BENZALKONIUM CHLORIDE

Benzalkonium chloride

cas no : 8001-54-5

SYNONYM : N-Alkyl-N-benzyl-N,N-dimethylammonium chloride; Alkyldimethylbenzylammonium chloride; ADBAC; BC50 BC80; Quaternary ammonium compounds; quats; Quaternary ammonium compounds, benzyl-C8-18-alkyldimethyl chlorides; Alkyldimethylbenzylammonium chloride; Alkyldimethyl(phenylmethyl) quaternary ammonium chloride; Ammonium alkyldimethyl(phenylmethyl) chloride; Ammonium alkyldimethylbenzyl chloride; Alkylbenzyldimethylammonium chloride; Alkyldimethylbenzylammonium chloride;ADBAC; Alkyl dimethylbenzyl ammonium chloride; Alkylbenzyldimethylammonium chloride; Alkyldimethyl(phenylmethyl)quaternary ammonium chlorides;  Alkyldimethylbenzylammonium chloride; Benzalconio cloruro; Benzalkonii chloridum; Benzalkonium chlorides; Chlorure de benzalkonium ; Cloruro de benzalconio; ALKYL DIMETHYL BENZYL AMMONIUM CHLORIDE; BENZALKONIUM CHLORIDE; BENZALKONIUM CHLORIDE SOLUTION; BENZYLCHLORIDE QUATERNARY SALT OF N,N'-DIMETHYLCOCOAMINE; N-COCO-N,N-DIMETHYLBENZENEMETHANAMINIUM CHLORIDE; QUATERNARY AMMONIUM COMPOUNDS; BENZYLCOCO ALKYLDIMETHYL CHLORIDES; Alkylbenzyldimethylammonium chloride; Alkyldimethylbenzylammonium chloride; Benirol; BTC; Capitol; Cequartyl; Drapolene; Drapolex; Enuclen; Germinol; Germitol; Osvan; Paralkan; Roccal; Rodalon; Zephiran Chloride; Zephirol; Alkyl dimethyl ethylbenzyl ammonium chloride Urea, N,N’’- methylenebis(N’-(1-(hydroxymethyl)-2,5-dioxo-4-imidazolidinyl)-; Alkyl dimethylbenzyl ammonium chloride; Alkylbenzyldimethylammonium chloride; Alkyldimethyl(phenylmethyl)quaternary ammonium chlorides; Alkyldimethylbenzylammonium chloride; Ammonium, alkyldimethyl(phenylmethyl)-, chloride; Ammonium, alkyldimethylbenzyl-, chloride; Benzalconio cloruro ;Benzalkonium chloride; Quaternary ammonium compounds,alkylbenzyldimethyl, chlorides

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.

Identifiers
CAS Number 8001-54-5 
ChEBI    CHEBI:3020 
ChEMBL    ChEMBL502109 
ECHA InfoCard    100.132.452 
EC Number  264-151-6
KEGG    D00857 
RTECS number  BO3150000
UNII    F5UM2KM3W7 
CompTox Dashboard (EPA)    DTXSID1048122 DTXSID9034317, DTXSID1048122 Edit this at Wikidata
Properties
Chemical formula    variable
Molar mass        variable
Appearance    100% is white or yellow powder; gelatinous lumps; Solutions BC50 (50%) & BC80 (80%) are colourless to pale yellow solutions
Density            0.98 g/cm3
Solubility in water    very soluble

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 slow. Aqueous solutions should be neutral to slightly alkaline. Solutions foam when shaken. Concentrated solutions have a bitter taste and a faint almond-like odour.

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 also 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]

Laundry detergents and treatments
Softeners for textiles
Phase transfer agent
Main article: Phase transfer catalysis
Benzalkonium chloride is a mainstay of phase-transfer catalysis, an important technology in the synthesis of organic compounds, including drugs.

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

Pharmaceutical products such as eye, ear and nasal drops or sprays, as a preservative
Personal care products such as hand sanitizers, wet wipes, shampoos, soaps, deodorants and cosmetics
Skin antiseptics and wound wash sprays, such as Bactine.[4][5]
Throat lozenges[6] and mouthwashes, as a biocide
Spermicidal creams
Cleaners for floor and hard surfaces as a disinfectant, such as Lysol and Dettol antibacterial spray and wipes.
Algaecides 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.[7] An advantage of benzalkonium chloride, not shared by ethanol-based antiseptics or hydrogen peroxide antiseptic, is that it does not cause a burning sensation when applied to broken skin.[citation needed] However, prolonged or repeated skin contact may cause dermatitis.[8]

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.[9] 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."[10]

Medicine
Benzalkonium chloride is a frequently used preservative in eye drops; typical concentrations range from 0.004% to 0.01%. Stronger concentrations can be caustic[11] and cause irreversible damage to the corneal endothelium.[12]

Avoiding the use of benzalkonium chloride solutions while contact lenses are in place is discussed in the literature.[13][14]

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.[15][16] It is not a failsafe method, and can cause irritation.

Beekeeping
It is used in beekeeping for the treatment of rotten diseases of the brood.[17]

Adverse effects
Although historically benzalkonium chloride has been ubiquitous as a preservative in ophthalmic preparations, its ocular toxicity and irritant properties,[18] 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.[citation needed]

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.[19] 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,[20] others have recommended that benzalkonium chloride in nasal sprays be avoided.[21][22] In the United States, nasal steroid preparations that are free of benzalkonium chloride include budesonide, triamcinolone acetonide, dexamethasone, and Beconase and Vancenase aerosol inhalers.[19]

Benzalkonium chloride is irritant to middle ear tissues at typically used concentrations. Inner ear toxicity has been demonstrated.[23]

Occupational exposure to benzalkonium chloride has been linked to the development of asthma.[24] 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.[25]

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:[26]

