Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Benzalkonium chloride: Difference between pages

{{short description|Surfactant and antiseptic agent}}

{{Chembox

|Verifiedfields = changed

|Watchedfields = changed

|verifiedrevid = 476992439

|ImageFile = Benzalkonium chloride Structure V.1.svg

|ImageSize = 220px

|OtherNames = ''N''-Alkyl-''N''-benzyl-''N'',''N''-dimethylammonium chloride; Alkyldimethylbenzylammonium chloride; ADBAC; BC50 BC80

|Section1={{Chembox Identifiers

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

|UNII = F5UM2KM3W7

|CASNo_Ref = {{cascite|correct|CAS}}

|CASNo = 8001-54-5

|CASNo_Comment = <!--and others, depending on the exact mixture-->

|EINECS = 264-151-6

|StdInChI_Ref = {{stdinchicite|changed|chemspider}}

|StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

|ChEBI_Ref = {{ebicite|changed|EBI}}

|ChEBI = 3020

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

|ChEMBL = 502109

|KEGG_Ref = {{keggcite|correct|kegg}}

|KEGG = D00857

|RTECS = BO3150000

|Section2={{Chembox Properties

|Appearance = {{ubli

|100% is white or yellow powder; gelatinous lumps;

|BC50 (50%) and BC80 (80%) solutions are colourless to pale yellow solutions.

}}

|Formula = Variable

|MolarMass = Variable

|Density = 0.98&nbsp;g/cm³

|Solubility = Very soluble

}}

|Section3={{Chembox Pharmacology

|ATCCode_prefix = D08

|ATCCode_suffix = AJ01

}}

|Section4={{Chembox Hazards

|GHSPictograms = {{GHS05}}{{GHS07}}{{GHS09}}

|GHSSignalWord = Danger

|HPhrases = {{H-phrases|302|312|314|410}}

|PPhrases = {{P-phrases|260|264|270|273|280|301+312|301+330+331|302+352|303+361+353|304+340|305+351+338|310|312|321|322|330|363|391|405|501}}

|NFPA-H = 3

|NFPA-F = 0

|NFPA-R = 0

|FlashPtC = 250

|FlashPt_notes = (if solvent based)

}}

}}

'''Benzalkonium chloride''' ('''BZK''', '''BKC''', '''BAK''', '''BAC'''), also known as '''alkyldimethylbenzylammonium chloride''' ('''ADBAC''') and by the trade name '''Zephiran''',<ref name="sanofi-zeph">{{cite web |title=Zephiran (benzalkonium chloride) |url=http://products.sanofi.us/zephiran/zephiran.pdf |publisher=Sanofi |access-date=28 April 2020}}</ref> is a type of [[Surfactant#Cationic head groups|cationic surfactant]]. It is an organic [[salt (chemistry)|salt]] classified as a [[quaternary ammonium compound]]. ADBACs have three main categories of use: as a [[biocide]], a [[cationic]] [[surfactant]], and a [[phase transfer agent]].<ref>Maximilian Lackner, Josef Peter Guggenbichler "Antimicrobial Surfaces" Ullmann's Encyclopedia of Industrial Chemistry, Wiley-VCH, Weinheim, 2013. {{doi|10.1002/14356007.q03_q01}}</ref> ADBACs are a [[mixture]] of alkylbenzyldimethylammonium chlorides, in which the alkyl group has various even-numbered alkyl chain lengths.

== Solubility and physical properties ==

Depending on purity, benzalkonium chloride ranges from colourless to a pale yellow (impure). Benzalkonium chloride is readily soluble in [[ethanol]] and [[acetone]]. Dissolution in water is ready, upon agitation. Aqueous solutions should be neutral to slightly alkaline. Solutions foam when shaken. Concentrated solutions have a bitter taste and a faint almond-like odour.{{citation needed|date=June 2021}}

Standard concentrates are manufactured as 50% and 80% w/w solutions, and sold under trade names such as BC50, BC80, BAC50, BAC80, etc. The 50% solution is purely aqueous, while more concentrated solutions require incorporation of [[rheology]] modifiers ([[Alcohol (chemistry)|alcohol]]s, [[polyethylene glycol]]s, etc.) to prevent increases in viscosity or gel formation under low temperature conditions.

== Cationic surfactant ==

Benzalkonium chloride possesses surfactant properties, dissolving the lipid phase of the tear film and increasing drug penetration, making it a useful [[excipient]], but at the risk of causing damage to the surface of the eye.<ref>{{cite book|last1=Bartlett|first1=J|title=Clinical Ocular Pharmacology|url=https://books.google.com/books?id=Eybg7fbs65MC&q=benzalkonium%20chloride%20and%20other%20surfactant|publisher=Elsevier|year=2013|isbn=978-1-483-19391-5|edition=2|page=20}}<!--ISBN 1-483-19391-8, ISBN 978-1-483-19391-5 --></ref>

* Laundry detergents and treatments.

* Softeners for textiles.

== Phase transfer agent ==

{{main|Phase transfer catalysis}}

Benzalkonium chloride is a mainstay of phase-transfer catalysis, an important technology in the synthesis of organic compounds, including drugs.{{cn|date=September 2023}}

== Bioactive agents ==

Especially for its antimicrobial activity, benzalkonium chloride is an active ingredient in many consumer products:

* Pharmaceutical products such as [[eye drop|eye]], [[ear drop|ear]] and nasal drops or [[nasal spray|sprays]], as a preservative.

