Benzalkonium chloride

Last updated
Benzalkonium chloride
Benzalkonium chloride Structure V.1.svg
Names
Other names
N-Alkyl-N-benzyl-N,N-dimethylammonium chloride; Alkyldimethylbenzylammonium chloride; ADBAC; BC50 BC80
Identifiers
ChEBI
ChEMBL
EC Number
  • 264-151-6
KEGG
RTECS number
  • BO3150000
UNII
Properties
Variable
Molar mass Variable
Appearance
  • 100% is white or yellow powder; gelatinous lumps;
  • BC50 (50%) and BC80 (80%) solutions are colourless to pale yellow solutions.
Density 0.98 g/cm3
Very soluble
Pharmacology
D08AJ01 ( WHO )
Hazards
GHS labelling:
GHS-pictogram-acid.svg GHS-pictogram-exclam.svg GHS-pictogram-pollu.svg
Danger
H302, H312, H314, H410
P260, P264, P270, P273, P280, P301+P312, P301+P330+P331, P302+P352, P303+P361+P353, P304+P340, P305+P351+P338, P310, P312, P321, P322, P330, P363, P391, P405, P501
NFPA 704 (fire diamond)
NFPA 704.svgHealth 3: Short exposure could cause serious temporary or residual injury. E.g. chlorine gasFlammability 0: Will not burn. E.g. waterInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
3
0
0
Flash point 250 °C (482 °F; 523 K) (if solvent based)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Benzalkonium chloride (BZK, BKC, BAK, BAC), also known as alkyldimethylbenzylammonium chloride (ADBAC) and by the trade name Zephiran, [1] is a type of cationic surfactant. It is an organic 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. [2] ADBACs are a mixture of alkylbenzyldimethylammonium chlorides, in which the alkyl group has various even-numbered alkyl chain lengths.

Contents

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 ]

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 (alcohols, polyethylene glycols, 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. [3]

Phase transfer agent

Benzalkonium chloride is a mainstay of phase-transfer catalysis, an important technology in the synthesis of organic compounds, including drugs.[ citation needed ]

Bioactive agents

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

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. [9]

During the course of the COVID-19 pandemic, from time to time there have been shortages of hand cleaner containing ethanol or 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. [10] 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." [11] 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. [12] This resulted in a growing consensus that BZK sanitizers are just as effective as alcohol-based sanitizers despite the CDC guidelines. [13] 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. [14] 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. [15]

Medicine

Benzalkonium chloride is a frequently used preservative in eye drops; typical concentrations range from 0.004% to 0.01%. [16] Stronger concentrations can be caustic [17] and cause irreversible damage to the corneal endothelium. [18]

Avoiding the use of benzalkonium chloride solutions while contact lenses are in place is discussed in the literature. [19] [20]

Due to its antimicrobial activity [21] when applied to skin, some topical medications for acne vulgaris have benzalkonium chloride added to increase the products’ efficiency or shelf-life. [22] [23]

Benzalkonium chloride has also been shown to be a spermicide. [24] In Russia and China, benzalkonium chloride is used as a contraceptive. Tablets are inserted vaginally, or a gel is applied, resulting in local spermicidal contraception. [25] [26] It is not a wholly reliable method, and can cause irritation.

Beekeeping

It is used in beekeeping for the treatment of rotten diseases of the brood. [27]

Adverse effects

Although historically benzalkonium chloride has been ubiquitous as a preservative in ophthalmic preparations, its ocular toxicity and irritant properties, [28] 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. [29]

Many mass-marketed inhaler and nasal spray formulations contain benzalkonium chloride as a preservative, despite substantial evidence that it can adversely affect ciliary motion, mucociliary clearance, nasal mucosal histology, human neutrophil function, and leukocyte response to local inflammation. [30] Although some studies have found no correlation between use of benzalkonium chloride in concentrations at or below 0.1% in nasal sprays and drug-induced rhinitis, [31] others have recommended that benzalkonium chloride in nasal sprays be avoided. [32] [33] In the United States, nasal steroid preparations that are free of benzalkonium chloride include budesonide, triamcinolone acetonide, dexamethasone, and Beconase and Vancenase aerosol inhalers. [30]

Benzalkonium chloride is an irritant to middle ear tissues at typically used concentrations. Inner ear toxicity has been demonstrated. [34]

Occupational exposure to benzalkonium chloride has been linked to the development of asthma. [35] 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. [36]

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 ]

Toxicology

RTECS lists the following acute toxicity data: [37]