Organism    Route of exposure    Dose (LD50)
Rat    Intravenous    13.9 mg/kg
Rat    Oral    240 mg/kg
Rat    Intraperitoneal    14.5 mg/kg
Rat    Subcutaneous    400 mg/kg
Mouse    Subcutaneous    64 mg/kg
Benzalkonium chloride is a human skin and severe eye irritant.[27] It is a suspected respiratory toxicant, immunotoxicant, gastrointestinal toxicant, and neurotoxicant.[28][29][30]

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.[31]

Poisoning by benzalkonium chloride is recognised in the literature.[32] A 2014 case study detailing the fatal ingestion of up to 8.1 oz (240ml) 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.[33] In 2018 a Japanese nurse was arrested and admitted to having poisoned approximately 20 patients at a hospital in Yokohama by injecting benzalkonium chloride into their intravenous drip bags.[34][35]

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.[36]

Biological activity
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.[37] 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.[38]

Advancements in the quality and efficacy of benzalkonium chloride in current non-alcohol hand sanitizers has addressed the CDC concerns regarding gram negative bacteria, with the leading products being equal if not more effective against gram negative, particularly New Delhi metallo-beta-lactamase 1 and other antibiotic resistant bacteria.[citation needed]

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]

Degradation

Biodegradation pathways of BAC with Fenton process (H2O2/Fe2+)[39]
Benzalkonium chloride degradation follows consecutive debenzylation, dealkylation, and demethylation steps producing benzyl chloride, alkyl dimethyl amine, dimethyl amine, long chain alkane, and ammonia.[39] 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 benzyl dimethyl amine as the first intermediate and dodecanal as the major product.[39]

From here, benzyl dimethyl amine 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. Benzyldimethylamine can then be converted into ammonia by performing demethylation twice, which removes both methyl groups, followed by debenzylation, removing the benzyl group using hydrogenation.[39] The diagram 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”. 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.[40] 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
In September 2016, the FDA announced a ban on nineteen ingredients in consumer antibacterial soaps citing a lack of evidence for safety and effectiveness. A ban on three additional ingredients, including benzalkonium chloride, was deferred to allow ongoing studies to be completed.[41]

Benzalkonium chlorides (BACs) are chemicals with widespread applications due to their broad-spectrum antimicrobial properties against bacteria, fungi, and viruses. This review provides an overview of the market for BACs, as well as regulatory measures and available data on safety, toxicity, and environmental contamination. We focus on the effect of frequent exposure of microbial communities to BACs and the potential for cross-resistant phenotypes to emerge. Toward this goal, we review BAC concentrations in consumer products, their correlation with the emergence of tolerance in microbial populations, and the associated risk potential. Our analysis suggests that the ubiquitous and frequent use of BACs in commercial products can generate selective environments that favor microbial phenotypes potentially cross-resistant to a variety of compounds. An analysis of benefits versus risks should be the guidepost for regulatory actions regarding compounds such as BACs.

KEYWORDS: alkyl dimethyl benzyl ammonium chlorides, antiseptic, BACs, benzalkonium chlorides, QACs, resistance

Benzalkonium chlorides (BACs), also known as alkyl dimethyl benzyl ammonium chlorides, alkyl dimethyl (phenylmethyl) quaternary ammonium chlorides, ammonium alkyl dimethyl (phenylmethyl) chlorides, or ammonium alkyl dimethyl benzyl chlorides, are a class of quaternary ammonium compounds (QACs) (Fig. 1A). They are usually commercialized as a mixture of compounds with different lengths for the alkyl chain, ranging from C8 to C18, with higher biocide activity for C12 and C14 derivatives
BACs were reported for the first time in 1935 by Gerhard Domagk, gaining the market as zephiran chlorides, and were marketed as promising and superior disinfectant and antiseptics (2). In 1947, the first product containing BACs was registered with the Environmental Protection Agency (EPA) in the United States (3). Since then, they have been used in a wide variety of products, both prescription and over the counter. Applications range from domestic to agricultural, industrial, and clinical (Fig. 1B). Domestic applications include fabric softeners (4), personal hygiene and cosmetic products, such as shampoos, conditioners, and body lotions (5), as well as ophthalmic solutions and medications that use the nasal route of delivery (6). BACs are also among the most common active ingredients in disinfectants (4) used in residential, industrial (7), agricultural, and clinical settings. Additional registered uses for BACs in the United States include applications on indoor and outdoor surfaces (walls, floors, toilets, etc.), agricultural tools and vehicles, humidifiers, water storage tanks, products for use in residential and commercial pools, decorative ponds and fountains, water lines and systems, pulp and paper products, and wood preservation (3). The recommended or allowed concentrations of BACs in different products vary considerably according to the application (Table 1). With perhaps the exception of countries which adopted stricter regulations toward BAC use, discussed in the next section, the potential use of BACs is likely on the rise. The global market for disinfectants alone, which includes BACs, is expected to grow over 6% from 2016 and reach over $8 billion by 2021 (8).

In Europe, the European Commission (EC) is involved in the regulation of BACs. Recent rules in the European market included a change in the maximum residual levels of BACs allowed in food products from 0.5 mg/kg to 0.1 mg/kg, values which will undergo an additional review by the end of 2019 (9). Additionally, recent changes in legislation, Decision (EU) 2016/1950 and the Biocidal Products Regulation (EU) no. 528/2012 (the BPR) (10, 11), meant that BACs are no longer approved for use in several biocidal products, such as consumer hand and body wash antiseptics, which is in contrast with current legislation in the United States.

In the United States, the Environmental Protection Agency (EPA) and the Food and Drug Administration (FDA) share the role of regulating BACs. Such agencies regularly update regulations based on current scientific data, occasionally limiting the use of compounds found not to be safe or effective. Final determinations, however, can be delayed by requests from the industry sector that commercializes such products. As an example, the FDA recently published three proposed and final decisions regarding the use of chemicals as consumer hand rub antiseptics, consumer hand and body wash antiseptics, and health care antiseptics (12,–14). The rules banned specific biocides, such as triclosan, or added additional and stricter regulatory approvals for several others, such as chlorhexidine, regarding the applications mentioned above. In all instances, however, BACs were excluded from the decisions and granted deferral letters as requested by manufacturers. The decisions granted manufacturers extra time to provide data to fill gaps related to safety and efficacy. Since 2015, letters and recommendations have been moving back and forth between the FDA and manufacturers and their representatives, such as the American Cleaning Institute, Lonza America, and Henkel Consumer Goods, Inc. (15,–19). Decisions to postpone any action regarding the regulation of BACs were taken based on the affirmation of lack of sufficient data in the literature. Yet, multiple researchers have studied the safety aspects of BACs over the years, which include data on the toxicity to humans and the environment, as we discuss next.

