Diethylene glycol
Overview
 
Diethylene glycol is an organic compound
Organic compound
An organic compound is any member of a large class of gaseous, liquid, or solid chemical compounds whose molecules contain carbon. For historical reasons discussed below, a few types of carbon-containing compounds such as carbides, carbonates, simple oxides of carbon, and cyanides, as well as the...

 with the formula (HOCH2CH2)2O. It is a colorless, practically odorless, poisonous, and hygroscopic liquid with a sweetish taste. It is miscible in water
Water
Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...

, alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....

, ether
Ether
Ethers are a class of organic compounds that contain an ether group — an oxygen atom connected to two alkyl or aryl groups — of general formula R–O–R'. A typical example is the solvent and anesthetic diethyl ether, commonly referred to simply as "ether"...

, acetone
Acetone
Acetone is the organic compound with the formula 2CO, a colorless, mobile, flammable liquid, the simplest example of the ketones.Acetone is miscible with water and serves as an important solvent in its own right, typically as the solvent of choice for cleaning purposes in the laboratory...

, and ethylene glycol
Ethylene glycol
Ethylene glycol is an organic compound widely used as an automotive antifreeze and a precursor to polymers. In its pure form, it is an odorless, colorless, syrupy, sweet-tasting liquid...

. DEG is a widely used solvent. Its use in adulterated consumer products has resulted in numerous epidemics of poisoning since the early 20th century.
DEG is produced by the partial hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...

 of ethylene oxide
Ethylene oxide
Ethylene oxide, also called oxirane, is the organic compound with the formula . It is a cyclic ether. This means that it is composed of two alkyl groups attached to an oxygen atom in a cyclic shape . This colorless flammable gas with a faintly sweet odor is the simplest epoxide, a three-membered...

.
Encyclopedia
Diethylene glycol is an organic compound
Organic compound
An organic compound is any member of a large class of gaseous, liquid, or solid chemical compounds whose molecules contain carbon. For historical reasons discussed below, a few types of carbon-containing compounds such as carbides, carbonates, simple oxides of carbon, and cyanides, as well as the...

 with the formula (HOCH2CH2)2O. It is a colorless, practically odorless, poisonous, and hygroscopic liquid with a sweetish taste. It is miscible in water
Water
Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...

, alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....

, ether
Ether
Ethers are a class of organic compounds that contain an ether group — an oxygen atom connected to two alkyl or aryl groups — of general formula R–O–R'. A typical example is the solvent and anesthetic diethyl ether, commonly referred to simply as "ether"...

, acetone
Acetone
Acetone is the organic compound with the formula 2CO, a colorless, mobile, flammable liquid, the simplest example of the ketones.Acetone is miscible with water and serves as an important solvent in its own right, typically as the solvent of choice for cleaning purposes in the laboratory...

, and ethylene glycol
Ethylene glycol
Ethylene glycol is an organic compound widely used as an automotive antifreeze and a precursor to polymers. In its pure form, it is an odorless, colorless, syrupy, sweet-tasting liquid...

. DEG is a widely used solvent. Its use in adulterated consumer products has resulted in numerous epidemics of poisoning since the early 20th century.

Preparation

DEG is produced by the partial hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...

 of ethylene oxide
Ethylene oxide
Ethylene oxide, also called oxirane, is the organic compound with the formula . It is a cyclic ether. This means that it is composed of two alkyl groups attached to an oxygen atom in a cyclic shape . This colorless flammable gas with a faintly sweet odor is the simplest epoxide, a three-membered...

. 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
Ethylene glycol
Ethylene glycol is an organic compound widely used as an automotive antifreeze and a precursor to polymers. In its pure form, it is an odorless, colorless, syrupy, sweet-tasting liquid...

 and triethylene glycol
Triethylene glycol
Triethylene glycol, TEG, or triglycol is a colorless odorless viscous liquid with molecular formula HOCH2CH2OCH2CH2OCH2CH2OH. It is used as a plasticizer for vinyl. It is also used in air sanitizer products, such as "Oust" or "Clean and Pure." When aerosolized it acts as a disinfectant...

. 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 coproduced with diethylene glycol and have the formula HOCH2CH2(OCH2CH2)nOH are:
  • n = 0 ethylene glycol
    Ethylene glycol
    Ethylene glycol is an organic compound widely used as an automotive antifreeze and a precursor to polymers. In its pure form, it is an odorless, colorless, syrupy, sweet-tasting liquid...

