Substance-Specific Issues

Diethylene glycol; classification with respect to acute toxicity

Substance:

Diethylene glycol, CAS No. 111-46-6: classification with respect to acute toxicity following ingestion.

Issue:

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

Background:

Diethylene glycol (DEG) is a clear, hygroscopic, odourless liquid that leaves a sweet taste in the mouth after ingestion. It is used as an industrial solvent, a dehydrating agent for natural gas, a raw material for the production of plasticizers and polyester resins, a textile lubricant and coupling agent, a constituent of hydraulic fluids, a raw material for the production of esters used as emulsifiers, demulsifiers, and lubricants. DEG is also illegally used and sold internationally as a component of counterfeit cough syrup, toothpaste, and mouthwash [1].

The major hazard from DEG occurs following the ingestion of relatively large single doses. There have been 105 reported fatalities among 353 people who ingested a solution of sulfanilamide in an aqueous mixture containing 72% DEG [2]. The estimated lethal dose of DEG for humans is approximately 1 ml/kg. The symptoms include nausea, dizziness, and pain in the kidney region, progressively leading to liver necrosis, renal tubular degeneration, and death [3]. In general, pathology observations in human victims show primarily the degeneration of the kidney with lesser lesions in the liver. Death in most cases is due to renal insufficiency [4].

When preparations of sufanilamide and DEG were consumed in divided doses for 6-13 days, victims exhibited nausea, vomiting, headache, diarrhea, and abdominal pain. Additional signs include those associated with acute renal failure, pulmonary edema, pericardial hemorrhage and distension of leptomeningeal veins [5].

DEG poisoning was shown to result in multi-organ dysfunction and to require a high index of suspicion for diagnosis. Eleven children suffering from DEG poisoning, all had renal failure and severe encephalopathy. The diagnosis was established by the presence of DEG in the paracetamol elixir they consumed; the amount ranged from 2.3 to 23% w/w. Large consumption of DEG resulted in severe encephalopathy and high mortality in these children [6].

Paracetamol elixirs with diethylene glycol as a diluent were responsible for a large outbreak of fatal renal failure in Bangladesh [7]. A case-control study was designed to determine the cause of a large increase in the number of children with unexplained renal failure. Cases of 339 children with initially unexplained renal failure were compared to 90 controls with known cause of renal failure. All children were admitted to the Children's hospital in Dhaka, Bangladesh during 35 months after January 1990. Children with initially unexplained renal failure were significantly (p< 0.05) more likely to have hepatomegaly (58% vs 33%), oedema (37% vs 20%), and hypertension (58% vs 23%); to have a higher serum creatinine concentration (mean 519 umol/l vs 12.4 mm/l) and lower serum bicarbonate concentration (10.1 mmol/l vs 12.4 mmol/l); to have been given a drug for fever (91% vs 31%); to have ingested a brand of paracetamol shown to contain diethylene glycol (20% vs 0%); and to have died in hospital (70% vs 33%). Diethylene glycol was identified in 19 bottles of paracetamol, from 7 of the 28 brands tested. In the 12 months after a government ban on the sale of paracetamol elixir, new cases of renal failure decreased by 54%, and cases of unexplained renal failure decreased by 84%.

An epidemic of severe systemic toxicity and deaths from DEG-contaminated acetaminophen syrup occurred in Haiti [8]. Glycerin, a raw material imported to Haiti and used in the acetaminophen formulation, was contaminated with 24% DEG. Diethylene glycol was found in patients' bottles in a median concentration of 14.4%. The median estimated toxic dose of DEG was 1.34 mL/kg (range, 0.22-4.42 mL/kg) and clinical syndrome included renal failure, hepatitis, pancreatitis, central nervous system impairment, coma, and death. Of 87 patients with follow-up information who remained in Haiti for treatment, 85 (98%) died; 3 (27%) of 11 patients transported to the United States for intensive care unit management died before hospital discharge.

EU classifies DEG as: Xn; R22 - Harmful. Harmful if swallowed [9].

Considerations:

Case reports of acute toxicity following ingestion of DEG related to exposure of adults have been reported [10] [11] [12] [13] [14] [15] [16] [17].

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:

Sufficient case reports of poisoning have been published to conclude that diethylene glycol falls within the CPR criteria for acute toxicity, i.e., Class D1B.

References:

1. Transcripts of FDA Press Conference on Toothpaste from China that Contains DEG, FTS-HHS FDA, June 1, 2007 2:00 pm CT.
2. Gossel, T.A., J.D. Bricker. Principles of Clinical Toxicology. 3rd ed. New York, NY: Raven Press, Ltd., 1994., p. 85.
3. Amdur, M.O., J. Doull, C.D. Klaasen (eds). Casarett and Doull's Toxicology. 4th ed. New York, NY: Pergamon Press, 1991., p. 704.
4. Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982., p. 3838.
5. Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976., p. 111-148.
6. Hari P, Jain Y, Kabra SK.: Fatal encephalopathy and renal failure caused by diethylene glycol poisoning. J Trop Pediatr 2006; 52(6): p. 442-4.
7. Hanif M, Mobarak MR, Ronan A, Rahman D, Donovan JJ Jr, Banish ML.: Fatal renal failure caused by diethylene glycol in paracetamol elixir: the Bangladesh epidemic. BMJ 1995;311(6997):p. 88-91.
8. O'brien KL, Selanikio JD, Hecdivert C, Placide MF, Louis M, Barr DB, Barr JR, Hospedales CJ, Lewis MJ, Schwartz BPhilen RM, St Victor S, Espindola J, Needham LL, Denerville K.: Epidemic of paediatric deaths from acute renal failure caused by diethylene glycol poisoning. Acute renal investigation team. JAMA 1998;279(15):1175-80.
9. 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.
10. Laine, R. Health effects of selected chemicals 4-5. 2,2'-Oxydiethanol (Diethylene glycol). Nordic Steering Group for Assessment of Health Effects of Chemicals. No. 15 (1999). p. 317-341.
11. Alfred, S., et al. Delayed neurologic sequelae resulting from epidemic diethylene glycol poisoning. Clinical Toxicology. Vol. 43, no. 3 (2005). p. 155-159.
12. Calvery, H.O., et al. The toxicity for human beings of diethylene glycol with sulfanilamide. Southern Medical Journal. Vol. 32, no. 11 (1939). p. 1105-1109.
13. Borron, S.W., et al. Intravenous 4-methylpyrazole as an antidote for diethylene glycol and triethylene glycol poisoning: a case report. Veterinary and Human Toxicology. Vol. 39, no. 1 (1997). p. 26-28.
14. Rollins, Y.D., et al. Fulminant ascending paralysis as a delayed sequela of diethylene glycol (Sterno) ingestion. Neurology. Vol. 59, no. 9 (Nov. 2002). p. 1560-1463.
15. Ferrari, L.A., et al. Clinical parameters, postmortem analysis and estimation of lethal dose in victims of a massive intoxication with diethylene glycol. Forensic Science International. Vol. 153 (2005). p. 45-51.
16. Schep, L.J., et al. Comments on diethylene glycol concentrations. Letter to the editor. Forensic Science International. Vol. 155, no. 2/3 (2005). p. 233.
17. Wax, P.M. It's happening again - another diethylene glycol mass poisoning. Clinical Toxicology. Vol. 35, no. 5 (1996). p. 517-520.