TOXICITY TO HUMANS
The toxicity of BACs to humans and other animals has been described in the literature, even though discordant conclusions arise from differences in experimental conditions. As reviewed elsewhere (20), BACs are known skin irritants, with occasional, rarer reports as allergens (skin sensitizers). Regarding acute toxicology data, BACs are classified by the EPA as toxicity category II by the oral and inhalation routes and toxicity category III via the dermal route (3). They are also considered to be highly irritating to the eyes and skin (toxicity category I) (3). Small but significant genotoxic effects in both plant and mammalian cells were observed in vitro for BAC concentrations as low as 1 mg/liter, which is lower than those reported to be found in the environment (21). Considerable cell toxicity was observed in vitro for human ocular cells exposed to BAC concentrations as low as 0.0001% (22).

In contrast, a few reports in the literature found BACs to be considered safe. A report from 2006 by the EPA did not recognize BACs as being carcinogenic, mutagenic, or genotoxic (3). Regarding their addition to intranasal products, a review of 18 studies from the literature revealed no major safety concerns when BACs were used in concentrations ranging from 0.00045% to 0.1% (23). A recent review of BAC safety in cosmetic products (5) regarded their use as possibly safe, based on calculations of the margin of safety (MOS), a formula which considered the concentration of BACs in products, use frequency, and amount, and estimated parameters such as no observed adverse effect level (NOAEL) and dermal absorption ratios.

For the specific application of ophthalmological solutions, a study sponsored by Alcon Laboratories concluded that there was no safety difference between those with or without the addition of BACs (24), even though multiple researchers reported pathological effects when ophthalmological solutions containing BACs as a preservative were used, compared to preservative-free solutions (25, 26). Multiple reports of BAC toxicity for such application have even motivated the development of preservative-free ocular solutions (27). Labeling recommendations from the European Commission for medicinal products containing BACs have also recognized eye irritation as a toxic effect from BACs (28).

In summary, most studies and governmental agencies agree that BACs are not innocuous substances, even when used in small concentrations (3, 20,–22, 25, 26, 28). Safety concerns regarding their use are frequently associated with long-term contact product use, such as in preservatives in medications used by glaucoma patients, which can be chronically exposed to BACs (22, 25, 26, 29).

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ENVIRONMENTAL CONTAMINATION
In a 2006 report, the EPA recognized the toxicity of BACs to the aquatic environment and its inhabitants, such as fish, oysters, shrimp, and invertebrates, advising against the release of BACs into lakes, oceans, or other waters (3). Since then, their toxicity to aquatic organisms, as well as other animals, has been well established by several research groups (30, 31). Despite that, BACs have been detected in wastewater effluents and other environments (Table 1).

Data regarding the detection of BACs in the environment are sparse in the literature, and recent measurements are lacking. BACs were reported in wastewater effluents from hospitals, reaching concentrations in the milligram-per-liter range (32,–34). Other effluents, such as those from laundry, dairy, community pools, also had the presence of BACs (32, 33) at various concentrations that were generally lower than those originating from hospitals. Typical wastewater treatment plants are not designed to treat QAC contaminants, resulting in the release of at least a portion of them into the environment as micropollutants (35). Concentrations varying in the ranges of microgram per liter or microgram per gram were found in ground and reclaimed water (36), as well as soil samples (37). BACs were also detected in up to 3.5% of over 4,000 food samples analyzed by the European Food Safety Authority (EFSA) (38).

From all the QACs tested by different research groups, BACs, mainly C12, C14, and C16, were found in higher concentrations than in other QACs (32, 33). The high incidence of BACs could be attributed, at least in part, to their popularity in various applications, from consumer products such as eye drops, shampoos, and mosquito insecticides, to disinfectants and antiseptics used in hospitals and food industries. Whether the widespread use of these compounds, a lack of proper disposal, or a combination of both contributed to the observed incidence in the environment is unknown. We estimate that BAC disposal in the environment is still considerable, especially in countries that have less-restrictive legislation, such as the United States. Deeper investigations, however, are required to establish the current levels of BACs in the environment, as well as the potential links for the development of resistant microbial strains, which we discuss next.

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MICROBIAL TOLERANCE AND RESISTANCE
The use of BACs for multiple applications, many of which unavoidably result in the generation and release of residual biocide, can result in the presence of environments in which there is a selection pressure over microbes to evolve resistance to such chemicals (35). The capacity of bacteria to survive and thrive in BACs has been demonstrated by tracking outbreaks usually associated with misuse or improper dilution and storage of disinfectants and antiseptic solutions (39). In fact, multiple outbreaks were associated with BACs throughout 4 decades (39), motivating a series of recommendations to discontinue their use as an antiseptic (40, 41).

Concerns about the use of BACs as antiseptics are not novel, and researchers have observed resistant strains capable of surviving in BAC solutions (0.1 to 0.4%) as early as the 1960s (42, 43). It is known that bacteria can adapt and increase their tolerance to stressful chemicals (44, 45), and such phenomena have been shown repeatedly for BACs. Frequently, the adaptive mutations that select for increased tolerance or resistance are stable at a population level and can be still observed for evolved strains even after the selection pressure has been lifted (46). Even though the reported concentrations vary depending on the study and the bacterial genera (Table 1), it has been demonstrated that bacteria can evolve to survive to BAC concentrations similar to those found in the environment and in consumer products (Table 1).

