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|ImageFile=Isothiazolinone.png |
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|ImageSize=100px |
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| verifiedrevid = 424992608 |
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|IUPACName=1,2-Thiazol-3-one |
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| ImageFileL1 = 1,2-Thiazol-3-one.png |
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|OtherNames=Isothiazolin-3-one; 3(2''H'')-Isothiazolone |
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| ImageSizeL1 = 100px |
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| ImageAltL1 = Skeletal formula of isothiazolinone |
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| ImageFileR1 = Isothiazolinone-3D-spacefill.png |
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| ImageSizeR1 = 120 |
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| ImageAltR1 = Space-filling model of the isothiazolinone molecule |
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| PIN = 1,2-Thiazol-3(2''H'')-one |
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| OtherNames = Isothiazolin-3-one; 3(2''H'')-Isothiazolone, isothiazolin |
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|Section1={{Chembox Identifiers |
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|Section1={{Chembox Identifiers |
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| CASNo_Ref = {{cascite|correct|??}} |
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| CASNo=1003-07-2 |
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| CASNo = 1003-07-2 |
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| PubChem=96917 |
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| UNII_Ref = {{fdacite|changed|FDA}} |
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| SMILES=O=C1NSC=C1 |
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| UNII = E57JT172V7 |
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}} |
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| PubChem = 96917 |
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| EINECS = 696-206-9 |
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| SMILES = O=C1NSC=C1 |
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| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} |
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| ChemSpiderID = 87509 |
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| SMILES2 = c1csnc1O |
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| InChI = 1/C3H3NOS/c5-3-1-2-6-4-3/h1-2H,(H,4,5) |
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| InChIKey = MGIYRDNGCNKGJU-UHFFFAOYAO |
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| StdInChI_Ref = {{stdinchicite|changed|chemspider}} |
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| StdInChI = 1S/C3H3NOS/c5-3-1-2-6-4-3/h1-2H,(H,4,5) |
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| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}} |
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| StdInChIKey = MGIYRDNGCNKGJU-UHFFFAOYSA-N |
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| RTECS = |
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| MeSHName = C001490 |
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|Section2={{Chembox Properties |
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|Section2={{Chembox Properties |
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| Formula = C<sub>3</sub>H<sub>3</sub>NOS |
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| C=3|H=3|N=1|O=1|S=1 |
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| MolarMass = 101.127 |
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| Appearance= |
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| Appearance = white solid |
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| MeltingPtC = 74–75 |
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| GHSSignalWord = Warning |
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'''Isothiazolinone''' ({{IPAc-en|,|aI|s|oU|,|T|aI|.|@|'|z|oU|l|I|n|oU|n}}; sometimes '''isothiazolone''') is an ] with the formula (CH)<sub>2</sub>SN(H)CO. A white solid, it is structurally related to ]. Isothiazolone itself is of limited interest, but several of its derivatives are widely used preservatives and ]s.<ref name=rev>{{cite journal |doi=10.3390/molecules25040991|title=Isothiazolinone Biocides: Chemistry, Biological, and Toxicity Profiles|year=2020|last1=Silva|first1=Vânia|last2=Silva|first2=Cátia|last3=Soares|first3=Pedro|last4=Garrido|first4=E. Manuela|last5=Borges|first5=Fernanda|last6=Garrido|first6=Jorge|journal=Molecules|volume=25|issue=4|page=991|pmid=32102175|pmc=7070760|doi-access=free }}</ref> |
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'''Isothiazolinone''' is a ] chemical compound. ] of isothiazolinone are used as ]s, including: |
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==Synthesis== |
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Compared to many other simple heterocycles, the discovery of isothiazolinone is fairly recent, with reports first appearing in the 1960s.<ref name="origin">{{cite journal |doi=10.1021/jo01019a037|title=3-Isothiazolone-cis-3-Thiocyanoacrylamide Equilibria1,2|year=1965|last1=Crow|first1=W. D.|last2=Leonard|first2=Nelson J.|journal=The Journal of Organic Chemistry|volume=30|issue=8|pages=2660–2665}}</ref> |
