Editing Chloroform (section)

==Safety==
===Exposure===
Chloroform is formed as a by-product of [[water chlorination]], along with a range of other [[disinfection by-product]]s, and it is therefore often present in municipal tap water and swimming pools. Reported ranges vary considerably, but are generally below the current health standard for total [[trihalomethanes]] (THMs) of 100 μg/L.<ref>{{cite journal|last1=Nieuwenhuijsen|first1=MJ|last2=Toledano|first2=MB|last3=Elliott|first3=P|title=Uptake of chlorination disinfection by-products; a review and a discussion of its implications for exposure assessment in epidemiological studies.|journal=Journal of Exposure Analysis and Environmental Epidemiology|date=8 August 2000|volume=10|issue=6 Pt 1|pages=586–99|pmid=11140442|doi=10.1038/sj.jea.7500139|doi-access=free}}</ref> However, when considered in combination with other trihalomethanes often present in drinking water, the concentration of THMs often exceeds the recommended limit of exposure.<ref>{{Cite web |title=EWG's Tap Water Database: Contaminants in Your Water |url=https://www.ewg.org/tapwater/reviewed-disinfection-byproducts.php |access-date=2023-08-08 |website=www.ewg.org |language=en}}</ref>


Historically, chloroform exposure may well have been higher, owing to its common use as an anesthetic, as an ingredient in cough syrups, and as a constituent of [[tobacco smoke]], where [[DDT]] had previously been used as a [[fumigant]].<ref>Yin-Tak Woo, David Y. Lai, Joseph C. Arcos [https://books.google.com/books?id=25H-BAAAQBAJ&dq=Chloroform+tobacco&pg=PA98 Aliphatic and Polyhalogenated Carcinogens: Structural Bases and Biological] {{webarchive|url=https://web.archive.org/web/20180605033237/https://books.google.com/books?id=25H-BAAAQBAJ&pg=PA98&lpg=PA98&dq=Chloroform+tobacco&source=bl&ots=GGoHCH5uup&sig=vJAm_Ecl4J_XuHn5EXIZ9Jpik4E&hl=en&sa=X&ved=0ahUKEwjPrLX9hbvUAhXDDsAKHeIOC3gQ6AEILzAC |date=5 June 2018 }}</ref>

===Pharmacology===
Chloroform is well absorbed, metabolized, and eliminated rapidly by mammals after oral, inhalation, or dermal exposure. Accidental splashing into the eyes has caused irritation.<ref name="cicad" /> Prolonged dermal exposure can result in the development of sores as a result of [[Defatting (medical)|defatting]]. Elimination is primarily through the lungs as chloroform and carbon dioxide; less than 1% is excreted in the urine.<ref name="pth" />

Chloroform is metabolized in the liver by the [[cytochrome P-450]] enzymes, by oxidation to trichloromethanol and by reduction to the dichloromethyl [[free radical]]. Other metabolites of chloroform include [[hydrochloric acid]] and diglutathionyl dithiocarbonate, with [[carbon dioxide]] as the predominant end-product of metabolism.<ref name="eot">{{cite encyclopedia| first=Anna M. |last=Fan | title=Chloroform | encyclopedia=Encyclopedia of Toxicology | edition=2nd | volume=1 | publisher=Elsevier | year=2005 | pages=561–565}}</ref>

Like most other general anesthetics and sedative-hypnotic drugs, chloroform is a [[Allosteric modulator|positive allosteric modulator]] at [[GABAA receptor|GABA<sub>A</sub> receptors]].<ref>{{Cite journal|last1=Jenkins|first1=Andrew|last2=Greenblatt|first2=Eric P.|last3=Faulkner|first3=Howard J.|last4=Bertaccini|first4=Edward|last5=Light|first5=Adam|last6=Lin|first6=Audrey|last7=Andreasen|first7=Alyson|last8=Viner|first8=Anna|last9=Trudell|first9=James R.|last10=Harrison|first10=Neil L.|date=2001-03-15|title=Evidence for a Common Binding Cavity for Three General Anesthetics within the GABAA Receptor|journal=Journal of Neuroscience|language=en|volume=21|issue=6|pages=RC136|doi=10.1523/JNEUROSCI.21-06-j0002.2001|issn=0270-6474|pmid=11245705|pmc=6762625|doi-access=free}}</ref> Chloroform causes depression of the [[central nervous system]] (CNS), ultimately producing deep [[coma]] and respiratory center depression.<ref name="eot" /> When ingested, chloroform causes symptoms similar to those seen after inhalation. Serious illness has followed ingestion of {{convert|7.5|g|oz|abbr=on}}. The mean lethal oral dose in an adult is estimated at {{convert|45|g|oz|abbr=on}}.<ref name="cicad" />

The anesthetic use of chloroform has been discontinued, because it caused deaths from respiratory failure and cardiac arrhythmias. Following chloroform-induced anesthesia, some patients suffered [[nausea]], [[vomiting]], [[hyperthermia]], [[jaundice]], and coma owing to [[hepatic dysfunction]]. At autopsy, liver [[necrosis]] and degeneration have been observed.<ref name="cicad" /> The hepatotoxicity and nephrotoxicity of chloroform is thought to be due largely to [[phosgene]], one of its metabolites.<ref name="eot" />

===Conversion to phosgene===
Chloroform converts slowly in the presence of UV light and air to the extremely poisonous gas [[phosgene]] ({{chem2|COCl2}}), releasing [[HCl]] in the process.<ref name="earlham">{{cite web|url=http://www.earlham.edu/chemical-hygiene-and-safety/safety-topics/chloroform-and-phosgene/|title=Chloroform and Phosgene, Chemical Hygiene and Safety|website=Earlham College|access-date=17 August 2017|url-status=live|archive-url=https://web.archive.org/web/20170819102644/http://www.earlham.edu/chemical-hygiene-and-safety/safety-topics/chloroform-and-phosgene/|archive-date=19 August 2017}}</ref>