It is important to highlight that the terms “tolerance” and “resistance” have been used interchangeably, especially when related to biocides, which could lead to misinterpretation of data (47, 48). Resistance is broadly understood as the “insusceptibility of a microorganism to a particular treatment under a particular set of conditions” (47, 48). Multiple researchers defined resistance based solely on an increase in the MIC (49, 50). The term tolerance has been used on several distinct occasions. Tolerant strains were defined as those in which the antimicrobial’s MIC for them did not increase, but the strain was able to survive killing by, for example, reducing growth (51). Tolerant strains were also defined as those in which the antimicrobial’s MIC for them increased compared to the controls (48). We believe that the broad term “decrease in susceptibility” is often more appropriate to describe the observed increases in MIC for biocides, including the following examples.

Methicillin-resistant Staphylococcus aureus (MRSA) strains were evolved in BACs (52), doubling the MIC of BACs from 5 to 10 mg/liter, after a period of adaptation. The MICs of BACs increased 4-fold for Campylobacter coli after exposure to the chemical for 15 days (46). Escherichia coli K-12 strains exposed to increasing concentrations of BACs were able to survive in a concentration of 92 mg/liter BACs, which was eight times higher than the concentration in which the parent strain could survive (53). Another study showed that the MICs of BACs changed from 4 to 256 mg/liter for Salmonella enterica serovar Virchow and reached over 1,000 mg/liter for E. coli O157 (54). The leading foodborne pathogen in the United States, Listeria monocytogenes, is also capable of decreasing its susceptibility to BACs. Three different strains (H7550, SK2802, and J0161) of L. monocytogenes from outbreaks and disease cases were exposed to BACs, and isolates with up to 3-fold increases (10 to 30 mg/liter) in the MICs of BACs were obtained for all strains (55).

The Pseudomonas sp. strains can naturally withstand the highest concentrations of BACs. Pseudomonas aeruginosa survives at up to 1,600 and 1,200 mg/liter BACs with or without a previous adaptation to the chemical, respectively (56). The MIC of BACs for the isolated strain Pseudomonas sp. BIOMIG1 was 1,024 mg/liter (57). The higher recalcitrance of Pseudomonas spp. may explain why, after exposing complex microbial communities to BACs, there was an enrichment in Pseudomonas species, with a decrease in microbial diversity (58, 59). In another study, P. aeruginosa NCIMB 10421 was cultivated in continuous culture, and the BAC concentration was progressively increased for about 30 days. The MICs of BACs increased from 25 mg/liter to over 350 mg/liter, and the adapted strain had higher fitness when competed with the parent strain in the presence of BACs, especially with magnesium depletion and the presence of glucose in the medium (60).

A recent study has questioned the use of aqueous solutions of BACs to determine their activity against microorganisms, demonstrating that BACs in real-use formulations (with surfactants and chelating agents) is more effective to control microbial growth (59). Despite this finding, strains with decreased susceptibility to BACs can not only develop and be selected for under controlled laboratory conditions, but they have also been isolated directly from real-case scenarios, environments in which BACs is frequently used as a biocide. Strains of the pathogen L. monocytogenes isolated from diverse environments, such as food-processing plants, food products, patients, and animals, were reported as having decreased susceptibility to BACs. Such strains ranged from 8% (49) and 10% (50) up to 40% (61) and 45% (62) of the total number of isolates in these environments.