* Personal care products such as [[hand sanitizer]]s, [[wet wipe]]s, [[shampoo]]s, [[soap]]s,<ref>Ingredient indicated on [[Dial (soap)|Dial brand soap]] wrapper: "Benzalkonium chloride 0.10%". Henkel Corporation, Rocky Hill, CT 06067, USA. © 2018. Retrieved: 2023-06-06.</ref> deodorants and cosmetics.<ref>{{Cite web|title=Benzalkonium Chloride {{!}} Cosmetics Info|url=https://cosmeticsinfo.org/ingredient/benzalkonium-chloride-0|access-date=2021-03-10|website=cosmeticsinfo.org|archive-date=2020-11-01|archive-url=https://web.archive.org/web/20201101003110/https://www.cosmeticsinfo.org/ingredient/benzalkonium-chloride-0|url-status=dead}}</ref>

* Skin antiseptics and wound wash sprays, such as [[Bactine]].<ref>{{Cite web|url=https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ea1ad81e-b658-4ba8-b78e-6acbfb9a8622&type=display|title=Bactine® Pain Relieving Cleansing Spray|website=dailymed.nlm.nih.gov|access-date=2020-03-04}}</ref><ref>{{Cite web|url=https://www.skinsafeproducts.com/bactine-original-first-aid-liquid-4-fl-oz|title=Bactine Original First Aid Liquid, 4 fl oz Ingredients and Reviews|website=SkinSAFE|language=en|access-date=2020-03-04}}</ref>

* Throat lozenges<ref>{{cite web|url=http://www.nhs.uk/medicine-guides/pages/MedicineOverview.aspx?medicine=Bradosol%20Sugar%20Free%20lozenges|title=Bradosol|access-date=2013-05-20|archive-url=https://web.archive.org/web/20141012085200/http://www.nhs.uk/medicine-guides/pages/MedicineOverview.aspx?medicine=Bradosol%20Sugar%20Free%20lozenges|archive-date=2014-10-12|url-status=dead}}</ref> and [[mouthwash]]es, as a biocide

* [[Spermicide|Spermicidal]] creams.

* Cleaners for floor and hard surfaces as a disinfectant, such as [[Lysol]] and [[Dettol]] antibacterial spray and wipes.

* [[Algaecide]]s for clearing of algae, moss, lichens from paths, roof tiles, swimming pools, masonry, etc.

Benzalkonium chloride is also used in many non-consumer processes and products, including as an active ingredient in surgical disinfection. A comprehensive list of uses includes industrial applications.<ref>{{cite book|last1=Ash|first1=M|title=Handbook of Preservatives|last2=Ash|first2=I|publisher=Synapse Info Resources|year=2004|isbn=978-1-890-59566-1|page=286}}<!--ISBN 1-890-59566-7, ISBN 978-1-890-59566-1 --></ref>

During the course of the [[COVID-19 pandemic]], from time to time there have been shortages of hand cleaner containing [[ethanol]] or [[Isopropyl alcohol|isopropanol]] as active ingredients. The FDA has stated that benzalkonium chloride is eligible as an alternative for use in the formulation of healthcare personnel hand rubs.<ref>{{cite web|url=https://www.fda.gov/about-fda/economic-impact-analyses-fda-regulations/safety-and-effectiveness-health-care-antiseptics-topical-antimicrobial-drug-products-over-counter|title=Safety and Effectiveness for Health Care Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use (Final Rule)|website=U.S. Food and Drug Administration|date=20 December 2017}}</ref> However, in reference to the FDA rule, the CDC states that it does not have a recommended alternative to ethanol or isopropanol as active ingredients, and adds that "available evidence indicates benzalkonium chloride has less reliable activity against certain bacteria and viruses than either of the alcohols."<ref>{{cite web|url=https://www.cdc.gov/coronavirus/2019-ncov/hcp/hand-hygiene.html|title=Hand Hygiene Recommendations; Guidance for Healthcare Providers about Hand Hygiene and COVID-19|website=Centers for Disease Control and Prevention|date=17 May 2020}}</ref> In November 2020 the ''Journal of Hospital Infection'' published a study on benzalkonium chloride formulations; it was found that laboratory and commercial disinfectants with as little as 0.13% benzalkonium chloride inactivated the SARS-CoV-2 virus within 15 seconds of contact, even in the presence of a soil or hard water.<ref name="Ogilvie">{{Cite journal

