Substance-Specific Issues

Ethylene Glycol; classification with respect to acute toxicity

Substance:

Ethylene glycol, CAS No. 107-21-1: classification with respect to acute toxicity following ingestion.

Issue:

Does ethylene glycol fall within the Controlled Products Regulations (CPR) criteria for acute toxicity based on human evidence?

Background:

Ethylene glycol (EG) is a colorless, odorless, sweet tasting, relatively non-volatile liquid and is completely soluble in water [1]. It is used in many products including automotive antifreeze, brake fluids and industrial solvents [2].

Ingestion of EG is uncommon but may cause serious poisoning. It is readily absorbed from the gastrointestinal tract, and the maximal blood concentration is reached within one to four hours [2]. Potential symptoms of overexposure by ingestion are nausea, vomiting, abdominal pain, weakness, dizziness, stupor, convulsions and CNS depression [3].

There are numerous reports of kidney injury, nervous system injury and deaths in people who accidentally or intentionally ingested ethylene glycol. The commonly cited minimum lethal oral dose in humans is 1110-1665 mg/kg (cited as 1-1.5 mL/kg) [4] [5] [6] [7]. However, it is very difficult to estimate a valid lethal or toxic dose for humans [7] [8].

Available data from acute poisoning cases (humans) and repeated-dose toxicity studies (experimental animals) indicate that the kidney is a critical organ for the toxicity of ethylene glycol in both humans and experimental animals [1]. As the toxicity progresses in untreated patients, cardiovascular and pulmonary signs and symptoms, such as tachypnea, cyanosis, and cardiogenic or noncardiogenic pulmonary edema, occur. Metabolic acidosis and elevated levels of serum creatinine and blood urea nitrogen (BUN) have been reported within 16 hours of ingestion. The metabolic acidosis is relatively refractory to sodium bicarbonate therapy. Frank renal failure is usually present within 48 to 72 hours post exposure. During this time, cerebral edema may manifest as progressive CNS depression, prolonged seizures, or a herniation syndrome. Generalized seizures are typical, but focal seizures, myoclonic jerks, and tetanic contractions secondary to hypocalcemia have also occurred. Pulmonary edema can be both cardiogenic and noncardiogenic in origin, and bronchopneumonia may develop. Myositis manifests as muscle tenderness and elevated levels of creatine kinase. Transient palsies of cranial nerves II, V, VI, VII, VIII, IX, and X have been reported 4 to 18 days post exposure in patients with delayed or inadequate treatment or no treatment [9].

Available data are inadequate to assess potential adverse neurological or immunological effects associated with long-term exposure to ethylene glycol, although neurobehavioural and neurological disorders have been reported in cases of acute ethylene glycol poisoning in humans. In the limited number of investigations identified to date, neurological effects have not been observed at doses below those that have induced renal toxicity [1].

Human ingestion of EG at a dose estimated at 1,000 mg/kg of body weight results in central nervous system and behavioural effects that include numbness, visual disturbances, light-headedness, headache and lethargy. At doses of 3,000 mg/kg, symptoms include ataxia, drowsiness, slurred speech and a changing mental status alternating between stupor and agitation. At higher doses, which may be fatal, effects include coma, delirium, convulsive seizures and loss of reflexes [10]. The most prominent toxic effects of EG exposure are (a) the formation of calcium oxalate crystals in the body that can have serious consequences if they form in the kidneys, brain or lungs and (b) metabolic acidosis, an upset of the acid-base balance in the body [11]. Moderately severe fatty metamorphosis of the liver with focal necrosis, as well as advanced hydropic degeneration of the liver cytoplasm, has been observed in cases of EG poisonings [6]. Interstitial inflammation of the diaphragm [12] and inflammation of skeletal muscle have also been reported after exposure to EG [13].

EU classifies ethylene glycol as: Xn; R22 - Harmful. Harmful if swallowed [14].

Considerations:

An 18 year old man with acute renal failure due to inadvertent ingestion of antifreeze that contained ethylene glycol is described. A relatively small amount of ethylene glycol was ingested, but nausea and vomiting were observed soon after ingestion. During admission to a local hospital, consciousness became impaired and generalized convulsion was noted. He was transferred to the hospital because of rapid deterioration of renal function. Emergency hemodialysis was begun. The patient underwent one treatment session of hemodialysis each day, for a total of 8 hemodialytic sessions before his renal function recovered. Examination of the renal biopsy specimen revealed degeneration of the renal tubular epithelium and presence of intratubular calcium oxalate crystals. The clinical features of the patient were mild except for acute renal failure. These findings suggest that even a small amount of ethylene glycol will have toxic effects on the kidney [15].

