomepizole (Antizole(R); 4-MP) is available in the United States for the treatment of methanol and ethylene glycol poisoning (Prod Info ANTIZOL(R) IV injection, 2006).

3) 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.

4) ADVERSE EFFECTS

a) Studies in NORMAL HUMAN VOLUNTEERS show less side effects and slower elimination rate compared to ethanol (McMartin et al, 1987).
b) The manufacturer reported the most frequent adverse effects in 78 patients and 63 normal volunteers receiving fomepizole to be headache (14%), nausea (11%), and dizziness, increased drowsiness, and bad taste (6% each) (Prod Info ANTIZOL(R) IV injection, 2006).
c) A placebo-controlled, double-blind, multiple dose, sequential, ascending dose study among HEALTHY volunteers showed mild, transient increase in liver function tests and slower elimination rate of fomepizole (4-methylpyrazole). The mild, sporadic, and transient elevations in blood pressure were not dose-related (Jacobsen et al, 1990).

F) ETHANOL

1) EFFICACY

a) The role of ethanol therapy in preventing toxicity of glycol monoalkyl ethers is uncertain. Putative evidence suggests that ethanol therapy is beneficial. No human studies evaluating efficacy in poisoned patients are available. The parent ether compound is relatively nontoxic compared to the acetic acid metabolite. It is predicted that glycol ether toxicity may be reduced by blocking the production of the toxic metabolite by competitive inhibition of alcohol dehydrogenase with ethanol (Browning & Curry, 1994).
b) The presence of acid metabolites in animals and in vitro studies showing the ethyl and methyl ether to be a substrate for alcohol dehydrogenase (ADH) would indicate a potential for therapeutic effect of ethanol (Blair & Vallee, 1966).
c) Ethanol was used in combination with hemodialysis in one case with a successful outcome (Bauer et al, 1992). In another case, McKinney et al (2000) reported treatment with IV ethanol over a 48 hour period (and no dialysis) with a successful outcome and no apparent sequelae in a patient with persistent hyperchloremic metabolic acidosis, hypotension and CNS depression prior to ethanol therapy (McKinney et al, 2000).
d) ANIMAL STUDY

1) In vivo animal studies have shown marked inhibition by ethanol of the elimination of the butyl (Johanson et al, 1986), methyl, and ethyl (Romer et al, 1985) ethers. However, the in vitro affinity of the ethyl ether for ADH is higher than the affinity of ethanol for ADH. The use of high ethanol/glycol ether ratios in these studies may have influenced the results, and may not reflect actual overdose situations.
2) In one volunteer study, an adult male was given 104 grams of ethanol and exposed to 316 parts per million of the ethyl ether. No difference in the elimination rate of ethanol was found. An effect of ethanol on the elimination of the ether was not studied (Pedersen et al, 1980).
3) The administration of pyrazole (an alcohol dehydrogenase inhibitor) to rats one hour prior to administration of the butyl ether inhibited metabolism to butoxyacetic acid and prevented hematologic, liver, and renal toxicity (Ghanayem et al, 1987).

2) INDICATIONS

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

3) AVAILABILITY

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) NO SERUM CONCENTRATIONS AVAILABLE - Ethanol therapy should be continued for a minimum of 3 days in the absence of dialysis, one day when dialysis has been performed, or until clinical findings resolve, whichever is longer.
4) Endpoint of ethanol therapy for treatment of glycol ethers is arbitrary. Additional studies are needed to demonstrate efficacy and duration of therapy. Glycol ether serum concentrations are not routinely available and a toxic range has not been established.
5) If the clinical findings have not resolved it may indicate the continued presence of glycol ether, metabolites, or both or some other etiology.
6) Metabolite concentrations have not been studied in blood (Rambourg-Schepens et al, 1988a; Groeseneken et al, 1986). The biological half-life of ethoxyacetic acid (ethylene glycol monoethyl ether metabolite) in humans following inhalation exposure is 21 to 24 hours (Groeseneken et al, 1986a).
7) Serum osmolality may not be indicative of exposure (Lund et al, 1983).

