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{{chembox {{chembox
| Verifiedfields = changed | Watchedfields = changed
| verifiedrevid = 414047867
| Watchedfields = changed
| Name =
| verifiedrevid = 402114375
| ImageFile = Ethyl-carbamate-2D-skeletal.png | ImageFile = Ethyl carbamate v2.svg
| ImageFile_Ref = {{Chemboximage|correct|??}} | ImageFile_Ref = {{Chemboximage|correct|??}}
| ImageSize = 121 | ImageSize = 121
| ImageClass = skin-invert
| ImageName = Structural formula of ethyl carbamate
| IUPACName = Ethyl carbamate | ImageName = Structural formula of ethyl carbamate
| SystematicName = <!-- Ethyl carbamate --> | ImageFile1 = Ethyl Carbamate 3D Balls.png
| ImageSize1 = 150
| OtherNames = Urethane
| PIN = Ethyl carbamate
| Section1 = {{Chembox Identifiers
| OtherNames = Carbamic acid ethyl ester, Urethane, Ethylurethane
| CASNo = 51-79-6
| Section1 = {{Chembox Identifiers
| CASNo_Ref = {{cascite|correct|CAS}}
| PubChem = 5641 | CASNo = 51-79-6
| PubChem_Ref = {{Pubchemcite|correct|PubChem}} | CASNo_Ref = {{cascite|correct|CAS}}
| ChemSpiderID = 5439 | PubChem = 5641
| ChemSpiderID = 5439
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| UNII = 3IN71E75Z5
| UNII_Ref = {{fdacite|correct|FDA}} | UNII = 3IN71E75Z5
| UNII_Ref = {{fdacite|correct|FDA}}
| EINECS = 200-123-1 | EINECS = 200-123-1
| UNNumber = 2811 | UNNumber = 2811
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB04827
| DrugBank = DB04827
| KEGG_Ref = {{keggcite|changed|kegg}}
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = C01537 | KEGG = C01537
| MeSHName = Urethane | MeSHName = Urethane
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 17967
| ChEBI = 17967
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 462547 | ChEMBL = 462547
| RTECS = FA8400000 | RTECS = FA8400000
| 3DMet = B00312 | 3DMet = B00312
| SMILES = CCOC(N)=O | SMILES = CCOC(N)=O
| SMILES1 = O=C(OCC)N | SMILES1 = O=C(OCC)N
| StdInChI = 1S/C3H7NO2/c1-2-6-3(4)5/h2H2,1H3,(H2,4,5) | StdInChI = 1S/C3H7NO2/c1-2-6-3(4)5/h2H2,1H3,(H2,4,5)
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| InChI = 1/C3H7NO2/c1-2-6-3(4)5/h2H2,1H3,(H2,4,5) | InChI = 1/C3H7NO2/c1-2-6-3(4)5/h2H2,1H3,(H2,4,5)
| StdInChIKey = JOYRKODLDBILNP-UHFFFAOYSA-N | StdInChIKey = JOYRKODLDBILNP-UHFFFAOYSA-N
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| InChIKey = JOYRKODLDBILNP-UHFFFAOYAY}} | InChIKey = JOYRKODLDBILNP-UHFFFAOYAY}}
| Section2 = {{Chembox Properties | Section2 = {{Chembox Properties
| C = 3 | C=3 | H=7 | N=1 | O=2
| Appearance = White crystals
| H = 7
| Density = 1.056 g cm<sup>−3</sup>
| N = 1
| O = 2 | MeltingPtC = 46 to 50
| BoilingPtC = 182 to 185
| ExactMass = 89.047678473 g mol<sup>-1</sup>
| Solubility = 0.480 g cm<sup>−3</sup> at 15&nbsp;°C
| Appearance = White crystals
| LogP = -0.190(4)
| Density = 1.056 g cm<sup>-3</sup>
| VaporPressure = 1.3 kPa at 78&nbsp;°C
| MeltingPtCL = 46
| MeltingPtCH = 50 | pKa = 13.58
| Dipole = 2.59 D<ref name="Exner pp. 1–92">{{cite book | last=Exner | first=Otto | title=Double-Bonded Functional Groups: Vol. 1 (1977) | chapter=Dipole moments, configurations and conformations of molecules containing X...Y groups | year=1977 | publisher=John Wiley & Sons, Ltd. | publication-place=Chichester, UK | isbn=978-0-470-77150-1 | doi=10.1002/9780470771501.ch1 | pages=1–92}}</ref><ref>{{cite web | title=ethyl carbamate | website=stenutz.eu | url=http://www.stenutz.eu/chem/solv6.php?name=ethyl%20carbamate | access-date=6 April 2021}}</ref>}}
| BoilingPtCL = 182
| Section3 = {{Chembox Hazards
| BoilingPtCH = 185
| MainHazards = Harmful if swallowed<br />May cause cancer
| Solubility = 0.480 g cm<sup>-3</sup> at 15 °C
| GHS_ref=<ref>{{GESTIS|ZVG=510233 |Name=Ethyl carbamate |Date=13 December 2021}}</ref>
| LogP = -0.190(4)
| GHSPictograms = {{GHS07}}{{GHS08}}
| VaporPressure = 1.3 kPa at 78 °C
| pKa = 13.58 | GHSSignalWord = Danger
| Dipole = 0.5206015862 D}} | HPhrases = {{H-phrases|302|350}}
| PPhrases = {{P-phrases|P201|P301+P312+P330|P308+P313}}
| Section3 = {{Chembox Hazards
| NFPA-H = 1
| EUIndex = 607-149-00-6
| NFPA-F = 2
| EUClass = {{Hazchem T}}
| NFPA-R = 0
| MainHazards = Harmful if swallowed<br />
| FlashPtC = 92}}
May cause cancer
| Section4 =
| RPhrases = {{R45}}
| Section5 =
| SPhrases = {{S45}}, {{S53}}
| NFPA-H = 1 | Section6 =
| Section8 = {{Chembox Related
| NFPA-F = 2
| NFPA-R = 0 | Related_ref =
| OtherAnions =
| FlashPt = 92 °C}}
| OtherCations =
| OtherFunction =
| OtherFunction_label =
| OtherCompounds = ]<br />]
}}
}} }}
'''Ethyl carbamate''' (also called '''urethane''') is a ] with the molecular formula C<sub>3</sub>H<sub>7</sub>N<sub></sub>O<sub>2</sub> first prepared in the nineteenth century. Structurally, it is an ] of ]. Despite its common name, it is not a component of ]s. '''Ethyl carbamate''' (also called '''urethane''') is an ] with the formula CH<sub>3</sub>CH<sub>2</sub>OC(O)NH<sub>2</sub>. It is an ] of ] and a white solid. Despite its name, it is not a component of ]s. Because it is a ], it is rarely used, but naturally forms in low quantities in many types of fermented foods and drinks.