A 41-year-old sailor died of EG poisoning which was ingested accidentally. On arrival at the hospital, he was almost unconscious and hyperventilating. He had metabolic acidosis, hypocalcemia and leucocytosis. He also developed fatal intractable ventricular fibrillation. The medico legal autopsy showed swollen kidneys with pale cortex and contrasting dark medulla. There was edema of lungs, generalized congestion of the internal organs, acute heart dilatation, degenerative changes of the liver and petechiea and eccyoses in several internal organs [2].

A 29-year old man was found sitting somnolent on a chair with a ¾ empty bottle containing 50% EG on the table in front of him. He was admitted to hospital and, upon arrival, was somnolent and vomiting. He had metabolic acidosis and developed generalized seizures. The medico legal autopsy revealed swollen kidneys, edema of lungs and brain, generalized congestion of the internal organs and fatty degeneration of the liver. Toxicology revealed EG in the stomach content but not in the blood and, upon microscopic examination, crystals with the typical morphology of calcium oxalate were found in the renal tubules, liver and cerebral vessels [2].

The criteria for acute toxicity set out in sections 46 and 49 of the CPR deal only with lethality in animals. However, specific chemicals may cause greater toxicity in humans than animals due to differences in the mechanism of toxicity between species. Although not explicit, subsection 33(2) indirectly supports the use of human data as evidence for classification in Class D - Poisonous and infectious material. The Reference Manual for the WHMIS Requirements of the Hazardous Products Act and Controlled Products Regulations states: In the case of a material (pure substance or tested mixture) which does not meet any of the criteria for Very Toxic Material or Toxic Material, but for which there is valid documented evidence based on established scientific principles that the material causes an adverse effect in humans following occupational exposure, this fact, by itself, is sufficient to include that material within Class D1. The WHMIS Information Bulletin Issue No. 8 indicates that suppliers may classify controlled products in Class D1 based on their professional judgement, if acute toxicity in humans is sufficiently documented.

Conclusion:

There are sufficient case reports in the literature relating to this widely used chemical to conclude that ethylene glycol falls within the CPR criteria for acute toxicity, i.e., Class D1B.

References:

1. World Health Organization/International Programme on Chemical Safety; Concise International Chemical Assessment Document No. 45, Ethylene Glycol: Human Health Aspects. (2002), p. 4-5.
2. Leth, P. M., Gregersen, M., Ethylene glycol poisoning, Forensic Science International, 155 (2005) p. 179-184.
3. O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc. (2001), p. 675.
4. American Conference of Governmental Industrial Hygienists (ACGIH). Threshold limit values and biological exposure indices for 2001. Cincinnati: ACGIH, 2001.
5. Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological profile for ethylene glycol and propylene glycol. Public Health Service, US Department of Health and Human Services, Sept. 1997.
6. LaKind, J. S., McKenna, E. A., Hubner, R. P., Tardiff, R.G., A review of the comparative mammalian toxicity of ethylene glycol and propylene glycol, Critical Reviews in Toxicology, 29 (4) (1999), p. 331-365.
7. Barceloux, D.G., et al. American Academy of Clinical Toxicology Practice guidelines on the treatment of ethylene glycol poisoning. Clinical Toxicology. Vol. 37, no. 5 (1999), p. 537-560.
8. Hess, R., et al. Ethylene glycol: an estimate of tolerable levels of exposure based on a review of animal and human data. Archives of Toxicology. Vol. 78 (2004). p. 671-680.
9. Ford MD, Delaney KA, Ling LJ, Erickson T; Clinical Toxicology. W.B. Saunders Company, Philadelphia, PA. (2001), p. 760.
10. Air Resources, Environmental Fact Sheet: Ethylene Glycol and Propylene Glycol: Health Information Summary. http://www.des.state.nh.us/factsheets/ehp/inc/12.html
11. Lewis, L. D., Brian, W., Mamourian, A. C., Delayed sequelae after acute overdoses or poisonings: Cranial neuropathy related to ethylene glycol ingestion, Clinical Pharmacology and Therapeutics, Vol 61, Number 6 (1997), p. 692-699.
12. Smith, D. E., Morphologic lesions due to acute and subacute poisoning with antifreeze (ethylene glycol), Archives of pathology, 51 (1951), p. 423.
13. Friedman, E. A., Greenberg, J.B., Merrill, J. P., Dammin, G. J., Consequences of ethylene glycol poisoning, American Journal of Medicine, 32 (1962), p. 891-902.
14. Regulation (EC) No 1272/2008 of the European parliament and of the council of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing, Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006, Official Journal of the European Union.
15. Tadokoro M, Ozono Y, Hara K,Taguchi T,Harada T, Ideguchi M, Senju M. : A case of acute renal failure due to ethylene glycol intoxication. Nippon Jinzo Gakkai Shi 1995;37(6):353-6.