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Diethylene glycol

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Diethylene glycol
Names
IUPAC name
(2-hydroxyethoxy)ethan-2-ol
Other names
diethylene glycol; ethylene diglycol; diglycol; 2,2'-oxybisethanol; 3-oxa-1,5-pentanediol;
dihydroxy diethyl ether
Identifiers
3D model (JSmol)
ECHA InfoCard 100.003.521 Edit this at Wikidata
  • OCCOCCO
Properties
C4H10O3
Molar mass 106.12 g/mol
Appearance Colorless liquid
Density 1.118 g/mL
Melting point -10.45 °C
Boiling point 244-245 °C
miscible
Related compounds
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Diethylene glycol (DEG) is an organic compound with the formula (HOCH2CH2)2O. It is a colorless, practically odorless, poisnous,viscous, 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]

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 one of several glycols derived from ethylene oxide. Related to and coproduced with diethylene glycol are have the formula HO(CH2CH2(OCH2CH2)nOH. They are:

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

Uses

NOTE: Although a diluted solution of diethylene glycol can be used as coolant, it should not be confused with ethylene glycol, which is the glycol most used in this type of products.

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.[4] It is also a component in antifreeze formulations (coolants), 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.

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 that minimum toxic dose is estimated at 0.14 mg/kg of body weight and lethal dose between 1 and 1.63 g/kg of body weight,[5] while some suggest that the LD50 in adults is of ~1 mL/kg,[1] and other suggest that 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.[6]

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 occurring within 30 to 120 minutes. Once DEG reaches the liver, it is metabolized by enzymes.[1][5]

Metabolism and elimination

At first, scientists thought that DEG metabolized into ethylene glycol, but subsequent observations demonstrated there was no calcium oxalate crystal deposition at the kidneys. Rat models suggest that 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 at the kidneys for elimination.[1][5]

Mechanisms of toxicity

Based on available literature, scientists suggests that 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][5]

Symptoms

The symptoms of poisoning typically occur in three characteristic intervals:[1]

  • First phase: gastrointestinal symptoms such as nausea, vomiting, abdominal pain, and diarrhea. Some patients may develop early neurological symptoms like altered mental status, central nervous system depression and coma and mild hypotension.
  • Second phase: developed usually between 1 – 3 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.
  • Final phase: at least 5 – 10 days after ingestion, most of the symptoms are related to neurological complications like progressive lethargy, facial paralysis, dysphonia, dilated and nonreactive pupils, quadriplegia, and coma leading to death.

Treatment

Although it is not an approved procedure and there are no studies supporting 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):

  • With no medication: the low molecular weight and little or no plasma protein binding suggest that DEG should be removed through this method.[1]
  • With Fomepizole: an ADH inhibitor with 8,000 times more affinity than ethanol and with minimal adverse effects because maintains constant serum concentration.[3] However, it is a very expensive medication (approximately $3,000 U.S. dollars per treatment)[7]
  • With Ethanol: 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

Prognosis depends in prompt diagnosis and treatment due to the high mortality rate that DEG intoxication produces. Patients that survive but develop renal failure remain dialysis dependent. All patients are likely to suffer significant morbidity.[3]

Epidemiology

Diethylene glycol physical properties make it an excellent counterfeit for pharmaceutical-grade glycerine (also called glycerol) or propylene glycol, causing many deaths in different countries. It was also used by China as a component of cheap toothpaste and winemakers as an adulterant to create a "sweet" wine.[8][9]

1937 – The Massengill Incident (United States)

Main article: Elixir Sulfanilamide

In 1937, S.E. Massengill Co. (a Tennessee drug company), manufactured sulfanilamide dissolved with diethylene glycol, to cover 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 drugs law didn’t require toxicological analysis before releasing for sale. When 105 people died in 15 states during the months of September and October and the trail led back to the elixir, the toxic potential of this chemical was revealed.[10][11][12] This episode was the impetus for the Federal Food, Drug, and Cosmetic Act of 1938.[13] This law, though extensively amended in subsequent years, remains the central foundation of FDA regulatory authority to the present day.[14]

1969 – South Africa

In Cape Town, South Africa, seven children died of renal failure after administration of over-the-counter sedative and developed vomiting, diarrhea and dehydration. 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 kidneys and liver and laboratory testing found DEG instead of propylene glycol on the sedatives.[1][13]

1985 – Spain

Patients being treated for burns, develop sudden anuric renal failure. Further investigations revealed that all patients were treated with topical silver sulfadiazine ointment that contained 7 g/kg of DEG. This event caused the death of five patients.[3][15][16]

1985 - Wine scandal

During the month of July, Austrian wines were found to contain up to 1,000 parts per million of DEG, giving them the 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 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.[17][18][19]

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 mixture of wine with salt to melt hazardous ice during winter. The primarily results revealed that the mixture was more effective than using salt alone.[20] The next year, an Australian electric power plant (Oesterreichischen Draukraftwerke) in Carinthia announced that technicians developed a way to produce energy burning 30 million liters of contaminated wine.[21]