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Isothiazolinones can be prepared on an industrial scale by the ring-closure of 3-mercaptopropanamides. These in turn are produced from ] via the ]: |
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:] |
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Ring-closure of the thiol-amide is typically effected by chlorination<ref name="origin" /> or oxidation of the 3-sulfanylpropanamide to the corresponding ].<ref>{{cite journal |last1=Taubert |first1=Kathleen |last2=Kraus |first2=Susanne |last3=Schulze |first3=Bärbel |title=Isothiazol-3(2H)-Ones, Part I: Synthesis, Reactions and Biological Activity |journal=Sulfur Reports |date=April 2002 |volume=23 |issue=1 |pages=79–121 |doi=10.1080/01961770208047968|s2cid=85374823 }}</ref> |
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:] |
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Many other routes have been developed, including addition of thiocyanate to propargyl amides.<ref name=rev/> |
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==Mechanism of action== |
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The antimicrobial activity of isothiazolinones is attributed to their ability to inhibit life-sustaining enzymes, specifically those enzymes with ]s at their ]s. It is established that isothiazolinones form mixed disulfides upon treatment with such species. |
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] |
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== Applications == |
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The principal isothiazolones are: |
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* ] (MIT, MI) |
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* ] (MIT, MI) |
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* ] (CMIT, CMI, MCI) |
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* ] (CMIT, CMI, MCI) |
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* ] (OIT, OI) |
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* ] (OIT, OI) |
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* ] (DCOIT, DCOI) |
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* ] (DCOIT, DCOI) |
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* ] (BBIT) |
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These compounds all exhibit ] properties. They are used to control ], ], and ] in ], ], ] and ] water systems, ] systems, ], and some paints. They are ] agents. They are frequently used in ]s and other ] products.<ref>{{cite journal | author = Collier PJ. Ramsey A. Waigh RD. Douglas KT. Austin P. Gilbert P. | title = Chemical reactivity of some isothiazolone biocides | journal = Journal of Applied Bacteriology | volume = 69 | pages = 578–584 | year = 1990 | pmid = 2292521 | issue = 4 | doi = 10.1111/j.1365-2672.1990.tb01551.x| last2 = Ramsey | last3 = Waigh | last4 = Douglas | last5 = Austin | last6 = Gilbert }}</ref><ref>{{cite journal|title=Cosmetic Ingredient Review. Final Report on the Safety Assessment of Methylisothiazolinone and Methylchloroisothiazolinone|journal=Journal of the American College of Toxicology |year=1992|volume=11|issue=1|pages=75–128|doi=10.3109/10915819209141993|s2cid= 208506926|doi-access=free}}</ref> |
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The derivative ] (BBIT) also exists, but does not have the same importance. |
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] (CMIT) and 2-methyl-4-isothiazolin-3-one (methylisothiazolinone or MIT) are popular derivatives. A 3:1 mixture of CMIT:MIT is sold as ''Kathon''. Kathon is supplied as a concentrated stock solution containing from 1.5 to 15% of CMIT/MIT. For applications the recommended use level is from 6 ppm to 75 ppm active isothiazolones. |
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== Applications == |
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Isothiazolinones are ]s used to control ], ], and ] in ], ], ] and ] water systems, ] systems, ] and ] agents. They are frequently used in ] products such as ]s and other ] products, as well as certain ] formulations. Often, combinations of MIT and CMIT (known as ''Kathon CG'') or MIT and BIT are used. |
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4,5-Dichloro-2-n-octyl-4-isothiazolino-3-one (DCOI or Sea-Nine 211) is used especially as an ], i.e. paint for ship hulls to prevent the formation of barnacles, etc. |
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== Biological implications == |
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Together with their wanted function, controlling or killing ]s, isothiazolinones also have undesirable effects: They have a high aquatic ] and some derivatives (namely CMIT) can cause ] by direct contact or via the air. |
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==Safety and environmental aspects == |
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Together with their wanted function, controlling or killing ]s, isothiazolinones also have undesirable effects. Many countries are looking at partial or full bans of the substance due to the known dangers in using the biocide.<ref>https://www.biobor.com/wp-content/uploads/2021/03/CMIT-MIT-Isothiazolone-Biocide-Assessment.pdf {{Bare URL PDF|date=March 2022}}</ref>{{Unreliable source?|date=December 2021}} |
