Diethylene glycol: Difference between revisions

|OtherFunction = {{ubl|[[ethyleneEthylene glycol]],|[[Triethylene glycol]]|[[triethylenePolyethylene glycol]]}}

'''Diethylene glycol''' ('''DEG''') is an [[organic compound]] with the formula (HOCH₂CH₂)₂O. It is a colorless, practically [[odor]]less, and [[hygroscopic]] liquid with a sweetish taste. It is a four [[carbon]] [[Dimer (chemistry)|dimer]] of [[ethylene glycol]]. It is [[miscible]] in [[water]], [[ethanol|alcohol]], [[diethyl ether|ether]], [[acetone]], and ethylene glycol.<ref name="Schep" /> DEG is a widely used solvent.<ref name=Ullmanns>Siegfried Rebsdat and Dieter Mayer "Ethylene Glycol" in Ullmann's Encyclopedia of Industrial Chemistry, 2002, Wiley-VCH, Weinheim.{{doi|10.1002/14356007.a10_101}}.</ref> It can be a [[contaminant]]normal ingredient in various consumer [[product (business)|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 thisuse has resulted in numerousmany epidemics of poisoning since the early 20th century.<ref name="Schep" />

Diethylene glycol is one of several glycols derived from ethylene oxide. Glycols related to and coproducedco-produced with diethylene glycol and havehaving the formula HOCH₂CH₂(OCH₂CH₂)_''n''OH are:

Diethylene glycol is used in the manufacture of saturated and unsaturated [[polyester resins]], [[polyurethanes]], and [[plasticizers]].<ref name="availability" /> DEG is used as a buildingprecursor block in [[organic synthesis]], e.g. ofto [[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 material|cork]], printing [[ink]], and [[glue]].<ref>O'Neil M. The Merck Index. 14th ed. Whitehouse Station, NJ: Merck & Co; 2006.</ref> It is also a component inof [[brake fluid]], [[lubricants]], wallpaper strippers, [[artificial fog]] and haze solutions, and heating/cooking fuel.<ref name="Schep" /> In personal care products (e.g. skin cream and lotions, and deodorants), DEG is often replaced by selected [[Glycol ethers|diethylene glycol ethers]]. A diluteMost solutiontypes of diethylene glycol can also be used as a [[cryoprotectant]]; however, [[ethylene glycol]] is much more commonly used. Most ethylene glycol [[antifreeze]] containscontain a few percent of diethylene glycol, present as a byproductby-product of ethylene glycol production.

Despite theThe [[Elixir sulfanilamide|discoverytoxicity of DEG's toxicity in 1937]] andwas its involvementdiscovered in mass poisonings around the world, the information available regarding human toxicity is limited1937. Some authors suggest the minimumThe toxic dose is estimated at 0.14&nbsp; mg/kg of body weight and the lethal dose is between 1.0 and 1.63&nbsp; g/kg of body weight,.<ref name="Kraut">{{cite journal |vauthors=Kraut JA, Kurtz I |title=Toxic alcohol ingestions: clinical features, diagnosis, and management|journal=Clin J Am Soc Nephrol |volume=3 |issue=1 |pages=208–225 |year=2008 |pmid=18045860 |doi=10.2215/CJN.03220807 |doi-access=free }}</ref> while someSome suggest that the [[median lethal dose|LD₅₀]] in adults is ofabout ~1&nbsp; mL/kg,<ref name="Schep" /> andwhile others suggest thisthat that is the [[lethal dose|LD]]₃₀.<ref name="Marraffa" /> Because of its adverse effects on humans, diethylene glycolDEG is notrarely allowed for use in foodfoods and drugs.<ref>DEG: application restrictions</ref> (in many countries). 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.<ref> [httpshttp://wwwfrwebgate5.kakao-anmaaccess.comgpo.gov/jamsilcgi-bin/waisgate.cgi?WAISdocID=98477222302+20+0+0&WAISaction=retrieve ADDITIVES PERMITTED FOR DIRECT 잠실출장마사지ADDITION TO FOOD FOR HUMAN: Polyethylene glycol]{{Dead link|date=July 2019 |bot=InternetArchiveBot |fix-attempted=yes }}, Code of Federal Regulations, Title 21, Vol.3, Part 172, Sec. 172.820, Revised as of April 1, 2006</ref> TheIn [[Government of Australia|Australia]] does not allow DEG as a food additive due to its toxicity;, it is only allowed at less than 0.25% w/w of DEG as an impurity ofin polyethylene glycol (PEG),<ref>[http://www.nicnas.gov.au/Publications/CAR/Other/DEG_Hazard_Assessment_Report_PDF.pdf Existing Chemical Hazard Assessment Report] {{Webarchive|url=https://web.archive.org/web/20100120041540/http://www.nicnas.gov.au/Publications/CAR/Other/DEG_Hazard_Assessment_Report_PDF.pdf |date=2010-01-20 }}, June 2009</ref> even in toothpaste.<ref name=tcmt>{{cite web|publisher=[[Australian Competition & Consumer Commission]]|title=Toothpaste containing more than 0.25 per cent by weight of diethylene glycol (DEG)|url=http://www.accc.gov.au/content/index.phtml/itemId/794351|access-date=1 December 2009|url-status=dead|archive-url=https://web.archive.org/web/20090621173806/http://www.accc.gov.au/content/index.phtml/itemId/794351|archive-date = 21 June 2009}}</ref>