|last1=Ogilvie|first1=Benjamin|last2=Solis-Leal|first2=Antonio|date=November 28, 2020|title=Alcohol-free hand sanitizer and other quaternary ammonium disinfectants quickly and effectively inactivate SARS-CoV-2|url=https://www.journalofhospitalinfection.com/article/S0195-6701(20)30547-8/fulltext|journal=Journal of Hospital Infection|volume=108|pages=142–145|doi=10.1016/j.jhin.2020.11.023|pmid=33259880|pmc=7700010|issn=0195-6701|doi-access=free}}</ref> This resulted in a growing consensus that BZK sanitizers are just as effective as alcohol-based sanitizers despite the CDC guidelines.<ref>{{Cite news|last=Hollingshead|first=Todd|date=December 1, 2020|title=Alcohol-free hand sanitizer just as effective against COVID as alcohol-based versions|work=EurekAlert!|publisher=AAAS|publication-place=BRIGHAM YOUNG UNIVERSITY|url=https://www.eurekalert.org/pub_releases/2020-12/byu-ahs120120.php|access-date=December 14, 2020}}</ref> As a hand sanitizer, use of BZK may be advantageous over ethanol in some situations because it has significantly more residual antibacterial action on the skin after initial application.<ref>{{Cite journal|last1=Bondurant|first1=Sidney W.|last2=Duley|first2=Collette M.|last3=Harbell|first3=John W.|date=August 2019|title=Demonstrating the persistent antibacterial efficacy of a hand sanitizer containing benzalkonium chloride on human skin at 1, 2, and 4 hours after application|journal=American Journal of Infection Control|volume=47|issue=8|pages=928–932|doi=10.1016/j.ajic.2019.01.004|issn=1527-3296|pmid=30777389|doi-access=free}}</ref> Benzalkonium chloride has demonstrated persistent antimicrobial activity for up to four hours after contact whereas ethanol-based sanitizer demonstrate skin protection for only 10 minutes post-application.<ref>{{Cite web|last=Reporter|first=JAMES ROSEN, Sinclair Investigative|date=2020-04-01|title=EXCLUSIVE: Sanitizer opposed by CDC kills coronavirus "surrogate" in lab tests|url=https://wjla.com/news/nation-world/exclusive-sanitizer-opposed-by-cdc-kills-coronavirus-surrogate-in-lab-tests|access-date=2021-03-16|website=WJLA}}</ref>

=== Medicine ===

Benzalkonium chloride is a frequently used preservative in [[eye drops]]; typical concentrations range from 0.004% to 0.01%.<ref>{{Cite web|date=22 October 2021|title=Quats applications - Ophthalmics|url=https://novonordiskpharmatech.com/products/ophthalmics/|url-status=live|archive-url=https://web.archive.org/web/20170517223151/http://novonordiskpharmatech.com:80/products/ophthalmics/ |archive-date=2017-05-17 }}</ref> Stronger concentrations can be caustic<ref name="Goldfrank">{{cite book|last1=Nelson|first1=L|title=Goldfrank's Toxicologic Emergencies|last2=Goldfrank|first2=L|publisher=McGraw-Hill Medical|year=2011|isbn=978-0-071-60593-9|edition=9|page=803}}<!--ISBN 0-071-60593-2, ISBN 978-0-071-60593-9 --></ref> and cause irreversible damage to the [[corneal endothelium]].<ref>{{cite book |title=Inflammatory Diseases of the Conjunctiva |last1=Baudouin |first1=C |last2=Creuzot-Garcher |first2=C |last3=Hoang-Xuan |first3=T |edition=1, illustrated |publisher=Thieme |year=2001 |isbn=978-3-131-25871-7 |page=141}}</ref>

Avoiding the use of benzalkonium chloride solutions while contact lenses are in place is discussed in the literature.<ref>{{cite journal | last1 = Otten | first1 = Mary | last2 = Szabocsik | first2 = John M. | title = Measurement of Preservative Binding with SOFLENS (polymacon) Contact Lens | journal = Clinical and Experimental Optometry | volume = 59 | issue = 8 | pages = 277 | year = 1976 | doi = 10.1111/j.1444-0938.1976.tb01445.x}}</ref><ref>M Akers, "Consideration in selecting antimicrobial preservative agents for parenteral product development", Pharmaceutical Technology, May, p. 36 (1984).</ref>

Due to its antimicrobial activity<ref>{{Cite patent|title=Antimicrobial compositions and methods for using the same|fdate=1996-12-03|country=US|number=5827870|pubdate=1998-10-27|assign=Woodward Laboratories Inc.|inventor1-last=Chodosh|inventor1-first=Daniel Frank}}</ref> when applied to skin, some topical [[pimple#trearment|medications]] for [[acne|acne vulgaris]] have benzalkonium chloride added to increase the products' efficiency or shelf-life.<ref>{{Cite patent|title=Composition containing anti-acne agent and method of using the same|fdate=2005-07-06|pubdate=2012-10-10|country=JP|number=5047476|inventor1-first=Jeffrey M.|inventor1-last=Wu|inventor2-first=Jue-Chen|inventor2-last=Liu|inventor3-first=Jeanette|inventor3-last=Chantalat|inventor4= SUN YING; JOHNSEN STEFANIE A; JAMPANI HANUMAN B

|assign= [[Johnson & Johnson]]}}</ref><ref>{{Cite journal|title=New Combination Acne Treatment Safe and Effective|url=https://www.pharmacytimes.com/view/2006-06-5628|access-date=2021-03-10|journal=Pharmacy Times|date=June 2006 |last1=Farley |first1=Susan }}</ref>

Benzalkonium chloride has also been shown to be a spermicide.<ref>{{Cite web|date=22 October 2021|title=Benzalkonium Chloride - Contraception formulations|url=https://novonordiskpharmatech.com/products/benzalkonium-chloride-bkcbacbak/|url-status=live|archive-url=https://web.archive.org/web/20170515233331/http://novonordiskpharmatech.com:80/products/benzalkonium-chloride-bkcbacbak/ |archive-date=2017-05-15 }}</ref> In Russia and China, benzalkonium chloride is used as a [[contraceptive]]. Tablets are inserted vaginally, or a gel is applied, resulting in local [[spermicide|spermicidal]] contraception.<ref>{{Cite web|url=http://www.isrctn.com/ISRCTN16203579|title=ISRCTN - ISRCTN16203579: Effectiveness of BenZalKonium chloride gel as vaginal contraceptive: a multicentric randomised controlled trial|website=www.isrctn.com}}</ref><ref>{{Cite journal|title=Effectiveness of an optimized benzalkonium chloride gel as vaginal contraceptive: a randomized controlled trial among Chinese women |first1=Weihua |last1=Li |first2=Zirong |last2=Huang |first3=Yu |last3=Wu |first4=Haiyun |last4=Wang |first5=Xiaobo |last5=Zhou |first6=Zhiqin |last6=Xia o|first7=Xuncheng |last7=Ding |first8=Jinxun |last8=Xu |date=June 26, 2013 |journal=Contraception |volume=87 |issue=6 |pages=756–765|doi=10.1016/j.contraception.2012.09.012|pmid=23089047}}</ref> It is not a wholly reliable method, and can cause irritation.