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===Environmental=== |
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] |
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Isothiazolinones have a high aquatic ].<ref>{{cite journal |doi=10.1684/ejd.2016.2951|title=Contact allergy caused by isothiazolinone derivatives: An overview of non-cosmetic and unusual cosmetic sources|year=2017|last1=Aerts|first1=Olivier|last2=Goossens|first2=An|last3=Lambert|first3=Julien|last4=Lepoittevin|first4=Jean-Pierre|journal=European Journal of Dermatology|volume=27|issue=2|pages=115–122|pmid=28174143|s2cid=43605688|doi-access=free}}</ref> DCOI has been detected in both port water and sediment samples in Osaka, Japan, especially in weakly circulating mooring areas.<ref>{{cite journal | author = Harino H. Mori Y. Yamaguchi Y. Shibata K. Senda T. | title = Monitoring of antifouling booster biocides in water and sediment from the port of Osaka, Japan | journal = Arch Environ Contam Toxicol | volume = 48 | issue = 3 | pages = 303–310 | year = 2005 | doi = 10.1007/s00244-004-0084-2 | pmid = 15750770| last2 = Mori | last3 = Yamaguchi | last4 = Shibata | last5 = Senda | bibcode = 2005ArECT..48..303H | s2cid = 44939806 }}</ref> DCOI levels threaten to various ]s.<ref>{{cite journal | author = Bellas J. | title = Comparative toxicity of alternative antifouling biocides on embryos and larvae of marine invertebrates | journal = Sci Total Environ | year = 2006 | doi = 10.1016/j.scitotenv.2006.01.028 | volume = 367 | issue = 2–3 | pages = 573–85 | pmid = 16545431| bibcode = 2006ScTEn.367..573B }}</ref> Isothiazolinones also are extremely toxic to fish.<ref name="ReferenceA">Rohm and Haas, Toxicology Department, “Evaluation of the toxicity of Kathon biocide,” August, 1984</ref> |
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] |
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] |
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===Dermatitis=== |
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] |
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In 2014 the European Commission Scientific Committee on Consumer Safety reported: |
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"The dramatic rise in the rates of reported cases of contact allergy to MI, as detected by diagnostic patch tests, is unprecedented in Europe; there have been repeated warnings about the rise (Gonçalo M, Goossens A. 2013). The increase is primarily caused by increasing consumer exposure to MI from cosmetic products; exposures to MI in household products, paints and in the occupational setting also need to be considered. The delay in re-evaluation of the safety of MI in cosmetic products is of concern to the SCCS; it has adversely affected consumer safety."<ref name=SCCS2014/> |
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"It is unknown what proportion of the general population is now sensitized to MI and has not been confirmed as sensitized."<ref name=SCCS2014>{{citation |url=http://ec.europa.eu/health/scientific_committees/consumer_safety/docs/sccs_o_145.pdf |title=SCCS (Scientific Committee on Consumer Safety), Opinion on Methylisothiazolinone (P94) – Submission II, 12 December 2013, SCCS/1521/13, revision of 27 March 2014}}</ref> In 2014, the European Commission Scientific Committee on Consumer Safety further issued a voluntary ban on "the mixture of Methylchloroisothiazolinone (and) Methylisothiazolinone (MCI/MI) from leave-on products such as body creams. The measure is aimed at reducing the risk from and the incidence of skin allergies. The preservative can still be used in rinse-off products such as shampoos and shower gels at a maximum concentration of 0.0015 % of a mixture in the ratio 3:1 of MCI/MI. The measure will apply for products placed on the market after 16 July 2015."<ref>{{Cite web|url=http://europa.eu/rapid/press-release_IP-14-1051_en.htm|title=European Commission – PRESS RELEASES – Press release – Consumers: Commission improves safety of cosmetics|website=europa.eu|access-date=2016-08-10}}</ref> Shortly thereafter, Canada moved to adopt similar measures in its Cosmetic Ingredients Hotlist.<ref>{{Cite web|url=http://www.hc-sc.gc.ca/cps-spc/cosmet-person/hot-list-critique/changes-modifications-eng.php|title=Health Canada – "December 2015 Changes to the Cosmetic Ingredient Hotlist"|last=|first=|date=2005-09-13|website=|publisher=|access-date=}}</ref> Additionally, new research into cross reactivity of MI-sensitized patients to variants ] and ] have found that reactions may occur if present in sufficient amounts.<ref>{{Cite journal|last1=Schwensen|first1=J. F.|last2=Menné Bonefeld|first2=C.|last3=Zachariae|first3=C.|last4=Agerbeck|first4=C.|last5=H.Petersen|first5=T|last6=Geisler|first6=C.|last7=E.Bollmann|first7=U|last8=Bester|first8=K.|last9=D.Johansen|first9=J|date=2016-06-01|title=Cross-reactivity between methylisothiazolinone, octylisothiazolinone and benzisothiazolinone using a modified local lymph node assay|journal=British Journal of Dermatology|volume=176|issue=1|language=en|pages=176–183|doi=10.1111/bjd.14825|pmid=27343839|s2cid=207075221 |issn=1365-2133}}</ref> |