Diethylene glycol has "moderate to low" [[acute toxicity]]<ref>Diethylene glycol toxicity</ref> in animal experiments. The [[median lethal dose|LD₅₀]] for small mammals has been tested atis between 2 and 25&nbsp; g/kg, less toxic than its relative [[ethylene glycol]], but still capable of causing toxicity in humans (in high concentrationconcentrations only).<ref>Diethylene glycol: Human toxicity data</ref> It appears that diethylene glycol may be more hazardous to humans<ref>DEG: why it more hazardous to humans, than animals?</ref> than implied by oral toxicity data in laboratory animals.<ref name="Schep">{{cite journal |vauthors=Schep LJ, Slaughter RJ, Temple WA, Beasley DM |title=Diethylene glycol poisoning |journal=Clin Toxicol |volume=47 |issue=6 |pages=525–35 |year=2009 |pmid=19586352 |doi=10.1080/15563650903086444 |s2cid=22023562 }}</ref>

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 throughvia the gastrointestinal tract and distributed by the bloodstream throughout the body, reaching peak blood concentrations within 30 to 120 minutes. Once DEG reachesIn the liver, itDEG is metabolized by enzymes.<ref name="Schep" /><ref name="Kraut" />

At first, scientists thought that DEG [[metabolized]]was intoconverted in the liver to ethylene glycol, which is [[Ethylene glycol poisoning|poisonous]] duebecause toof the metabolic production of [[glycolic acid]], [[glyoxylic acid]], and ultimately [[oxalic acid]].<ref name="Brent">{{cite journal | author = Brent, J. | title = Current Management of Ethylene Glycol Poisoning | journal = [[Drugs (journal)|Drugs]] | volume = 61 | issue = 7 | pages = 979–88 | year = 2001 | pmid = 11434452 | doi = 10.2165/00003495-200161070-00006 | s2cid = 22954381 | issn = 0012-6667}}</ref> The major cause of ethylene glycol toxicity is the accumulation of glycolic acid in the body,<ref>{{cite journal |author1=Clay, K. L. |author2=Murphy, R. C. |title=On the Metabolic Acidosis of Ethylene Glycol Intoxication |journal=[[Toxicology and Applied Pharmacology|Toxicol. Appl. Pharmacol.]] |volume=39 |issue=1 |pages=39–49 |year=1977 |pmid=14421 |doi= 10.1016/0041-008X(77)90175-2|issn=0041-008X}}</ref> but the accumulation of [[calcium oxalate]] [[crystal]]s in the [[kidney]]s can also lead to [[acute kidney failure]].<ref name="Brent" /> In the case of DEG, observations demonstrated there were no calcium oxalate crystal depositsare 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]] [[Nicotinamide adenine dinucleotide|NAD]]-dependent alcohol dehydrogenase (ADH) intoto a [[hydrogen ion]], NADH, and 2-hydroxyethoxyacetaldehyde (C₄H₈O₃). Shortly after that, 2-hydroxyethoxyacetaldehyde (C₄H₈O₃) is metabolized by the enzyme aldehyde dehydrogenase (ALDH) intoto 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.<ref name="Schep" /><ref name="Kraut" />

Based on available literature, scientists suggest that unmetabolized DEG and HEAA are partially reabsorbed through [[glomerular filtration]]. As a consequence, the concentrations of the weak acid HEAA and its metabolites may cause renal delay, leading to [[metabolic acidosis]] and further liver and kidney damage.<ref name="Schep" /><ref name="Kraut" />

*'''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, andas well as mild [[hypotension]].