=== Beekeeping ===

This chemical is used in beekeeping for the treatment of rotten diseases of the brood.<ref>{{Cite web|url=https://36i6.info/benzalkoniya-hlorid-benzalkonium-chloride/|title=БЕНЗАЛКОНИЯ ХЛОРИД (benzalkonium chloride) действующее вещество {{!}} 36i6.info|date=2017-04-15|website=36i6.info|language=ru-RU|access-date=2019-08-28|archive-date=2019-08-28|archive-url=https://web.archive.org/web/20190828145153/https://36i6.info/benzalkoniya-hlorid-benzalkonium-chloride/|url-status=dead}}</ref>

=== Adverse effects ===

Although historically benzalkonium chloride has been ubiquitous as a preservative in ophthalmic preparations, its ocular toxicity and irritant properties,<ref>{{cite journal |last1 = Baudouin |first1 = C |last2 = Labbé |first2 = A |last3 = Liang |first3 = H |last4 = Pauly |first4 = A |last5 = Brignole-Baudouin |first5 = F |s2cid = 24575844 |title = Preservatives in eyedrops: the good, the bad and the ugly |journal = Prog Retin Eye Res |volume = 29 |issue = 4 |pages = 312–34 |year = 2010 |pmid = 20302969 |doi=10.1016/j.preteyeres.2010.03.001}}</ref> in conjunction with consumer demand, have led pharmaceutical companies to increase production of preservative-free preparations, or to replace benzalkonium chloride with preservatives which are less harmful.<ref name="pmid34262161">{{cite journal | vauthors = Goldstein MH, Silva FQ, Blender N, Tran T, Vantipalli S | title = Ocular benzalkonium chloride exposure: problems and solutions | journal = Eye (Lond) | volume = 36 | issue = 2 | pages = 361–368 | date = February 2022 | pmid = 34262161 | pmc = 8277985 | doi = 10.1038/s41433-021-01668-x }}</ref>

Many mass-marketed inhaler and nasal spray formulations contain benzalkonium chloride as a preservative, despite substantial evidence that it can adversely affect [[cilia]]ry motion, [[mucociliary clearance]], nasal mucosal histology, human [[neutrophil]] function, and [[leukocyte]] response to local [[inflammation]].<ref name="Diseases of the Sinuses">{{cite book|last1=Kennedy|first1=D W|url=https://books.google.com/books?id=PARW6eQnpE8C&pg=PA162|title=Diseases of the Sinuses Diagnosis and Management|last2=Bolger|first2=W E|last3=Zinreich|first3=S J|publisher=B.C. Decker Inc.|year=2001|isbn=978-1-550-09045-1|page=162}}<!--ISBN 1-550-09045-3, ISBN 978-1-550-09045-1 --></ref> Although some studies have found no correlation between use of benzalkonium chloride in concentrations at or below 0.1% in nasal sprays and [[rhinitis medicamentosa|drug-induced rhinitis]],<ref name="Marple">{{cite journal |last1 = Marple |first1 = B |last2 = Roland |first2 = P |last3 = Benninger |first3 = M |s2cid = 24967410 |title = Safety review of benzalkonium chloride used as a preservative in intranasal solutions: an overview of conflicting data and opinions |journal = Otolaryngology–Head and Neck Surgery |volume = 130 |issue = 1 |pages = 131–41 |year = 2004 |pmid = 14726922 |doi = 10.1016/j.otohns.2003.07.005}}</ref> others have recommended that benzalkonium chloride in nasal sprays be avoided.<ref>{{cite journal |last1 = Beule |first1 = A. G. |title = Physiology and pathophysiology of respiratory mucosa of the nose and the paranasal sinuses |journal = GMS Current Topics in Otorhinolaryngology, Head and Neck Surgery |volume = 9 |pages = Doc07 |year = 2010 |pmid = 22073111 |doi= 10.3205/cto000071 |pmc=3199822 }}</ref><ref>{{cite journal |last1 = Graf |first1 = P |s2cid = 25175067 |title = Rhinitis medicamentosa: a review of causes and treatment. |journal = Treatments in Respiratory Medicine |volume = 4 |issue = 1 |pages = 21–9 |year = 2005 |pmid = 15725047 |doi=10.2165/00151829-200504010-00003}}</ref> In the United States, [[nasal steroid]] preparations that are free of benzalkonium chloride include [[budesonide]], [[triamcinolone acetonide]], [[dexamethasone]], and Beconase and Vancenase aerosol inhalers.<ref name="Diseases of the Sinuses" />

Benzalkonium chloride is an irritant to middle ear tissues at typically used concentrations. Inner ear toxicity has been demonstrated.<ref>{{cite book|last1=Snow|first1=J. B.|title=Ballenger's Otorhinolaryngology: Head and Neck Surgery|last2=Wackym|first2=P. A.|publisher=PMPH-USA|year=2009|isbn=978-1-550-09337-7|edition=revised|page=277}}<!--ISBN 1-550-09337-1, ISBN 978-1-550-09337-7 --></ref>