10) CONCURRENT ETHANOL/GLYCOL ETHER INGESTION

a) Patients who have concurrently ingested ethanol and an ethylene glycol ether may have a normal acid-base profile and urinalysis.
b) Consider implementing the ethanol treatment regimen in these patients. Determine blood ETOH level before beginning ETOH therapy.
c) ETHANOL DOSING (Concurrent ingested ethanol):

1) To modify the ethanol 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 following 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) / {754 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.

6.7.2)

A) GENERAL TREATMENT

1) Treatment is SYMPTOMATIC and SUPPORTIVE.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

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).

6.9.2)

A) SKIN ABSORPTION

1) Percutaneous LD50 values in animals were less than oral LD50 values for the methyl, ethyl, propyl, butyl, heptyl, and hexyl monoalkyl ethers of ethylene glycol (Ballantyne & Myers, 1987).
2) In a model evaluating absorption of some glycol ethers through isolated human abdominal epidermis in vitro, individual glycol ethers were shown to have high degrees of variability in skin permeability. Barrier function was compromised by four glycol ethers tested (2-methoxyethanol, 2-ethoxyethanol, 1-methoxypropan-2-ol, and 2-(2-ethoxyethoxy)ethanol) that damaged the skin in this model. This model used undiluted glycol ether (Dugard et al, 1984).

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) 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, inadvertent ingestions (taste or sip of a household product) , dermal or inhalation exposures may be managed 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 those with large or intentional ingestions should be referred to a healthcare facility for evaluation. Patients with significant ingestions should be observed for at least 24 hours. Delayed symptom onset of 8 to 18 hours has been seen following ingestion of some glycol ethers. Symptomatic patients with less significant exposures may be sent home if their symptoms are clearly improving and discharge is clinically indicated.

Abstracts

Case Reports

1) ADULT

a) A 44-year-old man was reported to ingest 8 ounces of methoxyethanol and an unknown amount of ethanol. He was admitted in coma and died 5 hours later. Autopsy revealed hemorrhagic gastritis, fatty liver degeneration, and renal tubule degeneration. The urine contained no methanol (Young & Woolner, 1946).
b) A 23-year-old woman was reported to ingest 500 mL of a window cleaner containing 12.7% ethylene glycol butyl ether (EGBE) and 3.2% ethanol. The total estimated dose of EGBE was 63.5 mL or 0.89 gram/kg. One hour postingestion she was comatose and hypotensive. Gastric suction removed 400 mL of a greenish fluid. Hypotension was treated with IV fluids and dopamine infusion. The admission EGBE level was 43.2 mg/dL. She awoke 4 hours postingestion. At 7 hours postingestion marked metabolic acidosis was noted, with the following laboratory values: pH 7.08, PCO2 8.2, HCO3 2.4 mEq/L, anion gap 27.8 mEq/L. No osmolal gap was present. Hemodialysis was performed to control the acidosis. On the second day the hemoglobin fell from 11.9 to 8.9 g/dL and hematuria was noted, concurrently with maximal urinary levels of the metabolite butoxyacetic acid. Urinary oxalate excretion remained unchanged, and renal function was unimpaired. The half-life of EGBE was 210 minutes (Gijsenbergh et al, 1989).
c) Two cases were reported of accidental ingestion of about 100 mL each of methoxyethanol (Nitter-Hauge, 1970).

1) In a 41-year-old man, confusion, agitation, disorientation, and motor restlessness began 8 hours postingestion. On admission, 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. 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 (Nitter-Hauge, 1970).