MICROBIAL MECHANISMS OF TOLERANCE AND RESISTANCE
The mode of action of QACs, including BACs, involves the perturbation and disruption of the membrane bilayers by the alkyl chains and disruption of charge distribution of the membrane by the charged nitrogen (63). Accordingly, susceptibility to BACs may emerge through a combination of mechanisms (56), with many of those related to the cell membrane. The mechanisms proposed in the literature include changes in the overall membrane composition, downregulation of porins, overexpression or modification of efflux pumps, horizontal gene transfer of transposon elements and stress factors, biofilm formation, and biodegradation (Fig. 1B).
Changes in the membrane composition have long been associated with decreased susceptibility to BACs (64, 65). Resistant strains of P. aeruginosa were shown to have different phospholipid and fatty acid compositions compared to a susceptible strain (64). Other work has demonstrated that exposure of Bacillus cereus to BACs induced genes involved in fatty acid metabolism and caused changes in the fatty acid composition of the membrane (66). The authors, however, did not evaluate whether exposed strains exhibited a tolerant phenotype. A strain of E. coli with reduced susceptibility to BACs was shown to have a lipopolysaccharide composition diverse from that of the susceptible strain (64). Recently, it was suggested that Pseudomonas strains could partially adapt to BACs by stabilizing the membrane charge through the increase in polyamine synthesis gene expression and mutations in pmrB (56).
The reduced influx of BACs has been suggested to collaborate to decreased susceptibility to the biocide. Since adsorption of QACs is believed to occur through porins (63), decreased susceptibility could be achieved, in theory, by the downregulation of porins. In accordance, the downregulation of genes for multiple porins has been associated with Pseudomonas (56, 67) and E. coli (53) strains less susceptible to BACs. A lower level of the porin OmpF in the E. coli membrane decreased the strain susceptibility to BACs (64). A causal relationship between a disinfectant product containing BACs and the downregulation of porins was demonstrated for Mycobacterium smegmatis; knockout mutants for Msp porins were less susceptible to the biocide than was the wild type (68). The use of a disinfectant formulation by the authors, however, limits the extent to which the observed effect can be attributed to BACs, other components of the formula, or the mixture. Further studies are required to reinforce the link between tolerance to BACs and the downregulation of porins.
The presence or upregulation of certain families of efflux pumps has been associated with multidrug resistance and decreased susceptibility to BACs across several genera of bacteria. Resistance via increased efflux lowers the concentration of biocide inside the cell, allowing the bacteria to survive against higher environmental concentrations of the chemical. One such case is the Qac proteins, a group of multidrug efflux proteins frequently associated with resistance to BACs (69). In the foodborne pathogen L. monocytogenes, the efflux pump Mrdl (70) and the efflux pump EmrE (71) have been associated with resistance to BACs. In isolates of L. monocytogenes, the susceptibility to BACs and antimicrobials could be restored when the efflux inhibitor was added to the medium containing a previously adapted and resistant strain. This suggested at least a partial role of efflux pumps for resistance to BACs in this organism (55). The efflux protein MdfA contributed to increased resistance to BACs in E. coli (72). For the plant pathogen Pseudomonas syringae, the resistance-nodulation-division (RND)-type pump MexAB-OprM knockout mutant showed increased sensitivity to BACs (73). Another efflux pump, the PmpM of the multidrug and toxin extrusion (MATE) family, from P. aeruginosa, contributed to decreased susceptibility to BACs when expressed in a plasmid in E. coli (74). Accordingly, the exposure of Pseudomonas strains to BACs for a long time resulted in the overexpression of multidrug efflux pump genes (56). Mutations in the nfxB, a regulator for the Mex efflux system, as well as overexpression of both MexAB-OprM and MexCD-OprJ efflux systems and downregulation of mexR, a repressor of the Mex system, was also correlated to decreased sensitivity to BACs in P. aeruginosa (60).
Resistance elements, like efflux pumps, often appear to be associated with other genes, such as mobile elements and transposases (75), which contributes to their dissemination in bacterial populations and maintenance of tolerant and resistant phenotypes. The transposon Tn6188 was associated with strains of L. monocytogenes with increased tolerance to BACs. It included three transposases and a protein which was similar to the Smr, EmrE, and Qac efflux proteins (75). Strains of L. monocytogenes responsible for outbreaks in Canada had a genomic island containing multiple resistance, stress response, and virulence-associated genes (76), which included an efflux pump involved in resistance to BACs (71). Successful horizontal gene transfer of resistance-associated genes from nonpathogenic BAC-resistant Listeria innocua and Listeria welshimeri to the pathogenic L. monocytogenes does occur, and it suggests that more common nonpathogenic strains frequently exposed to the biocide in food-processing plants can act as resistance reservoirs (77).
Factors such as the presence of biofilms can affect the ability of a biocide to control and eliminate microorganisms (78). Biofilms are communities of single- or multispecies microorganisms attached to solid surfaces surrounded by their secreted exopolysaccharide matrix. Biofilm formation represents one of the mechanisms of resistance and tolerance explored by bacteria to avoid and protect themselves against stressful environments (79). Bacterial communities in biofilms have increased ability to survive antiseptics and disinfectants, such as BACs, compared to planktonic cells (80). Exposure of Salmonella enterica to 0.02% of BACs (2-fold higher than the MIC for planktonic cells) for between 10 and 90 min, though it reduced the cell number, failed to eradicate the biofilm (79).
Tolerance to BACs can be greater for multispecies biofilms than for single-species biofilms, as was the case for a dual-species biofilm with L. monocytogenes and Pseudomonas putida (78, 81). This result can be partially explained by the selection pressure for the strain with higher intrinsic resistance to the biocide (78). As mentioned before, Pseudomonas species naturally have a better capacity to survive in higher concentrations of BACs (56, 57). Their presence in the biofilm community could contribute to the increased tolerance compared to other single-species biofilms.
The cases mentioned above demonstrate the better capacity of both single cells and multispecies cells to survive the presence of biocides when in biofilms versus planktonic cells. In addition, the exposure to the biocide can occasionally increase biofilm formation by bacteria (82,–84). Continuous exposure of bacteria to BACs resulted in thicker biofilms, as observed with scanning electron microscopy (SEM) (84). Strains of E. coli isolated from the dairy industry which were less susceptible to BACs and antibiotics also had an increased ability to form biofilms (82). The susceptible strains became strong biofilm formers as well after a period of adaptation (exposure) to BACs (82). Exposure to BACs induced biofilm formation by Staphylococcus epidermidis CIP53124, although the same effect was not observed for other species tested (83).
Last, some microbial communities and species such as Pseudomonas spp. are capable of degrading BACs, converting them into less toxic chemicals and utilizing them as secondary substrates and energy sources (58, 85). Degradation of BACs by dealkylation decreases its toxicity to microorganisms (86). A study of microbial communities suggested that Pseudomonas sp. strain BIOMIG1 was responsible for the biodegradation of BACs, possibly via dioxygenase (57). Degradation of BACs under nitrate-reducing conditions in the presence of a methanogenic culture obtained from an anaerobic digester has also been demonstrated (87). The transformation was determined to be abiotic by a nucleophilic substitution with nitrite that generated benzonitrile (87).
Given the mode of action of BACs through membrane disruption (63) and the above-described general mechanisms of bacterial response by membrane modification (64, 65), overexpression of multidrug efflux pumps (56, 70,–74), and biofilm formation (78, 79, 81), we expect some level of cross-resistance to other antimicrobials, which is described next.

