Diethylene glycol

Diethylene glycol is an organic compound with the formula ₂O. It is a colorless, practically odorless, and hygroscopic liquid with a sweetish taste. It is a four-carbon dimer of ethylene glycol. It is miscible in water, alcohol, ether, acetone, and ethylene glycol. DEG is a widely used solvent. It can be a normal ingredient in various consumer products, and it can be a contaminant. DEG has also been misused to sweeten wine and beer, and to viscosify oral and topical pharmaceutical products. Its use has resulted in many epidemics of poisoning since the early 20th century.

Preparation

DEG is produced by the partial hydrolysis of ethylene oxide. Depending on the conditions, varying amounts of DEG and related glycols are produced. The resulting product is two ethylene glycol molecules joined by an ether bond.
"Diethylene glycol is derived as a co-product with ethylene glycol and triethylene glycol. The industry generally operates to maximize MEG production. Ethylene glycol is by far the largest volume of the glycol products in a variety of applications. Availability of DEG will depend on demand for derivatives of the primary product, ethylene glycol, rather than on DEG market requirements."

Structure of DEG and related polyols

Diethylene glycol is one of several glycols derived from ethylene oxide. Glycols related to and co-produced with diethylene glycol and having the formula HOCH₂CH₂_nOH are:

n = 0 ethylene glycol ; monoethylene glycol MEG
n = 1 DEG
n = 2 triethylene glycol, TEG, or triglycol
n = 3 tetraethylene glycol
n = 4 pentaethylene glycol
n > 4 polyethylene glycol

These compounds are all hydrophilic, more so than most diols, by virtue of the ether functionality.

Uses

Diethylene glycol is used in the manufacture of saturated and unsaturated polyester resins, polyurethanes, and plasticizers. DEG is a precursor to morpholine and 1,4-dioxane. It is a solvent for nitrocellulose, resins, dyes, oils, and other organic compounds. It is a humectant for tobacco, cork, printing ink, and glue. It is also a component of brake fluid, lubricants, wallpaper strippers, artificial fog and haze solutions, and heating/cooking fuel. In personal care products, DEG is often replaced by selected diethylene glycol ethers. Most types of ethylene glycol antifreeze contain a few percent of diethylene glycol, present as a by-product of ethylene glycol production.
DEG is an important industrial desiccant. It absorbs water from natural gas, minimizing the formation of methane hydrates, which can block pipes.

Toxicology

The toxicity of DEG was discovered in 1937. The toxic dose is 0.14 mg/kg body weight and the lethal dose between 1.0 and 1.63 g/kg. Some suggest that the LD₅₀ in adults is about 1 mL/kg, while others suggest that that is the LD₃₀. Because of its adverse effects, DEG is rarely allowed in foods and drugs. The U.S. Code of Federal Regulations allows no more than 0.2% of diethylene glycol in polyethylene glycol when the latter is used as a food additive. In Australia, it is only allowed at less than 0.25% w/w of DEG as an impurity in polyethylene glycol, even in toothpaste.
Diethylene glycol has "moderate to low" acute toxicity in animal experiments. The LD₅₀ for small mammals is between 2 and 25 g/kg, less toxic than its relative ethylene glycol but still capable of causing toxicity in humans. It appears that diethylene glycol may be more hazardous to humans than implied by oral toxicity data in laboratory animals.

Toxicokinetics

Although there is limited information about toxicokinetics in humans, observations in mass poisonings and experimental studies suggest the following information:

Absorption and distribution

The principal method of absorption is through oral ingestion. Dermal absorption is very low, unless it is administered on broken or damaged skin. After ingestion, DEG is absorbed via the gastrointestinal tract and distributed by the bloodstream throughout the body, reaching peak blood concentrations within 30 to 120 minutes. In the liver DEG is metabolized by enzymes.

Metabolism and elimination

At first, scientists thought that DEG was converted in the liver to ethylene glycol, which is poisonous because of the metabolic production of glycolic acid, glyoxylic acid, and ultimately oxalic acid. The major cause of ethylene glycol toxicity is the accumulation of glycolic acid in the body, but accumulation of calcium oxalate crystals in the kidneys can also lead to acute kidney failure. In the case of DEG, calcium oxalate crystal are not deposited in the kidneys, implying that ethylene glycol is not on the DEG metabolic pathway. Rat models suggest that DEG is metabolized in the liver by enzyme NAD-dependent alcohol dehydrogenase to a hydrogen ion, NADH, and 2-hydroxyethoxyacetaldehyde. Shortly after that, 2-hydroxyethoxyacetaldehyde is metabolized by the enzyme aldehyde dehydrogenase to the weak acid 2-hydroxyethoxyacetic acid, chemical formula C₄H₈O₄. Later, HEAA leaves the liver through the bloodstream, being partially filtered in the kidneys for elimination.

