Quaternary Ammonium Compounds (QAC)

1. What are Quaternary Ammonium Compounds (QAC)?

Quaternary ammonium compounds (QAC) are positively-charged ammonium ions with four organic groups covalently bonded to nitrogen.

2. Examples of QAC commonly found in household products:

• Benzalkonium chloride (BAC)
• Benzethonium chloride (BEC)
• Alkyl dimethyl benzyl ammonium chloride (C12-16)
• Alkyl dimethyl benzyl ammonium chloride (C14: 60%, C16: 30%, C12: 5%, C18: 5%)
• Alkyl dimethyl ethylbenzyl ammonium chloride (C12-14)
• Alkyl dimethyl ethylbenzyl ammonium chloride (C12-18)
• Didecyldimethylammonium chloride (DDAC)
• Dioctyldimethylammonium chloride

3. Mode of Action of QAC

Although QAC are registered as pesticide by US FDA, but they are generally used as disinfectants in the medical, food preparation and food service environments. They have advantages of broad spectrum of antimicrobial activity against bacteria, virus, protozoa, fungi and algae^[1], non-staining, do not damage fabric or textiles, do not contain the unpleasant odour of chlorine bleach-based products, non-corrosive and cost-effective^[2]. QAC are membrane-active agents. They exhibit antimicrobial properties by interacting with cytoplasmic membrane of bacteria and plasma membrane of yeast, leading to autolysis and leakage of intracellular components of pathogens ^[1][3][4]. However, as QAC are non-volatile, they leave unacceptably high residue on the surfaces.

4. Statutory Maximum Residue Level (MRL)of QAC

(A) European Union: MRL of 0.1 mg/kg for All Food Products

The European Commission (EC) has adjusted the maximum residue level (MRL) of QAC, particularly BAC and DDAC, from 0.5 mg/kg to 0.1 mg/kg for all foodstuffs^[5]. The change is based on the result of monitoring data collected by European Food Safety Authority (EFSA) in the period of November 2012 to April 2013^[6][7]. Among a total of 5472 samples tested, about 5.6% of food samples have contained quantifiable BAC and DDAC residues^[6][7]. The most contaminated food category is milk and milk product, with 90 positive detections among 239 samples tested^[6][7]. BAC has 140 positive detections with the highest mean value of 14.4 mg/kg in the food category of fruits and nuts^[6][7]. DDAC has 191 positive detections with the highest mean value of 3.64 mg/kg in the food category of animal products^[6][7].

(B) United Kingdom: MRL of 0.1 mg/kg for All Food Products

In UK, the revised statutory MRL of 0.1 mg/kg is enforced for DDAC and BAC from August 2015 for all food products^[8]. Thus, a few disinfectant manufacturers carried out assessment of QAC uptake into foodstuffs (salmon, minced beef, sliced bread and lettuce). The surface tested is on polypropylene and stainless steel material after drying for 20 minutes and overnight, with and without prior to surface rinsing^[9]. The QAC concentration used is 2000 ppm in which it is a mixture of 500 ppm BAC (C14), 500 ppm BAC (C16) and 1000 ppm DDAC^[9]. Without rinsing, all the tested food stuffs have exceeded the MRL of QAC at 0.1 mg/kg, with the residue level always higher for polypropylene than stainless steel surfaces^[9]. In addition, the QAC residue level on the foodstuffs is always higher after drying for 20 mins than for overnight. Whereas with rinsing, the QAC residue level is well below MRL at 0.1 mg/kg for all the tested foodstuffs under all conditions^[9]. The results thus suggest that rinsing is required as the second step after disinfection of food contact surfaces with QAC-containing disinfectant^[9].

(C) United States: 200-400 ppm for QAC-containing Disinfectant

On the other hand, US EPA (Environmental Protection Agency) take a different approach for QAC residues on food contact surfaces. Referring to US Code of Federal Regulation (CFR) Title 40 Part 180 for Tolerances and Exemptions for Pesticide Chemical Residues in Food, QAC are exempted for MRL, provided that they are used as active or inert ingredient in antimicrobial pesticide formulations for food contact surface sanitising solutions^[10]. In addition, the application of QAC-containing sanitising solutions must be on semi-permanent or permanent food contact surface with sufficient draining before contact with food^[10]. Thus, the end-use concentration of a QAC-containing disinfectant is limited by EPA from 200 to 400 ppm,depending on the types of QAC^[10].

5. Health and Environmental Hazards of QAC

(A) Occupational Asthma

Studies in 1994 and 2000 has identified QAC as the inducer of occupational asthma in a worker of a household cleaning product factory and in female nurses respectively ^[11][12]. Based on the data collected from the French National Network of Occupational Health Surveillance and Prevention, the work-related asthma due to QAC exposure has increased over the period of 2001-2009, largely in medical and social sector ^[13]. In 2017, the Department of Public Health (Occupational Health Branch) of California has advised workers to avoid using disinfectants with bleach, QAC and glutaraldehyde as they can trigger work-related asthma. The Work-Related Asthma Prevention Program (WRAPP) in California has reported over 250 work-related asthma due to disinfectant exposures in many indoor work settings including hospitals, schools, offices, and manufacturing ^[14]. Besides that, QAC have showed adverse effect on the respiratory system particularly on nasal cavity and lungs in rats on a 14-day inhalation study ^[15].