*'''Second phase:''' In one to three days after ingestion (and dependentdepending on the dose ingested), patients develop a [[metabolic acidosis]], which causes [[acute kidney failure]], [[oliguria]], increasing [[blood serum|serum]] [[creatinine]] concentrations, and later [[anuria]]. Other symptoms reported and secondary to acidosis and/or [[kidney]] failure are: [[hypertension]], [[tachycardia]], and other [[cardiac dysrhythmia]]s, [[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.

[[Fomepizole]] or [[ethanol]] should be quickly administered to prevent diethylene glycol being metabolized to the compound or compounds that cause the realrenal damage.<ref name=Schep/>

*'''[[Fomepizole]]:''' an [[alcohol dehydrogenase]] (ADH) inhibitor with 8,0008000 times more affinity than ethanol. This treatment has minimal adverse effects because of constant serum concentration.<ref name="Marraffa" /> However, it is a very expensive medication (approximatelyabout $3,0003000 U.S. per treatment).<ref>[http://intmedweb.wfubmc.edu/blurbs/overdoses/methanol.html Internal Medicine Residency Program of the College of Medicine of Wake Forest University, North Caroline, U.S.A.] {{Webarchive|url=https://web.archive.org/web/20100719055007/http://intmedweb.wfubmc.edu/blurbs/overdoses/methanol.html |date=2010-07-19 }} Retrieved December 8, 2009.</ref>

*'''[[Ethanol]]:''' ethanol is a competitive ADH substrate. A constant blood concentration of 1 to 1.5&nbsp; g/L (corresponding to 0.5 to 0.75&nbsp; mg/L in the breath) should be maintained to acceptably saturate the enzyme. An initial dose of 0.6 to 0.7&nbsp; g ethanol per kilogram body weight should be given (caabout 0.8&nbsp; mL/kg or 0.013 [[fluid ounce|fl.oz.]]/lb). This will cause [[ethanol intoxication]]. To avoid adverse effects, frequent serum monitoring and dosage adjustments should be done.<ref name="Schep" />

For late diagnosis, wherewhen ethanol or [[fomepizole]] is ineffective, because DEG has already been metabolized, [[hemodialysis]] becomes the only treatment available.<ref name="Marraffa" /> Hemodialysis may either be administered either alone or in combination with ethanol or fomepizole.

The [[prognosis]] depends on prompt diagnosis and treatment, dueowing to the high mortality ratefrom DEG intoxication produces. Patients who survive but develop kidney failure remain dialysis-dependent. All patients are likely to suffer significant morbidity.<ref name="Marraffa" />

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 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.<ref>Ballentine, C. [https://www.fda.gov/downloads/AboutFDA/WhatWeDo/History/Origin/ucm125604.doc Taste of Raspberries, Taste of Death – The 1937 Elixir Sulfanilamide Incident]. FDA Consumer Magazine, June 1981.</ref><ref>{{cite news|title=Medicine: Post-Mortem |url=http://www.time.com/time/magazine/article/0,9171,758704,00.html |archive-url=https://web.archive.org/web/20090403071709/http://www.time.com/time/magazine/article/0,9171,758704,00.html |url-status=dead |archive-date=April 3, 2009 |quote=Then, two months ago, fatality knocked at its door. A new mixture of a new drug (sulfanilamide) with a new solvent (diethylene glycol), which Dr. Massengill's salesmen sold as Elixir Sulfanilamide-Massengill, was discovered to be killing its users |work=[[Time magazine]] |date=December 20, 1937 |access-date=2009-07-19}}</ref><ref>{{cite news |title=Wallace Reveals How Federal Agents Traced Elixir to Halt Fatalities |url=https://www.nytimes.com/1937/11/26/archives/death-drug-hunt-covered-15-states-wallace-reveals-how-federal.html |quote=A graphic story of a race against death from "elixir sulfanilamide," carried on by the Food and Drug Administration in fifteen States from Virginia to California, a race not won until ninety-three persons had died after taking the lethal dose, was told by Secretary Wallace today in a report responding to Senate and House resolutions. |work=[[The New York Times]] |date=November 26, 1937 |access-date=2009-07-20}}</ref> This episode was the impetus for the [[Federal Food, Drug, and Cosmetic Act]] of 1938.<ref name="Wax">{{cite journal|author =Wax P.M.|title = Elixirs, diluents, and the passage of the 1938 Federal Food, Drug and Cosmetic Act|journal = Ann Intern Med|volume = 122|issue = 6|pages = 456–61|year = 1995|pmid=7856995|doi=10.7326/0003-4819-122-6-199503150-00009|s2cid = 32387092}}</ref> This law, though extensively amended in subsequent years, remains the central foundation of FDA regulatory authority to the present day.<ref>[https://www.fda.gov/AboutFDA/WhatWeDo/History/Origin/ucm054819.htm The History of FDA] at FDA.gov</ref>