     ("antifreeze"); monoethylene glycol MEG
  • n = 1 DEG
  • n = 2 triethylene glycol
    Triethylene glycol
    Triethylene glycol, TEG, or triglycol is a colorless odorless viscous liquid with molecular formula HOCH2CH2OCH2CH2OCH2CH2OH. It is used as a plasticizer for vinyl. It is also used in air sanitizer products, such as "Oust" or "Clean and Pure." When aerosolized it acts as a disinfectant...

    , TEG, or triglycol
  • n = 3 tetraethylene glycol
  • n = 4 pentaethylene glycol
  • n > 4 polyethylene glycol
    Polyethylene glycol
    Polyethylene glycol is a polyether compound with many applications from industrial manufacturing to medicine. It has also been known as polyethylene oxide or polyoxyethylene , depending on its molecular weight, and under the tradename Carbowax.-Available forms:PEG, PEO, or POE refers to an...


These compounds are all hydrophilic, more so than most diol
Diol
A diol or glycol is a chemical compound containing two hydroxyl groups A geminal diol has two hydroxyl groups bonded to the same atom...

s, by virtue of the ether
Ether
Ethers are a class of organic compounds that contain an ether group — an oxygen atom connected to two alkyl or aryl groups — of general formula R–O–R'. A typical example is the solvent and anesthetic diethyl ether, commonly referred to simply as "ether"...

 functionality.

Uses

Diethylene glycol is used in the manufacture of unsaturated polyester resins, polyurethanes, and plasticizers.http://www.chemicalland21.com/petrochemical/DEG.htm
DEG is used as a building block in organic synthesis
Organic synthesis
Organic synthesis is a special branch of chemical synthesis and is concerned with the construction of organic compounds via organic reactions. Organic molecules can often contain a higher level of complexity compared to purely inorganic compounds, so the synthesis of organic compounds has...

, e.g. of morpholine
Morpholine
Morpholine is an organic chemical compound having the chemical formula O2NH. This heterocycle, pictured at right, features both amine and ether functional groups. Because of the amine, morpholine is a base; its conjugate acid is called morpholinium...

 and 1,4-dioxane
1,4-Dioxane
1,4-Dioxane, often called dioxane because the other isomers of dioxane are rare, is a heterocyclic organic compound. It is a colorless liquid with a faint sweet odor similar to that of diethyl ether. It is classified as an ether. This colorless liquid is mainly used as a stabilizer for the solvent...

. It is a solvent
Solvent
A solvent is a liquid, solid, or gas that dissolves another solid, liquid, or gaseous solute, resulting in a solution that is soluble in a certain volume of solvent at a specified temperature...

 for nitrocellulose
Nitrocellulose
Nitrocellulose is a highly flammable compound formed by nitrating cellulose through exposure to nitric acid or another powerful nitrating agent. When used as a propellant or low-order explosive, it is also known as guncotton...

, resins, dyes, oils, and other organic compounds. It is a humectant
Humectant
A humectant is a hygroscopic substance. It is often a molecule with several hydrophilic groups, most often hydroxyl groups, but amines and carboxyl groups, sometimes esterified, can be encountered as well; the affinity to form hydrogen bonds with molecules of water is crucial here.Since...

 for tobacco
Tobacco
Tobacco is an agricultural product processed from the leaves of plants in the genus Nicotiana. It can be consumed, used as a pesticide and, in the form of nicotine tartrate, used in some medicines...

, cork, printing ink
Ink
Ink is a liquid or paste that contains pigments and/or dyes and is used to color a surface to produce an image, text, or design. Ink is used for drawing and/or writing with a pen, brush, or quill...

, and glue
Glue
This is a list of various types of glue. Historically, the term "glue" only referred to protein colloids prepared from animal flesh. The meaning has been extended to refer to any fluid adhesive....

. It is also a component in brake fluid
Brake fluid
Brake fluid is a type of hydraulic fluid used in hydraulic brake and hydraulic clutch applications in automobiles, motorcycles, light trucks, and some bicycles. It is used to transfer force into pressure...

, lubricants, wallpaper strippers, artificial fog solutions, and heating/cooking fuel. In personal care products (e.g. skin cream and lotions, deodorants), DEG is often replaced by selected diethylene glycol ethers
Glycol Ethers
Glycol ethers are a group of solvents based on alkyl ethers of ethylene glycol commonly used in paints. These solvents typically have higher boiling point, together with the favorable solvent properties of lower molecular weight of ethers and alcohols. The word "Cellosolve" was registered in 1924...

. A dilute solution of diethylene glycol can also be used as a coolant
Coolant
A coolant is a fluid which flows through a device to prevent its overheating, transferring the heat produced by the device to other devices that use or dissipate it. An ideal coolant has high thermal capacity, low viscosity, is low-cost, non-toxic, and chemically inert, neither causing nor...