OrganismRoute of exposureDose (LD50)
RatIntravenous13.9 mg/kg
RatOral240 mg/kg
RatIntraperitoneal14.5 mg/kg
RatSubcutaneous400 mg/kg
MouseSubcutaneous64 mg/kg

Benzalkonium chloride is a human skin and severe eye irritant. [38] It is a respiratory toxicant, immunotoxicant, gastrointestinal toxicant, and neurotoxicant. [39] [40] [41]

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. [42]

Poisoning by benzalkonium chloride is recognised in the literature. [43] A 2014 case study detailing the fatal ingestion of up to 8.1 oz (240 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. [44] 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. [45] [46]

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. [47]

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. [48]

The greatest biocidal activity is associated with the C12 dodecyl and C14 myristyl alkyl derivatives. The mechanism of bactericidal/microbicidal action is thought to be due to disruption of intermolecular interactions. This can cause dissociation of cellular membrane lipid bilayers, which compromises cellular permeability controls and induces leakage of cellular contents. Other biomolecular complexes within the bacterial cell can also undergo dissociation. Enzymes, 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 ]

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. [49] 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. [50]

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 ] 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 ] The use of appropriate excipients can also greatly enhance the spectrum, performance and detergency, and prevent deactivation under use conditions.[ citation needed ] Formulation can also help minimise deactivation of benzalkonium solutions in the presence of organic and inorganic contamination.[ citation needed ]. 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. [51]

Degradation

Biodegradation pathways of BAC with Fenton process (H2O2/Fe ) Biodegradation pathways of BAC.jpg
Biodegradation pathways of BAC with Fenton process (H2O2/Fe )

Benzalkonium chloride degradation follows consecutive debenzylation, dealkylation, and demethylation steps producing benzyl chloride, an alkyl dimethyl amine, dimethylamine, a long chain alkane, and ammonia. [52] 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. [52]

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. [52] The diagram[ which? ] 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. [53] 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. [54] There is acknowledgement that more data are required on its safety, efficacy, and effectiveness, especially with relation to:

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. [55]

See also

Related Research Articles

A bactericide or bacteriocide, sometimes abbreviated Bcidal, is a substance which kills bacteria. Bactericides are disinfectants, antiseptics, or antibiotics. However, material surfaces can also have bactericidal properties based solely on their physical surface structure, as for example biomaterials like insect wings.

<span class="mw-page-title-main">Surfactant</span> Substance that lowers the surface tension between a liquid and another material

Surfactants are chemical compounds that decrease the surface tension or interfacial tension between two liquids, a liquid and a gas, or a liquid and a solid. The word "surfactant" is a blend of surface-active agent, coined c. 1950. As they consist of a water-repellent and a water-attracting part, they enable water and oil to mix; they can form foam and facilitate the detachment of dirt.

<span class="mw-page-title-main">Antibacterial soap</span> Cleaning agents containing germ-killing chemicals

Antibacterial soap is a soap which contains chemical ingredients that purportedly assist in killing bacteria. The majority of antibacterial soaps contain triclosan, though other chemical additives are also common. The effectiveness of products branded as being antibacterial has been disputed by some academics as well as the U.S. Food and Drug Administration (FDA).

<span class="mw-page-title-main">Disinfectant</span> Antimicrobial agent that inactivates or destroys microbes

A disinfectant is a chemical substance or compound used to inactivate or destroy microorganisms on inert surfaces. Disinfection does not necessarily kill all microorganisms, especially resistant bacterial spores; it is less effective than sterilization, which is an extreme physical or chemical process that kills all types of life. Disinfectants are generally distinguished from other antimicrobial agents such as antibiotics, which destroy microorganisms within the body, and antiseptics, which destroy microorganisms on living tissue. Disinfectants are also different from biocides—the latter are intended to destroy all forms of life, not just microorganisms. Disinfectants work by destroying the cell wall of microbes or interfering with their metabolism. It is also a form of decontamination, and can be defined as the process whereby physical or chemical methods are used to reduce the amount of pathogenic microorganisms on a surface.

<span class="mw-page-title-main">Quaternary ammonium cation</span> Polyatomic ions of the form N(–R)₄ (charge +1)

In organic chemistry, quaternary ammonium cations, also known as quats, are positively-charged polyatomic ions of the structure [NR4]+, where R is an alkyl group, an aryl group or organyl group. Unlike the ammonium ion and the primary, secondary, or tertiary ammonium cations, the quaternary ammonium cations are permanently charged, independent of the pH of their solution. Quaternary ammonium salts or quaternary ammonium compounds are salts of quaternary ammonium cations. Polyquats are a variety of engineered polymer forms which provide multiple quat molecules within a larger molecule.

