International Programme on Chemical Safety
Poisons Information Monograph 227
Chemical
Ethylene Glycol
Polyalcohols - Glycol
1,2-dihydroxyethane
1,2-ethane diol
2-hydroxyethanol
ethane-1,2-diol
ethylene alcohol
ethylene dihydrate
No data available.
The main risk is severe metabolic acidosis with CNS depression, cardio-pulmonary failure and acute renal failure. Lethal dose as little as 1 mL/kg.
Within 4 to 12 hours CNS-depression (like ethanol) and increasing metabolic acidosis. Later stages (>12 hours) severe metabolic acidosis with electrolyte disturbances, elevated blood pressure, cardiopulmonary failure. Decreasing diuresis (>24 hours) with development of acute oliguric renal failure.
The diagnosis is based on history of exposure, clinical features and laboratory findings.
Drowsiness, coma, elevated blood pressure, tachycardia and hyperventilation are the typical clinical features of ethylene glycol poisoning.
Severe metabolic acidosis with elevated anion and osmolal gap is typical. The degree of metabolic acidosis is related to the severity of poisoning. Urine microscopy may reveal presence of needle or envelope shaped calcium oxalate crystals (oxalate is one of the metabolites from ethylene glycol metabolism).
Concentrations of both ethylene glycol and the major acidic metabolite, glycolate, are best determined by gas-chromatography or HPLC (Jacobsen & McMartin, 1997).
Standard first aid and symptomatic treatment.
Gastric decontamination
Correction of metabolic acidosis with bicarbonate
Inhibition of ethylene glycol metabolism by giving ethanol or fomepizole as antidotes
Hemodialysis to remove ethylene glycol and its major toxic metabolite glycolic acid.
Manufactured by oxidation of ethylene in the presence of acetic acid followe by hydrolysis of the ethylene diacetate thus formed.
Molecular weight = 62,07
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Boiling point: |
198°C |
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Melting point: |
-13°C |
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Flash point: |
111°C closed cup |
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Explosive limits: |
3.2 – 15.3 volume % in air |
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Autoignition temperature: |
398°C |
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Relative density of vapour/air mixture at 20°C (air = 1): |
1.00 |
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Conversion factors: |
1 mg/m3 = 0.37 ppm (Atm 25°C) |
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1 ppm = 2.54 mg/m3 (Atm 25°C) |
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Solubility: |
Soluble in water, ethanol, acetone, acetic acid, glycerine, pyridine, aldehydes; |
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Little soluble in ether; |
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Insoluble in oil, fat, hydrocarbures halogènes. |
Odourless, colourless, viscous, hygroscopic liquid.
N.B. Domestic antifreeze is responsible for most cases of poisoning.
Due to its low volatility, ethylene glycol is not an occupational hazard.
The usual route of exposure, readily absorbed.
Well absorbed, but little risk because of low volatility. Inhalation may occur as aerosol, from hot products containing ethylene glycol.
Low absorption requiring application to large surface areas to reach toxic dose.
Local irritation.
Possible but no reports. Risk of hemolysis.
No data available.
Rapid absorption from the whole gastrointestinal tract (Gordon, 1982).
Rapidly distributed in total body water with a volume of distribution of 0.7 to 0.8 L/kg (Peterson, 1981; Jacobsen, 1982).
The calculated half-life in poisoned patients is 3 to 6 hours(Jacobsen & McMartin, 1997; Peterson, 1982; Winek, 1977).
- During ethanol therapy: t 1/2 = 17 hours(Peterson, 1981)
- During 4-methylpyrazole treatment: t 1/2 = 11.5 to 15 hours (Baud, 1986-1987; Brent et al, 1999).
Ethylene glycol undergoes enzymatic metabolism, principally in the liver and kidneys. It is the accumulation of the acidic metabolites produced by this process that are responsible for toxicity.
The initial step in metabolism is the conversion of ethylene glycol to glycoaldehyde mediated by alcohol dehydrogenase. Glycoaldehyde is subsequently metabolised to glycolate by the action of aldehyde dehydrogenase. Glycolate undergoes further metabolism to form glycoxylate and oxalate.
Only very small amounts of ethylene glycol and its principal metabolites are excreted in the urine. Oxalic acid excreted in the urine can give rise to dihydrate or monohydrate oxalate crystals.
Except for the initial CNS-depression caused by ethylene glycol itself, the toxicity is entirely due to its metabolites (see paragraph 6.4).
Toxic dose > 0.5 mL/kg (approx. 0.5 g/kg)
Lethal dose = 1.4 mL/kg (approx. 1.5 g/kg), or 100 mL for adults (70 kg).
With early diagnosis and correct treatment even patients who have ingested more than 500 mL of ethylene glycol have survived (Gabow, 1986; Turk, 1986; Vites, 1984; Peterson, 1981).