d) A 50-year-old woman ingested 250 to 500 mL of a window cleaner containing 12% EGBE (30 to 60 mL of pure EGBE). She was comatose 12 hours later, required mechanical ventilation, and had a metabolic acidosis with the following laboratory values: blood pH 7.23, PO2 11.18, PCO2 1.43, bicarb (5 mmol/L). Hypokalemia, increased serum creatinine, and oxaluria were noted. Supportive care was the only treatment given. Hemoglobinuria was present from the 3rd to 6th day. The patient recovered and was discharged on the 10th day (Rambourg-Schepens et al, 1988a).
e) An 87-year-old woman presented in coma after ingestion of an unknown amount of a disinfectant cleaner containing 6.5% EGBE. Initial laboratory results included metabolic acidosis and an ethylene glycol level of 110 mg/dL. Ethanol therapy was begun 3 hours after admission. Hemodialysis was attempted, but discontinued due to ventricular tachycardia. Complications included prolonged acidosis, hypotension, arrhythmias, hepatic and renal failure, and DIC. The patient had a cardiac arrest and died 3 days after admission (Litovitz et al, 1990).
f) A 53-year-old chronic alcoholic was admitted 10 hours after ingestion of 500 mL of a household cleaner containing 9.1% EGBE (total EGBE 45.5 mL). Shortly, he became comatose and hypotensive (BP 60/30 mmHg). Abnormal laboratory findings included lactic acidosis and hypoxia (anion gap 34; pH 7.05; PaO2 26.8 mmHg), hypokalemia (2.1 mmol/L), and elevated liver function tests (ASAT 105 U/L; ammonia 83 mcmol/L). Physical examination showed crackles in both lungs. Chest radiograph revealed diffuse pulmonary edema. Hemodynamic data were consistent with ARDS. Treatment included supportive care for shock (colloids, epinephrine), which was stabilized in 12 hours; sodium bicarbonate for acidosis, which was corrected in 4 hours; and hemodialysis for 3 six-hour sessions. The patient was discharged after full recovery on the 15th day (Bauer et al, 1992a).

Range Of Toxicity

Summary

Minimum Lethal Exposure

1) Ingestion of 8 ounces of methoxyethanol (EGME) resulted in death in a 44-year-old man. Autopsy revealed hemorrhagic gastritis, fatty liver degeneration, and renal tubule degeneration (Young & Woolner, 1946).
2) Ingestion of an unknown quantity of brake fluid, containing trimethylene glycol monomethyl ether and tetramethyl glycol monomethyl ether, resulted in a delayed onset (4 days) of severe brain stem abnormalities progressing to death more than one week after the ingestion due to respiratory failure (Mroz et al, 1996).

Maximum Tolerated Exposure

1) INHALATION

a) The acute inhalation toxicity in mice varied, with the methyl ether being the most toxic. The ethers are listed in decreasing order of toxicity (Werner et al, 1943)

1) Methoxyethanol (EGME)
2) Ethoxyethanol (EGEE)
3) Isopropoxyethanol
4) n-propoxyethanol
5) Butoxyethanol (EGBE)

2) EGBE

a) ORAL

1) ADULT TOXICITY

a) Severe toxicity (coma, acidosis) was noted in a 50-year-old woman who ingested 250 to 500 milliliters of a 12% solution, equivalent to 30 to 60 milliliters of pure EGBE (Rambourg-Schepens et al, 1988).
b) Severe toxicity (coma, acidosis, anemia, hematuria) was reported in a 23-year-old woman following ingestion of 500 milliliters of a window cleaner containing 12.7% EGBE. The total dose ingested was estimated to be 63.5 milliliters of pure EGBE or 0.89 gram/kilogram. Due to prompt gastric lavage, the authors estimated that one-half of this amount was actually absorbed (Gijsenbergh et al, 1989).
c) Severe toxicity (coma, acidosis, hypotension, acute lung injury/ARDS) was reported in a 53-year-old man following ingestion of 500 milliliters of a 9.1% solution (equivalent to 45.5 milliliters of pure EGBE) (Bauer et al, 1992).

2) PEDIATRIC TOXICITY

a) No symptoms developed in 24 children ingesting 5 to 300 milliliters of glass cleaner (0.5 to 9.9% ethylene glycol butyl ether). The 2 children ingesting more than 15 milliliters (approximately 3 milliliters EGBE in a 14-month-old and 24 milliliters in a 2-year-old) were treated with gastric emptying. All others were followed at home following simple dilution (Dean & Krenzelok, 1992).

3) Toxic hazard rating is between classes 3 and 4 with probable oral lethal dose of at least 50 to 500 milligrams per kilogram or the equivalent of 1 mL/kg or 1 ounce of pure EGBE for a 70 kilogram person (HSDB , 2000).

b) DERMAL

1) The percutaneous absorption of EGBE was investigated in 12 exposure experiments with five male volunteers. Exposure of four fingers to liquid butoxyethanol corresponds roughly to being exposed to butoxyethanol vapor at 20 parts per million (Johanson & Ferstrom, 1988).