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== Allergic contact dermatitis == |
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Methylisothiazolinone is used commonly in products in conjunction with ], a mixture sold under the registered trade name Kathon CG. A common indication of sensitivity to Kathon CG is ]. Sensitization to this family of preservatives was observed as early as the late 1980s.The use of isothiazolinone-based preservatives has resulted in many incidences of contact allergy. In 2013 the substance was declared the ''2013 Contact Allergen of the Year'' by the American Contact Dermatitis Society.<ref name=Castanedo>{{Cite journal |
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| last1 = Castanedo-Tardana | first1 = M. P. |
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| last2 = Zug | first2 = K. A. |
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| title = Methylisothiazolinone |
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| journal = Dermatitis: Contact, Atopic, Occupational, Drug |
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| volume = 24 |
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| issue = 1 |
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| pages = 2–6 |
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| year = 2013 |
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| doi = 10.1097/DER.0b013e31827edc73 |
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| pmid = 23340392 |
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| pmc = |
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| s2cid = 220573338 |
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}}</ref> In 2016 the Dermatitis Academy launched a call to action for patients to report their isothiazolinone allergy to the FDA.<ref></ref> |
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On December 13, 2013, the trade group, Cosmetics Europe,<ref></ref> following discussions with the European Society of Contact Dermatitis (ESCD),<ref>{{Cite web |url=http://www.escd.org/aims/ |title=European Society of Contact Dermatitis |access-date=2014-07-10 |archive-url=https://web.archive.org/web/20140714125525/http://www.escd.org/aims/ |archive-date=2014-07-14 |url-status=dead }}</ref> recommended to its members "that the use of Methylisothiazolinone (MIT) in leave-on skin products including cosmetic wet wipes is discontinued. This action is recommended in the interests of consumer safety in relation to adverse skin reactions. It is recommended that companies do not wait for regulatory intervention under the Cosmetics Regulation but implement this recommendation as soon as feasible."<ref></ref> |
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On March 27, 2014, the European Commission's Scientific Committee on Consumer Safety issued an opinion on the safety of Methylisothiazolinone. This report only considered the issue of contact sensitization. The committee concluded: |
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“Current clinical data indicate that 100 ppm MI in cosmetic products is not safe for the consumer. |
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"For leave-on cosmetic products (including ‘wet wipes’), no safe concentrations of MI for induction of contact allergy or elicitation have been adequately demonstrated. |
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"For rinse-off cosmetic products, a concentration of 15 ppm (0.0015%) MI is considered safe for the consumer from the view of induction of contact allergy. However, no information is available on elicitation.”<ref>European Commission Scientific Committee on Consumer Safety Opinion on Methylisothiazolinone (P94) Submission II (Sensitization only) SCCS/1521/13 </ref> |
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Colgate-Palmolive had added it as an ingredient in a mouthwash put onto the market in August 2014 with the name Colgate Total Lasting White.<ref>Abrams, Rachel, '''', The New York Times, January 23, 2015, and in the print edition of the New York edition, as ''An Unexpected Reaction'', January 24, 2015, p. B1</ref> |
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In industrial use, the greatest occupational inhalation exposure occurs during open pouring. Non-occupational exposure to isothiazolinones by the general population also occurs, albeit at much lower concentrations.<ref>U.S. Environmental Protection Agency (1998). R.E.D. Facts, Methylisothiazolinone. Publication EPA-738-F-98-008</ref> These compounds are present in a number of commonly used cosmetics.<ref>{{cite journal|last1=Rastogi SC|title=Kathon CG and cosmetic products|journal=Contact Dermatitis|year=1990|volume=22|pages=155–160|doi=10.1111/j.1600-0536.1990.tb01551.x|pmid=2335088|first1=SC|issue=3|s2cid=9575020}}</ref> |
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==References== |
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{{Reflist}} |
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==External links== |
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*{{Commonscatinline|Isothiazolinone}} |
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