(i) Acute toxicity
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DL50 mg/kg orally: |
mouse = |
8,000 to 15,000 |
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rabbit = |
5,000 |
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rat = |
6,000 to 13,000 |
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guinea pig = |
8,000 to 11,000 |
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dog = |
8,000 some survive up to 14,7008,000 some survive up to 14,700 |
OSHA PEL ceiling 50 ppm
Not classifiable as a human carcinogen
No data available.
Negative
The major metabolic interaction occurs with ethanol and is described in section 10.6.
After a latent period of 1 to 4 hours clinical features develop. Many authors present the clinical syndrome in stages: a CNS depression, then a cardiopulmonary and finally a renal phase. However in many cases, there is considerable overlap among these stages (Jacobsen & McMartin, 1997).
A. The initial CNS depression is much like that of ethanol with dizziness, agitation, nystagmus, nausea, tachycardia, elevated blood pressure and vomiting. In severe poisoning coma and convulsions occur. Hyperventilation increases as the metabolic acidosis becomes more and more pronounced.
B. Cardio-pulmonary phase:
This phase develops about 24 hours after the ingestion and is thought to be due to cardio-pulmonary failure. Dyspnea, hyperventilation, tachycardia, cyanosis, elevated blood pressure are typical clinical features at this stage and the patient may suffer pulmonary edema, especially if oliguria develops at this stage. Chest X-ray typically shows massive bilateral infiltrations. The patient may die at this stage (Gironimi, 1966; Jacobsen & McMartin, 1997).
C. Renal phase:
About 24 to 36 hours following ingestion oliguria gradually develops in severe cases not given correct treatment. The urine sediment contains various casts and in most patients also calcium oxalate crystals (needle or envelope shaped). The acute oliguric renal failure may be reversed upon correct treatment, but many patients must be treated with temporary dialysis for 2 to 3 weeks. The prognosis for the renal failure per se is good, but some patients may require dialysis for a longer period (Collins, 1970; Jacobsen & McMartin, 1997).
No data available.
No data available.
No data available.
No data available.
No data available.
No data available.
Due to its low volatility, inhalation of ethylene glycol vapours is not problematic.
No data available.
No data available.
No data available.
No data available.
This is a potentially lethal poisoning if diagnosis and treatment are delayed. With early diagnosis and treatment can be prevented, even if large doses are ingested (Turk, 1986; Stokes, 1980; Jacobsen & McMartin, 1999).
Death may occur due to aspiration of gastric contents during convulsions or due to cardiopulmonary failure 24 to 48 hours (or later) after ingestion (O'Donoghue, 1985; Ahmed, 197l, Berger, 198l, Gosselin, 1976).
In later stages mortality may be due to secondary (pulmonary) infections or various degree of brain damage (Maier, 1983; Jacobsen et al., 1982a).
The prognosis for the renal failure per se is usually good.
No direct toxicity reported.
Acute oliguric renal failure is typically seen if correct treatment is not initiated early. The mechanism behind the acute tubular necrosis is not completely understood but relates to metabolic injury and deposition of calcium oxalate crystals.
The presence of calcium oxalate crystals in the urine may be of diagnostic importance (microscopy).
No data available.
Non irritant.
Slightly irritating.
No data available.
No data available.
The underlying disorder in ethylene glycol poisoning is gradual development of severe metabolic acidosis with increased anion gap, mainly caused by accumulation of the metabolite glycolic acid.
Hyperkalemia is seen if severe metabolic acidosis or rhabdomyolysis occur.
Hypercalcaemia may occur but is rarely life-threatening.
Overhydration and pulmonary edema may be seen if acute oliguric renal failure develops.
No data available.
No data available.
No data available.
No data available.
Treatment consists of:
For ethylene glycol and glycolate determination and biomedical analyses, blood and urine should be collected.
Arterial blood gases, serum electrolytes, osmolality, BUN, creatinine and blood glucose. Urine microscopy to search for calcium oxalate crystals if diagnosis is uncertain.
Intensive supportive care for multiple organ/system failure is frequently necessary.
Since severe, recurrent metabolic acidosis is the underlying feature of ethylene poisoning, the correction of acidosis by administration of sodium bicarbonate is imperative, possibly life-saving. The degree of acidosis has been found to correspond closely to the severity of poisoning (Jacobsen et al., 1983). Repeated and frequent assessment of the acid/base status is necessary.
Correction of acidosis may require as much as 400 to 600 mmol of bicarbonate during the first few hours (Jacobsen & McMartin, 1986).
Fluids must be given orally or intravenously to maintain adequate urine output.
Hyperkalemia is usually corrected by bicarbonate administration (see also treatment guide: hyperkalaemia).