Mechanisms

Based on available literature, scientists suggest that unmetabolized DEG and HEAA are partially reabsorbed through glomerular filtration. As a consequence, the weak acid HEAA and its metabolites may cause renal delay, leading to metabolic acidosis and further liver and kidney damage.

Signs and symptoms

The symptoms of poisoning typically occur in three characteristic intervals:

First phase: Gastrointestinal symptoms, such as nausea, vomiting, abdominal pain, and diarrhea, develop. Some patients may develop early neurological symptoms like altered mental status, central nervous system depression, and coma, as well as mild hypotension.
Second phase: In one to three days after ingestion, patients develop a metabolic acidosis, which causes acute kidney failure, oliguria, increasing serum creatinine concentrations, and later anuria. Other symptoms reported and secondary to acidosis and/or kidney failure are: hypertension, tachycardia and other cardiac dysrhythmias, pancreatitis, and hyperkalemia or mild hyponatremia.
Final phase: At least five to ten days after ingestion, most of the symptoms are related to neurological complications, such as: progressive lethargy, facial paralysis, dysphonia, dilated and nonreactive pupils, quadriplegia, and coma, leading to death.
Treatment

or ethanol should be quickly administered to prevent diethylene glycol being metabolized to the compound or compounds that cause renal damage.

Fomepizole: an alcohol dehydrogenase inhibitor with 8000 times more affinity than ethanol. This treatment has minimal adverse effects. However, it is very expensive.
Ethanol: ethanol is a competitive ADH substrate. A constant blood concentration of 1 to 1.5 g/L should be maintained to acceptably saturate the enzyme. An initial dose of 0.6 to 0.7 g ethanol per kilogram body weight should be given. This will cause ethanol intoxication. To avoid adverse effects, frequent serum monitoring and dosage adjustments should be done.

For late diagnosis, when ethanol or fomepizole is ineffective, because DEG has already been metabolized, hemodialysis becomes the only treatment available. Hemodialysis may be administered either alone or in combination with ethanol or fomepizole.

Prognosis

The prognosis depends on prompt diagnosis and treatment, owing to the high mortality from DEG intoxication. Patients who survive but develop kidney failure remain dialysis-dependent. All patients are likely to suffer significant morbidity.

Epidemiology

The physical properties of diethylene glycol make it an excellent counterfeit for pharmaceutical-grade glycerine or propylene glycol, and has caused many deaths in different countries. Incidents include its use in China as a component of cheap toothpaste, and by winemakers in Europe as an adulterant to create a "sweet" wine. It has also been used in toxic cough syrup, resulting in many infant deaths.

1937 – The Massengill incident (United States)

In 1937, S. E. Massengill Co., manufactured sulfanilamide dissolved with diethylene glycol, to create a liquid alternative of this drug. The company tested the new product, Elixir sulfanilamide, for viscosity, appearance and fragrance. At the time, the food and drug laws did not require toxicological analysis before releasing for sale. When 105 people died in 15 states during the months of September and October, the trail led back to the elixir, and the toxic potential of this chemical was revealed. This episode was the impetus for the Federal Food, Drug, and Cosmetic Act of 1938. This law, though extensively amended in subsequent years, remains the central foundation of FDA regulatory authority to the present day.

1969 – South Africa

In Cape Town, South Africa, seven children developed vomiting, diarrhea, and dehydration, and died of kidney failure after administration of over-the-counter sedatives. Soon, patients started to present anuria, acidic breathing, hepatomegaly, and unresponsiveness. Patients were treated with fluid hydration and correction of acidosis, but some were not able to survive. Postmortem examination revealed damage in the kidneys and liver, and laboratory testing found DEG instead of propylene glycol in the sedatives.

1985 – Spain

Patients being treated for burns developed sudden anuric kidney failure. Further investigation revealed all patients were treated with topical silver sulfadiazine ointment that contained 7 g/kg of DEG. This event caused the death of five patients.

1985 – Wine scandal (Austria)

During the month of July 1985, Austrian wines were found to contain up to 1,000 parts per million of DEG, giving them a desirable sweetness. Austrian wine was banned in many countries and the U.S. Bureau of Alcohol, Tobacco and Firearms started to test all imported wine.
In November, The New York Times published a wine recall that the Federal Government released after the Bureau of Alcohol, Tobacco and Firearms tested 1,000 bottles. 45 Austrian, 5 German and 12 Italian wines tested positive for DEG. Some wines contained less than 10 parts per million of DEG, a small amount that could not be detected by laboratory analysis in Europe. This triggered the installation of more sensitive laboratory equipment in Banafi laboratories, Italy, and stronger alcohol regulations in Austria.
After recalling millions of wine bottles, the Austrian Government experienced difficulty in finding a way to destroy the product. During September 1986, the Ministry of Public Works started testing a mixture of wine with salt to melt hazardous ice during winter. The primary results revealed that the mixture was more effective than using salt alone. The next year, an Austrian electric power plant in Carinthia announced that technicians developed a way to produce energy through burning 30 million liters of contaminated wine.