Occupational exposure to benzalkonium chloride has been linked to the development of asthma.<ref>{{cite book|last1=Malo|first1=J|title=Asthma in the Workplace|last2=Chan-Yeung|first2=M|last3=Bernstein|first3=D I|publisher=CRC Press|year=2013|isbn=978-1-842-14591-3|edition=4, illustrated, revised|page=198}}<!--ISBN 1-842-14591-6, ISBN 978-1-842-14591-3 --></ref> In 2011, a large clinical trial designed to evaluate the efficacy of hand sanitizers based on different active ingredients in preventing virus transmission amongst schoolchildren was re-designed to exclude sanitizers based on benzalkonium chloride due to safety concerns.<ref name="Gerald Gerald McClure Harrington 2011 pp. 311–319">{{cite journal |last1=Gerald |first1=Lynn B |last2=Gerald |first2=Joe K |last3=McClure |first3=Leslie A |last4=Harrington |first4=Kathy |last5=Erwin |first5=Sue |last6=Bailey |first6=William C |title=Redesigning a large school-based clinical trial in response to changes in community practice |journal=Clinical Trials: Journal of the Society for Clinical Trials |volume=8 |issue=3 |year=2011 |issn=1740-7745 |doi=10.1177/1740774511403513 |pages=311–319 |pmid=21730079 |pmc=3145214}}</ref>

Benzalkonium chloride has been in common use as a pharmaceutical preservative and antimicrobial since the 1940s. While early studies confirmed the corrosive and irritant properties of benzalkonium chloride, investigations into the adverse effects of, and disease states linked to, benzalkonium chloride have only surfaced during the past 30 years. {{Citation needed|reason=Cites years and general statement without any backing|date=August 2020}}

== Toxicology ==

RTECS lists the following acute toxicity data:<ref name=RTECS>{{cite web | title=RTECS BO3150000 Ammonium, alkyldimethylbenzyl - , chloride | date=28 March 2018| url=https://www.cdc.gov/niosh-rtecs/bo3010b0.html}}</ref>

{| class="wikitable"

|-

! Organism !! Route of exposure !! Dose (LD₅₀)

|-

| Rat || Intravenous || align=right|13.9&nbsp;mg/kg

|-

| Rat || Oral || align=right|240&nbsp;mg/kg

|-

| Rat || Intraperitoneal || align=right|14.5&nbsp;mg/kg

|-

| Rat || Subcutaneous || align=right|400&nbsp;mg/kg

|-

| Mouse || Subcutaneous || align=right|64&nbsp;mg/kg

|}

Benzalkonium chloride is a human skin and severe eye irritant.<ref>{{cite book|author=Lewis R J Sr|title=Sax's Dangerous Properties of Industrial Materials|publisher=Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ|year=2004|isbn=978-0471701347|editor1-last=Lewis|editor1-first=Richard J|edition=11|page=104|doi=10.1002/0471701343|quote=SAFETY PROFILE: Poison by ingestion. Moderately toxic by skin contact. A severe eye irritant. A bactericide and fungicide. Dangerous; when heated to decomposition it emits toxic fumes of Cl- and NOx.}}<!--ISBN 978-0-471-70134-7 --></ref> It is a respiratory toxicant, immunotoxicant, gastrointestinal toxicant, and neurotoxicant.<ref>{{cite web | title=TOXNET Benzalkonium Chloride Compounds | url=http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+hsdb:@term+@DOCNO+234}}</ref><ref>{{cite web | title=Haz-Map Benzalkonium Chloride | url=http://hazmap.nlm.nih.gov/category-details?id=839&table=copytblagents | access-date=2014-11-11 | archive-date=2014-10-06 | archive-url=https://web.archive.org/web/20141006091441/http://hazmap.nlm.nih.gov/category-details?table=copytblagents&id=839 | url-status=dead }}</ref><ref>{{cite web | title=NIOSH ICSC Benzalkonium Chloride | url=https://www.cdc.gov/niosh/ipcsneng/neng1584.html | access-date=2017-09-08 | archive-url=https://web.archive.org/web/20171116074822/https://www.cdc.gov/niosh/ipcsneng/neng1584.html | archive-date=2017-11-16 | url-status=dead }}</ref>

Benzalkonium chloride formulations for consumer use are dilute solutions. Concentrated solutions are toxic to humans, causing corrosion/irritation to the skin and mucosa, and death if taken internally in sufficient volumes. 0.1% is the maximum concentration of benzalkonium chloride that does not produce primary irritation on intact skin or act as a sensitizer.<ref name="Block2001">{{cite book|author=Seymour Stanton Block|url=https://books.google.com/books?id=3f-kPJ17_TYC&pg=PA303|title=Disinfection, sterilization, and preservation|publisher=Lippincott Williams & Wilkins|year=2001|isbn=978-0-683-30740-5|edition=5, illustrated|page=311}}<!--ISBN 0-683-30740-1, ISBN 978-0-683-30740-5 --></ref>