Convulsions should be controlled (see treatment guide: convulsions).
Correct hypocalcaemia if severe (see treatment guide: hypocalcaemia).
The usual decontamination procedures are required in cases of percutaneous exposure, or exposure to vapours: removal from the exposure, removal of clothes, adequate prolonged washing of skin and eyes.
Consider emptying the stomach by gastric lavage only following recent ingestion (< 1 hour) of a large amount.
Hemodialysis (or peritoneal dialysis) removes ethylene glycol and its toxic metabolite glycolate (Jacobsen & McMartin, 1997). It is not possible to set up strict indications for dialysis as it depends also on which antidote is used, the degree of metabolic acidosis and whether renal failure is present or not. If the patient is seen early before severe metabolic acidosis develops, and fomepizole (4-methylpyrazole) is the antidote used, hemodialysis is usually not necessary. However, if the patient is admitted in later stages with severe metabolic acidosis, hemodialysis should always be performed (Jacobsen & McMartin1997; Brent et al, 1999).
Hemoperfusion is not effective in removing ethylene glycol (Sangster, 1980).
There are two alternative antidotes, both of which act by blocking the alcohol dehydrogenase-mediated metabolism of ethylene glycol: ethanol, fomepizole.
(i) Ethanol
Effective because it has a much greater affinity for alcohol dehydrogenase than ethylene glycol. A blood ethanol concentration of 100 mg/dL (22 mmol/L) will almost completely block ethylene glycol metabolism (Jacobsen & McMartin, 1986). However, ethanol is sometimes technically difficult to administer because of its rapid and unpredicatable rate of methabolism (Jacobsen & McMartin, 1986). A loading dose followed by titrated maintenance therapy is necessary.
Suggested dosing regime:
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Oral |
Intravenous |
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Loading dose |
1 mL/kg of 95% ethanol, diluted |
10 mL/kg of 10% ethanol in 5% dextrose over 30 minutes |
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Maintenance dose |
0.1 – 0.2 mL/kg/hour of 95% ethanol, diluted |
1-2 mL/kg of 10% ethanol in 5% dextrose over 30 minutes |
Notes:
In an emergency, an equivalent amount of any alcoholic drink may be administered orally.
The maintenance dosing needs to be adjusted according blood ethanol concentration, ideally measured hourly, to maintain the concentration >100 mg/dL.
Prolonged ethanol administration may cause hypoglycaemia, especially in children, and frequent blood glucose determinations are mandatory (Bayer et al., 1984). If haemodialysis is started, the ethanol infusion should be increased as detailed in Section 10.5.
(ii) Fomepizole is easily administrated intravenously as a loading dose of 15 mg/kg, followed by bolus doses of 10 mg/kg every 12 hours. After 48 hours, the bolus doses should be increased to 15 mg/kg every 12 hours because of induced metabolism over time. The same dose may be administered orally. No side effects have been reported with this dosage regimen and effectiveness is clearly demonstrated (Brent et al., 2001). If dialysis is performed, the dose of fomepizole must be increased as fomepizole is eliminated at the same rate as urea.
Although there have been fewer reports of ethanol therapy in children, comparable doses may be used. Ethanol is more likely to cause hypoglycaemia in children (Bayer et al., 1984).
Ahmed MM (1974) Ocular effects of antifreeze poisoning. Brit. J. Ophthal., 55: 12, 854-855.
Baud FJ, Bismuth C, Garnier R, Galliot M, Astier A, Maistre G & Soffer M (1986-87) 4-methylpyrazole may be an alternative to ethanol therapy for ethylene glycol intoxication in man. Clin. Toxicol., 24: 6, 463-83.
Bayer MJ, Rumack BB & Wanke LA (1984) Methanol and ethylene glycol poisoning. Toxicologic emergencies, p.209-215.
Berger JR & Ayyar DR (1981) Neurological complications of ethylene glycol intoxication. Report of a case. Arch. Neurol., 39: 11, 724-726.
Bove KE (1966) Ethylene glycol toxicity. Am. J. Clin. Pathol., 45, 46-50.
Brent J. McMartin K. Phillips S. Burkhart KK. Donovan JW. Wells M. Kulig K. (1999) Fomepizole for the treatment of ethylene glycol poisoning. Methylpyrazole for Toxic Alcohols Study Group. [see comments]. [Clinical Trial. Journal Article] New England Journal of Medicine. 340(11):832-8,
Brent J. McMartin K. Phillips S. Aaron C. Kulig K (2001) Methylpyrazole for Toxic Alcohols Study Group. Fomepizole for the treatment of methanol poisoning. [Clinical Trial. Journal Article. Multicenter Study] New England Journal of Medicine. 344(6):424-9.