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, 1937a; Greenburg, 1937a).
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, 1994a).
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) Ingestion of 100 milliliters each of methoxyethanol by two men resulted in significant toxicity (acidosis, renal dysfunction, confusion) with eventual recovery (Nitter-Hauge, 1970).
b) Renal failure has occurred with ingestion of 100 mL of ethylene glycol monomethyl ether in adults (Nitter-Hauge, 1970a).
c) 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).

1) Ethylene glycol monoethyl ether is considered low in acute oral toxicity, not significantly irritating to skin, mildly irritating to eyes and mucous membranes and of low toxicity after dermal exposure (Clayton & Clayton, 1994).
2) 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 parts ppm (Donlet, 1936; Greenburg et al, 1937a; Greenburg, 1937) .

a) A 44-year-old woman ingested 40 mL of 2-Ethoxyethanol, developing vertigo, unconsciousness, cyanosis, tachypneumonary edema, and tonic-clonic spasms (Occupational Safety & Health Administration (OSHA), 2012).

3) One study reported that exposure to airborne concentrations less than 25 ppm for 8 hours each day would not be expected to produce acute adverse effects (Paustenbach, 1988).

1) TOXICITY ESTIMATE

a) Assuming that the glycol ethers are equipotent as ethylene glycol (EG), the following approximations may be used to assess the potential for intoxication. A 3 milliliter ingestion of EG by a child weighing 10 kilograms is capable of producing a toxic blood level (20 milligrams/deciliter) (see Glycols management).
b) Since the glycol ethers are probably at least twice as toxic as EG, the amount of glycol ether equivalent to 1.5 milliliters of EG is given below.

GLYCOL ETHER CONCENTRATION
(Amount equivalent to 1.5 mL EG)
.	5%	10%	100%
Methyl ether	35 mL	17.5 mL	1.75 mL
Butyl ether	37 mL	18.5 mL	1.85 mL
Ethyl ether	36 mL	18 mL	1.8 mL

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) SPECIFIC SUBSTANCE

a) Two days after ingestion of an unknown quantity of brake fluid containing trimethylene glycol monomethyl ether and tetramethyl glycol monomethyl ether, serum methanol and ethylene glycol levels of 9.2 mg/dL and 22 mg/dL, respectively, were reported. One week after the ingestion, levels of 6.2 mg/dL and 8.2 mg/dL, respectively, were reported (Mroz et al, 1996).

Workplace Standards

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-Butoxyethanol (EGBE)

a) TLV:

1) TLV-TWA: 20 ppm
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: A3
2) Codes: Not Listed
3) Definitions:

a) A3: Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.

c) TLV Basis - Critical Effect(s): Eye and URT irr
d) Molecular Weight: 118.17

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) ACGIH TLV Values for CAS109-86-4 (American Conference of Governmental Industrial Hygienists, 2010):

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:

C) ACGIH TLV Values for CAS110-80-5 (American Conference of Governmental Industrial Hygienists, 2010):

a) Adopted Value

1) 2-Ethoxyethanol (EGEE)

a) TLV:

1) TLV-TWA: 5 ppm
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

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

a) BEI: The BEI notation is listed when a BEI is also recommended for the substance listed. Biological monitoring should be instituted for such substances to evaluate the total exposure from all sources, including dermal, ingestion, or non-occupational.
b) 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): Male repro dam; embryo/fetal dam
d) Molecular Weight: 90.12

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:

D) ACGIH TLV Values for CAS109-59-1 (American Conference of Governmental Industrial Hygienists, 2010):

a) Adopted Value

1) 2-Isopropoxyethanol

a) TLV:

1) TLV-TWA: 25 ppm
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

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

c) TLV Basis - Critical Effect(s): Hematologic eff
d) Molecular Weight: 104.15

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:

E) NIOSH REL and IDLH Values for CAS111-76-2 (National Institute for Occupational Safety and Health, 2007):

1) Listed as: 2-Butoxyethanol
2) REL:

a) TWA: 5 ppm (24 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: 700 ppm
b) Note(s): Not Listed

