Icaridin: Difference between revisions

| Verifiedfields = changed

| verifiedrevid = 446677390

| ImageFileL1 = IcaridinSVG.svg

| PIN = Butan-2-yl 2-(2-hydroxyethyl)piperidine-1-carboxylate

| OtherNames= {{bulletedlist|KBR 3023| Hydroxyethyl isobutyl piperidine carboxylate | ''sec''-Butyl 2-(2-hydroxyethyl)piperidine-1-carboxylate }}

|Section1={{Chembox Identifiers

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = N51GQX0837

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 2104314

| CASNo_Ref = {{cascite|correct|??}}

| SMILES = O=C(OC(C)CC)N1C(CCO)CCCC1

| PubChem=125098

|Section2={{Chembox Properties

| C=12 | H=23 | N=1 | O=3

| Appearance = colorless liquid

| Odor = odorless

| Density = 1.07 g/cm³

| MeltingPtC = -170

| BoilingPtC = 296

| Solubility = 0.82 g/100 mL

| SolubleOther = 752 g/100mL ([[acetone]])

| RefractIndex = 1.4717

'''Icaridin''', also known as '''picaridin''', is an [[insect repellent]] which can be used directly on skin or clothing.<ref name=":1">{{Cite web|url=http://npic.orst.edu/ingred/picaridin.html|title=Picaridin|website=npic.orst.edu|access-date=2020-03-29}}</ref> It has broad efficacy against various arthropods such as mosquitos, ticks, gnats, flies and fleas, and is almost colorless and odorless. A study performed in 2010 showed that picaridin spray and cream at the 20% concentration provided 12 hours of protection against ticks.<ref>https://archive.epa.gov/hsrb/web/pdf/2a_lnx003_primary_report_mrid_480538011.pdf {{Bare URL PDF|date=March 2022}}</ref> Unlike [[DEET]], icaridin does not dissolve plastics, synthetics or sealants,<ref>[https://web.archive.org/web/20110809050453/http://www.picaridin.com/science.htm Picaridin]. Archived from [http://www.picaridin.com/science.htm the original] on August 9, 2011.</ref> is odorless and non-greasy<ref>{{cite web |title=Picaridin vs DEET: Which Is the Best Insect Repellent? |url=https://www.outdoors.org/resources/amc-outdoors/outdoor-resources/picaridin-vs-deet-which-is-the-best-insect-repellent/ |publisher=Appalachian Mountain Club |access-date=7 August 2023 |date=4 August 2023}}</ref> and presents a lower risk of toxicity when used with sunscreen, as it may reduce skin absorption of both compounds.<ref>{{Cite journal |vauthors=Rodriguez J, Maibach HI |date=2016-01-02 |title=Percutaneous penetration and pharmacodynamics: Wash-in and wash-off of sunscreen and insect repellent |url=https://www.tandfonline.com/doi/full/10.3109/09546634.2015.1050350 |journal=Journal of Dermatological Treatment |volume=27 |issue=1 |pages=11–18 |doi=10.3109/09546634.2015.1050350 |pmid=26811157 |s2cid=40319483 |issn=0954-6634}}</ref>

The name ''picaridin'' was proposed as an [[International Nonproprietary Name]] (INN) to the [[World Health Organization]] (WHO), but the official name that has been approved by the [[WHO]] is ''icaridin''. The chemical is part of the [[piperidine]] family,<ref name=":1" /> along with many pharmaceuticals and [[alkaloid]]s such as [[piperine]], which gives [[black pepper]] its spicy taste.

Trade names include '''Bayrepel''' and '''Saltidin''' among others. The compound was developed by the German chemical company [[Bayer]] in the 1980s <ref>{{cite web |url=http://npic.orst.edu/factsheets/archive/Picaridintech.html |website=National Pesticide information Center |title=Picaridin Technical Fact Sheet }}</ref> and was given the name ''Bayrepel''. In 2005, [[Lanxess]] AG and its subsidiary Saltigo GmbH were spun off from Bayer<ref>{{cite web|url=http://www.azom.com/news.aspx?newsID=2476|title=Bayer Completes Spin Off of Lanxess AG|date=31 January 2005}}</ref> and the product was renamed ''Saltidin'' in 2008.<ref>[http://cen.acs.org/articles/86/i20/Saltigo-Renames-Insect-Repellant.html Saltigo renames insect repellant], [[Chemical & Engineering News]]</ref>