; however, ethylene glycol
Ethylene glycol
Ethylene glycol is an organic compound widely used as an automotive antifreeze and a precursor to polymers. In its pure form, it is an odorless, colorless, syrupy, sweet-tasting liquid...

 is much more commonly used. Most ethylene glycol antifreeze
Antifreeze
Antifreeze is a freeze preventive used in internal combustion engines and other heat transfer applications, such as HVAC chillers and solar water heaters....

 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, while some suggest the LD50 in adults is of ~1 mL/kg, and others suggest this is the LD
Lethal dose
A lethal dose is an indication of the lethality of a given substance or type of radiation. Because resistance varies from one individual to another, the 'lethal dose' represents a dose at which a given percentage of subjects will die...

30. 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. 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) even in toothpaste.

Diethylene glycol has moderate acute toxicity
Acute toxicity
Acute toxicity describes the adverse effects of a substance that result either from a single exposure or from multiple exposures in a short space of time...

 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
Ethylene glycol
Ethylene glycol is an organic compound widely used as an automotive antifreeze and a precursor to polymers. In its pure form, it is an odorless, colorless, syrupy, sweet-tasting liquid...

, 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.

Toxicokinetics

Although there is limited information about toxicokinetics
Toxicokinetics
Toxicokinetics is the description of what rate a chemical will enter the body and what happens to it once it is in the body. It is an application of pharmacokinetics to determine the relationship between the systemic exposure of a compound in experimental animals and its toxicity...

 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.

Metabolism and elimination

At first, scientists thought that DEG metabolized into ethylene glycol, which is poisonous
Ethylene glycol poisoning
Ethylene glycol poisoning is caused by the ingestion of ethylene glycol . It is a toxic, colorless, odorless, almost nonvolatile liquid with a sweet taste and is occasionally consumed by children and dogs for its sweetness...

 due to the metabolic production of glycolic acid
Glycolic acid
Glycolic acid is the smallest α-hydroxy acid . This colorless, odorless, and hygroscopic crystalline solid is highly soluble in water. It is used in various skin-care products. Glycolic acid is found in some sugar-crops...

, glyoxylic acid
Glyoxylic acid
Glyoxylic acid or oxoacetic acid is an organic compound. Together with acetic acid, glycolic acid, and oxalic acid, glyoxylic acid is one of the C2 carboxylic acids. It is a colourless solid that occurs naturally and is useful industrially....

, and ultimately oxalic acid
Oxalic acid
Oxalic acid is an organic compound with the formula H2C2O4. This colourless solid is a dicarboxylic acid. In terms of acid strength, it is about 3,000 times stronger than acetic acid. Oxalic acid is a reducing agent and its conjugate base, known as oxalate , is a chelating agent for metal cations...

. The major cause of ethylene glycol toxicity is the accumulation of glycolic acid in the body, but the accumulation of calcium oxalate
Calcium oxalate
Calcium oxalate is a chemical compound that forms needle-shaped crystals, known in plants as raphides. A major constituent of human kidney stones, the chemical is also found in beerstone, a scale that forms on containers used in breweries...

 crystal
Crystal
A crystal or crystalline solid is a solid material whose constituent atoms, molecules, or ions are arranged in an orderly repeating pattern extending in all three spatial dimensions. The scientific study of crystals and crystal formation is known as crystallography...

s in the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...

s can also lead to acute kidney failure. 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
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

 NAD
Nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide, abbreviated NAD, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide.In metabolism, NAD is involved...

-dependent alcohol dehydrogenase (ADH) into a hydrogen ion
Hydrogen ion
Hydrogen ion is recommended by IUPAC as a general term for all ions of hydrogen and its isotopes.Depending on the charge of the ion, two different classes can be distinguished: positively charged ions and negatively charged ions....

, NADH and 2-hydroxyethoxyacetaldehyde (C4H8O3). Shortly after, 2-hydroxyethoxyacetaldehyde (C4H8O3) is metabolized by the enzyme aldehyde dehydrogenase (ALDH) into the weak acid
Weak acid
A weak acid is an acid that dissociates incompletely. It does not release all of its hydrogens in a solution, donating only a partial amount of its protons to the solution...

 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.

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
Metabolic acidosis
In medicine, metabolic acidosis is a condition that occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, i.e., blood pH is low due to increased production of hydrogen by the body or the...

 and further liver and kidney damage.

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, coma and mild hypotension.
  • Second phase: In one to three days after ingestion (and dependent on dose ingested), patients develop metabolic acidosis
    Metabolic acidosis
    In medicine, metabolic acidosis is a condition that occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, i.e., blood pH is low due to increased production of hydrogen by the body or the...