Poisoning by benzalkonium chloride is recognised in the literature.<ref name="Dart">{{cite book|last1=Dart|first1=R C|title=Medical Toxicology|publisher=Lippincott Williams & Wilkins|year=2004|isbn=978-0-781-72845-4|edition=illustrated, revised|page=125}}<!--ISBN 0-781-72845-2, ISBN 9780-781-72845-4 --></ref> A 2014 case study detailing the fatal ingestion of up to 8.1&nbsp;oz (240&nbsp;ml) of 10% benzalkonium chloride in a 78-year-old male also includes a summary of the currently published case reports of benzalkonium chloride ingestion. While the majority of cases were caused by confusion about the contents of containers, one case cites incorrect pharmacy dilution of benzalkonium chloride as the cause of poisoning of two infants.<ref>{{cite book|last1=Gossel|first1=T A|url=https://books.google.com/books?id=dAoFh3vGsFQC&q=benzalkonium+chloride+history&pg=PA239|title=Principles Of Clinical Toxicology, Third Edition|publisher=CRC Press|year=1994|isbn=9780781701259|edition=3, illustrated, revised}}<!--ISBN 0-781-70125-2, ISBN 978-0-781-70125-9--></ref> In 2018 a Japanese nurse was arrested and admitted to having murdered approximately 20 patients at a hospital in Yokohama by injecting benzalkonium chloride into their intravenous drip bags.<ref>{{Cite web|last=Adelstein|first=Jake|date=2018-09-01|title=Examining the motives behind mass murder in Japan|url=https://www.japantimes.co.jp/news/2018/09/01/national/media-national/examining-motives-behind-mass-murder-japan/|access-date=2020-08-04|website=The Japan Times|language=en-US}}</ref><ref>{{Cite news|last=Ryall|first=Julian|date=2018-07-10|title=Japanese nurse investigated over 20 killings at end of shifts to avoid 'nuisance' of telling families of deaths|language=en-GB|work=The Telegraph|url=https://www.telegraph.co.uk/news/2018/07/10/japanese-nurse-investigated-20-killings-end-shifts-avoid-nuisance/|access-date=2018-08-26|issn=0307-1235}}</ref>

Benzalkonium chloride poisoning of domestic pets has been recognised as a result of direct contact with surfaces cleaned with disinfectants using benzalkonium chloride as an active ingredient.<ref>{{cite book|last1=Campbell|first1=A|title=Handbook of Poisoning in Dogs and Cats|last2=Chapman|first2=M|publisher=John Wiley & Sons|year=2008|isbn=978-0-470-69844-0|page=17}}<!--ISBN 0-470-69844-6, ISBN 978-0-470-69844-0 --></ref>

== Biological activity ==

The antimicrobial activity is dependent on the chain length. For example, yeast and fungi are most affected by C12, gram positive by C14, and gram negative by C16.<ref>{{Cite journal |last1=Daoud |first1=N. N. |last2=Dickinson |first2=N. A. |last3=Gilbert |first3=P. |date=1983 |title=Antimicrobial activity and physico-chemical properties of some alkyldimethylbenzylammonium chlorides |url=https://pubmed.ncbi.nlm.nih.gov/6413825 |journal=Microbios |volume=37 |issue=148 |pages=73–85 |issn=0026-2633 |pmid=6413825}}</ref>

The greatest biocidal activity is associated with the C12 dodecyl and C14 [[1-Tetradecanol|myristyl]] alkyl derivatives. The mechanism of [[bactericide|bactericidal]]/[[microbicide|microbicidal]] action is thought to be due to disruption of intermolecular interactions. This can cause dissociation of [[cellular membrane]] [[lipid bilayer]]s, which compromises cellular permeability controls and induces leakage of cellular contents. Other biomolecular complexes within the bacterial cell can also undergo dissociation. [[Enzyme]]s, which finely control a wide range of respiratory and metabolic cellular activities, are particularly susceptible to deactivation. Critical intermolecular interactions and tertiary structures in such highly specific biochemical systems can be readily disrupted by cationic surfactants.{{Citation needed|reason=Source for this?|date=August 2020}}

Benzalkonium chloride solutions are fast-acting biocidal agents with a moderately long duration of action. They are active against bacteria and some viruses, fungi, and protozoa. Bacterial spores are considered to be resistant. Solutions are [[bacteriostatic]] or bactericidal according to their concentration. [[Gram-positive bacteria]] are generally more susceptible than [[gram-negative bacteria]]. Its activity depends on the surfactant concentration and also on the bacterial concentration (inoculum) at the moment of the treatment.<ref>{{cite journal|last1=García|first1=MR|last2=Cabo|first2=ML|title=Optimization of ''E. coli'' Inactivation by Benzalkonium Chloride Reveals the Importance of Quantifying the Inoculum Effect on Chemical Disinfection.|journal=Frontiers in Microbiology|date=June 2018|volume=9|pages=1259|doi=10.3389/fmicb.2018.01259|pmid=29997577|pmc=6028699|doi-access=free}}</ref> Activity is not greatly affected by pH, but increases substantially at higher temperatures and prolonged exposure times.