==Synthesis== ==Synthesis==
Ethyl carbamate is a white crystalline substance produced by the action of ] on ] or by heating ] and ]:<ref>'']'', 11th Edition, '''9789'''</ref> It is produced by organically heating ] and ].<ref>{{Ullmann|date=2012|first1=Peter|last1=Jäger|first2=Costin N.|last2=Rentzea|first3=Heinz|last3=Kieczka|title=Carbamates and Carbamoyl Chlorides|doi=10.1002/14356007.a05_051}}</ref> It also arises by the action of ] on ].<ref>'']'', 11th Edition, '''9789'''</ref>
]
:]
{{clear|left}}


==Uses== ==Uses==
===Biomedical applications===
Ethyl carbamate has been produced commercially in the United States for many years. It has been used as an ] agent and for other medicinal purposes but this ended after it was discovered to be carcinogenic in 1943. However, Japanese usage in medical injections continued and from 1950 to 1975 an estimated 100 million 2 ml ampules of 7 to 15% solutions of ethyl carbamate were injected into patients as a co-solvent in water for dissolving water-insoluble analgesics used for post-operation pain. These doses were estimated by Nomura (''Cancer Research'', 35, 2895–2899, October 1975) to be at levels that are carcinogenic in mice. This practice was stopped in 1975. "This regrettable medical situation appears to have involved the largest number (millions) of humans exposed to the largest doses of a pure carcinogen that is on record" (''Japanese Journal of Cancer Research'', 82, 1323–1324, December 1991). The author, U.S. cancer researcher James A. Miller, called for studies to determine the effects on Japanese cancer rates to be performed but apparently none were ever done.
Ethyl carbamate has been used as an ] agent and for other medicinal purposes, but this application ended after it was discovered to be ] in 1943. However, Japanese usage in medical injections continued and from 1950 to 1975 an estimated 100&nbsp;million 2&nbsp;ml ampules of 7-to-15% solutions of ethyl carbamate were injected into patients as a co-solvent in water for dissolving water-insoluble analgesics used for post-operation pain. These doses were estimated to be at levels that are carcinogenic in mice.<ref>{{cite journal| url=https://cancerres.aacrjournals.org/content/canres/35/10/2895.full.pdf |journal=Nomura Cancer Research |volume=35 |pages=2895–2899 |date=October 1975 |title=Urethan (Ethyl Carbamate) as a Cosolvent of Drugs Commonly Used Parenterally in Humans|pmid=1157055 |last1=Nomura |first1=T. |issue=10 }}</ref> This practice was stopped in 1975. "This regrettable medical situation appears to have involved the largest number (millions) of humans exposed to the largest doses of a pure carcinogen that is on record".<ref name="Miller1991">{{cite journal | last=Miller | first=James A. | title=The Need for Epidemiological Studies of the Medical Exposures of Japanese Patients to the Carcinogen Ethyl Carhamate (Urethane) from 1950 to 1975 | journal=Japanese Journal of Cancer Research | publisher=Wiley | volume=82 | issue=12 | year=1991 | issn=0910-5050 | doi=10.1111/j.1349-7006.1991.tb01799.x | pages=1323–1324| pmid=1778753 | pmc=5918349 | doi-access=free }}</ref> The author, U.S. cancer researcher James A. Miller, called for studies to determine the effects on Japanese cancer rates to be performed but apparently none were ever done.{{citation needed|date=April 2021}}