    , which causes acute kidney failure, oliguria
    Oliguria
    Oliguria is the low output of urine, It is clinically classified as an output below 300-500ml/day. The decreased output of urine may be a sign of dehydration, renal failure, hypovolemic shock, HHNS Hyperosmolar Hyperglycemic Nonketotic Syndrome, multiple organ dysfunction syndrome, urinary...

    , increasing serum
    Blood serum
    In blood, the serum is the component that is neither a blood cell nor a clotting factor; it is the blood plasma with the fibrinogens removed...

     creatinine
    Creatinine
    Creatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body...

     concentrations, and later anuria
    Anuria
    Anuria means nonpassage of urine, in practice is defined as passage of less than 50 milliliters of urine in a day. Anuria is often caused by failure in the function of kidneys. It may also occur because of some severe obstruction like kidney stones or tumours. It may occur with end stage renal...

    . Other symptoms reported and secondary to acidosis and/or renal failure are: hypertension
    Hypertension
    Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...

    , tachycardia
    Tachycardia
    Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...

    , cardiac dysrhythmia
    Cardiac dysrhythmia
    Cardiac dysrhythmia is any of a large and heterogeneous group of conditions in which there is abnormal electrical activity in the heart. The heart beat may be too fast or too slow, and may be regular or irregular.Some arrhythmias are life-threatening medical emergencies that can result in cardiac...

    , pancreatitis
    Pancreatitis
    Pancreatitis is inflammation of the pancreas. It occurs when pancreatic enzymes that digest food are activated in the pancreas instead of the small intestine. It may be acute – beginning suddenly and lasting a few days, or chronic – occurring over many years...

    , hyperkalemia
    Hyperkalemia
    Hyperkalemia refers to the condition in which the concentration of the electrolyte potassium in the blood is elevated...

     or mild hyponatremia
    Hyponatremia
    Hyponatremia is an electrolyte disturbance in which the sodium concentration in the serum is lower than normal. In the vast majority of cases, hyponatremia occurs as a result of excess body water diluting the serum sodium and is not due to sodium deficiency. Sodium is the dominant extracellular...

    .
  • 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
    Paralysis
    Paralysis is loss of muscle function for one or more muscles. Paralysis can be accompanied by a loss of feeling in the affected area if there is sensory damage as well as motor. A study conducted by the Christopher & Dana Reeve Foundation, suggests that about 1 in 50 people have been diagnosed...

    , dysphonia
    Dysphonia
    Dysphonia is the medical term for disorders of the voice: an impairment in the ability to produce voice sounds using the vocal organs . Thus, dysphonia is a phonation disorder...

    , dilated and nonreactive pupils, quadriplegia
    Quadriplegia
    Tetraplegia, also known as quadriplegia, is paralysis caused by illness or injury to a human that results in the partial or total loss of use of all their limbs and torso; paraplegia is similar but does not affect the arms...

    , and coma
    Coma
    In medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...

     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
Hemodialysis
In medicine, hemodialysis is a method for removing waste products such as creatinine and urea, as well as free water from the blood when the kidneys are in renal failure. Hemodialysis is one of three renal replacement therapies .Hemodialysis can be an outpatient or inpatient therapy...

 might be administered alone or with ethanol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...

 or fomepizole
Fomepizole
Fomepizole or 4-methylpyrazole is indicated for use as an antidote in confirmed or suspected methanol or ethylene glycol poisoning. It may be used alone or in combination with hemodialysis...

, which are competitive inhibitors of the enzyme NAD-dependent alcohol dehydrogenase (ADH):
  • With no medication: the low molecular weight and little or no plasma protein binding suggest DEG should be removed through this method.
  • With fomepizole: an ADH inhibitor with 8,000 times more affinity than ethanol, this treatment has minimal adverse effects because of constant serum concentration. However, it is a very expensive medication (approximately $3,000 U.S. dollars per treatment).
  • 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.


For late diagnosis where ethanol or fomepizole is ineffective, because DEG has already been metabolized, hemodialysis becomes the only treatment available.

Prognosis

The prognosis
Prognosis
Prognosis is a medical term to describe the likely outcome of an illness.When applied to large statistical populations, prognostic estimates can be very accurate: for example the statement "45% of patients with severe septic shock will die within 28 days" can be made with some confidence, because...

 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.

Epidemiology

The physical properties of diethylene glycol make it an excellent counterfeit for pharmaceutical-grade glycerine (also called glycerol) or propylene glycol
Propylene glycol
Propylene glycol, also called 1,2-propanediol or propane-1,2-diol, is an organic compound with formula C3H8O2 or HO-CH2-CHOH-CH3...