Having been sold in Europe since 1998,<ref>{{cite web |title=Icaridin - an overview |url=https://www.sciencedirect.com/topics/nursing-and-health-professions/icaridin |website=ScienceDirect |access-date=29 December 2023}}</ref> on 23 July 2020, icaridin was approved again by the EU Commission for use in repellent products. The approval entered into force on 1 February 2022 and is valid for ten years.<ref>{{Cite web|title=Commission Implementing Regulation (EU) 2020/1086 of 23 July 2020 approving icaridin as an existing active substance for use in biocidal products of product-type 19.|url=https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32020R1086&qid=1598456259170&from=EN|access-date=31 August 2020}}</ref>

== Effectiveness ==

Icaridin and [[DEET]] are the most effective insect repellents available. A 2018 systematic review found no consistent performance difference between icaridin and DEET in [[Field research|field studies]] and concluded that they are equally preferred mosquito repellents, noting that 50% DEET offers longer protection but is not available in some countries.<ref>{{Cite journal |last1=Goodyer |first1=Larry |last2=Schofield |first2=Steven |date=2018-05-01 |title=Mosquito repellents for the traveller: does picaridin provide longer protection than DEET? |url=https://academic.oup.com/jtm/article/25/suppl_1/S10/4990399 |journal=Journal of Travel Medicine |language=en |volume=25 |issue=Suppl_1 |pages=S10–S15 |doi=10.1093/jtm/tay005 |pmid=29718433 |issn=1708-8305|doi-access=free }}</ref>

Icaridin has been reported to be as effective as DEET at a 20% concentration without the irritation associated with DEET.<ref name="undefined">Journal of Drugs in Dermatology (Jan-Feb 2004) http://jddonline.com/articles/dermatology/S1545961604P0059X/1</ref><ref>{{cite journal | vauthors = Van Roey K, Sokny M, Denis L, Van den Broeck N, Heng S, Siv S, Sluydts V, Sochantha T, Coosemans M, Durnez L | display-authors = 6 | title = Field evaluation of picaridin repellents reveals differences in repellent sensitivity between Southeast Asian vectors of malaria and arboviruses | journal = PLOS Neglected Tropical Diseases | volume = 8 | issue = 12 | pages = e3326 | date = December 2014 | pmid = 25522134 | pmc = 4270489 | doi = 10.1371/journal.pntd.0003326 | doi-access = free }}</ref> According to the WHO, icaridin “demonstrates excellent repellent properties comparable to, and often superior to, those of the standard DEET.”

Icaridin-based products have been evaluated by ''[[Consumer Reports]]'' in 2016 as among the most effective insect repellents when used at a 20% concentration.<ref>{{cite web | url = http://www.consumerreports.org/insect-repellents/mosquito-repellents-that-best-protect-against-zika/ | title = Mosquito Repellents That Best Protect Against Zika | date = 30 May 2018 | publisher=[[Consumer Reports]], April, 2016}}</ref> Icaridin was earlier reported to be effective by ''[[Consumer Reports]]'' (7% solution)<ref>[https://web.archive.org/web/20080201140313/https://www.consumerreports.org/cro/cu-press-room/pressroom/archive/2005/07/eng0507det.htm?resultPageIndex=2&resultIndex=15&searchTerm=mosquito - Consumer Reports Confirms Effectiveness Of New Alternative To Deet] (link recreated from Wayback Machine Internet Archive - 19 May 2019)</ref> and the Australian Army (20% solution).<ref>{{cite journal | vauthors = Frances SP, Waterson DG, Beebe NW, Cooper RD | title = Field evaluation of repellent formulations containing deet and picaridin against mosquitoes in Northern Territory, Australia | journal = Journal of Medical Entomology | volume = 41 | issue = 3 | pages = 414–417 | date = May 2004 | pmid = 15185943 | doi = 10.1603/0022-2585-41.3.414 | doi-access = free }}</ref> ''Consumer Reports'' retests in 2006 gave as result that a 7% solution of icaridin offered little or no protection against ''[[Aedes]]'' mosquitoes ([[Disease vector|vector]] of [[dengue fever]]) and a protection time of about 2.5 hours against ''[[Culex]]'' (vector of West Nile virus), while a 15% solution was good for about one hour against ''Aedes'' and 4.8 hours against ''Culex''.<ref>"Insect repellents: which keep bugs at bay?" ''Consumer Reports'', June 2006, vol 71 (issue 6), p.&nbsp;6.</ref>

