Utilization of physical and chemical microbial load reduction agents for SARS-Co V-2 : Toxicity and development of drug resistance implications

2Department of Pharmaceutical and Medicinal Chemistry, Bayero University Kano, Kano, Nigeria. 3Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Bayero University Kano, Kano, Nigeria. 4National Biotechnology Development Agency, Abuja, Nigeria. 5School of Medicine, American University of Integrative Sciences, Bridgetown, Barbados. 6Department of Physiology, Medical College for Women and Hospital, Dhaka, Bangladesh. 7Department of Microbiology, Jahangirnagar University, Dhaka, Bangladesh. 8Faculty of Medicine and Defence Health, Universiti Pertahanan Nasional Malaysia (National Defence University of Malaysia), Kem Perdana Sungai Besi, Kuala Lumpur, Malaysia.


INTRODUCTION
The outbreak of severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) disease, mostly called coronavirus disease-19 , has proven that new infectious diseases *Corresponding Author Mainul Haque, Faculty of Medicine and Defence Health, Universiti Pertahanan Nasional Malaysia (National Defence University of Malaysia), Kem Perdana Sungai Besi, Kuala Lumpur, Malaysia E-mail: runurono @ gmail.com can spread in humans rapidly to pose a global public health challenge, especially where the containment of the disease is difficult (García de Abajo et al., 2020). This sudden outbreak of COVID-19 has surprised the vast majority of healthcare practitioners and scientists, who are working tirelessly to educate people and combat the pandemic (Rai et al., 2020). The SARS-CoV-2 is an enveloped positive-sense, single-stranded ribonucleic acid (RNA) virus belonging to the class of betacoronaviruses Rahman et al., 2021). Severe Acute Respiratory Syndrome Corona Virus-1 (SARS-CoV-1) and Middle East Respiratory-Corona Virus (MERS-CoV) are endemic viruses that have previously wreaked havoc on human healthcare systems through animal-to-human, human-tohuman, and, recently reported, human-to-animal transmissions making it spread quickly (Ayipo et al., 2021;Banik et al., 2015;Cleary et al., 2020). Currently, no approved antiviral drug is used to treat SARS-CoV and MERS-CoV infections, but the deployment of several effective vaccines against SARS-CoV-2 infection is in progress Amanat and Krammer, 2020;Habas et al., 2020;Rahman et al., 2021). The SARS-CoV-1 and MERS-CoV are responsible for the epidemics of SARS in 2003 and MERS in 2012. The viruses are easily transmitted through droplets and air . The effective and quick control of SARS-CoV-2 outbreaks can be achieved through the epidemiological knowledge of the disease, accurate viral detection, preventive strategies, and acceptable hygiene practices to decrease the risk of transmission. Although health practitioners in both developed and developing countries are overwhelmed with the pandemic, the need for a solid motivation to limit the spread and adopt future strategic plans for effective prevention remains necessary (Boyce and Pittet, 2002).
Viruses such as influenza, the common cold rhinovirus, and CoVs can be easily transmitted from an infected person to a healthy individual through coughing, sneezing, talking, and sometimes breathing (Asadi et al., 2020). Suggestively, these physiological actions produce aerosol droplets of various sizes and may carry infectious viruses that could initiate new infections, especially when inhaled by individuals (García de Abajo et al., 2020). The people at high risk of hospital-acquired infections such as SARS-CoV-2 are the healthcare professionals (HCPs) and emergency rescue workers . This was evident from early reports of several HCPs infected from the origin of SARS-CoV-2, Wuhan, China . Not only are these exposed HCPs at higher risk, but they are also potential carriers of the virus, especially those with closer contact with patients such as dentists, emergency physicians, and maxillofacial surgeons. Hence, there is a need for regular disinfection, decontamination, and proper sterilization techniques to prevent viral transmission (Krajewska et al., 2020;Peng et al., 2020).
One of the recommended practices for inactivating and removing pathogenic organisms from surfaces is disinfecting and sterilizing agents through stipulated procedures and protocols. Disinfection is a process of reducing virtually all recognizable pathogenic microorganisms using chemical agents only (Rai et al., 2020). Meanwhile, sterilization eliminates or destroys all microbial life forms by applying both chemicals and heat methods. Both sterilization methods at large are routinely carried out in healthcare facilities (Hassandarvish et al., 2020).
There are scientific guidelines and protocols for selecting and using disinfectants in hospitals, laboratories, homes, and public places. This is to minimize health risks and ensure the appropriate use of chemicals (Rutala et al., 2000). However, recently, due to the outbreak of COVID-19, there has been an upsurge in the indiscriminate use of alcohol-and iodinebased agents with no adherence to the stipulated guidelines and monitoring protocols for preventing and inactivating SARS- CoV-2 (McDonnell and Russell, 1999). This malpractice exposes humans to public health dangers and environmental hazards. It also has negative consequences on biodiversity due to the toxicological effects of such disinfectants (Agnelo et al., 2020;Nabi et al., 2020). Therefore, the excessive use of these antimicrobial agents has raised much public health and environmental concerns.
irradiation (Abraham et al., 2015). Ultraviolet (UV) and visible light inactivation is often used along with solar power and can be used alone, such as for black-box solar heaters or solar water heat exchangers. Light is not exposed to the media (Safapour and Metcalf, 1999). It is necessary to use a thermometer or indicator as sunlight may not supply enough heat (Ray and Jain, 2014).

b. Microwave
1-350 GHz is the lethal range of microwave for microbes, with deadly peak effects at 60 GHz (Fleming, 1944;Green et al., 1997). Microwaves kill microbes by affecting proteins and depend highly on the molecules' bound water content. Absorbed energy is converted to heat energy (Hong et al., 2014;Park et al., 2006). It has the advantage of fast heating and lowers energy expenditure, but they need more equipment and technical expertise (Green et al., 1997).

Sonication
Sonic or supersonic waves kill microbes by a rapid compression and liquid release, tearing the suspended cells into pieces (Otte et al., 2018;Rahn, 1945).

Radiation processes
Electromagnetic radiation (UV light and gamma rays) and particulate radiation such as accelerated electrons are used for sterilization. Radiation targets microbial DNA to kill them. Free radical is produced when exposed to gamma rays, whereas UV light causes excitation. Cobalt-60 is the source of gamma rays. 260 nm is the optimum wavelength of UV sterilization, and a mercury lamp that gives peak emission at 254 nm is a suitable source (Rattanakul and Oguma, 2018).

Pulsed electric field
A system that produces an electric field utilizing twoelectrode generates acoustic and shock waves, UV irradiation, and reactive oxygen species. Although it is unaffected by particles, this process is expensive and very effective for disinfection (Anpilov et al., 2002;Frey et al., 2013;Gusbeth et al., 2009;Poyatos et al., 2011;Yadollahpour et al., 2014).

Hydrodynamic cavitation
Despite having a similar mechanism as sonication, high pressure and local temperatures are achieved by rapid mixing or pumping the process solution. Steam injection, shock wave, highspeed homogenizer, high-pressure systems, and liquid whistle are the types of reactors used (Gogate, 2011;Gogate and Pandit, 2010).