, and has caused many deaths in different countries. It was also used by China as a component of cheap toothpaste and winemakers as an adulterant
Adulterant
An adulterant is a chemical substance which should not be contained within other substances for legal or other reasons. Adulterants may be intentionally added to more expensive substances to increase visible quantities and reduce manufacturing costs or for some other deceptive or malicious purpose...

 to create a "sweet" wine.

1937 – The Massengill Incident (United States)

In 1937, S.E. Massengill Co. (a Tennessee drug company), manufactured sulfanilamide dissolved with diethylene glycol, to create a liquid alternative of this drug. The company tested the new product, Elixir Sulfanilamide, for flavor, 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
Federal Food, Drug, and Cosmetic Act
The United States Federal Food, Drug, and Cosmetic Act , is a set of laws passed by Congress in 1938 giving authority to the U.S. Food and Drug Administration to oversee the safety of food, drugs, and cosmetics. A principal author of this law was Royal S. Copeland, a three-term U.S. Senator from...

 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
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...

, diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...

, and dehydration
Dehydration
In physiology and medicine, dehydration is defined as the excessive loss of body fluid. It is literally the removal of water from an object; however, in physiological terms, it entails a deficiency of fluid within an organism...

, and died of renal failure after administration of over-the-counter sedatives. Soon, patients started to present anuria
Anuria
Anuria means nonpassage of urine, in practice is defined as passage of less than 50 milliliters of urine in a day. Anuria is often caused by failure in the function of kidneys. It may also occur because of some severe obstruction like kidney stones or tumours. It may occur with end stage renal...

, acidic breathing, hepatomegaly
Hepatomegaly
Hepatomegaly is the condition of having an enlarged liver. It is a nonspecific medical sign having many causes, which can broadly be broken down into infection, direct toxicity, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdominal mass...

, and unresponsiveness. Patients were treated with fluid hydration and correction of acidosis, but some were not able to survive. Postmortem examination revealed damage in 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 renal 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

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 characteristic. The news spread throughout the world, where many countries performed massive wine recalls. As a result, the U.S. Bureau of Alcohol, Tobacco and Firearms started to test all imported wine.

In November, The New York Times
The New York Times
The New York Times is an American daily newspaper founded and continuously published in New York City since 1851. The New York Times has won 106 Pulitzer Prizes, the most of any news organization...

 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 had no idea how 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 (Oesterreichischen Draukraftwerke) in Carinthia announced that technicians developed a way to produce energy through burning 30 million liters of contaminated wine.

1986 – India

At a hospital in Bombay, India
India
India , officially the Republic of India , is a country in South Asia. It is the seventh-largest country by geographical area, the second-most populous country with over 1.2 billion people, and the most populous democracy in the world...

, patients were admitted to be treated for diverse health problems. Doctors prescribed glycerine for its osmotic diuretic effect, but patients started to develop renal failure. Fourteen patients received hemodialysis, but the treatment failed. The episode resulted in the deaths of 21 patients and the discovery of glycerin contaminated with 18.5% v/v of DEG.

1990 - Nigeria

During the summer months, 47 children were admitted to the Jos University teaching hospital, Nigeria
Nigeria
Nigeria , officially the Federal Republic of Nigeria, is a federal constitutional republic comprising 36 states and its Federal Capital Territory, Abuja. The country is located in West Africa and shares land borders with the Republic of Benin in the west, Chad and Cameroon in the east, and Niger in...

, with anuria, fever and vomiting. The children later developed renal failure and died. All the children had received acetaminophen syrup to treat upper respiratory infections related with malaria. Once physicians identified a suspect paracetamol syrup, samples were shipped to Centers for Disease Control and Prevention
Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention are a United States federal agency under the Department of Health and Human Services headquartered in Druid Hills, unincorporated DeKalb County, Georgia, in Greater Atlanta...

 (CDC), which identified DEG. It was assumed that DEG was used as a substitute of propylene glycol, and this incident encouraged the Nigerian government to develop pharmaceutical quality control guidelines.

1990-1992 - Bangladesh

In Bangladesh
Bangladesh
Bangladesh , officially the People's Republic of Bangladesh is a sovereign state located in South Asia. It is bordered by India on all sides except for a small border with Burma to the far southeast and by the Bay of Bengal to the south...

 between 1990 and 1992, 339 children developed kidney failure, and most of them died, after being given paracetamol
Paracetamol
Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...