<span class="mw-page-title-main">Rhinitis medicamentosa</span> Medical condition

Rhinitis medicamentosa is a condition of rebound nasal congestion suspected to be brought on by extended use of topical decongestants and certain oral medications that constrict blood vessels in the lining of the nose, although evidence has been contradictory.

<span class="mw-page-title-main">Hand sanitizer</span> Alternative to hand washing

Hand sanitizer is a liquid, gel or foam generally used to kill many viruses/bacteria/microorganisms on the hands. It can also come in the form of a cream, spray, or wipe. In most settings, hand washing with soap and water is generally preferred. Hand sanitizer is less effective at killing certain kinds of germs, such as norovirus and Clostridium difficile, and unlike hand washing, it cannot physically remove harmful chemicals. People may incorrectly wipe off hand sanitizer before it has dried, and some are less effective because their alcohol concentrations are too low.

<span class="mw-page-title-main">Benzethonium chloride</span> Chemical compound

Benzethonium chloride, also known as hyamine is a synthetic quaternary ammonium salt. This compound is an odorless white solid, soluble in water. It has surfactant, antiseptic, and anti-infective properties, and it is used as a topical antimicrobial agent in first aid antiseptics. It is also found in cosmetics and toiletries such as soap, mouthwashes, anti-itch ointments, and antibacterial moist towelettes. Benzethonium chloride is also used in the food industry as a hard surface disinfectant.

<span class="mw-page-title-main">Lysol</span> Cleaning products brand name

Lysol is a brand of American cleaning and disinfecting products distributed by Reckitt, which markets the similar Dettol or Sagrotan in other markets. The line includes liquid solutions for hard and soft surfaces, air treatment, and hand washing. The active ingredient in many Lysol products is benzalkonium chloride, but the active ingredient in the Lysol "Power and Free" line is hydrogen peroxide. Lysol has been used since its invention in the late 19th century as a household and industrial cleaning agent, and previously as a medical disinfectant.

<span class="mw-page-title-main">Polyaminopropyl biguanide</span> Chemical compound

Polyaminopropyl biguanide (PAPB) is a disinfectant and a preservative used for disinfection on skin and in cleaning solutions for contact lenses. It is also an ingredient in many deodorant bodysprays. It is a polymer or oligomer where biguanide functional groups are connected by propyl hydrocarbon chains. PAPB is specifically bactericidal at very low concentrations (10 mg/L) and is also fungicidal.

<span class="mw-page-title-main">Dequalinium</span> Chemical compound

Dequalinium is a quaternary ammonium cation and bolaamphiphile commonly available as the dichloride salt. It is useful as an antiseptic and disinfectant. The bromide, iodide, acetate, and undecenoate salts are known as well. Dequalinium chloride is the active ingredient of several medications.

<span class="mw-page-title-main">Cleaning agent</span> Substance used to remove dirt or other contaminants

Cleaning agents or hard-surface cleaners are substances used to remove dirt, including dust, stains, foul odors, and clutter on surfaces. Purposes of cleaning agents include health, beauty, removing offensive odor, and avoiding the spread of dirt and contaminants to oneself and others. Some cleaning agents can kill bacteria and clean at the same time. Others, called degreasers, contain organic solvents to help dissolve oils and fats.

Stearalkonium chloride is a type of benzalkonium chloride which is used as an anti-static agent, a surfactant and an antimicrobial. It is an ingredient in some cosmetics and hair care products, particularly conditioners. It was originally designed by the fabric industry for use as a fabric softener.

A virucide is any physical or chemical agent that deactivates or destroys viruses. The substances are not only virucidal but can be also bactericidal, fungicidal, sporicidal or tuberculocidal.

<span class="mw-page-title-main">Cetalkonium chloride</span> Chemical compound

Cetalkonium chloride (CKC) is a quaternary ammonium compound of the alkyl-benzyldimethylammonium chloride family, the alkyl group having a chain length of C16 . It is used in pharmaceutical products either as an excipient or as an active ingredient. It may be found in very small amount in the excipient benzalkonium chloride mixture. Cetalkonium chloride is purchased as a raw material in dry form as a white powder.

Alkaline copper quaternary, usually abbreviated ACQ, is a type of water-based wood preservative product containing a soluble copper(II) complex and quaternary ammonium alkyl- or aryl-substituted compounds ("quats"). Thus the product was originally called ammoniacal copper/quaternary ammonium.

<span class="mw-page-title-main">Polyquaternium-7</span> Chemical compound

Polyquaternium-7 is an organic compound in the polyquaternium class of chemicals and used in the personal care industry. It is the copolymer of acrylamide and the quaternary ammonium salt diallyldimethylammonium chloride.

