Benzalkonium chloride

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Benzalkonium chloride
Benzalkonium chloride Structure V.1.svg
Identifiers
CAS number 8001-54-5 YesY
UNII F5UM2KM3W7 YesY
EC number 264-151-6
KEGG D00857 YesY
ChEMBL CHEMBL502109 N
ATC code D08AJ01D09AA11 (dressing), R02AA16
Properties
Molecular formula variable
Molar mass variable
Appearance 100% is white or yellow powder; gelatinous lumps; Solutions BC50 (50%) & BC80 (80%) are colorless to pale yellow solutions
Density 0.98 g/cm3
Solubility in water very soluble
Hazards
EU classification C, N [1]
R-phrases R21/22, R34, R50 [1]
S-phrases S36/37/39, S45, S61 [1]
NFPA 704
Flammability code 0: Will not burn. E.g., water Health code 3: Short exposure could cause serious temporary or residual injury. E.g., chlorine gas Reactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g., liquid nitrogen Special hazards (white): no codeNFPA 704 four-colored diamond
Flash point 250 °C (if solvent based)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 N (verify) (what is: YesY/N?)
Infobox references

Benzalkonium chloride, also known as BZK, BKC, alkyldimethylbenzylammonium chloride and ADBAC, is a cationic surface-acting agent belonging to the quaternary ammonium group. It has three main categories of use: as a biocide, a cationic surfactant, and phase transfer agent in the chemical industry. The chemical is a nitrogenous mixture of alkylbenzyldimethylammonium chlorides of various even-numbered[2] alkyl chain lengths.

Properties[edit]

Benzalkonium chloride is readily soluble in ethanol and acetone. Although dissolution in water is slow, aqueous solutions are easier to handle and are preferred. Solutions should be neutral to slightly alkaline, with colour ranging from colourless to a pale yellow. Solutions foam profusely when shaken, have a bitter taste and a faint almond-like odour which is only detectable in concentrated solutions.

Availability[edit]

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.

Applications[edit]

The applications of benzalkonium chloride are extremely wide ranging,[3] from disinfectant formulations, such as being an active ingredient in Dettol and Lysol brand products, to microbial corrosion inhibition in the oilfield sector, and a multi-surface mould, algae and moss remover.

It is used in:

  • Pharmaceuticals such as eye, ear and nasal drops or sprays, as a preservative
  • Personal care products such as hand sanitizers
  • Skin antiseptics, such as Bactine, to protect scrapes and cuts
  • Throat lozenges[4] and mouthwashes, as a biocide
  • Spermicidal creams
  • Over-the-counter single-application treatments for herpes, cold-sores, and fever blisters, such as RELEEV and Viroxyn
  • Soak solutions for surgical/dental instruments prior to high-level sterilisation
  • Hygienic towelettes and wet wipes
  • Cleaners for floor and hard surfaces as a disinfectant
  • Spray disinfectants for hard surface sanitisation
  • Algaecide for clearing of algae, moss, lichens from paths, roof tiles, swimming pools, masonry and in horticultural greenhouse disinfection

Hand sanitizers based on benzalkonium chloride have been shown to have better residual activity and to be less irritant than alcohol gels.

An advantage of benzalkonium chloride not shared by ethanol-based antiseptics or hydrogen peroxide antiseptic is that benzalkonium chloride-based antiseptics do not cause a burning sensation when applied to broken skin.

Biological activity[edit]

The greatest biocidal activity is associated with the C12 dodecyl & 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.

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. Activity is not greatly affected by pH, but increases substantially at higher temperatures and prolonged exposure times. In a 1998 study utilizing the FDA protocol, a non-alcohol sanitizer utilizing the active ingredient benzalkonium chloride met the FDA performance standards, while Purell, a popular alcohol-based sanitizer, did not. The study found that a benzalkonium chloride-based sanitizer was the most favorable non-alcohol-based hand sanitizer.[5] 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.