During the summer months, 47 children were admitted to the [[Jos University Teaching Hospital|Jos University teaching hospital]], [[Nigeria]], with [[anuria]], fever and vomiting. The children later developed kidney failure and died. All the children had received [[paracetamol]] (acetaminophen) syrup to treat upper respiratory infections related with malaria. Once physicians identified a suspect [[paracetamol]] syrup, samples were shipped to the [[Centers for Disease Control and Prevention]] (CDC) in the U.S., 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.<ref name="Schep" /><ref name="Wax" /><ref name=1998-JAMA-DEG /><ref>{{cite journal |vauthors=Okuonghae HO, Ighogboja IS, Lawson JO, Nwana EJ |title=Diethylene glycol poisoning in Nigerian children |journal=Ann Trop Paediatr|volume= 12|issue=3|pages=235–8|year=1992|pmid=1280035|doi=10.1080/02724936.1992.11747577 }}</ref>

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 QiquiharQiqihar 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 QiquharQiqihar No. 2 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. Wang was caught and QiquiharQiqihar No. 2 Pharmaceutical was shut down by the authorities. Besides Wang, five employees of Qiquihar were prosecuted.<ref name="Bogdanich2">{{cite news|author1=Bogdanich, W |author2=Hooker, J.|title=From China to Panama, a trail of Poisoned Medicine.|newspaper=The New York Times|date=June 2007|url=https://www.nytimes.com/2007/05/06/world/americas/06poison.html?pagewanted=print}}</ref>

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.<ref>Bogdanich, W. "Toxic Toothpaste Made in China Is Found in U.S. ", ''The New York Times'', June 2, 2007.</ref><ref>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.</ref> Days later, [[Colgate-Palmolive]] found counterfeit toothpaste with its name, which was contaminated with DEG and found at [[Variety store|dollar-type]] [[Discountdiscount store|discount stores]]s in [[New York (state)|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".<ref>Colgate Palmolive Company Press Release. [http://investor.colgate.com/ReleaseDetail.cfm?Archive=&ReleaseDate={ts%20%272007-06-14%2000:00:00%27}&ReleaseID=249085&ReleaseType=Company&header= "Counterfeit Colgate Toothpaste Found"] {{Webarchive|url=https://web.archive.org/web/20090328191943/http://investor.colgate.com/ReleaseDetail.cfm?ReleaseID=249085&ReleaseType=Company&ReleaseDate=%7Bts%20%272007-06-14%2000:00:00%27%7D&header=&Archive= |date=2009-03-28 }}, June 14, 2007.</ref><ref>U.S. Food and Drug Administration Press Release. "Counterfeit Colgate Toothpaste Found", June 14, 2007.</ref> Although there were no reports of anyone harmed, several people in the eastern US reported experiencing headaches and pain after using the product.<ref>{{Cite web |url=http://abclocal.go.com/wabc/story?section=alerts_recalls&id=5399483 |title=7online.com: Toothpaste recall expands 6/18/07 |access-date=2007-06-21 |archive-url=https://web.archive.org/web/20070706085804/http://abclocal.go.com/wabc/story?section=alerts_recalls&id=5399483 |archive-date=2007-07-06 |url-status=dead }}</ref> It was later discovered that a great number of tubes with poison ended up in [[Psychiatric hospital|hospitals for the mentally ill]], [[Prison|prisonsprison]]s, [[Youth detention center|juvenile detention centers]], other hospitals and many other state institutions.<ref>Bogdanich, W. "Wider Sale Is Seen for Toothpaste Tainted in China ", ''The New York Times'', June 28, 2007.</ref>