<span class="mw-page-title-main">Ethyl lauroyl arginate</span> Chemical compound

Ethyl lauroyl arginate (LAE) is a food preservative, antimicrobial compound, and drug more commonly known as E243. It is used to treat dermatological disorders and is often provided in the form of its hydrochloride salt. LAE is an amino acid-based surfactant with broad-spectrum antimicrobial activity, high biodegradability and low toxicity. Due to these features, LAE is a preservative used in food and cosmetic formulations.

Penetration enhancers are chemical compounds that can facilitate the penetration of active pharmaceutical ingredients (API) into or through the poorly permeable biological membranes. These compounds are used in some pharmaceutical formulations to enhance the penetration of APIs in transdermal drug delivery and transmucosal drug delivery. They typically penetrate into the biological membranes and reversibly decrease their barrier properties.

References

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  37. ↑ "RTECS BO3150000 Ammonium, alkyldimethylbenzyl - , chloride". 28 March 2018.
  38. ↑ Lewis R J Sr (2004). Lewis, Richard J (ed.). Sax's Dangerous Properties of Industrial Materials (11 ed.). Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. p. 104. doi:10.1002/0471701343. ISBN   978-0471701347. 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.
  39. ↑ "TOXNET Benzalkonium Chloride Compounds".
  40. ↑ "Haz-Map Benzalkonium Chloride". Archived from the original on 2014-10-06. Retrieved 2014-11-11.
  41. ↑ "NIOSH ICSC Benzalkonium Chloride". Archived from the original on 2017-11-16. Retrieved 2017-09-08.
  42. ↑ Seymour Stanton Block (2001). Disinfection, sterilization, and preservation (5, illustrated ed.). Lippincott Williams & Wilkins. p. 311. ISBN   978-0-683-30740-5.
  43. ↑ Dart, R C (2004). Medical Toxicology (illustrated, revised ed.). Lippincott Williams & Wilkins. p. 125. ISBN   978-0-781-72845-4.
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  45. ↑ Adelstein, Jake (2018-09-01). "Examining the motives behind mass murder in Japan". The Japan Times. Retrieved 2020-08-04.
  46. ↑ Ryall, Julian (2018-07-10). "Japanese nurse investigated over 20 killings at end of shifts to avoid 'nuisance' of telling families of deaths". The Telegraph. ISSN   0307-1235 . Retrieved 2018-08-26.
  47. ↑ Campbell, A; Chapman, M (2008). Handbook of Poisoning in Dogs and Cats. John Wiley & Sons. p. 17. ISBN   978-0-470-69844-0.
  48. ↑ Daoud, N. N.; Dickinson, N. A.; Gilbert, P. (1983). "Antimicrobial activity and physico-chemical properties of some alkyldimethylbenzylammonium chlorides". Microbios. 37 (148): 73–85. ISSN   0026-2633. PMID   6413825.
  49. ↑ García, MR; Cabo, ML (June 2018). "Optimization of E. coli Inactivation by Benzalkonium Chloride Reveals the Importance of Quantifying the Inoculum Effect on Chemical Disinfection". Frontiers in Microbiology. 9: 1259. doi: 10.3389/fmicb.2018.01259 . PMC   6028699 . PMID   29997577.
  50. ↑ Closed Access logo transparent.svg Dyer, David L.; Gerenratch, Kenneth B.; Wadhams, Peter S. (1998). "Testing a New Alcohol-Free Hand Sanitizer to Combat Infection". AORN Journal. 68 (2): 239–251. doi:10.1016/s0001-2092(06)62517-9. ISSN   0001-2092. PMID   9706236.
  51. ↑ Chacón, Luz; Kuropka, Benno; González-Tortuero, Enrique; Schreiber, Frank; Rojas-Jiménez, Keilor; Rodríguez-Rojas, Alexandro (2023-06-02). "Mechanisms of low susceptibility to the disinfectant benzalkonium chloride in a multidrug-resistant environmental isolate of Aeromonas hydrophila". Frontiers in Microbiology. 14. Frontiers Media SA: 1180128. doi: 10.3389/fmicb.2023.1180128 . ISSN   1664-302X. PMC   10272739 . PMID   37333642.
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  53. ↑ "Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use". 2016-09-06. Retrieved 2016-10-05.
  54. ↑ "FDA issues final rule on safety and effectiveness of consumer hand sanitizers". United States Food and Drug Administration. Retrieved 23 March 2020.
  55. ↑ 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

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