1986 – India

At a hospital in Bombay, India, patients were admitted to be treated for diverse health problems. Doctors prescribed glycerine for its osmotic diuretic effect, in contrast, patients started to develop renal failure. Fourteen patients received hemodialysis, but the treatment failed. The episode resulted in the death of 21 patients and the discovery of glycerin contaminated with 18.5% v/v of DEG.[1][13][22]

1990 - Nigeria

During the summer months, 47 children were admitted to the Jos University teaching hospital, Nigeria, with anuria, fever and vomiting, that later developed renal failure and died. All children received acetaminophen syrup to treat upper respiratory infections related with malaria. Once physicians identified a paracetamol syrup, samples were shipped to Centers for Disease Control and Prevention (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.[1][13][23][24]

1990-1992 - Bangladesh

In Bangladesh between 1990 and 1992, 339 children developed kidney failure, and most of them died, after being given paracetamol (acetaminophen) syrup contaminated with diethylene glycol. The outbreak forced the government to ban the sale of paracetamol elixirs din 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.[25]

1992 - Argentina

A propolis syrup manufactured by Huilen Laboratories in Buenos Aires, Argentina, contained between 24 and 66.5% DEG, caused the death of 29 persons.[26][27][28]

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, Haiti, presented acute renal failure. Epidemiologists discovered consumption of Afebril or Valodon (acetaminophen preparations), manufactured by the same pharmaceutical. Due to the strong relationship between the company and the government, the Pan American Health Organization (PAHO); World Health Organization (WHO); the Caribbean Epidemiology Center, and the Centers for Disease Control and Prevention were invited to participate in the investigation.[23][29][30]

After collecting the samples and sending them to CDC for analysis, experimental trials revealed DEG presence in all 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, CDC determined that glycerin was used in the syrup preparation, but was contaminated with approximately 24% DEG.[23] Only 88 children deaths were recalled by doctors or had medical records. Nearly half of the victims were under the age of 2.[31]

Ending June 1996, the F.D.A. counterfeited glycerin to Chemical Trading and Consulting (a German broker), who bought 72 barrels of the syrup to Vos B.V., a Dutch company. Vos records revealed that the syrup had been bought from Sinochem International Chemicals Company through a German trader, Metall-Chemie. For July, the American Embassy in China contacted Sinochem and requested a list of Chinese glycerin makers, but the company refused to reveal the names. After a third attempt to find out who was the manufacturer, it was not until September 1996 that Sichonem provided a name, Tianhong Fine Chemicals Factory, and a phone number. While the F.D.A. tried to find out Tianhong’s address, Chinese officials were reluctant to become involved. One year and a half after the F.D.A. began to trace the poisonous shipment, agent Ted Sze, finally visited the Tianhong Fine Chemicals Factory in Dalian, northeastern China. But 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., by not alerting anyone when they tested the syrup and found impurities.[31]

2006 - China

Wang Guiping discovered of how easy 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. Time later, Wang found in a chemical book, diethylene glycol: a cheaper and odorless syrup. After manufacturing the second batch of syrup for Qiquhar Pharmaceutical, not taste-test was made. 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. But soon, 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.[32]

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, symptom not related to Guillain-Barré. The death rate of this mysterious illness was near 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 and diabetes pressure history. About half was receiving Lisinopril (a blood pressure medicine) and many did not remembered clearly if they had been taking other drugs. Suspecting something wrong with Lisinopril, the medicine was pulled out from the pharmacies[32] while the U.S. Food and Drug Administration conducted lab analyses, revealing that the blood pressure drug was safe and CDC epidemiologists were invited participate.[23]

When a patient admitted by a heart attack developed the mysterious illness inside the hospital, Dr. Nestor Sosa, an infectious disease specialist, analyzed the medical record: Because patients treated with Lisinopril developed a cough (common side effect of ACE inhibitor), they were prescribed a expectorant.[32] 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 false, CDC scientists recalled 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 on, raw glycerin was analyzed and results revealed 22.2% v/v DEG.[23]

Panamanian Government made nationwide campaign, collecting around 6,000 cough syrup and other three products manufactured by the Social Security Laboratories with the tainted glycerin.[33] The forty-six barrels of syrup were bought by the Social Security 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, who in turn bought it to 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 that it is not under their jurisdiction because the factory is not certified to make medicine.[32][34]

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” (pronounced tee-die), meaning “substitute”.[32] 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.[35]

In August 2009, the Supreme Court decided to send the diethylene glycol file to the Public Ministry for an extension.[36] 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 has 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.[33] Two months later, findings have revealed that 145 have been proven to die by DEG intoxication, but the DA still has to investigate 953 demands.[36]