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

Toxicology[edit]

Benzalkonium chloride is highly toxic to fish (LC50 = 280 μg ai/L), very highly toxic to aquatic invertebrates (LC50 = 5.9 μg ai/L), moderately toxic to birds (LD50 = 136 mg/kg-bw), and slightly toxic to mammals (LD50 = 430 mg/kg-bw).[6]

The lung and kidney appear to be the target organs of benzalkonium chloride toxicity.[7]

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.[8] A 2014 case study detailing the fatal ingestion of up to 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.[9]

Safety[edit]

Benzalkonium chloride is effective at exceptionally low concentrations; contact lens solutions typically contain exceptionally low (0.002% to 0.01%) concentrations of benzalkonium chloride for effective preservative action.[10] Swan found that repeated use of benzalkonium chloride at 10-fold higher concentrations of 1:5000 (0.02%) or stronger can denature corneal protein and cause damage to the eye.[11] Intraocular benzalkonium chloride is highly toxic to the corneal endothelium in concentrations commonly used extraocularly.[12] Avoiding the use of benzalkonium chloride solutions while contact lenses are in place is discussed in the literature.[13][14] Concentrations of 1% to 2% benzalkonium chloride completely destroy the ocular anterior chamber of small animals within a week.[15] Although historically benzalkonium chloride has been ubiquitous as a preservative in ophthalmic preparations, its toxicity and irritant properties,[16] in conjunction with consumer demand, have led pharmaceutical companies to increase production of preservative-free preparations, or to use preservatives which are less harmful.

Many mass-marketed inhaler and nasal spray formulations contain benzalkonium chloride as a preservative, despite substantial evidence that it interferes with the function of respiratory epithelium cilia. Although some studies have found no correlation between use of benzalkonium chloride in nasal sprays and drug-induced rhinitis,[17] others have found benzalkonium chloride in oxymetazoline nasal spray to worsen rhinitis medicamentosa in healthy volunteers after both long-term use[18] and short-term use.[19] A review of the literature to 2004 by Marple et al.[17] revealed very limited data that demonstrated statistically significant safety concerns for benzalkonium chloride concentrations at or below 0.1%. Graf's review of the literature in 2001 was more balanced in its evaluation of studies finding adverse clinical effects on human nasal tissue, advocating that "without conclusive data regarding BKC and the possibility of harmful effects, the use of nasal formulations without BKC might be a reasonable alternative".[20] A 2006 clinical trial on 43 healthy volunteers reinforced Graf's findings, concluding that "BKC in the concentration used in nasal preparations impaired mucociliary clearance in healthy individuals after 3 weeks of use. Presently, when preservative-free alternatives are available, BKC could be a risk without benefit."[21] These views support Berg et al., who in 1997 demonstrated that degenerative morphological changes in the nasal mucosa of rats were directly attributed to the benzalkonium chloride in topical nasal steroid sprays. They concluded that the deleterious effects of benzalkonium chloride in topical nasal steroid sprays outweighed any benefit, and that “rhinosinusitis can be effectively treated without it”.[22] An extensive review of the literature by Beule in 2010 supports the nasal toxicity of benzalkonium chloride and its role in drug-induced rhinitis and rhinitis medicamentosa.[23] Beule also notes the trend towards substitution of benzalkonium chloride with safer preservatives in nasal decongestant sprays throughout Europe, in line with similar trends in ophthalmic and eye care preparations.

The ototoxicity of benzalkonium chloride was established by Aursnes in 1982 when it was found that solutions of 0.1% benzalkonium chloride instilled into the ears of guinea pigs produced damage to the vestibulum and cochlear. In addition, pathological changes to the tympanic cavity and the perilymphatic spaces of vestibulum and cochlea were found.[24]

As with antibiotics, the use of biocides at sub-inhibitory concentrations can potentially result in resistant organisms, and should be used at recommended dilutions and extended contact time to ensure effective disinfection. While resistance is rarely linked to disinfectant usage at low concentrations, a 2009 study suggested that when used in less than lethal concentrations, benzalkonium chloride solutions could result in increased resistance Pseudomonas aeruginosa, and an increase in resistance of the bacteria to the ciprofloxacin antibiotic, even though the bacterial colonies had not been previously exposed to the antibiotic.[25]