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CROSS-RESISTANCE TO ANTIBIOTICS
Cross-resistance is the phenomenon in which exposure to one chemical grants an advantage for survival in a distinct chemical (44, 45). Cross-resistance between antiseptics, disinfectants, and antibiotics has been thoroughly described in the literature, including cases involving BACs.
The antibiotics oxacillin, cefazolin, and ofloxacin had higher MICs in methicillin-resistant S. aureus (MRSA) strains evolved in the presence of BACs (52). MRSA strains nonadapted to BACs were already resistant to ofloxacin, as defined by EUCAST standards (88), and the MICs of the antibiotic increased up to 4-fold for the adapted strains (52). Similar results were observed with E. coli (53, 54, 89). The laboratory strain E. coli K-12 adapted to increasing concentrations of BACs. This resulted in several antibiotics, such as ampicillin, ciprofloxacin, and nalidixic acid, increasing the MIC on such a strain (53). MICs for multiple antibiotics also increased after adaptation to BACs for the pathogen strain E. coli O157 (54), and the same was observed for E. coli ATCC 11775 and DSM 682 (89). In some cases, E. coli strains adapted to BACs became resistant to antibiotics, as defined by EUCAST (88), such as chloramphenicol (54, 89) and ampicillin (89). The MICs of multiple antibiotics also increased after adaptation to BACs for the bacteria of Salmonella serovar Virchow (54). Such strains became resistant to amoxicillin, as defined by EUCAST (88), after exposure to BACs. L. monocytogenes strains adapted to BACs showed decreased sensitivities to both ciprofloxacin and gentamicin (55). P. aeruginosa evolved in the presence of BACs in continuous culture, on the other hand, exhibited varied sensitivities to antibiotics. The adapted strain PA-29 was less sensitive to ciprofloxacin but more sensitive to minocycline, which is an antibiotic similar to tetracycline (60). The authors believed that the increased sensitivity to minocycline was due to a decrease in the expression of the MexXY-OprM efflux pump system observed for the adapted strain (60), which plays a role in the resistance to an analogue of minocycline (90). They did not confirm this hypothesis, however.
Besides isolated strains, evidence of cross-resistance between BACs and antibiotics has been shown for microbial communities. The exposure of complex microbial communities to BACs not only decreased the overall diversity of the population but also resulted in decreased susceptibility to three clinically relevant antibiotics, penicillin, tetracycline, and ciprofloxacin (58).
Evidence of cross-resistance between BACs and antibiotics is not exclusively limited to controlled laboratory experiments and strains. Following the isolation of S. aureus strains from patients, the MIC of BACs increased for over 100 isolates, which corresponded to approximately half of the isolates. BAC-resistant isolates harboring plasmids with qacA and qacB genes were also less sensitive to multiple antibiotics than were BAC-sensitive ones. The incidence of qac and β-lactamase bla genes in the same plasmids provided strong evidence of a linkage between the selection pressure for resistance to disinfectants, such as BACs, and antibiotics, such as penicillin (91). A similar association occurred for over 50 isolates of carbapenem-resistant Acinetobacter baumannii. Strains obtained from four different hospitals had a high prevalence of both qac and bla genes (92).
In contrast, a study conducted by the Unilever group (93) questioned the correlation between biocide use and cross-resistance to antibiotics for P. aeruginosa. Their statistical analysis revealed a stronger link between biocides and antibiotic susceptibility between strains isolated from clinical settings than from industrial settings, which made the authors conclude that misuse of antibiotics, and not disinfectants, were driving the results. Though interesting, additional studies would be necessary to demonstrate such a conclusion. It is also not clear whether such a correlation would hold for other bacterial species.
The exposure and adaptation to BACs can result in decreased susceptibility to several clinically relevant antibiotics in some species (52, 54, 55, 58, 89, 91), but not all, and several studies have also reported the opposite result, i.e., increased susceptibility to antibiotics (60, 94, 95). Most studies do not report whether the observed increases in MIC for the antibiotics are within the definition of resistance according to clinical standards (88, 96). Such a fact often motivates questioning of the relevance of such studies (48, 93). However, an increase in MIC by itself demonstrates the existence of a cross-resistance effect and should not be ignored. Researchers showed that bacteria that are merely tolerant to antibiotics can develop resistance to them faster (51). The ability of bacteria to survive the presence of the antibiotics, even before the MIC has reached clinical standards, helps keep and accumulate mutations that can eventually result in the emergence of strains resistant to the antibiotics (51).

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CONCLUSION
This review of the literature explored the data currently available on the potential implications of BACs to human safety and the environment in general. There is evidence that the continuous use of biocides and their release to the environment in subinhibitory concentrations may lead to the emergence of tolerant, resistant, and cross-resistant microbial strains, even though there are occasional controversial reports in the literature. Given the reported side effects of BACs, we believe that a thorough analysis of benefits versus risks should be the guidepost for future regulatory and manufacturing use of the compound. Based on the analysis presented here, we have a few recommendations.
We propose restrictions for BAC use in consumer products. Currently, the Centers for Disease Control and Prevention (CDC) recommends (97), and the FDA endorses (98), the use of only water and plain soap by regular consumers (which does not include professionals in health care settings). Despite that, BACs are still commercialized in over-the-counter antimicrobial soaps in the United States. The FDA has recently regulated other chemicals, such as triclosan and chlorhexidine, postponing any decisions regarding the use of BACs (12, 13).
Additionally, updated data regarding the presence of BACs in the environment, water, and soil are required to determine the need for monitoring such a compound and establishing a baseline of its concentration in various environments. Based on the available data, bacteria can survive BAC concentrations found in the environment (Table 1), and cross-resistance between BACs and antibiotics has been reported (52,–55, 58, 89, 91).
Finally, we urge further research on the effect of BAC exposure, both in free form and as part of consumer products, to microbial populations and tissues to elucidate its toxigenic and long-term potential to alter the microbial flora in both a clinical and environmental context. We still have a limited understanding of the mechanistic underpinnings and basis of adaptation and how these link to the emergence of global health challenges like antibiotic resistance. Another link that remains to be determined is the impact of BACs and QACs in general to the human microbiota of the skin, gut, and others, which are lately associated with numerous diseases and performance outcomes (99, 100).
Balancing the concentrations that effectively inhibit bacteria in products, are not toxic to users, and will not leave residual pollutants after disposal is certainly challenging. Limiting the use and regulating and monitoring chemicals such as BACs are important to reduce the negative impacts on humans and the environment.