Plasma emission and shock waves
Plasma emission and shock waves, visible light emission, and UV are used for disinfection. The inactivation mechanism is thought to be irreversible destruction of membrane for bacteria and DNA and RNA damage for viruses (Mosqueda-Melgar et al., 2008;Sale and Hamilton, 1967;Sabino et al., 2020;Stratton et al., 2015).

Ultrasound
It is a complex process that inactivates microbes by the growth of bubbles. Dust or bacteria become part of the bubbles in company with vapor and gas. When the bubble collapse, microbes are exposed to high pressure (100 MPa) and temperature (5,000 K) for a few seconds, which cause their inactivation (Crum, 1994;Flint and Suslick, 1991;Suslick et al., 1999;Tandiono et al., 2011).

Magnetic treatment
Magnetic treatment is a new method of physical disinfection of water. The magnetic field creates a polarizing effect on ions and water molecules when the water and its impurities are in a state of thermodynamic equilibrium. There are several different hypotheses about the mechanism of magnetic treatment, and more research is needed for a better understanding (Biryukov et al., 2005;Li et al., 2020b;Vaskina et al., 2020).

Filtration
It is the process that removes microbes without destroying them. Trapping, sieving, and adsorption within the matrix of filter material is the mechanism involved in the filtration technique (Nnadozie et al., 2015).

Chemical disinfectants and sterilant
Disinfectants are chemically diverse agents with small and usually lipophilic molecules that eliminate many pathogenic organisms and penetrate the skin quickly to induce a direct reaction. Therefore, they can destroy pathogenic microorganisms on surfaces (Chernyshov and Kolodzinska, 2020). There are different types of chemical disinfectants, and they kill microbes through other mechanisms.

Alcohols
Other than bacterial spores, alcohol can kill microbes efficiently. The antimicrobial effect of alcohol depends on the presence of water, as proteins tend to denature quickly in the presence of water. Ethyl alcohol and isopropyl alcohol are most commonly used in healthcare settings, and their optimum bactericidal concentration is 60%-90% v/v in water. Alcoholbased disinfectant activity against microbes drops when the concentration is below 50% (Block, 2001;Morton, 1950;Jing et al., 2020;McDonnell and Russell, 2001). Concentration between 60% and 80% of ethyl alcohol is an effective virucidal agent for all lipophilic viruses and many hydrophilic viruses such as rotavirus and adenovirus, but not hepatitis A virus or poliovirus (Mbithi et al., 1990;Tyler et al., 1990). On the other hand, isopropyl alcohol is active against lipid viruses (Armstrong and Froelich, 1964;Kampf et al., 2020).

Chlorine and chlorine compounds
The most commonly used chlorine disinfectants are the hypochlorites, available in solid (sodium hypochlorite) and liquid (calcium hypochlorite) forms as a household bleach sodium hypochlorite is used as an aqueous solution at 5.25%-6.15% concentration (Rutala and Weber, 1997). Sodium dichloroisocyanurate, chlorine dioxide, and chloramine-T are the chlorine-releasing agents used in healthcare settings as their bactericidal effect is more prolonged (Clasen and Edmondson, 2006;Coates and Wilson, 1989). There are various possible mechanisms of action for these compounds, although the precise mechanism is not known. Sulfhydryl enzymes and amino acids oxidation, losing intracellular contents, protein synthesis inhibition, decreasing uptake of nutrients and oxygen, respiratory component oxidation, DNA breaks, decreased production of adenosine triphosphate, ring chlorination of amino acids, and depressed DNA synthesis are the possible modes of action of these disinfectants (Block, 2001). The combination of these factors or the effect of the disinfectant on a binding site may cause the death of microbes (Hernández-Navarrete et al., 2014).

Formaldehyde
Formaldehyde is an effective disinfectant and sterilant in its aqueous and gaseous form (Kinyoun, 2006;Lin et al., 2020). The aqueous solution of formaldehyde is known as formalin which contains 37% formaldehyde (McCulloch and Costigan, 1936). Alkylation of the ring nitrogen atoms present in purine bases and sulfhydryl amino groups of the proteins by formaldehyde causes the microbe to be inactivated (Block, 2001). Formaldehyde is a potent carcinogen, and the US Federal Agency on Occupational Safety and Health Administration instructed it to be handled carefully in the workplace. It can be fatal if ingested by employees and can cause skin irritation and respiratory problems (Costa et al., 2019;Sweatt, 2020).

Glutaraldehyde
It is a saturated dialdehyde which is not only an effective disinfectant but also a sterilant. An aqueous solution of glutaraldehyde is not sporicidal unless activated by adding an alkylating agent (pH 7.5-8.5) with a shelf-life of a minimum of 14 days. To overcome this limitation, a novel formulation such as glutaraldehyde-phenol-sodium phenate, potentiated acid glutaraldehyde, and stabilized alkaline glutaraldehyde is used, having its microbicidal activity for 28-30 days (Miner et al., 1977;Sehmi et al., 2016). Glutaraldehyde kills microbes by altering DNA, RNA, and proteins by alkylating the hydroxyl, carboxyl, sulfhydryl, and amino groups (Block, 2001). Because of its excellent biocidal property, ability to work even in the presence of organic load (20% bovine serum), and noncorrosive action to various equipment, it is used widely in healthcare facilities Rutala et al., 1991).

Quaternary ammonium compounds (QACs)
They are an established disinfectant and good cleaning agent. However, cotton and gauze pad-like materials and highwater hardness can make them less microbicidal. The active ingredient can be absorbed by cotton and gauze materials and insoluble precipitates, respectively (Gerba, 2015;Nasr et al., 2018). The disintegration of the cell membrane, essential cellular protein denaturation, and energy-producing enzyme inactivation caused by these compounds kill microbes Ogilvie et al., 2021;Pratelli, 2008;Saknimit et al., 1988). Alkyl didecyl dimethyl ammonium chloride, alkyl dimethyl benzyl ammonium chloride, and dialkyl dimethyl ammonium chloride are some of the QACs used in healthcare settings. Fourthgeneration QACs, also referred to as twin-chain or dialkyl quaternary (e.g., dioctyl dimethyl ammonium bromide and didecyl dimethyl ammonium bromide), are capable of retaining their activity in hard water and also can tolerate anionic residues (Block, 2001).

Phenolics
Phenols are protoplasmic poisons at high concentrations; they precipitate the cellular proteins by penetrating and distorting the cell wall. Phenol derivatives of low molecular weight and phenols of low concentration inactivate (Walsh et al., 2019), essential enzyme systems cause critical metabolite leakage, resulting in bacterial death (Block, 2001). Ortho-phenylphenol and orthobenzyl-para-chlorophenol are commonly used phenol derivatives found in hospital disinfectants, and they work more efficiently than the parent compound. Porous materials absorb the phenolics, and the residual disinfectant is capable of irritating tissue. Para-tertiary butyl-phenol and para-tertiary amyl phenol in phenolic detergent can cause skin depigmentation (Kahn, 1970).