Prior to World War II, ethyl carbamate saw relatively heavy use in the treatment of ] before it was found to be toxic, carcinogenic and largely ineffective.<ref>{{cite journal | pmid = 5933438 | year = 1966 | last1 = Holland | first1 = JR | last2 = Hosley | first2 = H | last3 = Scharlau | first3 = C | last4 = Carbone | first4 = PP | last5 = Frei E | first5 = 3rd | last6 = Brindley | first6 = CO | last7 = Hall | first7 = TC | last8 = Shnider | first8 = BI | last9 = Gold | first9 = GL | title = A controlled trial of urethane treatment in multiple myeloma | volume = 27 | issue = 3 | pages = 328–42 | journal = Blood}}</ref> By US FDA regulations, ethyl carbamate has been withdrawn from pharmaceutical use. However, small quantities of ethyl carbamate are also used in laboratories as an anesthetic for animals.<ref>Virginia Commonwealth University, The Chemical/Biological Safety Section (CBSS) of the Office of Environmental Health and Safety, , 2006. Accessed May 13, 2006</ref> Prior to World War II, ethyl carbamate saw relatively heavy use in the treatment of ] before it was found to be toxic, carcinogenic, and largely ineffective.<ref>{{cite journal | pmid = 5933438 | year = 1966 | last1 = Holland | first1 = JR | last2 = Hosley | first2 = H | last3 = Scharlau | first3 = C | last4 = Carbone | first4 = PP | last5 = Frei | first5 = E, 3rd | last6 = Brindley | first6 = CO | last7 = Hall | first7 = TC | last8 = Shnider | first8 = BI | last9 = Gold | first9 = GL | last10 = Lasagna | first10 = L | last11 = Owens | first11 = AH Jr | last12 = Miller | first12 = SP | title = A controlled trial of urethane treatment in multiple myeloma | volume = 27 | issue = 3 | pages = 328–42 | journal = Blood| doi = 10.1182/blood.V27.3.328.328 | doi-access = free }}</ref> By US FDA regulations, ethyl carbamate has been withdrawn from pharmaceutical use. However, small quantities of ethyl carbamate are also used in laboratories as an anesthetic for animals.<ref>Virginia Commonwealth University, The Chemical/Biological Safety Section (CBSS) of the Office of Environmental Health and Safety, {{Webarchive|url=https://web.archive.org/web/20130511205145/http://www.vcu.edu/oehs/chemical/biosafe/urethane.pdf |date=2013-05-11 }}, 2006. Accessed May 13, 2006</ref>


Ethyl carbamate was upgraded to a Group 2A carcinogen by IARC in 2007. Ethyl carbamate was reclassified as a Group 2A carcinogen by IARC in 2007.


Ethyl carbamate is used as an ] in ], with more than 100 animal studies using ethyl carbamate published each year.<ref>{{cite journal | last1 = Hara | first1 = K. | last2 = Harris | first2 = R.A. | year = 2002 | title = The anesthetic mechanism of urethane: the effects on neurotransmitter-gated ion channels | journal = Anesthesia & Analgesia | volume = 94 | issue = 2| pages = 313–8 | doi=10.1213/00000539-200202000-00015| pmid = 11812690 | s2cid = 13806836 }}</ref> One advantage of using ethyl carbamate is that it has a very long duration of action, with some adult rats remaining anaesthetised 24 hours after administration of the drug.<ref>{{cite journal | last1 = Field | first1 = K.J. | last2 = White | first2 = W.J. | last3 = Lang | first3 = C.M. | year = 1993 | title = Anaesthetic effects of chloral hydrate, pentobarbitone and urethane in adult male rats | journal = Laboratory Animals | volume = 27 | issue = 3| pages = 258–69 | doi=10.1258/002367793780745471| pmid = 8366672 | doi-access = free }}</ref> It also does not depress neuronal activity in the ] to the same extent as ].<ref>{{cite journal | last1 = Rojas | first1 = M.J. | last2 = Navas | first2 = J.A. | last3 = Rector | first3 = D.M. | s2cid = 18569834 | year = 2006 | title = Evoked response potential markers for anesthetic and behavioral states | journal = American Journal of Physiology. Regulatory, Integrative and Comparative Physiology | volume = 291 | issue = 1 | pages = R189–96 | doi=10.1152/ajpregu.00409.2005| pmid = 16455771 }}</ref>
Formerly, crosslinking agents for permanent press textile treatments were synthesized from ethyl carbamate.<ref>NTP National Toxicology Program, NIEHS, National Institutes of Health, , 2005. Accessed May 13, 2006</ref>