Benzalkonium Chloride
Benzalkonium chloride accentuated the severity of rhinitis medicamentosa and increased histamine sensitivity in a 30-day study with oxymetazoline nasal spray in healthy volunteers [7,8].
Benzalkonium chloride is widely used as a preservative in eye-drops, in higher concentrations it is used as an antiseptic and disinfectant. In a randomized crossover study two concentrations of benzalkonium chloride, 0.1% and 0.4%, used as a sanitary wipe were compared with a 62% ethyl alcohol emollient gel for safety and acceptability in male genital antisepsis [3]. Of the 39 participants one reported dry skin with 0.1% benzalkonium and a genital ulcer was reported in one patient assigned to 0.4% benzalkonium. No adverse effects were observed during use of the ethanol gel, which was preferred by most men.
Benzalkonium chloride is a quaternary ammonium compound and it is the most commonly used antimicrobial preservative. It was initially used in hard contact lens solutions but is now ubiquitous. Currently, it can be found in most topical multi-use ophthalmic preparations.6
BAK is a detergent that denatures proteins and causes lysis of cytoplasmic membranes and is therefore a potent broad-spectrum antiseptic. As a surfactant, BAK can solubilize the intercellular junctions within the corneal epithelium to enhance drug delivery.10 This also allows increased penetration of BAK and long-term accumulation in ocular tissue leading to amplification of its side effects.
Chronic changes include corneal epithelial cell loss, conjunctival metaplasia, and tear film disruption.11 Increased concentrations of BAK and chronicity of exposure correlate with the severity of these changes.12 Of note, conjunctival cells that were repeatedly exposed to BAK overexpressed the marker Apo2.7, which is associated with apoptosis.13 BAK is also known to induce necrosis of corneal epithelial cells at concentrations of 0.05–0.1% and cellular apoptosis at concentrations of 0.01%.12 Higher concentrations of BAK have demonstrated disruptions in the lipid layer of the tear film and increased tear break up time.11 This is particularly important for patients that already have baseline ocular surface disease and taking multiple topical medications since the side effects of BAK may exacerbate their disease.
Benzalkonium chloride is the most widely used preservative in ophthalmology. It is a quaternary ammonium compound that acts as an antimicrobial agent by denaturing proteins and disrupting cytoplasmic membranes.
Sensory systems Ocular surface disturbances secondary to the toxic effects of benzalkonium chloride lead to a shift in inflammatory mediators and migration of Langerhans cells. Increases in the Langerhans cell count during benzalkonium chloride therapy may be a reliable sign of inflammatory stimulation. In a double-blind, randomized study there was a significant increase in Langerhans cells in the central cornea of 20 healthy volunteers after 12 weeks of application of a benzalkonium chloride solution 0.01% [13c]. This was not associated with dry eyes and the Langerhans cell count returned to normal 4 weeks after the end of the benzalkonium chloride administration.
Benzalkonium Chloride
Benzalkonium chloride (benzalkonium chloride 50% concentrate, National Fish Pharmacy, Tucson, Ariz) is a quaternary ammonium disinfectant occasionally used as an antifungal medication for fish and amphibians. A bath of 2 mg/L benzalkonium chloride applied for 30 minutes on alternate days for a total of three treatments with the cycle repeated once after an 8-day treatment-free interval was used in Western Dwarf Clawed Frogs (Hymenochirus curtipes) diagnosed with Basidiobolus ranarum infection (subsequently determined to be Bd infection).9 This treatment reduced the overall number of deaths in affected animals; however, organisms consistent with Bd were still observed on histopathologic examination, suggesting a fungistatic rather than fungicidal effect. Benzalkonium at 1 mg/L reduced the prevalence but did not eliminate Bd infection in Great Barred Frog tadpoles.114

   
     SYMPTOMS    PREVENTION    FIRST AID
Inhalation    Sore throat. Sore throat. Cough. Laboured breathing.     Use local exhaust or breathing protection.     Fresh air, rest. Fresh air, rest. Half-upright position. Refer for medical attention. 
Skin    Redness. Skin burns. Pain.     Protective gloves. Protective clothing.     Remove contaminated clothes. Rinse skin with plenty of water or shower. Refer for medical attention . 
Eyes    Redness. Pain. Blurred vision. Severe deep burns.     Wear face shield.     First rinse with plenty of water for several minutes (remove contact lenses if easily possible), then refer for medical attention. 
Ingestion    Abdominal pain. Nausea. Vomiting. Burning sensation. Diarrhoea. Shock or collapse.     Do not eat, drink, or smoke during work.     Give one or two glasses of water to drink. Give one or two glasses of water to drink. Refer for medical attention . 

Benzalkonium

Benzalkonium is a quaternary ammonium compound used as a biocide, a cationic surfactant, and as a phase transfer agent Label. Benzalkonium is more commonly contained in consumer products in its salt form, benzalkonium chloride Label. This salt is used in a great variety of international pharmaceutical products such as eye, ear, and nasal drops or sprays as an excipient ingredient serving as an antimicrobial preservative Label. When used as an ingredient in antiseptic and disinfectant products however, it is an active antimicrobial agent 2.

What is benzalkonium chloride?
Benzalkonium chloride is an organic salt used in cleaning agents, classified as a quaternary ammonium cationic detergent. It can be used as an antiseptic and preservative in personal care, healthcare, household, pharmaceutical, and industrial products [1,2].

What is benzalkonium chloride contact dermatitis?
When benzalkonium chloride comes into contact with the skin, it can cause irritant contact dermatitis or allergic contact dermatitis in some individuals.

Benzalkonium chloride is a well-known irritant [1]. Irritant contact dermatitis due to benzalkonium chloride is more common than allergic contact dermatitis from its use.

Who gets benzalkonium chloride contact dermatitis?
Irritant contact dermatitis due to benzalkonium chloride can affect anyone. Allergic contact dermatitis can affect any individual who becomes sensitised or allergic to benzalkonium chloride.

Both irritant and allergic contact dermatitis due to benzalkonium chloride are more likely to occur in people with a compromised skin barrier, such as in people with atopic dermatitis (eczema).

Healthcare workers are also at greater risk of developing contact dermatitis to benzalkonium chloride, given the use of benzalkonium chloride use in sterilisation solutions and antiseptics and disinfectants in healthcare settings [2,3].