The United States [[Centers for Disease Control and Prevention]] recommends using repellents based on icaridin, DEET, [[ethyl butylacetylaminopropionate]] (IR3535), or oil of [[Corymbia citriodora|lemon eucalyptus]] (containing [[p-Menthane-3,8-diol|''p''-menthane-3,8-diol]], PMD) for effective protection against [[mosquito]]es that carry the [[West Nile virus]], [[Eastern Equine Encephalitis|eastern equine encephalitis]] and other illnesses.<ref>{{cite web | url = http://wwwnc.cdc.gov/travel/page/avoid-bug-bites | title = Traveler's Health: Avoid bug bites | publisher = [[Centers for Disease Control and Prevention]]}}</ref>

== Adverse effects ==

Icaridin can cause mild to moderate eye irritation on contact and is slightly toxic if ingested.<ref>{{cite web |title=Picaridin Technical Fact Sheet |url=http://npic.orst.edu/factsheets/archive/Picaridintech.html |publisher=National Pesticide Information Center |access-date=6 August 2023 |date=March 2009}}</ref>

== Environmental impact ==

A 2018 study found that a commercial repellent product containing 20% icaridin, in what the authors described as "conservative exposure doses", is highly toxic to larval salamanders, a major predator of mosquito larvae. <ref>{{cite journal | vauthors = Almeida RM, Han BA, Reisinger AJ, Kagemann C, Rosi EJ | title = High mortality in aquatic predators of mosquito larvae caused by exposure to insect repellent | journal = Biology Letters | volume = 14 | issue = 10 | pages = 20180526 | date = October 2018 | pmid = 30381452 | pmc = 6227861 | doi = 10.1098/rsbl.2018.0526 }}</ref> The study observed high larval salamander mortality occurring delayed after the four days of exposure. Because the widely used LC50 test for assessing a chemical's environmental toxicity is based on mortality within four days, the authors suggested that icaridin would be incorrectly deemed as "safe" under the test protocol.<ref>{{cite web |url=https://www.sciencedaily.com/releases/2018/10/181031080627.htm |title=Widely used mosquito repellent proves lethal to larval salamanders |agency=Cary Institute of Ecosystem Studies |date=31 October 2018 |website=Science News |publisher=ScienceDaily |access-date=12 December 2018}}</ref> However, icaridin was also non-toxic in a 21-day reproduction test on the water flea ''Daphnia magna''<ref>{{Cite web|title=ECHA - Information on biocides|url=https://echa.europa.eu/documents/10162/838cdf06-2434-4444-e464-e58107e9d49a|access-date=31 August 2020|pages=231–245}}</ref> and a 32-day early life-stage test in zebrafish.<ref>{{Cite web|title=ECHA - Information on biocides.|url=https://echa.europa.eu/documents/10162/838cdf06-2434-4444-e464-e58107e9d49a|access-date=31 August 2020|pages=220–229}}</ref>

Since only the icaridin content of the tested repellent product is known, the observed effects cannot be readily attributed to icaridin. Furthermore, the effects of the repellent product showed no dose-response relationship, i.e., there was neither an increase of the magnitude or severity of the observed effects (mortality, tail deformation), nor did the effects occur at earlier time points. The study has been regarded as invalid by the Danish Environmental Protection Agency,<ref>{{Cite web|title=ECHA - Information on biocides|url=https://echa.europa.eu/home?p_p_state=maximized&p_p_mode=view&saveLastPath=false&_58_struts_action=/login/login&p_p_id=58&p_p_lifecycle=0|access-date=2020-08-31|website=echa.europa.eu|pages=3|language=en-GB}}</ref><ref>{{Cite web|date=10 December 2019|title=Opinion on the application for approval of the active substance Icaridin, Product type: 19.|url=https://echa.europa.eu/documents/10162/dd9931c7-d32e-ef8a-6815-279c22dd9d28|access-date=31 August 2020}}</ref> which has evaluated icaridin prior to its approval under the EU Biocidal Product Regulation. The reasons for rejection were the testing of a mixture of undisclosed composition, the use of a non-standard test organism, the lack of analytical verification of actual test concentrations, and the fact that the test solution was never renewed with the 25 days of study duration.