F) 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]

f) Note(s):

3) IDLH:

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

G) NIOSH REL and IDLH Values for CAS110-80-5 (National Institute for Occupational Safety and Health, 2007):

1) Listed as: 2-Ethoxyethanol
2) REL:

a) TWA: 0.5 ppm (1.8 mg/m(3))
b) STEL:
c) Ceiling:
d) Carcinogen Listing: (Not Listed) Not Listed
e) Skin Designation: [skin]

f) Note(s):

3) IDLH:

a) IDLH: 500 ppm
b) Note(s): Not Listed

H) NIOSH REL and IDLH Values for CAS109-59-1 (National Institute for Occupational Safety and Health, 2007):

1) Listed as: 2-Isopropoxyethanol
2) REL:

a) TWA:
b) STEL:
c) Ceiling:
d) Carcinogen Listing: (Not Listed) Not Listed
e) Skin Designation: Not Listed
f) Note(s): See Appendix D

3) IDLH: Not Listed

I) Carcinogenicity Ratings for CAS111-76-2 :

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A3 ; Listed as: 2-Butoxyethanol (EGBE)

a) A3 :Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.

2) EPA (U.S. Environmental Protection Agency, 2011): Not likely to be carcinogenic to humans ; Listed as: Ethylene glycol monobutyl ether (EGBE) (2-Butoxyethanol)
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): 3 ; Listed as: 2-Butoxyethanol

a) 3 : The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.

4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: 2-Butoxyethanol
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

J) 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

K) Carcinogenicity Ratings for CAS110-80-5 :

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed ; Listed as: 2-Ethoxyethanol (EGEE)
2) EPA (U.S. Environmental Protection Agency, 2011): Not Assessed under the IRIS program. ; Listed as: 2-Ethoxyethanol
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: 2-Ethoxyethanol
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

L) Carcinogenicity Ratings for CAS109-59-1 :

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed ; Listed as: 2-Isopropoxyethanol
2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
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: 2-Isopropoxyethanol
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

M) OSHA PEL Values for CAS111-76-2 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Listed as: 2-Butoxyethanol
2) Table Z-1 for 2-Butoxyethanol:

a) 8-hour TWA:

1) ppm: 50

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

2) mg/m3: 240

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

N) 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

O) OSHA PEL Values for CAS110-80-5 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Listed as: 2-Ethoxyethanol (Cellosolve)
2) Table Z-1 for 2-Ethoxyethanol (Cellosolve):

a) 8-hour TWA:

1) ppm: 200

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

2) mg/m3: 740

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

P) OSHA PEL Values for CAS109-59-1 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Not Listed

Toxicity Information

7.7.1)

A) LD50- (ORAL)MOUSE:

1) 7.5 g/kg

B) LD50- (ORAL)RAT:

1) 8.54 g/kg

C) LD50- (ORAL)RAT:

1) 2.46 g/kg

D) LD50- (ORAL)MOUSE:

1) 4.3 g/kg

E) LD50- (ORAL)RAT:

1) 3 g/kg

F) LD50- (ORAL)MOUSE:

1) 1.23 g/kg

G) LD50- (ORAL)RAT:

1) 1.48 g/kg

H) LD50- (ORAL)RAT:

1) 1.26 g/kg

I) BUTOXYETHANOL (BE)

1) LD50- (ORAL)RAT:

a) 1.48 g/kg (Smyth et al, 1941)

J) ETHOXYETHANOL (EE)

1) LD50- (ORAL)RAT:

a) 5500 mg/kg (Carpenter et al, 1956)

K) METHOXYETHANOL (ME)

1) LD50- (ORAL)RAT:

a) 2.46 g/kg
b) 2.3-3.13 mL/kg (Ballantyne & Myers, 1987)

L) PROPOXYETHANOL (PE)

1) LD50- (ORAL)RAT:

a) 4.89 mL/kg (Ballantyne & Myers, 1987)

Pharmacology Toxicology

Toxicologic Mechanism

Physicochemical

Physical Characteristics

Molecular Weight

Animal Toxicology

References

General Bibliography

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GLYCOL ETHERS

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

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