===Other uses===
Formerly, ethyl carbamate was used as a chemical intermediate in the preparation of amino resins, that were in turn used as crosslinking agents for permanent-press textile treatments to create "wash-and-wear" fabrics. Other uses included as solvent or intermediary in the manufacture of pesticides, cosmetics and pharmaceuticals.<ref>{{cite web | url=https://ntp.niehs.nih.gov/ntp/roc/content/profiles/urethane.pdf |publisher=NTP National Toxicology Program, NIEHS, National Institutes of Health |title=Fourteenth Report on Carcinogens, Urethane |date=2016| access-date=6 April 2021}}</ref>


==Occurrence in beverages and food== ==Occurrence in beverages and food==
The widespread presence of ethyl carbamate in ]s was discovered during the mid-1980s. To raise public awareness of this issue, the U.S. Center for Science in the Public Interest published, in 1987, ''Tainted Booze: The Consumer's Guide to Urethane in Alcoholic Beverages''. Studies have shown that most, if not all, yeast-fermented ] contain traces of ethyl carbamate (15 ppb to 12 ppm).<ref name="Segal">{{cite web | last=Segal | first=Marian | title=FDA/CFSAN FDA Consumer: Too Many Drinks Spiked with Urethane (April, 1988) | website=cfsan.fda.gov | date=20 June 2006 | url=http://www.cfsan.fda.gov/~frf/fc0488ur.html | archive-url=https://web.archive.org/web/20060620015521/http://www.cfsan.fda.gov/~frf/fc0488ur.html | archive-date=20 June 2006 | access-date=6 April 2021}}</ref> Other foods and beverages prepared by means of fermentation also contain ethyl carbamate. For example, bread has been found to contain 2&nbsp;ppb;<ref>{{cite journal |author1=Haddon W F |author2=M I Mancini |author3=M Mclaren |author4=A Effio |author5=L A Harden |author6=R I Egre |author7=J L Bradford|title=Occurrence of ethyl carbamate (urethane) in US and Canadian breads:measurements by gas chromatography-mass spectrometry | journal = Cereal Chemistry | volume = 71 | issue = 2 | pages = 207–215 | year = 1994}}</ref> as much as 20&nbsp;ppb has been found in some samples of soy sauce.<ref>{{cite journal |author1=Matsudo T |author2=T Aoki |author3=K Abe |author4=N Fukuta |author5=T Higuchi |author6=M Sasaki |author7=K Uchida | journal = J Agric Food Chem | volume = 41 | issue = 3 | pages = 352–356 | year = 1993 | doi = 10.1021/jf00027a003 | title = Determination of ethyl carbamate in soy sauce and its possible precursor}}</ref> Amounts of both ethyl carbamate and ] have also been found in wines, sake, beer, brandy, whiskey and other fermented alcoholic beverages.


It has been shown that ethyl carbamate forms from the reaction of ] with ]:
The discovery of the widespread presence of ethyl carbamate in alcoholic beverages first occurred during the mid-1980s. In 1987, the U.S. Center for Science in the Public Interest published ''Tainted Booze: The Consumer's Guide to Urethane in Alcoholic Beverages'' to raise public awareness of this issue. Studies have shown that most, if not all, yeast-fermented ] contain traces of ethyl carbamate (15 ppb to 12 ppm).<ref name=Segal>Segal, M , US Food and Drug Administration, September 1988</ref> Other foods and beverages prepared by means of fermentation also contain ethyl carbamate. For example, bread has been found to contain 2&nbsp;ppb;<ref>{{cite journal | author = Haddon W F, M I Mancini, M Mclaren, A Effio, L A Harden, R I Egre, & J L Bradford | journal = Cereal Chemistry | volume = 71 | issue = 2 | pages = 207–215 | year = 1994}}</ref> as much as 20&nbsp;ppb has been found in some samples of soy sauce.<ref>{{cite journal | author = Matsudo T, T Aoki, K Abe, N Fukuta, T Higuchi, M Sasaki & K Uchida | journal = J Agric Food Chem | volume = 41 | issue = 3 | pages = 352–356 | year = 1993 | doi = 10.1021/jf00027a003 | title = Determination of ethyl carbamate in soy sauce and its possible precursor}}</ref> Amounts of both ethyl carbamate and ] have also been found in wines, sake, beer, brandy, whiskey and other fermented alcoholic beverages.


:]
It has been shown that ethyl carbamate forms from the reaction of alcohol (]) with ]:
This reaction occurs much faster at higher temperatures, and therefore higher concentrations of ethyl carbamate are found in beverages that are heated during processing, such as brandy, whiskey, and other ]. Additionally, heating after bottling either during shipping or in preparation will cause ethyl carbamate levels to rise further.