The New York Times reported that Taixing was closed by the Chinese government and CNSC Fortune Way was never sanctioned, in fact, Fortune Way is owned by the government.[35] In Spain, Rasfer International declared in bankruptcy after the lawyer of Medicom filed a lawsuit by $400 million dollars during July 2008.[37] 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. Other 17 persons have also been charged related to this incident. Panama awaits the extradition of Criado for her hearing.[38]

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[23]. 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 recommending appropriate testing procedures for use of glycerin.[39]

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 $0.59 dollar toothpaste was labeled as containing DEG. Panamanian officials traced the toothpaste to a local company in Colon Free Zone. 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.[40][41][42] For the end of the month, the Chinese government accepted to investigate the “supposedly” tainted toothpaste that had been recalled in Panama and Dominican Republic, but stated that en essay written in 2000, a toothpaste containing 15.6% was not dangerous.[43]

For 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.[44][45] Days later, Colgate-Palmolive found counterfeit toothpaste with its name, which contaminated with DEG and were 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".[46][47] Although there were no reports of anyone harmed, several people in eastern US reported experiencing headaches and pain after using the product.[48] It was later discovered that a great number of tubes with poison ended up in hospitals for mentally ill, prisons, juvenile detention centers, other hospitals and many other state institutions.[49]

In July, England detected a counterfeit Sensodyne toothpaste on a sale at a car boot in Derbyshire.[50] Soon, authorities in Belize, Canada, Mozambique, Saudi Arabia, New Zealand, Spain, Italy, Japan, Ireland and an Indianapolis 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 thirty countries and involving more than thirty brands.[51] The world outcry made Chinese officials ban the practice of using diethylene glycol in toothpaste.[52]

2008 - Nigeria

Ending November, 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 2 months and 7 years.[53][54]

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 pulled off the shelves the tainted product. They also arrested 12 people in connection with the incident. Being the second incident involving counterfeit glycerine, the National Agency For Food And Drug Administration and Control (NAFDAC) has become zero-tolerant against counterfeits.[55][56][57]

Restrictions

Australian government does not allow DEG as a food additive; it is only allowed less than 0.25% w/w of DEG as an impurity of polyethylene glycol (PEG)[58] even in toothpaste.[35] [59]

See also

References

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  30. ^ "Fatalities Associated with Ingestion of Diethylene Glycol-Contaminated Glycerin Used to Manufacture Acetaminophen Syrup — Haiti, November 1995–June 1996" (Free full text). Morbidity and Mortality weekly report. 1996. {{cite journal}}: Unknown parameter |month= ignored (help); line feed character in |title= at position 100 (help)
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  39. ^ http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070347.pdf Guidance for Industry - Testing of Glycerin for Diethylene Glycol
  40. ^ Bogdanich, W.; McLean, R. "Poisoned Toothpaste in Panama Is Believed to Be From China", New York Times, May 19, 2007.
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  44. ^ Bogdanich, W. "Toxic Toothpaste Made in China Is Found in U.S. ", New York TImes, June 2, 2007.
  45. ^ U.S. Food and Drug Administration Press Release. "FDA Advises Consumers to Avoid Toothpaste From China Containing Harmful Chemical. FDA Detains One Contaminated Shipment, Issues Import Alert", June 1, 2007.
  46. ^ Colgate Palmolive Company Press Release. "Counterfeit Colgate Toothpaste Found", June 14, 2007.
  47. ^ U.S. Food and Drug Administration Press Release. "Counterfeit Colgate Toothpaste Found", June 14, 2007.
  48. ^ 7online.com: Toothpaste recall expands 6/18/07
  49. ^ Bogdanich, W. "Wider Sale Is Seen for Toothpaste Tainted in China ", New York Times, June 28, 2007.
  50. ^ BBC NEWS | Business | Toxin found in fake UK toothpaste
  51. ^ "Tainted toothpaste across the world", New York Times, September 30, 2007. http://www.nytimes.com/imagepages/2007/09/30/world/20071001_PANAMA_GRAPHIC.html
  52. ^ Bogdanich, W. "The Everyman Who Exposed Tainted Toothpaste ", New York Times, October 1, 2007.
  53. ^ News.yahoo.com Nigeria child deaths from tainted syrup rise to 84
  54. ^ Nigeria child deaths from tainted syrup rise to 84
  55. ^ [1]
  56. ^ http://www.nytimes.com/2009/02/07/world/africa/07nigeria.html
  57. ^ http://www.nafdac.gov.ng/index.php?option=com_content&view=article&id=72:nafdac-negotiates-state-of-the-art-anti-counterfeiting-equipment&catid=51:press-statements&Itemid=113
  58. ^ http://www.nicnas.gov.au/Publications/CAR/Other/DEG_Hazard_Assessment_Report_PDF.pdf
  59. ^ Australian Competition and Consumer Commission. "Toothpaste containing more than 0.25 per cent by weight of diethylene glycol (DEG)". Retrieved 1 December 2009. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)

References

  • Merck Index, 12th Edition, 3168.
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