==Mechanism of action==

In 2014, a potential odorant receptor for icaridin (and DEET), CquiOR136•CquiOrco, was suggested for ''[[Culex quinquefasciatus]]'' mosquito.<ref>{{cite journal | vauthors = Xu P, Choo YM, De La Rosa A, Leal WS | title = Mosquito odorant receptor for DEET and methyl jasmonate | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 46 | pages = 16592–16597 | date = November 2014 | pmid = 25349401 | pmc = 4246313 | doi = 10.1073/pnas.1417244111 | doi-access = free | bibcode = 2014PNAS..11116592X }}</ref>

Recent crystal and solution studies showed that icaridin binds to ''Anopheles gambiae'' odorant binding protein 1 (AgamOBP1). The crystal structure of AgamOBP1•icaridin complex (PDB: [http://www.rcsb.org/pdb/explore/explore.do?structureId=5EL2 5EL2]) revealed that icaridin binds to the DEET-binding site in two distinct orientations and also to a second binding site (sIC-binding site) located at the C-terminal region of the AgamOBP1.<ref name="Drakou, CE. et al">{{cite journal | vauthors = Drakou CE, Tsitsanou KE, Potamitis C, Fessas D, Zervou M, Zographos SE | title = The crystal structure of the AgamOBP1•Icaridin complex reveals alternative binding modes and stereo-selective repellent recognition | journal = Cellular and Molecular Life Sciences | volume = 74 | issue = 2 | pages = 319–338 | date = January 2017 | pmid = 27535661 | doi = 10.1007/s00018-016-2335-6 | s2cid = 12211128 | pmc = 11107575 }}</ref>

Recent evidence with ''[[Anopheles gambiae]]'' mosquitoes suggests icaridin does not strongly activate olfactory receptors neurons, but instead functions to reduce the volatility of the odorants to which it is mixed.<ref name=":0">{{cite journal | vauthors = Afify A, Betz JF, Riabinina O, Lahondère C, Potter CJ | title = Commonly Used Insect Repellents Hide Human Odors from Anopheles Mosquitoes | journal = Current Biology | volume = 29 | issue = 21 | pages = 3669–3680.e5 | date = November 2019 | pmid = 31630950 | pmc = 6832857 | doi = 10.1016/j.cub.2019.09.007 | bibcode = 2019CBio...29E3669A }}</ref> By reducing odor volatility, icaridin functions to "mask" the ability of volatile odorants on the skin to activate olfactory neurons and attract mosquitoes.<ref name=":0" />

Icaridin contains two [[stereocenter]]s: one where the hydroxyethyl chain attaches to the ring, and one where the [[sec-butyl|''sec''-butyl]] attaches to the oxygen of the [[carbamate]]. The commercial material contains a mixture of all four stereoisomers.

==Commercial products==

Commercial products containing icaridin include Cutter Advanced, Muskol, Repeltec,<ref>{{cite web |url=https://www.repeltec.com/}}</ref> Skin So Soft Bug Guard Plus, Off! FamilyCare, Autan, Smidge, PiActive and MOK.O.<ref>Cha, Ariana Eunjung. "[http://search.proquest.com/docview/1761035571/ Zika virus FAQ: What is it, and what are the risks as it spreads?] ''The Washington Post''. January 21, 2016.</ref>

== See also ==

* [[DEET]]

* [[Ethyl butylacetylaminopropionate]] (IR3535)

* [[Permethrin]], a [[pyrethroid]] [[insecticide]] that can be applied to clothing to help prevent bites

* [[p-Menthane-3,8-diol]] (PMD)

* [[SS220]], another substituted-piperidine insect repellent

{{reflist}}

* [http://npic.orst.edu/factsheets/PicaridinGen.html Picaridin General Fact Sheet - National Pesticide Information Center]

* [https://www3.epa.gov/pesticides/chem_search/reg_actions/registration/fs_PC-070705_01-May-05.pdf EPA fact sheet]

[[Category:Primary alcohols]]

[[Category:Sec-Butyl esters]]