 (acetaminophen) syrup contaminated with diethylene glycol. The outbreak forced the government to ban the sale of paracetamol elixirs in December 1992, causing a decline of 53% in the admission of patients with renal failure and a 84% decline in admissions by unexplained renal failure.

1992 - Argentina

A propolis syrup manufactured by Huilen Laboratories in Buenos Aires
Buenos Aires
Buenos Aires is the capital and largest city of Argentina, and the second-largest metropolitan area in South America, after São Paulo. It is located on the western shore of the estuary of the Río de la Plata, on the southeastern coast of the South American continent...

, Argentina
Argentina
Argentina , officially the Argentine Republic , is the second largest country in South America by land area, after Brazil. It is constituted as a federation of 23 provinces and an autonomous city, Buenos Aires...

, contained between 24 and 66.5% DEG, and caused the death of 29 persons.

1995-1996 - Haiti

In the poorest country in the Western Hemisphere, diseases are not recognized unless they become large or unusual. Between November 1995 and June 1996, almost 109 children admitted to the University Hospital in Port-au-Prince
Port-au-Prince
Port-au-Prince is the capital and largest city of the Caribbean nation of Haiti. The city's population was 704,776 as of the 2003 census, and was officially estimated to have reached 897,859 in 2009....

, Haiti
Haiti
Haiti , officially the Republic of Haiti , is a Caribbean country. It occupies the western, smaller portion of the island of Hispaniola, in the Greater Antillean archipelago, which it shares with the Dominican Republic. Ayiti was the indigenous Taíno or Amerindian name for the island...

, presented with acute renal failure. Epidemiologists discovered the victims had consumed either Afebril or Valodon (acetaminophen preparations), manufactured by the same pharmaceutical company. Due to the strong relationship between the company and the government, the Pan American Health Organization (PAHO); World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...

 (WHO); the Caribbean Epidemiology Center, and the Centers for Disease Control and Prevention
Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention are a United States federal agency under the Department of Health and Human Services headquartered in Druid Hills, unincorporated DeKalb County, Georgia, in Greater Atlanta...

 were invited to participate in the investigation.

After collecting the samples and sending them to the CDC for analysis, experimental trials revealed the presence of DEG in all of the samples. Then, the manufacturer and the Haitian Minister of Health requested identification of the contaminated production lots and percentage of DEG in the syrups. With the available technology of the era, the CDC determined the glycerin used in the syrup preparation was contaminated with approximately 24% DEG. Only 88 children deaths were recalled by doctors or had medical records. Nearly half of the victims were under the age of two.

Ending June 1996, the FDA had discovered counterfeit glycerin traced back to Chemical Trading and Consulting (a German broker), which bought 72 barrels of the syrup from Vos B.V., a Dutch
Netherlands
The Netherlands is a constituent country of the Kingdom of the Netherlands, located mainly in North-West Europe and with several islands in the Caribbean. Mainland Netherlands borders the North Sea to the north and west, Belgium to the south, and Germany to the east, and shares maritime borders...

 company. Vos records revealed the syrup had been bought from Sinochem International Chemicals Company through a German trader, Metall-Chemie. In July 1996, the American Embassy in China contacted Sinochem and requested a list of Chinese glycerin makers, but the company refused to reveal the names. It was not until September 1996 that Sinochem provided a name of the manufacturer of the tainted syrup. They identified Tianhong Fine Chemicals Factory as the manufacturer. While the FDA tried to find out Tianhong’s address, Chinese officials were reluctant to become involved. One year and a half after the FDA began to trace the poisonous shipments, an inspector, Ted Sze, finally visited the Tianhong Fine Chemicals Factory in Dalian, northeastern China. Once he was inside, there was nothing to do: the plant had already been shut down. The Dutch authorities assessed a $250,000 fine against Vos B.V., for not alerting anyone when they tested the syrup and found impurities.

2006 - China

Wang Guiping discovered how easy it was to enter China’s pharmaceutical supply business and earn extra money. Records also revealed that to fool buyers, Wang falsified his license and laboratory analysis reports.

Wang declared that after making the first order of counterfeit syrup, he swallowed some of it. Once verifying that he was fine, he shipped it to Qiquihar No. 2 Pharmaceutical in 2005. Some time later, Wang found a reference to diethylene glycol in a chemical book. After manufacturing a second batch of syrup containing diethylene glycol for Qiquhar Pharmaceutical, no taste-test was performed. The counterfeit syrup ended in ampules of Amillarisin A, a medication for gall bladder problems; special pediatric enema fluid; blood vessel disease injections; intravenous pain reliever; and an arthritis medication.