Peracetic acid
It is an effective agent that works against all microbes and has several advantages. It does not leave any residue, can remove organic material, and does not disintegrate into harmful products such as acetic acid and reactive oxygen species (Ao et al., 2021;Block, 2001;Kahn, 1970). Although not clearly understood, it is assumed to work similarly to other oxidizing agents such as protein denaturation, disruption of cell walls permeability oxidation of sulfhydryl and sulfur bonds in enzymes, proteins, and other metabolites (Block, 2001;McDonnell and Russell, 1999). Diluted peracetic acid solution (e.g., 1%) is less stable, but with higher concentration (e.g., 40%), it retains its activity for a more extended period. Its corrosive effect on several metals (e.g., steel, galvanized iron, copper, bronze, and brass) can be minimized by pH modification and additives (Ao et al., 2021;Block, 2001;Kahn, 1970).

Hydrogen peroxide
Hydrogen peroxide is a strong and effective biocidal agent and works against a wide range of microbes and spores. It produces destructive hydroxyl free radicals that attack DNA, essential cell components, and membrane lipids. Although aerobic and facultative anaerobes with cytochrome systems can withstand metabolically produced hydrogen peroxide, they cannot tolerate the concentration of hydrogen peroxide in disinfectants (Block, 2001;Ríos-Castillo et al., 2017). 3% hydrogen peroxide is an effective disinfectant when used on inanimate surfaces, and 3%-6% concentration is used for soft contact lenses (Silvany et al., 1990), ventilator (Judd et al., 1968, endoscope (Vesley et al., 1992), fabrics (Neely and Maley, 1999), and tonometer biprisms (Lingel and Coffey, 1992).

Ortho-phthalaldehyde
Ortho-phthalaldehyde (OPA) is a clear, pale-blue liquid that contains 0.55% 1,2-benzenedicarboxaldehyde with a pH of 7.5. Despite having a similar mode of action as glutaraldehyde, OPA has less potency in cross-linking. It is reimbursed by its lipophilic aromatic nature that assists its uptake by the outer layer of Gram-negative bacteria and mycobacteria (Simons et al., 2000;Walsh et al., 1999). OPA kills spores by blocking their germination process (Cabrera-Martinez et al., 2002). Although excellent material compatibility, it stains protein in gray and should be handled carefully .

Iodophors
Iodophors are a mixture of iodin and its solubilizing agent or carrier. They are iodine-releasing agents. The released iodine can penetrate the microbial cell membrane and damage proteins by attacking the sulfuryl and disulfide bonds. It can also damage nucleic acid. Povidone-iodine is the most common and widely used iodophor. They are nonstaining, nontoxic, and nonirritating (Block, 2001;Eggers et al., 2018a;2018b;Gharpure et al., 2020;Kariwa et al., 2006).

CORONAVIRUSES
The main component of the virus, a nucleic acid, is surrounded by capsids which protect the nucleic acid and facilitate binding of the virus to the host cell. The nucleic acid is the component that codes for the essential element for viral replication (Martin, 2003). Viruses are incapable of replicating when they are outside of the host cell. Still, they can survive for a defined time depending on the environment and infect a suitable host cell to replicate. Viruses use the host cell machinery to replicate (Yeargin et al., 2016). They can infect various host cells, including bacteria, and cause disease (Sidwell et al., 1966). CoVs are the member of the subfamily Orthocoronavirinae from the family Coronaviridae of the order Nidovirales. They are +ssRNA enveloped viruses (V'kovski et al., 2021). They can infect a wide range of hosts (Saif et al., 2019) and cause respiratory disease. Although human coronaviruses (HCoVs) cause mild respiratory diseases and common cold in humans, the adapted forms from the nonhuman host such as SARS-CoV-1, MERS-CoV, and SARS-CoV-2 are capable of causing severe illness (Xu, 2020a).
The novel coronavirus, SARS-CoV-2, contains spike glycoprotein that binds to the sialic acid receptor of the host cell (Tortorici et al., 2019). It is an enveloped virus and causes respiratory infection (V'kovski et al., 2021;Xu, 2020b). The binding of the spike glycoprotein to the specific receptor of the human respiratory tract, angiotensin-converting enzyme-2, facilitates viral entry. The low endosomal pH helps with the proteolytic activation of the spike glycoprotein. So, the coating structure that enables the access of the virus to the host cell is a crucial target of antiviral drug discovery . The disinfectants inactivate viruses by causing damage to either their proteins or their genome (Alvarez and O'Brien, 1982;Dennis Jr et al., 1979;Kim et al., 1980;O'Brien and Newman, 1979;Roy et al., 1981). Disinfecting agents used for different coronaviruses are shown in Table 1.

STABILITY OF SARS-COV-2 IN AIR AND ON DIFFERENT SURFACES
The SARS-CoV-2 is spread on the dry surfaces through respiratory droplets secreted from the infected person's nose, mouth, and eyes and is considered the primary route of transmission of this virus . Low humidity and temperatures increase the viability of SARS-CoV-2 in the droplets (Moriyama et al., 2020). HCoVs can remain infectious for 2 hours to 9 days at room temperature on different surfaces . This time can be up to 28 days for veterinary coronaviruses, and an increase in the temperature to 30°C or more induces shorter endurance of coronavirus . Studies by Kampf et al. (2020) and van Doremalen et al. (2020) also showed that SARS-CoV-2 could survive on a variety of surfaces from hours to days (Table 2) (Choi et al., 2021;van Doremalen et al., 2020). The SARS-CoV-2 was more stable on plastic and stainless steel than on copper and cardboard, and the viable virus was detected up to 72 hours, and its titer was significantly reduced afterward (van Doremalen et al., 2020). The virus can remain infectious and feasible in aerosols for 3 hours and on surfaces up to days (van Doremalen et al., 2020). The persistence time on inanimate surfaces varied from minutes to days, depending on environmental conditions. SARS-CoV-2 can be sustained in the air in closed unventilated buses for at least 30 minutes without losing infectivity. Additionally, MERS-CoV can survive 28 days or more . Absorbent materials like cotton are safer than unabsorbent materials for protection from virus infection. The risk of transmission via touching contaminated paper is low . However, the significance of indirect communication through contamination of inanimate surfaces is uncertain and requires further investigation (Armstrong and Froelich, 1964;Choi et al., 2021;Moriyama et al., 2020;van Doremalen et al., 2020).