In a 1998 study using the FDA protocol, a non-alcohol sanitizer with benzalkonium chloride as the active ingredient met the FDA performance standards, while [[Purell]], a popular alcohol-based sanitizer, did not. The study, which was undertaken and reported by a leading US developer, manufacturer and marketer of topical antimicrobial pharmaceuticals based on quaternary ammonium compounds, found that their own benzalkonium chloride-based sanitizer performed better than alcohol-based hand sanitizer after repeated use.<ref name="Dyer Gerenratch Wadhams 1998 pp. 239–251">{{closed access}} {{cite journal |last1=Dyer |first1=David L. |last2=Gerenratch |first2=Kenneth B. |last3=Wadhams |first3=Peter S. |title=Testing a New Alcohol-Free Hand Sanitizer to Combat Infection |journal=AORN Journal |volume=68 |issue=2 |year=1998 |issn=0001-2092 |doi=10.1016/s0001-2092(06)62517-9 |pmid=9706236|pages=239–251 }}</ref>

Newer formulations using benzalkonium blended with various [[quaternary ammonium]] derivatives can be used to extend the biocidal spectrum and enhance the efficacy of benzalkonium based disinfection products.{{Citation needed|date=November 2014}} Formulation techniques have been used to great effect in enhancing the virucidal activity of quaternary ammonium-based disinfectants such as Virucide 100 to typical healthcare infection hazards such as [[hepatitis]] and [[HIV]].{{Citation needed|date=November 2014}} The use of appropriate [[excipient]]s can also greatly enhance the spectrum, performance and [[detergent|detergency]], and prevent deactivation under use conditions.{{Citation needed|date=November 2014}} Formulation can also help minimise deactivation of benzalkonium solutions in the presence of organic and inorganic contamination.{{Citation needed|date=November 2014}}. However, recent studies have demonstrated the capacity of environmental microorganisms to develop reduced susceptibility to benzalkonium chloride by employing strategies such as modifying bacterial membranes: increasing pump activity, and reducing the expression of certain porins.<ref name="Chacón Kuropka González-Tortuero Schreiber 2023 p. 1180128">{{cite journal |last1=Chacón |first1=Luz |last2=Kuropka |first2=Benno |last3=González-Tortuero |first3=Enrique |last4=Schreiber |first4=Frank |last5=Rojas-Jiménez |first5=Keilor |last6=Rodríguez-Rojas |first6=Alexandro |title=Mechanisms of low susceptibility to the disinfectant benzalkonium chloride in a multidrug-resistant environmental isolate of Aeromonas hydrophila |journal=Frontiers in Microbiology |publisher=Frontiers Media SA |volume=14 |date=2023-06-02 |issn=1664-302X |doi=10.3389/fmicb.2023.1180128 |pmid=37333642 |pmc=10272739 |page=1180128 |doi-access=free }}</ref>

== Degradation ==

[[File:Biodegradation pathways of BAC.jpg|thumb|Biodegradation pathways of BAC with Fenton process (H₂O₂/Fe²⁺)<ref name=":0">{{Cite book|title = Handbook of Pharmaceutical Excipients 6th Edition|last = Rowe|first = Raymond|publisher = Pharmaceutical Press|year = 2009|isbn = 978-1-58212-135-2|location = London, UK|pages = 56–58}}</ref>]]

Benzalkonium chloride degradation follows consecutive debenzylation, dealkylation, and demethylation steps producing [[benzyl chloride]], an alkyl dimethyl amine, [[dimethylamine]], a long chain alkane, and [[ammonia]].<ref name=":0" /> The intermediates, major, and minor products can then be broken down into CO₂, H₂O, NH₃, and Cl^–. The first step to the biodegradation of BAC is the fission or splitting of the alkyl chain from the quaternary nitrogen as shown in the diagram. This is done by abstracting the hydrogen from the alkyl chain by using a hydroxyl radical leading to a carbon centered radical. This results in [[dimethylbenzylamine]] as the first intermediate and [[dodecanal]] as the major product.<ref name=":0" />

From here, dimethylbenzylamine can be oxidized to benzoic acid using the [[Fenton process]]. The [[trimethyl amine]] group in dimethylbenzylamine can be cleaved to form a benzyl that can be further oxidized to [[benzoic acid]]. Benzoic acid uses [[hydroxylation]] (adding a hydroxyl group) to form [[p-hydroxybenzoic acid]]. Dimethylbenzylamine can then be converted into ammonia by performing [[demethylation]] twice, which removes both methyl groups, followed by debenzylation, removing the benzyl group using [[hydrogenation]].<ref name=":0" /> The diagram{{which|reason=Fenton isn’t very biological |date=November 2022}} represents suggested pathways of the biodegradation of BAC for both the hydrophobic and the hydrophilic regions of the surfactant. Since [[stearalkonium chloride]] is a type of BAC, the biodegradation process should happen in the same manner.

== Regulation ==

Benzalkonium chloride is classed as a Category III antiseptic active ingredient by the United States [[Food and Drug Administration]] (FDA). Ingredients are categorized as Category III when "available data are insufficient to classify as safe and effective, and further testing is required”.

In September 2016, the FDA announced a ban on nineteen ingredients in consumer antibacterial soaps citing a lack of evidence for safety and effectiveness.<ref>{{Cite web|url=https://www.federalregister.gov/documents/2016/09/06/2016-21337/safety-and-effectiveness-of-consumer-antiseptics-topical-antimicrobial-drug-products-for|title=Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use|date=2016-09-06|access-date=2016-10-05}}</ref> A ban on three additional ingredients, including benzalkonium chloride, was deferred at that time to allow ongoing studies to be completed.

Benzalkonium chloride was deferred from further rulemaking in the 2019 FDA Final Rule on safety and effectiveness of consumer hand sanitizers, "to allow for the ongoing study and submission of additional safety and effectiveness data necessary to make a determination" on whether it met these criteria for use in OTC hand sanitizers, but the agency indicated it did not intend to take action to remove benzalkonium chloride-based hand sanitizers from the market.<ref name="FDAfinalRule2019">{{cite web |title=FDA issues final rule on safety and effectiveness of consumer hand sanitizers |url=https://www.fda.gov/news-events/press-announcements/fda-issues-final-rule-safety-and-effectiveness-consumer-hand-sanitizers |publisher=United States Food and Drug Administration |access-date=23 March 2020}}</ref> There is acknowledgement that more data are required on its safety, efficacy, and effectiveness, especially with relation to:

* Human pharmacokinetic studies, including information on its metabolites

* Studies on animal absorption, distribution, metabolism, and excretion

* Data to help define the effect of formulation on dermal absorption

* Carcinogenicity

* Studies on developmental and reproductive toxicology

* Potential hormonal effects

* Assessment of the potential for development of bacterial resistance

* Risks of using it as a contraceptive method.