In April 2006, the Guangdong Province Hospital of Guangzhou began administering Amillarisin A to their patients. Soon thereafter, patients died after receiving the medication. Mr. Wang was caught and Qiquihar was shut down by the authorities. Besides Wang, five employees of Qiquihar were prosecuted.

2006 - Panama

Ending September 2006, the Arnulfo Arias Madrid Hospital at Panama City was getting full with patients with contradictory symptoms. The symptoms seemed to match with Guillain-Barré syndrome, but these patients were also losing their ability to urinate, a symptom not related to Guillain-Barré. The death rate of this mysterious illness was nearly 50%, when hospital management decided to isolate all the patients with the illness in a large room and doctors could compare notes and theories. Soon, patients from other parts of the country started to arrive at hospitals. Doctors had no idea what was happening: the mysterious illness was attacking elderly citizens with hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...

 and diabetes history. About half were receiving Lisinopril (a blood pressure medicine), and many did not remember clearly if they had been taking other drugs. Suspecting something wrong with Lisinopril, the medicine was removed from the pharmacies while the U.S. Food and Drug Administration conducted lab analyses, revealing the blood pressure drug was safe; CDC
Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention are a United States federal agency under the Department of Health and Human Services headquartered in Druid Hills, unincorporated DeKalb County, Georgia, in Greater Atlanta...

 epidemiologists were then invited to participate.

When a patient admitted for a heart attack developed the mysterious illness at the hospital, Dr. Nestor Sosa, an infectious disease specialist, analyzed the medical record. Because patients treated with Lisinopril developed a cough (a common side effect of ACE inhibitors), they were prescribed an expectorant. Immediately, biological samples and the syrup were sent by jet to CDC for analysis. When urine analyses for a series of metals, pesticides or their metabolites resulted negative, CDC scientists recalled the Nigeria and Haiti incidents. The CDC employed modern laboratory equipment to analyze the samples and confirm the results: the samples contained approximately 8% v/v DEG. Later, raw glycerin was analyzed and results revealed 22.2% v/v DEG.

The Panamanian Government made a nationwide campaign, collecting around 6,000 bottles of cough syrup and three other products with the tainted glycerin manufactured by Social Security Laboratories. The 46 barrels of syrup were bought by Social Security Laboratories through a Panamanian middleman, Grupo Comercial Medicom, who bought the product from Rasfer Internacional, a Spanish company. In fact, Rasfer received the product from CNSC Fortune Way, which in turn bought it from the Taixing Glycerine Factory. At the request of the United States, the State Food and Drug Administration of China investigated Taixing Glycerine Factory and CNSC Fortune Way, but the agency concluded it is not under their jurisdiction because the factory is not certified to make medicine.

Taixing sold the syrup as “TD glycerin”, wording that neither Chinese inspectors nor Spanish medical authorities comprehended. Unfortunately, Taixing used “TD” for the Chinese word tidai, meaning “substitute”. A New York Times reporter tried to obtain a comment from CNSC Fortune Way at the CPhI worldwide (the world’s largest annual pharmaceutical convention) held in Milan, Italy, during 2007, but their representatives refused to comment.

In August 2009, the Supreme Court decided to send the diethylene glycol file to the Public Ministry for an extension. The following month, the Toxicology Department of the Institute of Legal Medicine and Forensic Science published a list of 1,155 names whose medicine bottles tested positive for DEG. Only approximately 3,000 bottles had been analyzed from the total 6,000 bottles collected. The fiscal attorney urged affected citizens to approach the Public Ministry to update the official legal file and for further medical analysis. Two months later, findings revealed that 145 were proven to die by DEG intoxication, but the DA still has to investigate 953 demands.

The New York Times reported that Taixing was closed by the Chinese government and CNSC Fortune Way was never sanctioned, which is also owned by the Chinese government. In Spain, Rasfer International declared bankruptcy after the lawyer of Medicom filed a lawsuit of $400 million in July 2008. Spanish authorities are prosecuting Asunción Criado, general manager of Rasfer Internacional, S.A., and await Panamanian citizens, René Luciani (former Social Security Director) and Jéssica Rodríguez (former Purchase National Director) for their hearings. Meanwhile, in Panama, De la Cruz, legal representative of Medicom, remains in jail pending a trial. Seventeen other persons have also been charged related to this incident. Panama awaits the extradition of Criado for her hearing.

Panama’s case made CDC set standardized methodology for DEG identification, hoping to have more timely response in future events. The agency also identified urinary DEG as a biomarker for DEG exposures. The United States Food and Drug Administration also issued an Industry Guidance Document “intended to alert pharmaceutical manufacturers, pharmacy compounders, repackers, and suppliers to the potential public health hazard of glycerin contaminated with diethylene glycol (DEG)” and recommended appropriate testing procedures for the use of glycerin.