PHYSICAL INACTIVATION OF SARS-COV-2
The inactivation of airborne viruses and those deposited on active surfaces reduces disease transmission, which is a necessary counterpreventive measure in combating the COVID-19 pandemic. Physical factors such as temperature and humidity greatly influence the survival of viruses on surfaces. However, scientists reported the rapid inactivation of gastroenteritis virus (TGEV) and mouse hepatitis virus (MHV) at all humidity levels (Casanova et al., 2010). Furthermore, in an indoor space, heat and irradiation such as UV inactivated TGEV and MHV (Casanova et al., 2010;Garcia de Abajo et al., 2020). Nevertheless, a study has shown that the spread of SARS-CoV-2 is not strongly affected by the change in weather conditions (Casanova et al., 2010). Therefore, it is crucial to efficiently decrease viral transmission rates within indoor spaces such as shared offices, classrooms, healthcare facilities, and public transport vehicles. The use of physical disinfecting agents in such areas is easily deployable and economically affordable (Garcia de Abajo et al., 2020).
Moreover, UV-C is recently used in reducing air transmission of viruses. It is also an essential method of inactivating viruses and, therefore, can experiment in the disinfection process against the SAR-CoV-2 (Beck et al., 2017;Mphaphlele et al., 2015;Xia et al., 2019). However, precautionary measures should be adopted in applying UV-C light as a sterilization method because it can significantly damage eyes and produce carcinogenic effects considerably if the recommended limit exceeds (Garcia de Abajo et al., 2020).
Several other scientific studies also highlighted the importance of UV-induced viral inactivation. Inagaki et al. (2020) reported the concentration-dependent rapid inactivation of SARS-CoV-2 upon exposure to UV light-emitting diode (LED) of wavelength 280 ± 5 nm and subsequent decrease in cytopathic effect. In addition to heat and UV, sunlight is one of the physical inactivation processes of the SARS-CoV-2 virus. It was reported that bright day sunlight above sea level causes variations in the life cycle of CoVs and rapidly inactivates the virus on the surface. This implies that viruses in indoor and outdoor spaces are affected by the different amounts of radiation. However, this needs to be further investigated to ascertain the effects of sunlight ( Fig. 2) (Ratnesar-Shumate et al., 2020). The variations in the reported cases of CoV infection across various temperate regions have not realistically proven the hypothesis. For instance, the total reported cases in France as of November 2020 stand at 2,086,288 (3.19%). In comparison, a less temperate Ukraine recorded 583,510 (1.34%) with a death rate of 2.26% and 1.78%, respectively (Quinn et al., 2021), indicating the need for further investigation to assert the hypothesis.
It is imperative to note that fomites, inanimate objects contaminated with infectious agents, serve as a medium for spreading endemic diseases, including coronaviruses. Therefore, there is a need to decontaminate and inactivate surfaces and other indoor places to avoid spreading the disease (Castaño et al., 2021;Choi et al., 2021). Physical inactivation is relevant to disease control due to the destruction of the glycoprotein and the lipid membrane bilayer of the virus leading to molecular structural damage. The UV-C light is proven to effectively reduce the cytopathic effects of the virus, reducing the air transmission of viruses. Hence, UV-C light is essential for further advances in curbing the spread of viral diseases, including SARS-CoV-2.  Inactivation rates for SARS-CoV-2 suspended in simulated saliva as a function of UVB irradiance. Linear regression fits SARS-CoV-2 suspended in simulated saliva and recovered from stainless steel coupons following exposure to different light conditions. Inactivation rates for exposure to any level of UVB irradiance were significant than those observed in darkness (p < 0.001). Additionally, the inactivation rates observed for UVB irradiances of 1.6 and 0.7 W/m 2 were significantly greater than those observed for 0.3 W/m 2 (p ≤ 0.065). The slope of the regression line for darkness was not significantly different from zero. Goodness of fit parameters, specifically r 2 and standard deviation of the residuals (RMSE), for each fit were (

CHEMICAL INACTIVATION OF SARS-COV-2
Some of the most influential and domestic-friendly disinfectants are recommended by the World Health Organization (WHO) for hand rubbing include ethanol (80% v/v) and isopropanol (75% v/v) . Classes and examples of common disinfectants are depicted (Table 3) (Al-Sayah, 2020; Benzoni and Hatcher, 2019;Kim et al., 2018), commonly applied during the COVID-19 pandemic (Chernyshov and Kolodzinska, 2020). Unfortunately, disinfection alone may not prevent the spread of any pandemic. General hygienic conditions such as hand washing using soap and water, antiseptic, and hand sanitization, especially using alcohol-based sanitizers or hand rubs, are essential in curbing pandemic spread (Gold et al., 2021). Gold and Avva (2018) reported the WHO definition of alcohol-based hand rub (ABHR) as "an alcohol-containing preparation (liquid, gel or foam) designed for application to the hands to inactivate microorganisms and temporarily suppress their growth. Such preparations may contain one or more types of alcohol, other active ingredients with excipients, and humectants" (WHO, 2009). Other classes that are nonalcohol-based are also available. Still, they are less preferred by health agencies like the Centre for Disease Control and Prevention (CDC) (Berardi et al., 2020) and the WHO (Kampf and Kramer, 2004;Todd et al., 2010) in fighting COVID-19. They have low efficacy and a narrow spectrum of activity compared to alcohol-based products and hence the recommendation and acceptability of alcohol-based products .
Most disinfectant products contain additional ingredients which aid in fighting several pathogenic organisms. Such active ingredients include QACs, hydrogen peroxide, peroxyacetic acid, isopropanol, ethanol, sodium hypochlorite, octanoic acid, phenolic, trimethylene glycol, L-lactic acid, and glycolic acid ( Table 2) (Nawrocki et al., 2010). On many occasions, the products are designed to achieve particular needs and avoid the harmful effects of the chemicals involved. For instance, isopropanol is irritating to the skin; as such, emollients (glycerol or propylene glycol) are added to decrease possible skin irritations when applied (Berardi et al., 2020). It is essential to carefully read the labels of all products before use to avoid toxic and harmful effects on human health.