The urea in wines results from the metabolism of ] or ] by ] or other organisms. The urea waste product is initially metabolised inside the yeast cell until it builds up to a certain level. At that point, it is excreted externally where it is able to react with the alcohol to create ethyl carbamate.
:]


In 1988, wine and other alcoholic beverage manufacturers in the ] agreed to control the level of ethyl carbamate in wine to less than 15&nbsp;ppb (parts per billion), and in stronger alcoholic drinks to less than 125&nbsp;ppb.<ref name=Segal/>
This reaction occurs much faster at higher temperatures, and therefore higher concentrations of ethyl carbamate are found in beverages that are heated during processing, such as brandy, whiskey, and other ]. Additionally, heating after bottling either during shipping or in preparation will cause ethyl carbamate levels to rise further.


Although the urea cannot be eliminated, it can be minimized by controlling the fertilization of grape vines, minimizing their heat exposure, using self-cloning yeast<ref>{{cite journal|vauthors = Coulon J, Husnik JI, Inglis DL, van der Merwe GK, Lonvaud A, Erasmus DJ, van Vuuren HJ| title=Metabolic Engineering of Saccharomyces cerevisiae to Minimize the Production of Ethyl Carbamate in Wine|journal = American Journal of Enology and Viticulture | year = 2006 | volume = 57 | issue = 2 | pages = 113–124| doi=10.5344/ajev.2006.57.2.113| s2cid=44808594}}</ref> and other actions.<ref>Butzke, C E & L F Bisson, {{Webarchive|url=https://web.archive.org/web/20060619072456/http://www.cfsan.fda.gov/~frf/ecaction.html |date=2006-06-19 }}, Department of Viticulture & Enology, U. of CA, Davis, CA, for US FDA, 1997 accessed May 13, 2006</ref> Furthermore, some strains of yeast have been developed to help reduce ethyl carbamate during commercial production of alcoholic beverages.<ref>{{cite web|url=http://www.ec.gc.ca/subsnouvelles-newsubs/default.asp?lang=En&n=AECC21AD-1|title=New substances: risk assessment summary EAU-288 - Canada.ca|first=Environment and Climate Change|last=Canada|website=www.ec.gc.ca|date=2010-02-15}}</ref>
The urea in wines results from the metabolism of ] or ] by yeast or other organisms. The urea waste product is initially metabolised inside the yeast cell until it builds up to a certain level. At that point, it is excreted externally where it is able to react with the alcohol to create ethyl carbamate.


Another important mechanism for ethyl carbamate formation in alcoholic beverages is the reaction from cyanide as precursor, which causes comparably high levels in spirits derived from cyanogenic plants, such as ].<ref>{{cite journal |vauthors=Lachenmeier DW, Lima MC, Nóbrega IC, Pereira JA, Kerr-Corrêa F, Kanteres F, Rehm J | journal = BMC Cancer | volume = 10 | page = 266 | year = 2010 | pmid = 20529350 | pmc = 2892455 | doi = 10.1186/1471-2407-10-266 | title = Cancer risk assessment of ethyl carbamate in alcoholic beverages | doi-access = free }}</ref>
In 1988, wine and other alcoholic beverage manufacturers in the ] agreed to control the level of ethyl carbamate in wine to less than 15&nbsp;ppb, and in stronger alcoholic drinks to less than 125&nbsp;ppb.<ref name=Segal/>


==Hazards==
Although the urea cannot be eliminated, it can be minimized by controlling the fertilization of grape vines, minimizing their heat exposure, using self-cloning yeast<ref>{{cite journal | journal = American Journal of Enology and Viticulture | year = 2006 | volume = 57 | issue = 2 | pages = 113–124}}</ref> and other actions.<ref>Butzke, C E & L F Bisson, , Depart. of Viticulture & Enology, U. of CA, Davis, CA, for US FDA, 1997 accessed May 13, 2006</ref>
{{Text-source|date=May 2019}}


Ethyl carbamate is not acutely toxic to humans, as reflected by its use as a medicine. Acute toxicity studies show that the lowest fatal dose in rats, mice, and rabbits equals 1.2&nbsp;g/kg or more. When ethyl carbamate was used medicinally, about 50% of the patients exhibited nausea and vomiting, and long-time use led to gastroenteric hemorrhages.<ref>Office of Toxic Substances, Chemical Hazard Information Profile Urethane, CAS No. 51-79-6, U.S. EPA, Washington, D.C., 12 pages, 26 references, 1979, accessed May 13, 2006 at http://toxnet.nlm.nih.gov.{{full citation needed|date=May 2019}}</ref> The compound has almost no odor and a cooling, saline, bitter taste.<ref name="HSDB 2006a">National Library of Medicine, Hazardous Data Bank, Ethyl Carbamate 2006a, accessed May 13, 2006 at http://toxnet.nlm.nih.gov/.{{full citation needed|date=May 2019}}</ref>
Another important mechanism for ethyl carbamate formation in alcoholic beverages is the reaction from cyanide as precursor, which causes comparably high levels in spirits derived from cyanogenic plants (i.e. predominantly stone-fruit spirits and cachaca).<ref>{{cite journal | author = Lachenmeier DW, Lima MC, Nóbrega IC, Pereira JA, Kerr-Corrêa F, Kanteres F, Rehm J. | journal = BMC Cancer | volume = 10 | pages = 266 | year = 2010 | pmid = 20529350 | pmc = 2892455 | doi = 10.1186/1471-2407-10-266 | title = Cancer risk assessment of ethyl carbamate in alcoholic beverages from Brazil with special consideration to the spirits cachaça and tiquira.}}</ref>