Bunuan HD (1978) Radiator fluid poisoning in Saudi Arabia. J. Trop. Med. Hyg., 81: 8, 151-152.
Collins JM, Hennes DM, Holzgang CR, Gourley RT & Porter GA (1970) Guérison après oligurie prolongée due à une intoxication par l'éthylène glycol. Arch. Int. Med., 125: 6, 1059-1062.
Gabow PA, Clay K, Sullivan JB & Lepoff R (1986) Organic acids in ethylene glycol intoxication. Ann. Intern. Med., 105: 1, 16-20.
Gabow P, Clay K, Sullivan JB & Lepoff R (1986) Organic acids in ethylene glycol intoxication (letters). Ann. Intern. Med., 105: 5, 799-800.
Gaultier M, Conso F, Rudler M, Leclerc JP & Mellerio F (1976) Intoxication aiguë par l'éthylène-glycol. J.E.T., 9: 6, 373-379.
Giromini M, de Freudenreich J, Jenny M & Haenni B. (1964) Acidose métabolique par intoxication à l'antigel (éthylène-glycol). Description clinique et anatomopathologique d'un cas mortel. Schweiz. Med. Wachr., 94: 48, 1687-1690.
Giromini M, de Freudenreich J, Jenny M & Haenni B (1966) Acidose métabolique par intoxication à l'antigel (éthylène-glycol). Bull. Med. Légale, 9: 4, 262-263.
Gosselin RE, Hodge HC, Gleason MJ & Smith RP (1976) Clinical toxicology of commercial products. Acute poisoning. Ethylene glycol. Williams & Wilkins Co. 4th Ed. 145-153.
Jacobsen D. McMartin KE (1997) Antidotes for methanol and ethylene glycol poisoning. [see comments]. [Review] [80 refs] [Journal Article. Review. Review, Tutorial] Journal of Toxicology - Clinical Toxicology. 35(2):127-43.
Jacobsen D (1986) Organic acids in ethylene glycol intoxication (letters). Ann. Intern. Med., 105: 5, 799-800.
Jacobsen D, Bresen JD, Eide I & Ostborg J (1982a) Anion and osmolal gaps in the diagnosis of methanol and ethylene-glycol poisoning. Acta Med. Scand., 212: 1-2, 17-20.
Jacobsen D, Ostby N & Bredesen JE (1982b) Studies on ethylene glycol poisoning. Acta Med. Scand., 212: 1-2, 11-15.
Maier W (1983) Cerebral computed tomography of ethylene glycol intoxication. Neuroradiology, 24: 3, 175-177.
O'Donoghue (1985) Neurotoxicity of industrial and commercial chemicals. CRC Press, vol. 2, 85.
Peterson CD, Collins AJ, Himes JM, Bullock ML & Keane WF (198l) Ethylene glycol poisoning. Pharmacokinetics during therapy with ethanol and hemodialysis. New Engl. J. Med., 304, 1, 21-23.
Peterson DI, Peterson JE, Hardinge MG & Wacker WEC (1963) Intoxication par l'éthylène-glycol. JAMA, l86: 10, 955-957.
Sangster B, Prenen JAC & De Groot G (1980) Case 38-1979. Ethylene glycol poisoning. N. Engl. J. Med., 302: 8, 465.
Stokes JBV & Aueron F (1980) Prevention of organ damage in massive ethylene glycol ingestion. J. Amer. Med. Ass., 243: 20, 2065-2066.
Turk J, Morrell L & Avioli LV (1986) Ethylene glycol intoxication. Arch. Intern. Med., 146: 8, 1601-1603.
Vites NP, Payne CR & Gokal R (1984) Recovery after potentially lethal amount of antifreeze. Lancet, 1: 8376, 562.
Winek CL, Shingleton DP & Shanor SP (1978) Ethylene and diethylene glycol toxicity. Clin. Toxicol., 13: 297-324.
Zech P (1974) Oxalose rénale au cours d'une tubulopathie aiguë anurique par intoxication accidentelle méconnue à l'éthylène-glycol. Nouv. Presse Méd., 3: 16, 1009-1112.
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Author: |
Dr Jacqueline Jouglard |
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Date: |
February 1988 |
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Reviewer: |
Dr P. Munne |
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Date: |
April 1988 |
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Peer review: |
Hamilton, Canada, May 1989 |
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Peer review: |
London, United Kingdom, March 1990 |
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Update: |
Cardiff, United Kingdom, March 1995 |
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Update: |
Geneva, Switzerland, August 2001 (Professor D. Jacobsen) |
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Peer review: |
L. Lefevre, M. Mathieu-Nolf, L. Murray, A. Nantel, Edinburgh, Scotland, September 2001. |
See Also:
Toxicological Abbreviations
Ethylene glycol (ICSC)
Ethylene glycol (PIM 227F, French)