IODINE-BASED AGENTS
Povidone-iodine, chemically known as polyvinylpyrrolidone (PVP-I), is an iodine-based synthetic polymer obtained by polymerizing a monomeric compound N-vinylpyrrolidone. The PVP-I can incorporate hydrophilic and hydrophobic compounds due to its chemical characteristics such as nontoxic, stability of pH, high temperature-resistant, compatibility, inert, and biodegradable properties. These properties enable the PVP-I to be formulated in various domestic personal hygiene solutions to effectively prevent pathogenic microorganisms, including the CoVs disease (Kurakula and Rao, 2020). The virucidal activities of five personal hygiene products including antiseptic solution (10%), skin cleanser (7.5%), gargle/mouth wash (1%), gargle/mouth wash (1.0%, 1:2 dilution), and throat spray (0.45%) were reported to contain PVP-I at different percentages. They have been assessed against SARS-CoV-2 using suspension, cytotoxicity (on Vero E6 cells), and virus kill-time assays. The products demonstrated satisfactory virucidal activity of ≥ 99.99%, equivalent to 4 log 10 reductions of viral titer against SARS-CoV-2 just within a 30 s period of contact. Anderson et al. (2020) reported the virucidal activity of different PVP-I products (Table 4) (Hassandarvish et al., 2020). Similar action has been previously Table 2. Sustainability of SARS-CoV-2 on different surfaces as reported by Choi et al. (2021) and van Doremalen et al. (2020).  reported for the products against SARS-CoV-1 and MERS-CoV, suggesting their applicability as effective disinfectants in preventing CoV infections (Hassandarvish et al., 2020). In another separate study, the virucidal effects of an oral antiseptic PVP-I solution at concentrations of 0.5%, 1.0%, and 1.5% were evaluated in vitro against SARS-CoV-2 using 70% ethanol as a positive control. The infectivity of the virus was demonstrated and quantified using dilution assay and the reduction of log value (LRV) in comparison with the positive control (ethanol) and negative control (water). The results indicate that SARS-CoV-2 viruses become inactivated by all tested concentrations after 15 s of administration better than 70% ethanol, whose inactivation effect was later 30 s. At each concentration, 0.5%, 1.0%, and 1.5% solutions show a virus titer and LRV of < 0.67 and 3.0, respectively, compared to 70% ethanol with virus titer of 1.5 and LRV 2.17 after 15 s. The oral antiseptics display a potent virucidal activity even at a low concentration of 0.5%, suggesting its applicability and effectiveness in preprocedural oral rinsing as adjunctive treatment in patients infected with SARS-CoV-2 (Bidra et al., 2020b). Similarly, PVP-I oral antiseptic rinses show more potent virucidal activity in vitro at concentrations of 0.5%, 1.25%, and 1.5% compared to hydrogen peroxide (H 2 O 2 ) at 1.5% and 3.0%. At the same time, ethanol and water serve as positive and negative controls, respectively. Subsequently, the SARS-CoV-2 strains were entirely inactivated by the tested concentrations of PVP-I after 15 and 30 s of contact time. Simultaneously, minimal virucidal effects were observed with H 2 O 2 at lower and higher concentrations, suggesting PVP-I preprocedural oral rinsing preference over H 2 O 2 (Bidra et al., 2020a). The PVP-I at a concentration of 0.23% was reported to rapidly inactivate SARS-CoV, MERS-CoV, influenza virus A (H1N1), and rotavirus after 15 s of exposure. In another study, when used as mouthwash at 7% concentration, PVP-I possesses virucidal activity against SARS-CoV-1, MERS-CoV, and influenza virus A quantitatively using suspension assay. Furthermore, PVP-I at a dilution ratio of 1:30 with water (concentration of 0.23%) inactivated SARS-CoV-1, MERS-CoV, influenza virus A, and rotavirus and significantly decreased viral titer value from 4.00 to 6.00 log 10 TCID 50 /ml, equivalent to ≥ 99.99% just after 15 seconds of contact time. However, Eggers et al. (2018a) and Bidra et al. (2020b) reported little or no significant change when extending contact time (Table 5). Therefore, PVP- Table 4. Virucidal activity of PVP-I products against SARS-CoV-2 virus with 30s contact time as rreported by Hassandarvish et al. (2020).
I's comprehensive coverage and effective inactivation make it an oropharyngeal agent of choice for protecting individuals from viral infections (Eggers et al., 2018a). Some PVP-I products were reported to effectively reduce SARS-CoV-2 infectivity below detectable limits, similar to 70% ethanol (Kariwa et al., 2006). They have overwhelming acceptability as disinfectants due to their broad virucidal activity against many pathogens. Therefore, this suggests a strong indication that PVP-I products are adequate for the inactivation of SARS-CoV-2 and other pathogenic microorganisms. However, the inefficiency of iodine-based compounds has been documented earlier for environmental/ surface disinfection of hepatitis A virus (HAV). Similarly, few other studies found Iodophors with less virucidal efficacy (Bond et al., 1983;Lloyd-Evans et al., 1986;Sattar et al., 1989). In addition, many iodine-based products and their by-products such as diatrizoate, iomeprol, and iopamidol are unavailable for surface disinfection due to their staining and toxicity pollution properties to the environment and in some instances highly persistent and difficult to remove from surfaces. Accumulation of such compounds in large amounts might pose potential threats and destabilization of the ecosystem. Therefore, iodine-based products are mostly not recommended for surface disinfection (Steger-Hartmann et al., 2002).

ALCOHOL-BASED AGENTS
Alcohol-based hand preparations containing isopropanol, ethanol, n-propanol, or their combinations are undoubtedly some of the most frequently used hand rubs during the SARS-CoV-2 pandemic and other viral pandemics such as MERS. The effectiveness of the preparations depends on the type of alcohol and the quantity applied, concentration, and time of exposure (Boyce and Pittet, 2002;Todd et al., 2010). The enveloped viruses, including SARS-CoV-2, SARS-CoV-1, and MERS-CoV, possess a lipid layer protecting the viral core, of which most antiseptic agents can effectively inactivate within 1 min of exposure . One of the strategic approaches to inactivate CoVs is to target the lipid envelope, representing the organism's virucidal potency. In the 2003 SARS outbreak, the strategy was applied using 60%-70% ethanol concentration to decontaminate viral material detected on surfaces within a hospital effectively. Therefore, ethanol at higher concentrations will effectively interfere with the lipid envelope of CoV (Hulkower et al., 2011;Sattar et al., 1989). Studies have also indicated that, to effectively inactivate the lipid envelope of some viruses, alcohol-based antiseptic preparations such as isopropanol at 70%-91.3% and ethanol at 60%-71% concentrations are highly recommended (Berardi et al., 2020;Kampf et al., 2020). The United States Federal Drug Agency reaffirmed the concentration-dependent effectiveness of some alcohol-based disinfectants and recommended them during the COVID-19 health emergency (Baye et al., 2021). Furthermore, the CDC recommends a baseline concentration of 60% for ethanol preparations meant for healthcare and the public for adequate disinfection, especially when foam and water are not easily accessible (Ramphul and Mejias, 2020). Moreover, a recent study conducted on Zika virus, Ebola virus, SARS-CoV-1, and MERS-CoV indicated that alcohol-based formulations such as ethanol 80% (v/v), isopropyl alcohol 75% (v/v), or the combination of both preparations effectively killed the envelope viruses and therefore, the WHO recommended the concentrations during the SARS-CoV-2 pandemic (Siddharta et al., 2017). To further buttress this point, commercially available alcohol-based hand sanitizers in the US market with a concentration of 70% ethanol effectively decreased the amount of SARS-CoV-2 virus below the threshold limit of >3 log10 reductions (Leslie et al., 2021). Similarly, ethanol at >30% concentration efficiently inactivated the virus when exposed within 30 seconds (Kratzel et al., 2020). The alcohol-based sanitizers have a significant setback in skin dryness, primarily when used for a long time. Therefore, emollients such as glycerol and glycerine are added to overcome such effects (Ahmed-Lecheheb et al., 2012).
Generally, alcohol-based hand sanitizers are the most commonly employed hand rubbing disinfecting agents against SARS-CoV-2 and other endemic viruses. One of the most common added ingredients in alcohol-based disinfectants with potential antiviral activity is the QACs, with a broad spectrum of activity against enveloped viruses and CoVs. Illustrations regarding different types of disinfectants that are physical and chemical inactivation of SARS-CoV-2 are shown in Figure 3.