Studies with rats, mice, and hamsters have shown that ethyl carbamate causes cancer when administered orally, injected, or applied to the skin, but no adequate studies of cancer in humans caused by ethyl carbamate has been reported due to the ethical considerations of such studies.<ref>IARC, 1974{{Clarify|date=June 2010}}<!--full citation needed--></ref> However, in 2007, the International Agency for Research on Cancer raised ethyl carbamate to a Group 2A carcinogen that is "probably carcinogenic to humans", one level below fully carcinogenic to humans. IARC has stated that ethyl carbamate can be "reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity in experimental animals".<ref>NTP 2005{{Clarify|date=June 2010}}<!--full citation needed--></ref> In 2006, the Liquor Control Board of Ontario in Canada rejected imported cases of sherry due to excessive levels of ethyl carbamate.
==Hazards==


Studies in Hong Kong (2009)<ref>{{cite web |url=https://docs.google.com/viewer?url=https%3A%2F%2Fwww.cfs.gov.hk%2Fenglish%2Fprogramme%2Fprogramme_rafs%2Ffiles%2FRA39_EC_in_food_e.pdf |title=RA39_EC_in_food_e.pdf |access-date=2020-04-12}}</ref> and Korea (2015)<ref name="Ryu Choi Kim Park pp. 289–297">{{cite journal | last1=Ryu | first1=Dayeon | last2=Choi | first2=Bogyoung | last3=Kim | first3=Eunjoo | last4=Park | first4=Seri | last5=Paeng | first5=Hwijin | last6=Kim | first6=Cho-il | last7=Lee | first7=Jee-yeon | last8=Yoon | first8=Hae Jung | last9=Koh | first9=Eunmi | title=Determination of Ethyl Carbamate in Alcoholic Beverages and Fermented Foods Sold in Korea | journal=Toxicological Research | publisher=The Korean Society of Toxicology | volume=31 | issue=3 | date=2015-09-30 | issn=1976-8257 | doi=10.5487/tr.2015.31.3.289 | pages=289–297| pmid=26483888 | pmc=4609976 }}</ref> outline the extent of the accumulative exposure to ethyl carbamate in daily life. Fermented foods such as soy sauce, kimchi, soybean paste, breads, rolls, buns, crackers and bean curd, along with wine, sake and plum wine, were found to be the foods with the highest ethyl carbamate levels in traditional Asian diets.
Ethyl carbamate is not acutely toxic to humans, as shown by its use as a medicine. Acute toxicity studies show that the lowest fatal dose in rats, mice, and rabbits equals 1.2&nbsp;grams/kg or more. When ethyl carbamate was used medicinally, about 50 percent of the patients exhibited nausea and vomiting, and long time use led to gastroenteric hemorrhages.<ref>Office of Toxic Substances, “Chemical Hazard Information Profile Urethane, CAS No. 51-79-6 , U.S. EPA, Washington, D.C., 12 pages, 26 references, 1979, accessed May 13, 2006 at http://toxnet.nlm.nih.gov</ref> The compound has almost no odor and a cooling, saline, bitter taste.<ref name="HSDB 2006a">National Library of Medicine, Hazardous Data Bank, Ethyl Carbamate 2006a, accessed May 13, 2006 at http://toxnet.nlm.nih.gov/</ref>