{{block indent|{{chem2|2 CHCl3 + O2 → 2 COCl2 + 2 HCl}}}}

To prevent accidents, commercial chloroform is stabilized with [[ethanol]] or [[pentene|amylene]], but samples that have been recovered or dried no longer contain any stabilizer. Amylene has been found to be ineffective, and the phosgene can affect analytes in samples, lipids, and nucleic acids dissolved in or extracted with chloroform.<ref>{{cite journal|url=http://pubs.acs.org/cen/safety/19980302.html|last=Turk|first=Eric|title=Phosgene from Chloroform|journal=Chemical & Engineering News|date=2 March 1998|volume=76|issue=9|page=6|doi=10.1021/cen-v076n009.p006|doi-access=free|access-date=13 August 2012|archive-date=24 July 2008|archive-url=https://web.archive.org/web/20080724065839/http://pubs.acs.org/cen/safety/19980302.html|url-status=live}}</ref> When ethanol is used as a stabiliser for chloroform, it reacts with phosgene (which is soluble in chloroform) to form the relatively harmless [[diethyl carbonate]] ester:

{{block indent|{{chem2|2 CH3CH2OH + COCl2 → CO3(CH2CH3)2 + 2 HCl}}}}

Phosgene and HCl can be removed from chloroform by washing with saturated aqueous [[carbonate]] solutions, such as [[sodium bicarbonate]]. This procedure is simple and results in harmless products. Phosgene reacts with water to form [[carbon dioxide]] and HCl,<ref>{{cite web |url=https://www.britannica.com/EBchecked/topic/457363/phosgene |title=phosgene (chemical compound) |website=Encyclopædia Britannica |access-date=16 August 2013 |url-status=live |archive-url=https://web.archive.org/web/20130605183448/https://www.britannica.com/EBchecked/topic/457363/phosgene |archive-date=5 June 2013}}</ref> and the carbonate salt [[Neutralization (chemistry)|neutralizes]] the resulting acid.<ref>{{Cite journal |last1=Manogue |first1=W. H. |last2=Pigford |first2=R. L. |date=September 1960 |title=The kinetics of the absorption of phosgene into water and aqueous solutions |url=https://onlinelibrary.wiley.com/doi/10.1002/aic.690060329 |journal=AIChE Journal |language=en |volume=6 |issue=3 |pages=494–500 |doi=10.1002/aic.690060329 |bibcode=1960AIChE...6..494M |issn=0001-1541}}</ref>

Suspected samples can be tested for phosgene using filter paper which when treated with 5% [[diphenylamine]], 5% [[dimethylaminobenzaldehyde]] in [[ethanol]], and then dried, turns yellow in the presence of phosgene vapour.<ref>{{Cite web |title=American Chemical Society: Chemical & Engineering Safety Letters |url=https://pubsapp.acs.org/cen/safety/19980302.html#:~:text=Filter%20paper%20strips,%20wetted%20with,alkenes,%20reacts%20quickly%20with%20phosgene. |access-date=2024-03-18 |website=pubsapp.acs.org}}</ref> There are several [[colorimetry|colorimetric]] and [[fluorometry|fluorometric]] reagents for phosgene, and it can also be quantified using [[mass spectrometry]].<ref>{{Cite journal |last1=Cheng |first1=Xueheng |last2=Gao |first2=Quanyin |last3=Smith |first3=Richard D. |last4=Simanek |first4=Eric E. |last5=Mammen |first5=Mathai |last6=Whitesides |first6=George M. |date=1996 |title=Characterization of Hydrogen-Bonded Aggregates in Chloroform by Electrospray Ionization Mass Spectrometry |url=https://www.academia.edu/33298377 |archive-url=https://archive.today/20220731041555/https://www.academia.edu/33298377/Characterization_of_Hydrogen_Bonded_Aggregates_in_Chloroform_by_Electrospray_Ionization_Mass_Spectrometry |archive-date=2022-07-31 |url-status=live |journal=The Journal of Organic Chemistry |volume=61 |issue=6 |pages=2204–2206 |doi=10.1021/jo951345g |issn=0022-3263}}</ref>

===Regulation===
Chloroform is suspected of causing [[cancer]] (i.e. it is possibly [[carcinogen]]ic, [[IARC Group 2B]]) as per the [[International Agency for Research on Cancer]] (IARC) Monograph. There is no convincing evidence that chloroform causes cancer in humans.<ref>{{Cite web |title=Chloroform |url=https://monographs.iarc.who.int/wp-content/uploads/2018/06/mono73-10.pdf |access-date=December 5, 2023}}</ref>

It is classified as an [[List of extremely hazardous substances|extremely hazardous substance]] in the United States, as defined in Section 302 of the US [[Emergency Planning and Community Right-to-Know Act]] (42 U.S.C. 11002), and is subject to strict reporting requirements by facilities that produce, store, or use it in significant quantities.<ref name="gov-right-know">{{Cite journal |journal = [[Code of Federal Regulations]]| publisher = [[United States Government Publishing Office|Government Printing Office]] | title = 40 C.F.R.: Appendix A to Part 355—The List of Extremely Hazardous Substances and Their Threshold Planning Quantities | url = http://edocket.access.gpo.gov/cfr_2008/julqtr/pdf/40cfr355AppA.pdf | edition = 1 July 2008 | access-date = 29 October 2011  | archive-url = https://web.archive.org/web/20120225051612/http://edocket.access.gpo.gov/cfr_2008/julqtr/pdf/40cfr355AppA.pdf | archive-date = 25 February 2012}}</ref>