Diethylene glycol (DEG) is an organic compound with the formula (HOCH2CH2)2O. It is a colorless, practically odorless, poisonous, and hygroscopic liquid with a sweetish taste. It is miscible in water, alcohol, ether, acetone, and ethylene glycol.[1] DEG is a widely used solvent.[2] It can be a contaminant in consumer products; this has resulted in numerous epidemics of poisoning since the early 20th century.[1]
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.[3]
"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."[4]
Structure of DEG and related polyols
Diethylene glycol is one of several glycols derived from ethylene oxide. Glycols related to and coproduced with diethylene glycol and have the formula HOCH2CH2(OCH2CH2)nOH are:
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 unsaturated polyester resins, polyurethanes, and plasticizers.[1] DEG is used as a building block in organic synthesis, e.g. of 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.[5] It is also a component in brake fluid, lubricants, wallpaper strippers, artificial fog solutions, and heating/cooking fuel.[1] In personal care products (e.g. skin cream and lotions, deodorants), DEG is often replaced by selected diethylene glycol ethers. A dilute solution of diethylene glycol can also be used as a coolant; however, ethylene glycol is much more commonly used. Most ethylene glycol antifreeze contains a few percent diethylene glycol, present as an inadvertent byproduct of ethylene glycol production.
Toxicology
Despite the discovery of DEG’s toxicity in 1937 and its involvement in mass poisonings around the world, the information available regarding human toxicity is limited. Some authors suggest the minimum toxic dose is estimated at 0.14 mg/kg of body weight and the lethal dose is between 1.0 and 1.63 g/kg of body weight,[6] while some suggest the LD50 in adults is of ~1 mL/kg,[1] and others suggest this is the LD30.[3] Because of its adverse effects on humans, diethylene glycol is not allowed for use in food 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.[7] The Australian government does not allow DEG as a food additive; it is only allowed at less than 0.25% w/w of DEG as an impurity of polyethylene glycol (PEG)[8] even in toothpaste.[9]
Diethylene glycol has moderate acute toxicity in animal experiments. The LD50 for small mammals has been tested at between 2 and 25 g/kg, less toxic than its relative ethylene glycol, but still capable of causing toxicity in humans. It appears diethylene glycol is more hazardous to humans than implied by oral toxicity data in laboratory animals.[1]
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 through the gastrointestinal tract and distributed by the bloodstream throughout the body, reaching peak blood concentrations within 30 to 120 minutes. Once DEG reaches the liver, it is metabolized by enzymes.[1][6]
Metabolism and elimination
At first, scientists thought that DEG metabolized into ethylene glycol, which is poisonous due to the metabolic production of glycolic acid, glyoxylic acid, and ultimately oxalic acid.[10] The major cause of ethylene glycol toxicity is the accumulation of glycolic acid in the body,[11] but the accumulation of calcium oxalate crystals in the kidneys can also lead to acute kidney failure.[10] In the case of DEG, observations demonstrated there were no calcium oxalate crystal deposits in the kidneys, implying ethylene glycol is not on the DEG metabolic pathway. Rat models suggest DEG is metabolized in the liver by enzyme NAD-dependent alcohol dehydrogenase (ADH) into a hydrogen ion, NADH and 2-hydroxyethoxyacetaldehyde (C4H8O3). Shortly after, 2-hydroxyethoxyacetaldehyde (C4H8O3) is metabolized by the enzyme aldehyde dehydrogenase (ALDH) into the weak acid 2-hydroxyethoxyacetic acid (HEAA) with chemical formula C4H8O4. Later on, HEAA leaves the liver through the bloodstream, being partially filtered in the kidneys for elimination.[1][6]
Mechanisms of toxicity
Based on available literature, scientists suggest unmetabolized DEG and HEAA are partially reabsorbed through glomerular filtration. As a consequence, the concentrations of the weak acid HEAA and metabolites may cause renal delay, leading to metabolic acidosis and further liver and kidney damage.[1][6]
Symptoms
The symptoms of poisoning typically occur in three characteristic intervals:[1]
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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, coma and mild hypotension.
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Second phase: In one to three days after ingestion (and dependent on dose ingested), patients develop metabolic acidosis, which causes acute kidney failure, oliguria, increasing serum creatinine concentrations, and later anuria. Other symptoms reported and secondary to acidosis and/or renal failure are: hypertension, tachycardia, cardiac dysrhythmia, pancreatitis, hyperkalemia or mild hyponatremia.
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Final phase: At least five to 10 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
Although it is not an approved procedure and no studies support successful removal of DEG, patients are subject to hemodialysis once diagnosis is made. Hemodialysis might be administered alone or with ethanol or fomepizole, which are competitive inhibitors of the enzyme NAD-dependent alcohol dehydrogenase (ADH):
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With no medication: the low molecular weight and little or no plasma protein binding suggest DEG should be removed through this method.[1]
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With fomepizole: an ADH inhibitor with 8,000 times more affinity than ethanol, this treatment has minimal adverse effects because of constant serum concentration.[3] However, it is a very expensive medication (approximately $3,000 U.S. dollars per treatment).[12]
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With ethanol: ethanol is an ADH inhibitor used when fomepizole is not available. A constant high blood concentration of ethanol should be maintained to acceptably saturate the enzyme, which can cause ethanol intoxication. To avoid this adverse effect, frequent serum monitoring and dosage adjustment is necessary.[1]
For late diagnosis where ethanol or fomepizole is ineffective, because DEG has already been metabolized, hemodialysis becomes the only treatment available.[3]
Prognosis
The prognosis depends on prompt diagnosis and treatment due to the high mortality rate DEG intoxication produces. Patients who survive but develop renal failure remain dialysis-dependent. All patients are likely to suffer significant morbidity.[3]
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