During June 2011, the number of confirmed deaths according to the official list rose to 219 victims

2007 - Worldwide toothpaste incident

The mass recall of four different medicines in Panama taught citizens that DEG is harmful. In May 2007, a Panamanian named Eduardo Arias discovered a 59-cent toothpaste that was labeled containing DEG. Panamanian officials traced the toothpaste to a local company in the Colón Free Trade Zone
Colón Free Trade Zone
The Colón Free Trade Zone is a gigantic entity at the Atlantic gateway to the Panamá Canal, dedicated to re-export an enormous variety of merchandise to Latin America and the Caribbean. It is also the largest free zone in the Americas and second largest in the world.It started operations in 1948...

. In fact, the company bought the product in China and had already re-exported toothpaste to Costa Rica, Dominican Republic and Haiti, making Panama kick off a local warning. For the end of the month, the Chinese government committed to investigate the “supposedly” tainted toothpaste that had been recalled in Panama and Dominican Republic, but stated that, as per an essay written in 2000, a toothpaste containing 15.6% was not dangerous.

On June 1, 2007, the FDA warned consumers to avoid toothpaste from China, although there was no information if these toothpastes had already entered the US, and started testing any imported Chinese toothpaste. Days later, Colgate-Palmolive found counterfeit toothpaste with its name, which was contaminated with DEG and found at dollar-type discount stores in New York, New Jersey, Pennsylvania and Maryland. The toothpaste was labeled as “Manufactured in South Africa” and contained misspellings like "isclinically", "SOUTH AFRLCA" and "South African Dental Assoxiation". Although there were no reports of anyone harmed, several people in the eastern US reported experiencing headaches and pain after using the product. It was later discovered that a great number of tubes with poison ended up in hospitals for the mentally ill, prisons, juvenile detention centers, other hospitals and many other state institutions.

In July 2007, England detected a counterfeit Sensodyne toothpaste on sale at a car boot in Derbyshire. Soon, authorities in Belize, Canada, Mozambique, Saudi Arabia, New Zealand, Spain, Italy, Japan, Ireland and an Indianapolis, Indiana US hotel supplier that distributed Chinese toothpaste in Barbados, Belgium, Bermuda, Britain, Canada, Dominican Republic, France, Germany, Ireland, Italy, Mexico, Spain, Switzerland, Turks and Caicos, the United Arab Emirates and United States were also recalling Chinese-made toothpaste. What began as a local alert revealed a global problem in more than 30 countries and involving more than thirty brands. The world outcry made Chinese officials ban the practice of using diethylene glycol in toothpaste.

2008 - Nigeria

Ending November 2008, infants started to die after developing unexplained fevers and vomiting.  Investigations revealed that all had taken a medicine called “My Pikin Baby”, a teeth mixture tainted with diethylene glycol. The poison had caused the death of at least 84 Nigerian children between ages of two months and seven years.

The Nigerian government traced the diethylene glycol to an unlicensed chemical dealer in Lagos, who sold it to a local pharmaceutical manufacturer. Barewa Pharmaceuticals was shut down and the product was pulled off the shelves. They also arrested 12 people in connection with the incident. Being the second incident involving counterfeit glycerine, the Nigerian National Agency for Food And Drug Administration and Control (NAFDAC) had become zero-tolerant against counterfeits.

See also

  • Counterfeit medications
    Counterfeit medications
    A counterfeit medication or a counterfeit drug is a medication or pharmaceutical product which is produced and sold with the intent to deceptively represent its origin, authenticity or effectiveness...

  • Ethylene
    Ethylene
    Ethylene is a gaseous organic compound with the formula . It is the simplest alkene . Because it contains a carbon-carbon double bond, ethylene is classified as an unsaturated hydrocarbon. Ethylene is widely used in industry and is also a plant hormone...

  • Elixir sulfanilamide incident
  • Ethylene glycol poisoning
    Ethylene glycol poisoning
    Ethylene glycol poisoning is caused by the ingestion of ethylene glycol . It is a toxic, colorless, odorless, almost nonvolatile liquid with a sweet taste and is occasionally consumed by children and dogs for its sweetness...

  • Polyethylene glycol
    Polyethylene glycol
    Polyethylene glycol is a polyether compound with many applications from industrial manufacturing to medicine. It has also been known as polyethylene oxide or polyoxyethylene , depending on its molecular weight, and under the tradename Carbowax.-Available forms:PEG, PEO, or POE refers to an...


External links

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