In 2005, the JECFA (Joint FAO/WHO Expert Committee On Food Additives) risk-assessment evaluation of ethyl carbamate<ref>{{cite web |url=http://www.fao.org/3/a-at877e.pdf |title=www.fao.org |access-date=2020-04-12}}</ref> concluded that the MOE intake of ethyl carbamate from daily food and alcoholic beverages combined is of concern, and mitigation measures to reduce ethyl carbamate in some alcoholic beverages should continue. There is little doubt<ref>{{cite web |url=https://apps.who.int/food-additives-contaminants-jecfa-database/chemical.aspx?chemID=5199 |title=WHO &#124; JECFA |access-date=2020-04-12}}</ref> that ethyl carbamate in alcoholic beverages is very important to health authorities, while the cumulative daily exposure in the typical diet is also an issue of rising concern that merits closer observation. The Korean study concluded: "It would be desirable to closely monitor ethyl carbamate levels in Korean foods and find ways to reduce the daily intake."
Studies with rats, mice, and hamsters has shown that ethyl carbamate will cause cancer when it is administered orally, injected, or applied to the skin, but no adequate studies of cancer in humans caused by ethyl carbamate has been reported due to the ethical considerations of such studies.<ref>IARC, 1974{{Clarify|date=June 2010}}<!--full citation needed--></ref> However, in 2007, the International Agency for Research on Cancer raised ethyl carbamate to a Group 2A carcinogen that is "probably carcinogenic to humans," one level below fully carcingenic to humans. IARC has stated that ethyl carbamate can be “reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity in experimental animals.”<ref>NTP 2005{{Clarify|date=June 2010}}<!--full citation needed--></ref> In 2006, the Liquor Control Board of Ontario in Canada rejected imported cases of sherry due to excessive levels of ethyl carbamate.


The IARC evaluation has led to the following US regulatory actions:{{citation needed|date=May 2019}}
Alcoholic beverages, particularly certain stone-fruit spirits and whiskies, tend to contain much higher concentrations of urethane. Heating (e.g., cooking) the beverage increases the ethyl carbamate content, and some concern exists over shipping wines to overseas markets in containers that tend to overheat. In addition, urethane has a tendency to accumulate in the human body from a number of daily dietary sources, e.g., alcohols, bread and other fermented grain products, soy sauce, orange juice and commonly consumed foods. Hence, exposure risk to human health is increasingly evaluated on the total ethyl carbamate intake from the daily diet (WHO refers to this as "margin of exposure" or MOE), of which alcoholic beverages often provide the most significant portion.
* ]: Listed as a Hazardous Air Pollutant (HAP)
* Comprehensive Environmental Response, Compensation, and Liability Act: Reportable Quantity (RQ) = 100&nbsp;lb
* Emergency Planning and Community Right-To-Know Act, EPA's Toxics Release Inventory: A listed substance subject to RCRA reporting requirements
* ] Listed Hazardous Waste: substance - U238


==Detection in alcoholic beverages==
Studies in Korea (2000) and Hong Kong (2009) outline the extent of the accumulative exposure to ethyl carbamate in daily life. Fermented foods such as soy sauce, kimchi, soybean paste, breads, rolls, buns, crackers and bean curd, along with wine, sake and plum wine, were found to be the foods with the highest ethyl carbamate levels in traditional Asian diets.
The concerns raised by the toxicological aspects of EC together with the low concentration levels (μg/L) found in wines, as well as the occurrence of interferences on detection, has motivated several researchers to develop new methods to determine it in wines. Several extraction and chromatographic techniques have been used, including continuous liquid–liquid extraction (LLE) with Soxhlet apparatus, derivatization with 9-xanthydrol followed by high-performance liquid chromatography (HPLC) with fluorescence detection and even LLE after derivatization, followed by gas chromatography coupled with mass spectrometry detection (GC–MS). On the other hand, the reference method set by the International Organization of Vine and Wine (OIV) uses solid phase extraction (SPE) preceding GC–MS quantification. Other methods also make use of SPE, but use gas chromatography with mass spectrometry (MDGC/MS) and liquid chromatography with tandem mass spectrometry (LC–MS/MS) for detection. Most of the methodologies found in the literature to quantify EC use gas chromatography, using LLE and SPE as extraction techniques. Nevertheless, several efforts have also been done to develop new methodologies to determine EC without using long procedures and hard-working analyses, combining precision to high sensitivity. In this regard, headspace solid phase microextraction (HS-SPME) has been gaining great highlighting and alternative methodologies has been proposed using the most recent identification and quantification technology, such as gas chromatography with tandem mass spectrometry detection (GC–MS/MS) and two-dimensional gas chromatography with time-of-flight mass spectrometry (GC × GC–ToFMS).