However, recent studies have demonstrated the capacity of environmental microorganisms to develop reduced susceptibility to benzalkonium chloride by employing strategies such as modifying bacterial membranes: increasing pump activity, and reducing the expression of certain porins.<ref>Chacón L, Kuropka B, González-Tortuero E, Schreiber F, Rojas-Jiménez K and Rodríguez-Rojas A (2023) Mechanisms of low susceptibility to the disinfectant benzalkonium chloride in a multidrug-resistant environmental isolate of ''Aeromonas hydrophila''. Front. Microbiol. 14:1180128. doi: 10.3389/fmicb.2023.1180128 </ref>

== See also ==

* {{annotated link|Stearalkonium chloride}}

* {{annotated link|Polyaminopropyl biguanide}} – an alternative preservative for contact lens solutions

* {{annotated link|Ethylenediaminetetraacetic acid}}

* {{annotated link|Triclosan}}

* {{annotated link|Thiomersal}}

== References ==

{{reflist|30em}}

== Further reading ==

* {{cite journal | last1 = Rieger | first1 = M M | year = 1997 | title = The Skin Irritation Potential of Quaternaries | url = http://journal.scconline.org/pdf/cc1997/cc048n06/p00307-p00317.pdf | journal = Soc. Cosmet. Chem. | volume = 48 | pages = 307–317 | url-status = dead | archive-url = https://web.archive.org/web/20141207082124/http://journal.scconline.org/pdf/cc1997/cc048n06/p00307-p00317.pdf | archive-date = 2014-12-07 }}

* Thorup I: Evaluation of health hazards by exposure to Quaternary ammonium compounds, The Institute of Food Safety and Toxicology, Danish Veterinary and Food Administration, [https://web.archive.org/web/20160305021506/http://www2.mst.dk/common/Udgivramme/Frame.asp?http://www2.mst.dk/udgiv/publications/2000/87-7944-210-2/html/kap04_eng.htm]

* {{cite journal | last1 = Verret | first1 = DJ | last2 = Marple | first2 = BF. | s2cid = 33686959 | date=Feb 2005 | title = Effect of topical nasal steroid sprays on nasal mucosa and ciliary function | journal = Curr Opin Otolaryngol Head Neck Surg | volume = 13 | issue = 1| pages = 14–8 | pmid = 15654209 | doi=10.1097/00020840-200502000-00005}}

== External links ==

* [http://www.inchem.org/documents/icsc/icsc/eics1584.htm International Programme on Chemical Safety, International Chemical Safety Card (ICSC) - Benzalkonium Chloride]

* [https://web.archive.org/web/20171116074822/https://www.cdc.gov/niosh/ipcsneng/neng1584.html National Institute for Occupational Safety and Health (NIOSH), International Chemical Safety Card (ICSC) - Benzalkonium Chloride]

* [https://www.inchem.org/documents/pims/chemical/pimg022.htm International Programme on Chemical Safety, Poisons Information Monograph (PIMs) - Benzalkonium Chloride]

* [https://web.archive.org/web/20141006091441/http://hazmap.nlm.nih.gov/category-details?table=copytblagents&id=839 Haz-Map Category Details - Benzalkonium Chloride]

* [https://www.epa.gov/pesticide-worker-safety/recognition-and-management-pesticide-poisonings Recognition and Management of Pesticide Poisonings, United States Environmental Protection Agency, Office of Pesticide Programs, Sixth Edition, 2013]

* [https://www.cdc.gov/infectioncontrol/guidelines/disinfection/index.html CDC Healthcare Infection Control Practices Advisory Committee (HICPAC), Guideline for Disinfection and Sterilization in Healthcare Facilities, 2008]

* [https://datasheets.scbt.com/sc-227342.pdf Santa Cruz Biotechnology, Inc. MSDS]

* [https://web.archive.org/web/20141006101538/http://eu.spectrumlabs.com/lit/MSDS100104.pdf Spectrum Labs "Clear Bath" Algae Inhibitor MSDS]

* [http://www.nilechemicals.com/BENZALKONIUM%20CHLORIDE%20MSDS%20LAB.htm Nile Chemicals MSDS]

* [https://www.spectrumchemical.com/media/sds/TCI-B0414.pdf TCI America MSDS]

* [https://web.archive.org/web/20121021032011/http://www.sciencelab.com/msds.php?msdsId=9923038 Sciencelab.com, Inc. MSDS]

* [http://www.ent-consult.com/salineadditives.html Nasal Saline Sprays - The Additives May Be the Problem]

{{Antiseptics and disinfectants}}

{{Medicated dressings}}

{{Throat preparations}}

{{DEFAULTSORT:Benzalkonium Chloride}}

[[Category:Algaecides]]

[[Category:Antiseptics]]

[[Category:Benzyl compounds]]

[[Category:Cationic surfactants]]

[[Category:Chlorides]]

[[Category:Disinfectants]]

[[Category:Quaternary ammonium compounds]]