(B) Skin Irritant

QAC are also significant skin irritant which can lead to red, itchy rashes. For example, one of the common QAC, benzalkonium chloride (BAC) has reported to cause allergic contact dermatitis and has considered as skin sensitizer^[16]. BAC can penetrate skin, initiating skin irritation and inflammation at very low concentration of 0.01 % ^[17]. There are cases of flexural allergic contact dermatitis reported due to the use of antiseptic bath oil which contains about 6 % of BAC^[18]. DDAC has identified as strong dermal sensitizing chemical that can trigger allergic diseases based on the epidemiological studies^[19]. As QAC commonly present in disinfectant products, it can cause contact dermatitis in consumers or nurses, doctors, physicians and cleaning workers due to occupational exposure^[20]. For example, occupational dermatitis has reported for health care workers and cleaners after they used QAC-containing cleaning product to clean floors and surfaces.

(C) Neural Tube Defects and Decrease in Fertility in Rats

In addition, exposure of QAC can cause neural tube defects in both mice and rats. Neural birth defects are birth defects of brain or spinal cord, for example spina bifida (fetal spinal column doesn’t close completely) and anencephaly (absence of a major brain part). The neural tube birth defects in rodents persisted for two generations even after the end of QAC exposure ^[21]. Furthermore, the extensive use of QAC has decreased the fertility in mice or rats due to lower sperm quality and fewer ovulation ^[22].

(D) Environmental Toxicity

The widespread use of QAC as antiseptic, disinfectant, detergents and preservatives has also believed to cause environmental toxicity due to their eventual release into the surface water and wastewater from sewage-treatment plant. QAC are acutely toxic to invertebrates and fish at around 1 ppm and sometimes as low as 0.1 ppm ^[23]. For example, annelids and rotifers species can be killed in 4 h and 19 h respectively at 1 ppm^[23]. Furthermore, at 3-5 ppm QAC concentration, it inhibited the plant growth for green algae and great duckweed^[23]. As QAC are positively charged, it is adsorbed strongly to negative surfaces of sludge, soil and sediments^[24]. High QAC concentration can affect the performance of activated sludge system by inhibiting methanogenesis, resulting in methane inhibition and accumulation of volatile fatty acids^[24]. Also, QAC in wastewater could greatly inhibit the nutrients uptake by algae by decreasing the photosynthesis activities of algal cell^[24]. This results in higher occurrence of eutrophication for wastewater treatment plants ^[24][25].

(E) Evolution of Superbugs

Lastly, long-term exposure of microbial communities to QAC has resulted in change of microbial community structure and increased in the antimicrobial resistance ^[26]. Researchers observed that there are QAC-resistance genes in Staphylococci and Pseudomonas strains in both medical and food industry ^[27]. Besides the increase in QAC-resistant bacteria, exposure of QAC to microbes has potentially increased the co-resistance to clinically relevant antibiotics, by means of a wide range of multidrug efflux pump^[26]. This is a major threat to both environmental and human health due to the evolution of superbugs^[26].

Reference

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[3] Christopher J. Ioannou, Geoff W. Hanlon, Stephen P. Denyer, Action of Quaternary Ammonium Compounds against Staphylococcus Aureus, Antimicrobial Agents and Chemotherapy, 2007, 51(1), 296-306. https://doi.org/10.1128/AAC.00375-06
[4] Gregory Wickham, An Investigation into the Relative Resistances of Common Bacterial Pathogens to Quaternary Ammonium Cation Disinfectants, Bioscience Horizons, 2017, 10, 1-9. https://doi.org/10.1093/biohorizons/hzx008
[5] Commission Regulation (EU) No 1119/2014 of 16 October 2014 amending Annex III to Regulation (EC) No 396/2005 of the European Parliament and of the Council as regards maximum residue levels for benzalkonium chloride and didecyldimethylammonium chloride in or on certain products, Official Journal of European Union, 2014.
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[8] UK Enforcement of MRLs for Benzalkonium Chloride (BAC) and Didecyl Dimethyl Ammonium Chloride (DDAC), Health and Safety Executive, 2015.
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[10] Title 40 – Protection of Environment, Part 180 – Tolerances and Exemptions for Pesticide Chemical Residues in Food, Code of Federal Regulations, 2014.
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[17] Choon Fu Goh, Long Chiau Ming, Li Ching Wong, Dermatologic Reactions to Disinfectant Use During The COVID-19 Pandemic, Clinics in Dermatology, 2020. https://doi.org/10.1016/j.clindermatol.2020.09.005
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[25] Zhijie Liang, Fei Ge, Hui Zeng, Yin Xu, Fang Peng, Minghung Wong, Influence of Cetyltrimethyl Ammonium Bromide on Nutrient Uptake and Cell Responses of Chlorella vulgaris, 2013, 138-139, 81-87. https://doi.org/10.1016/j.aquatox.2013.04.010
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[27] G.Sundheim, S.Langsrud, E.Heir, A.L.Holck, Bacterial Resistance to Disinfectants Containing Quaternary Ammonium Compounds, International Biodeterioration & Biodegradation, 1998, 41(3-4), 235-239. https://doi.org/10.1016/S0964-8305(98)00027-4