Microextraction by packed sorbent (MEPS) is also feasible. MEPS/GC–MS methodology has been applied to quantify EC in wines.<ref>{{cite journal | last1 = Leça | first1 = J. M. | last2 = Pereira | first2 = V. | last3 = Pereira | first3 = A. C. | last4 = Marques | first4 = J. C. | year = 2014 | title = Rapid and sensitive methodology for determination of ethyl carbamate in fortified wines using microextraction by packed sorbent and gas chromatography with mass spectrometric detection | url =https://estudogeral.sib.uc.pt/bitstream/10316/27137/1/Rapid%20and%20sensitive%20methodology%20for%20determination%20of%20ethyl%20carbamate%20in%20fortified%20wines.pdf | journal = Analytica Chimica Acta | volume = 811 | pages = 29–35 | doi = 10.1016/j.aca.2013.12.018 | pmid = 24456591 | bibcode = 2014AcAC..811...29L | hdl = 10316/27137 | hdl-access = free }}</ref><ref>{{cite journal | last1 = Weber | first1 = J. V. | last2 = Sharypov | first2 = V. I. | year = 2009 | title = Ethyl carbamate in foods and beverages: a review | journal = Environmental Chemistry Letters | volume = 7 | issue = 3| pages = 233–247 | doi=10.1007/s10311-008-0168-8| bibcode = 2009EnvCL...7..233W | s2cid = 95933716 }}</ref>
In 2005, the JECFA (Joint FAO/WHO Expert Committee On Food Additives) risk assessment evaluation of ethyl carbamate concluded that the MOE intake of ethyl carbamate from daily food and alcoholic beverages combined is of concern and mitigation measures to reduce ethyl carbamate in some alcoholic beverages should continue. There is little doubt that ethyl carbamate in alcoholic beverages is very important to health authorities, while the cumulative daily exposure in the typical diet is also an issue of rising concern that merits closer observation. The Korean study concluded, "It would be desirable to closely monitor ethyl carbamate levels in Korean foods and find ways to reduce the daily intake."


Miniaturized liquid-liquid extraction (mLLE) followed by LC-MS/MS can be used to determine EC in wine, without using derivatizing agents.<ref>{{Cite journal|last1=Leça|first1=João M.|last2=Pereira|first2=Vanda|last3=Pereira|first3=Ana C.|last4=Marques|first4=José C.|date=2017-08-15|title=A Sensitive Method for the Rapid Determination of Underivatized Ethyl Carbamate in Fortified Wine by Liquid Chromatography-Electrospray Tandem Mass Spectrometry|journal=Food Analytical Methods|volume=11|issue=2|language=en|pages=327–333|doi=10.1007/s12161-017-1002-3|hdl=10400.13/3725|s2cid=102508529|issn=1936-9751|hdl-access=free}}</ref>
The IARC evaluation has led to the following US regulatory actions:
*]: Listed as a Hazardous Air Pollutant (HAP)
*Comprehensive Environmental Response, Compensation, and Liability Act: Reportable Quantity (RQ) = 100&nbsp;lb
*Emergency Planning and Community Right-To-Know Act, EPA’s Toxics Release Inventory: A listed substance subject to RCRA reporting requirements
*] Listed Hazardous Waste: substance - U238


==Related compounds== ==Related compounds==
Other carbamates include ] (urethylane, m. p.&nbsp;52-54 °C),<ref name="HSDB 2006b">National Library of Medicine, Hazardous Data Bank, Methyl Carbamate 2006b, accessed May 13, 2006 at http://toxnet.nlm.nih.gov</ref> ],<ref name="HSDB 2006c">National Library of Medicine, Hazardous Data Bank, Butyl Carbamate 2006c, accessed May 13, 2006 at http://toxnet.nlm.nih.gov</ref> and ] (m. p.&nbsp;149-152 °C),<ref>Dean, JA (editor), ''Lange’s Handbook of Chemistry'', 13th Ed., 1985, p. 7-586, #p191.</ref> which can also be prepared from the corresponding ] and ]. These esters are white, crystalline solids at room temperature. Except for the phenyl carbamate, they sublime at moderate temperatures; methyl carbamate sublimes at room temperatures. The first two and ethyl carbamate are very soluble in water, benzene, and ether.<ref name="HSDB 2006a"/><ref name="HSDB 2006b"/><ref name="HSDB 2006c"/> These other carbamates (], butyl, and phenyl) are only used in small quantities for research purposes. Other carbamates include ],<ref name="HSDB 2006b">National Library of Medicine, Hazardous Data Bank, Methyl Carbamate 2006b, accessed May 13, 2006 at http://toxnet.nlm.nih.gov</ref> ],<ref name="HSDB 2006c">National Library of Medicine, Hazardous Data Bank, Butyl Carbamate 2006c, accessed May 13, 2006 at http://toxnet.nlm.nih.gov</ref> and ] (m.&nbsp;p.&nbsp;149–152&nbsp;°C),<ref>Dean, J. A. (editor), ''Lange's Handbook of Chemistry'', 13th Ed., 1985, p. 7-586, #p191.</ref> which can also be prepared from the corresponding ] and ]. These esters are white, crystalline solids at room temperature. Except for the phenyl carbamate, they sublime at moderate temperatures; methyl carbamate sublimes at room temperatures. The first two and ethyl carbamate are very soluble in water, benzene, and ether.<ref name="HSDB 2006a"/><ref name="HSDB 2006b"/><ref name="HSDB 2006c"/> These other carbamates (], butyl, and phenyl) are only used in small quantities for research purposes.


==See also== ==See also==
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==References== ==References==

{{Reflist}} {{Reflist}}


==External links== ==External links==
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{{DEFAULTSORT:Ethyl Carbamate}} {{DEFAULTSORT:Ethyl Carbamate}}
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