Several human case studies have identified allergic and irritant reactions to benzalkonium chloride, including asthma,[26] contact dermatitis[27][28][29][30][31] and ocular hypersensitivity.[32] Animal studies support the toxicity of benzalkonium chloride on the lung,[33][34][35] including the induction of bronchoconstriction.[36]

Several larger studies, including epidemiological studies, have identified a strong link between the occupational use of quaternary ammonium compounds, specifically benzalkonium chloride, with an increased incidence of asthma[37][38][39][40][41][42][43][44] and rhinitis,[45] especially amongst nurses, cleaners and farmers. Whether these are irritant or immune-mediated responses is not clear, though the hypothesis that bronchial hyperresponsiveness is secondary to epithelial cell damage is supported by the literature.[46] More recently, biopsy results on mucosal epithelium suggest that neurogenic inflammation as a result of epithelial injury may be responsible for irritant-induced asthma and rhinitis.[47][48] Studies on exposure of atopic subjects to ozone[49] and to diesel exhaust particles (DEPs)[50] have identified that co-exposure to irritants and allergens leads to allergic sensitization.

A 2012 study reported that simultaneous ocular exposure to an inert antigen and benzalkonium chloride leads to a significant change in the systemic immune response to the administered antigen in mice, thus suggesting that the preservative's effects could be more profound than the local disruption of the epithelial barrier integrity and raising the question of whether benzalkonium chloride has a role in the induction of allergy.[51]

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.

Benzalkonium chloride is classed as a Category III antiseptic active ingredient by the United States Food and Drug Administration. Ingredients are categorised as Category III when "available data are insufficient to classify as safe and effective, and further testing is required”. Benzalkonium chloride is excluded from the current United States Food and Drug Administration review of the safety and effectiveness of consumer antiseptics and topical antimicrobial over-the-counter drug products, meaning it will remain a Category III ingredient.[52] 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

See also[edit]

References[edit]

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Further reading[edit]

  • Armengot M, Basterra J, Garcia-Bartual E, The influence of anesthetics and vasoconstrictors on nasal mucociliary transport. Acta Otorhinolaryngol Belg. 1989;43(2):149-56. Review. PMID 2481378
  • Bernstein I L, Is the use of benzalkonium chloride as a preservative for nasal formulations a safety concern? A cautionary note based on compromised mucociliary transport. J Allergy Clin Immunol 2000 Jan; 105(1 Pt 1): 39-44. Comment in: J Allergy Clin Immunol. 2000 Sep;106(3):595-6.
  • Graf P, Adverse effects of benzalkonium chloride on the nasal mucosa: allergic rhinitis and rhinitis medicamentosa. Clin Ther 1999 Oct; 21(10):1749-55. PMID 10566570
  • Graf P, Rhinitis medicamentosa: aspects of pathophysiology and treatment.' Allergy. 1997;52(40 Suppl):28-34. Review. PMID 9353558
  • Illum L. Nasal clearance in health and disease. J Aerosol Med. 2006 Spring;19(1):92-9. Review. PMID 16551220
  • Riechelmann H, Deutschle T, Stuhlmiller A, Gronau S, Bürner H: Nasal toxicity of benzalkonium chloride. Am J Rhinol. 2004 Sep-Oct;18(5):291-9. PMID 15586800
  • Rieger, M M: The Skin Irritation Potential of Quaternaries, Soc. Cosmet. Chem., 48, 307-317 (November/December 1997), http://journal.scconline.org/pdf/cc1997/cc048n06/p00307-p00317.pdf
  • Thorup I: Evaluation of health hazards by exposure to Quaternary ammonium compounds, The Institute of Food Safety and Toxicology, Danish Veterinary and Food Administration, http://www2.mst.dk/common/Udgivramme/Frame.asp?http://www2.mst.dk/udgiv/publications/2000/87-7944-210-2/html/kap04_eng.htm
  • Verret DJ, Marple BF. Effect of topical nasal steroid sprays on nasal mucosa and ciliary function. Curr Opin Otolaryngol Head Neck Surg. 2005 Feb;13(1):14-8. Review. PMID 15654209

External links[edit]