OTHER DISINFECTANTS
Other essential disinfectants effective in decontaminating and inactivating viruses include chlorinebased, halogen compounds, potent oxidizing agents, and sodium hypochlorite (Chernyshov and Kolodzinska, 2020;Pradhan et al., 2020). Recently, large amounts of chlorine-based disinfectants have been widely used to control the spread of the SARS-CoV-2 outbreak in environments due to low cost and effectiveness on viral infection. Chlorine-based disinfectants are the most common agents that threaten aquatic life and the environment. Halogen compounds such as hypochlorous acid and hypochlorite ions are effective in decontamination and inactivating viruses and pathogenic microorganisms. Scheme 1 represents how sodium hypochlorite solutions can be prepared by reacting chlorine and sodium hydroxide solutions to give hypochlorous acid (HOCl) and sodium hypochlorite (NaOCl) solution (Pradhan et al., 2020).

Scheme 1. Formation of sodium hypochlorite solution.
The hypochlorous acid is a potent oxidizing agent with higher biocidal potency compared to NaOCl. The recommended disinfectant concentration of sodium hypochlorite is 5% in 1:100 dilutions for effective mopping of nonporous surfaces at ≥ 10 min contact time. In contrast, 30 min contact time is required (Carr et al., 1996;Chen et al., 2016). Sodium chlorite is another essential disinfectant with proven efficacy against HAV compared to other disinfectants such as chlorhexidine digluconate, sodium hypochlorite, phenol, sodium phenate, and diethylenetriamine disinfectants (Abad et al., 1997). However, sodium chlorite was ineffective at 0.275% concentration against HAV (Mbithi et al., 1990). Recently, a more environmentally friendly chemical, N-decyl dimethyl ammonium chloride or bromide, effectively inactivates SARS-CoV-2 on surfaces within 0.5 min in a laboratory experiment. Therefore, this could be suggested to disinfect surfaces contaminated with the virus (Xiling et al., 2021).
Oxidizing agents are one of the most effective disinfectants that inactivate viruses and other pathogenic microorganisms. Oxidizing solid compounds such as 1% hydrogen peroxide are disinfectants in intraoral procedures due to their effectiveness (Ather et al., 2020;Diegritz et al., 2020;Izzetti et al., 2020;Jamal et al., 2021;Zimmermann and Nkenke, 2020). Hydrogen peroxide is recommended because it can inactivate SARS-CoV-2 through an oxidation mechanism (Peng et al., 2020). Furthermore, it is worth noting that 62%-71% ethanol, 0.5% hydrogen peroxide or 0.1% sodium hypochlorite, and povidone-iodine can rapidly inactivate CoVs such as SARS and MERS on inanimate surfaces within 1 min of exposure . A study by Mileto and coworkers reported the inactivation of SARS-CoV-2 using a diluted solution of 3% H 2 O 2 with citric acid and an aqueous solution of sodium percarbonate on surfaces within 5 and 15 minutes, respectively, while H 2 O 2 with no additives displayed little or no virucidal activity (Ayipo et al., 2021;Brown et al., 2021).
Similarly, a combination of 0.1% chlorhexidine, 0.05% cetylpyridinium chloride, H 2 0 2 0.1% chlorhexidine, and 0.05% cetylpridiniumchloride inactivated SARS-CoV-2 particles within 30 s application as a mouth rinse, while H 2 O 2 and chlorhexidine alone have no virucidal effects. Therefore, the combination might be used in preprocedural mouth rinse during dental treatments (Koch-Heier et al., 2021). Moreover, in SARS-CoV-2 positive subjects, 1% hydrogen peroxide used as mouth rinse could not reduce oral viral load. Therefore, hydrogen peroxide preparation alone is not recommended as an oral rinse to destroy the SARS-CoV-2 virus (Gottsauner et al., 2020). Other commonly used disinfectants include peroxides and peracids, which act by generating free radicals. These free radicals oxidize the important biochemical content of the virus, including nucleic acid, proteins, and lipids bilayer, and subsequently inactivate the virus. However, the free radicals-based preparations are usually considered the last option as disinfectants, replacing formaldehyde due to their severe systematic and neurological toxicity associated with their exposure. Hence, this limited their use against the SARS-CoV-2 virus (Songur et al., 2010).
Most disinfectants meant for household use have additional ingredients, such as the same amount of 0.50% triclosan, 0.12% parachlorometaxylenol, 0.23% pine oil, and 0.10% QACs, which are invariably reported to inactivate hepatitis virus. Among these compounds, QACs are the most common ingredients in more than 200 disinfectant preparations against the SARS-CoV-2 pandemic (Cegolon et al., 2020;Dellanno et al., 2009). There are three classes of QACs identified to have antiviral activity against CoVs and other pathogenic microorganisms, namely, (i) cetylpyridinium chloride, which is used to reduce pathogenic organisms in the mouth. It is also used in cosmetics as cleaning and personal care agents, (ii) ammonium chloride, an antiviral agent in many disinfectant preparations, and (iii) miramistin, which has a broad spectrum of activity against nonenveloped and enveloped viruses (Cegolon et al., 2020;Sanderson et al., 2003). Therefore, these agents can be formulated with other disinfectants for effective decontamination and inactivating viruses and other pathogenic microorganisms through additive and synergistic activity (Dellanno et al., 2009). This is evident when two formulated detergents containing QACs demonstrated an efficient inactivation of the SARS-CoV-2 by disrupting the lipid envelope and the spike glycoprotein of the virus, which eventually would have invaded lung cells of the host when interacting with the angiotensin-converting enzyme-receptor of the infected person (Schrank et al., 2020). In another research, it was indicated that a combination of commercially available disinfectants containing about 70% alcohol with N-alkyldimethylbenzylammonium chloride produced a reduction in viral titer by 2.03-fold. Table 6. Effective antiseptics for different HCoVs (Chin et al., 2020, Eggers et al., 2018a, Kratzel et al., 2020, Rabenau et al., 2005a, Rabenau et al., 2005b, Saadatpour and Mohammadipanah, 2020, Saknimit et al., 1988, Sattar et al., 1989, Siddharta et al., 2017.

Antiseptics
Substances that arrest microbial growth or activity, especially in or on living tissue, by either inhibiting their action or destroying them are antiseptics (Patterson, 1932). Skin can be contaminated directly when contact with patient secretions or indirectly by touching contaminated surfaces (L'Huillier et al., 2015). Some chemical disinfectants that are safe to use in or on tissue are used as antiseptics. Table 6 shows the efficacy of the antiseptics used for HCoVs.