Where is benzalkonium chloride found?
Benzalkonium chloride can be found in:

Household cleaning products, such as laundry rinses/detergents [4]
Personal care products [5]
Moisturisers, make-up removers, and cleansers
Shampoos and hair products
Wet wipes
Antiseptics [6]
Eye drops and ophthalmic solutions, including [7]:
Glaucoma treatments
Antibacterial eye drops
Corticosteroid eye drops
Antihistamine eye drops
Lubricating eye drops/artificial tears
Contact lens solutions
Nasal sprays and asthma inhalers (tiotropium)
Dental products
Plaster of Paris [8,9]
Sterilisation solutions for medical instruments [2]
Industrial products used in:
Metallurgy
Agriculture
Fabrication of textiles and dyes [2].
How does benzalkonium chloride contact dermatitis present?
Both allergic and irritant contact dermatitis start at the site of contact with benzalkonium chloride. In prolonged or severe cases, dermatitis may spread to other sites [10,11]. The affected skin may be red, itchy, dry, or scaly, and may also blister or peel.

Symptoms may start to occur hours or days after contact with benzalkonium chloride. Some people may develop periorbital or eye dermatitis or conjunctivitis (red and itchy eyes) after the use of ophthalmic solutions containing benzalkonium chloride [1].

A small subset of people exposed to benzalkonium chloride may develop a rash called granular parakeratosis [4]. Granular parakeratosis is a red or brown patchy and scaly rash that most commonly affects skin folds such as the armpits and groin. As the skin heals, it might peel [12].

It is thought that, in addition to being provoked by occlusion, friction, and sweating, granular parakeratosis can also be provoked by contact with benzalkonium chloride. People with atopic dermatitis are predisposed to this condition [4,12].

Granular parakeratosis due to contact with benzalkonium chloride
Granular parakeratosis due to contact with benzalkonium chloride
Granular parakeratosis due to contact with benzalkonium chloride

How is benzalkonium chloride contact dermatitis diagnosed?
Patch testing is used to diagnose allergic contact dermatitis (type IV/delayed hypersensitivity) to benzalkonium chloride. Benzalkonium chloride is included in the Australian baseline series for patch testing (tested as benzalkonium chloride 0.1% aqueous) [13].

Doubtful or weakly positive patch test reactions to benzalkonium chloride should be interpreted cautiously. These weak positive reactions may represent irritant reactions, rather than allergic reactions [5,14].

The open application test may also be useful to confirm reactions [14].

Doubtful patch test reaction to benzalkonium chloride
Borderline patch test reaction to benzalkonium chloride
Borderline patch test reaction to benzalkonium chloride

What is the treatment for benzalkonium chloride contact dermatitis?
Once the diagnosis of contact dermatitis is confirmed, it is important to avoid contact with any product containing benzalkonium chloride. The affected individual should be aware of the types of products that can contain benzalkonium chloride and should carefully read product ingredient labels.

The avoidance of benzalkonium chloride along with treatment for the acute dermatitis usually results in resolution of the rash over weeks.

In cases of contact allergy, it is likely that the individual will remain allergic to benzalkonium chloride indefinitely, or at least for many years.

Potential cross-reactors
Benzalkonium chloride can cross-react with other quaternary ammonium compounds (preservatives), such as behentrimonium methosulfate, cetrimonium (cetrimide) chloride, and benzethonium chloride [5]. If someone is found to have allergic contact dermatitis to benzalkonium chloride, they should avoid the following ingredients as well:

Alkyl dimethyl benzyl ammonium chloride
Alkyl dimethyl ethyl benzyl ammonium chloride
Behentrimonium methosulfate
Benzethonium chloride
Cetrimonium (cetrimide) chloride
Cetylpyridinium chloride
Distearoylethyl dimonium chloride
Guar hydroxypropyltrimonium chloride [5].
Active dermatitis can be treated, as with any acute eczema/dermatitis, with:

Emollients
Topical steroids
Tacrolimus ointment or pimecrolimus cream
Oral medications if required.

Benzalkonium Chloride is a powerful antiseptic and a cationic surfactant. Benzalkonium Chloride is also known as BZK, BKC, BAK, alkyl dimethyl benzyl ammonium chloride and ADBAC.

Our FeF Benzalkonium Chloride products have proven efficacy against a broad spectrum of microorganisms (gram + and – & acid fast bacteria, yeasts, moulds and enveloped vira such as HIV, herpes and corona). They are effective through a wide pH range, are surface active/adhesive cationic agents and do not add unpleasant odour/colour to finished formulations.

Benzalkonium Chloride biocide, preservative and surfactant associated with severe skin, eye, and respiratory irritation and allergies, benzalkonium chloride is a sensitizer especially dangerous for people with asthma or skin conditions such as eczema. Benzalkonium chloride is found in many household disinfectants and cleaning supplies. Regular use of products containing antimicrobials such as benzalkonium chloride could leads to the development of resistant bacteria in homes and food processing facilities.
functions antimicrobial agent, antistatic agent, cosmetic biocide, deodorant agent, surfactant -suspending agent, antimicrobial, antistatic, deodorant, preservative, and surfactant

a white or yellowish-white, water-soluble mixture of ammonium chloride derivatives having the structure C8H10NRCl, where R is a mixture of radicals ranging from C8H17– to C18H37–, that occurs as an amorphous powder or in gelatinous lumps: used chiefly as an antiseptic and a disinfectant.
A yellow-white powder prepared in an aqueous solution and used as a detergent, fungicide, bactericide, and spermicide. Benzalkonium chloride is a mixture of the chlorides of various organic compounds having a benzene ring attached to an ammoniated alkane.

Industrial Applications of Benzalkonium Chloride (Alkyl Dimethyl Benzyl Ammonium Chloride)

Oil & gas    Biocorrosion presents a major operational hazard for the oil and gas production industries. Benzalkonium chloride (BAC 50 & BAC 80) is used to control the activities of sulphate-reducing bacteria (SRB) in sulphate rich waters and cause deposition of ferrous sulphides which causes pitting of steel equipment and pipelines. SRB are also implicated in oil well souring, and responsible for the liberation of toxic H2S gas. Additional applications of benzalkonium chloride include enhanced oil extraction thro