Antimicrobial Resistance
Antimicrobial agents are natural, synthetic, or semisynthetic substances capable of killing or inhibiting microbial growth in vivo by interacting specifically with a target component (Donaghy et al., 2019). The ability of a microorganism to grow despite an antimicrobial agent is referred to as antimicrobial resistance (AMR), which can be acquired or intrinsic (Wales and Davies, 2015). Unlike antimicrobial agents, disinfectants and sanitizers nonspecifically target multiple components of microbes, frequently causing lethal damage to their membranes or damaging their proteins by reacting with a functional group. Because of their nonspecific nature and multiple modes of action, the microbes are less likely to become resistant to these chemicals (Donaghy et al., 2019;Wales and Davies, 2015). It is unclear that the COVID-19 pandemic has increased AMR. Many patients infected with COVID-19 were treated with antibiotics due to secondary bacterial coinfection (Rodrigo et al., 2020). About 70% of the COVID-19 patient who was hospitalized received antibiotics and often broadspectrum antibiotics, whereas only 16% developed secondary coinfections (Abelenda-Alonso et al., 2020;Beović et al., 2020;Langford et al., 2020). The increased use of antibiotics is seen in nursing homes and long-term care facilities. A possible increase in self-medication with antibiotics is seen in some countries or regions of the world, increasing the risk of rising AMR (Nasir et al., 2020).
Despite having huge factors that increase the risk of raising AMR during this pandemic, some factors might favor decreasing AMR. A study result shows that only 1.3% of COVID-19 patients from the Intensive care unit and no other units got infected with nosocomial superinfection with AMR bacteria (Fattorini et al., 2020). Another study shows that only 3.5% of COVID-19 patients got bacterial coinfection (Langford et al., 2020). A significant decrease in international air travel also decreased AMR bacteria and genes (Kommenda, 2020;Murray, 2020).

RESISTANCE OF PATHOGENIC ORGANISMS TO INACTIVATING AGENTS
A considerable number of disinfectants containing antibiotics have been used in public. The high concentration of these disinfectants wastewater and the soil leads to environmental and aquatic toxicity and, in some cases, resistance to viruses Wang et al., 2020b). Resistance poses a serious global concern, thereby exposing the vast, vulnerable population to devastating situations. Many disinfectants contain chlorinereleasing agents. Excessive use of these can give rise to chlorinetolerant microbes, which are also competent cells and can more efficiently transfer plasmids (Jin et al., 2020). Therefore, it is pertinent to monitor disinfectants for potential risks of developing resistance due to the discriminate application of the agents during the pandemic period (Berardi et al., 2020;Dellanno et al., 2009;Okeke et al., 2005).
Moreover, the CDC and the European Committee for Standardization recommend methods and testing protocols for disinfectant preparations to effectively determine efficiency and inactivation potential against viruses, especially on enveloped viruses. This represents the vast majority of emerging infectious diseases. Therefore, it is recommended to use tested and well-recommended formulations such as PVP-I and ethanol preparations less susceptible to resistance development when used appropriately (Boyce and Pittet, 2002;Eggers, 2019). As discussed under iodine-based disinfecting products, PVP-I is one of the most widely used alternative antiseptics to alcohol prepared in clinical settings for disinfecting skin during and after surgical operations. It inactivates resistant strains of pathogenic microorganisms effectively (Gottrup et al., 2014). It was demonstrated by Eggers et al. (2018), that iodine has superior activity against enveloped and nonenveloped viruses (Table 7), hence its lack of crossresistance among many pathogens. Besides its inability to develop resistance, PVP-I has been more effective and superior to chlorhexidine against pathogenic microorganisms, especially handwashing disinfectants (Eggers, 2019).
So far, no significant resistance has been acquired by iodine, mainly when used for specific purposes and stipulated Table 7. Comparison of anti-viral activities of standard antiseptic classes as indicated by Eggers et al. (2019).

Ethanol + Variable
Iodine + + Phenolic + Variable procedures (Eggers, 2019). Iodine maintains equilibrium due to constant replacement by the PVP-bound iodine, leading to disruptions and leakage of the organism (Mayer et al., 2001). Therefore, the long-lasting efficacy and continuous supply of iodine during its action suggest decreased possibility of resistance developed by many pathogenic organisms (Eggers, 2019). In summary, PVP-I and ethanol preparations are less susceptible to resistance development when used appropriately and adequately. PVP-I's constant equilibrium supply and efficacy during its action against viruses make it one of the disinfectants of choice for many decades. The development of resistance to various disinfectants and antimicrobial agents is demonstrated (Fig. 4).

TOXICITY OF INACTIVATING AGENTS
The WHO's declaration of COVID-19 as a global pandemic and misinformation on the public health emergency leads to misconceptions, rumors, and subsequently cynicism on the disease by some individuals . In addition, misinformation on the use of disinfectants triggers panic, anxiety, and hysteria in people. Thus, individuals adopt inappropriate, excessive, and unethical actions such as the application of equipment sterilizers on the skin, washing food products with disinfectants, and in some instances, ingesting chemicals, all in the name of preventive measures. The SARS-CoV-2 pandemic has skyrocketed the demand for disinfectants globally, exposing human, environmental, and aquatic life to the toxic effects of these chemicals (Sefah et al., 2020). This could culminate in increasing secondary disasters detrimental to the fragile healthcare system (Rai et al., 2020). Residual chemicals left on the surfaces can be inhaled and cause serious health problems such as allergic reactions and asthma (Medina-Ramón et al., 2005). The long-term effect of such substances could be harmful to health, causing chronic diseases like cancer and central nervous system (CNS) impairment. Other effects include oxidative damage and reproductive disorders . Most of these cleaning agents contain harmful materials and are corrosive to both humans and the environment; therefore, caution and strict adherence to safety and protocol measures must be exercised when applying disinfecting agents on both humans and the environment (Arevalo-Silva et al., 2006;Nabi et al., 2020;Sawalha, 2007;Sharafi et al., 2020).
In humans, toxicity due to disinfectants is usually experienced upon long-term exposure to the agents through mouth, skin, and inhalation routes. The toxicological effects vary according to the course and the type of the disinfecting agent. For instance, alcohol-based disinfectants and sanitizers display short contact time on humans due to their volatility. They are considered less harmful than other less volatile agents with extended contact time. Therefore, alcohol-based disinfectants are mostly recommended for homes and hospitals . Other agents such as hypochlorous and peroxides are primarily used in dental clinics due to their ability to produce aerosols at a low cost to prevent contact with most patients (Scarano et al., 2020). It was reported that most chemical disinfectant by-products increased the risk of chronic obstructive pulmonary disease (COPD) like asthma and irritation of the eyes and skin, primarily when misused. Other hazards include cancers and reproductive and respiratory disorders Rume and Islam, 2020;Sharafi et al., 2020). Children are the most affected when exposed to hazardous chemicals, with reported cases of dysbiosis in the infant gut leading to overweight and obesity . Excessive use of alcohol-based hand sanitizer as a protective measure for the current pandemic has caused alcohol toxicity (Ghafoor et al., 2021). It can also increase the risk of other viral infections such as norovirus outbreaks (Blaney et al., 2011). Some ABHR or sanitizers contain nonvolatile biocides such as benzalkonium chloride, chlorhexidine digluconate, didecyldimethylammonium chloride, polihexanide, triclosan, or octenidine dihydrochloride (Kampf, 2016). Although they do not have any proven health benefit or superior bactericidal efficacy, they can raise AMR (Kampf, 2016;Kampf et al., 2017;Palumbo et al., 2017). Chlorhexidine, povidone-iodine, benzalkonium chloride, or octenidine are used in some alcohol-based skin antiseptics (Kampf, 2016). Of these, only chlorhexidine and octenidine have proven health benefits in preventing infection despite some risks (Chaiyakunapruk et al., 2002;Darouiche et al., 2010;Dettenkofer et al., 2010;Harnoss et al., 2018;Mimoz et al., 2015;Tuuli et al., 2016). Other agents such as glutaraldehyde and ethylene oxide were also reported to cause severe lung disease (Dumas et al., 2019). Therefore, caution should be exercised, especially when mixtures of disinfectants are preferred. For instance, the combination of bleach with an acid-based cleaner could release gaseous chlorine or hypochlorous acid. When inhaled, even in small amounts, it may cause acute severe lung injury (Bracco et al., 2005). People are exposed to toxic effects of these chemicals with an increased risk of COPD, asthma, and eye irritation due to the knowledge gap in safe preparations of cleaning and disinfecting agents, even among adults. Therefore, discourage self-preparation without the requisite skills and knowledge (Casey et al., 2017;Dumas et al., 2019;Gharpure et al., 2020;Weinmann et al., 2019). Moreover, a study indicated that about 5% of cancer in children and 30% of childhood asthma are linked to long-term chemical exposures due to the inability to handle or use the chemicals properly and subsequently damaging essential organs in the body (Landrigan et al., 2002). Another necessary caution is excessive, frequent, and vigorous hand rubbing when using alcohol-based antiseptics, which could be inhaled and may generate potential threats to eyes and skin and subsequently lead to contact and allergic dermatitis to mild or moderate inflammatory effects (Shetty et al., 2020).
During the COVID-19 pandemic, there was an increase in biomedical and untreated wastes , which endangers both humans and the environment. Chlorine-based disinfectants are the most widely used agents on environments during the SARS-CoV-2 pandemic, thereby causing high residual concentrations in water bodies, soil, and the environment. Ultimately, these affect agricultural production due to excessive chlorine (Cl -), soil degradation, and ecosystem destruction. A high chlorine residue concentration on the soil affects the ecosystem by reacting with bromide in raw materials or soil and organic matter. This subsequently leads to disinfectants-by-products formations, especially trihalomethanes and bromides, toxic to the environment (soil), human, and aquatic animals (Srivastav et al., 2020). Chlorine-based disinfectants are prone to the formation of carcinogenic chloramines and nitrosamines, observed in drinking water around Washington D.C (Montazeri et al., 2017;National Research Council, 1980). However, chlorine-based disinfectants' toxic effects on plants are short-lived and quickly neutralized by some organic matters in the soil (Montazeri et al., 2017). The aquatic animals are also endangered due to exposure to toxic byproducts of the disinfecting chemicals (Nabi et al., 2020;Sharafi et al., 2020). Also, disinfecting water for consumption using chlorine produces products and, when used for the long-term, may be harmful to aquatic and human life, causing chronic diseases such as cancer (Agnelo et al., 2020;Srivastav et al., 2020). The excessive applications of disinfectants undoubtedly increase their presence within the ecosystem, causing air, water, and soil pollution.
In summary, even though some disinfectants are toxic to individuals and the environment, they are essential in curbing the spread of COVID-19. The vast majority of the disinfectants, such as alcohol and chlorine-based products, are mainly used on humans and the environment, respectively. Frequent exposure to disinfectants during the COVID-19 pandemic poses risks of chronic diseases such as cancers, respiratory, and reproductive disorders. Therefore, guidelines, procedures, and recommendations made by WHO, CDC, and other recognized health agencies should be followed to minimize the health risks associated with exposure to chemical disinfectants. Possible toxicity and other health hazards resulting from disinfectant use are demonstrated (Fig. 5).

MITIGATING STRATEGIES TO REDUCE THE TOXIC EFFECTS OF INACTIVATING AGENTS
The COVID-19 pandemic posed several challenges and seemed unmanageable through current preventive measures and strategies (Habas et al., 2020;Rahman et al., 2021). Disinfectants are essential prophylactic agents; however, there is indiscriminate disinfectant use during the pandemic. Despite having a beneficial role in controlling and preventing SARS-CoV-2, there are concerns regarding the large-scale use of disinfectants, including the toxic effect on human health and the chance of developing drug resistance. Various national and international healthcare authorities, that is, WHO (2020) and CDC (Government, 2021), have developed recommendations for the appropriate utilization of suitable disinfectants to prevent the pandemic.
The following essential mitigation strategies are recommended to reduce the toxic effects of disinfectants in humans and the environment (Chen, 2020; Dhama et al., 2021): 1. Use of natural disinfectants, for example, sunlight and plantbased disinfectants. 2. Use only recommended dose of disinfection. 3. Substitute cleaning and disinfectant sprays with liquid products that are manually applied with a cloth. 4. Increase ventilation during and following treatment. 5. Follow label usage instructions and avoid mixing cleaning and disinfectant products. 6. Avoid using cleaning and disinfectant products around children. 7. Allow the area being treated to air out the following application. 8. Clearly label disinfectants and store them away from children and pets. 9. Avoid any accidental leakage of disinfectants into water. 10. Development of nanomaterials or nanoparticles for surface decontamination. 11. Improve personal protective equipment (PPE) worn by users. 12. Incorporation of nanobiotechnology to develop PPEs and sanitization. 13. Efficient disposal of PPEs and medical waste using techniques like incineration and vitrification.
14. Provide proper worker training in safe cleaning and disinfection practices. 15. Strictly follow national health and safety guidelines for using disinfectants.

CONCLUSION AND RECOMMENDATIONS
COVID-19 is a highly infectious and transmissible disease. The inability to detect symptoms within a few days of getting infected by individuals further complicates its proper prevention and disinfection process, especially in a frequented indoor space. Initially, when the disease was declared a public healthcare emergency by the WHO, different nations adopted temporary confinement of people indoor to curb the disease spread. Nonetheless, this policy has negatively impacted the global economies, individuals' psychological and mental health, and the overwhelming healthcare system. Briefly, this article highlighted the relevance of physical inactivation, such as temperature and humidity, controlling the viral survival on the surfaces, and ultimately reducing the virus's transmission through droplets. Although the SARS-CoV-2 is highly stable at 4°C, it becomes inactive when exposed to high temperatures. The UV radiation, incredibly the UV-C light, has also proven to effectively reduce air transmission of several pathogenic diseases, including airborne viruses, hence essential in curbing the spread of SARS-CoV-2. However, due to the harmful effects of UV radiation on normal cells, especially at high wavelengths, its use is limited.
Consequently, the application of UV radiation for the control of SARS-CoV-2 infection requires specifications with lesser health-damaging effects on humans and animals. Furthermore, the literature review emphasized the commonly used disinfectants during the SARS-CoV-2 pandemic, such as alcohol-and iodinebased products. The alcohol-based disinfectant represents the widest hand-rub antiseptics recommended by various health agencies and organizations, including the WHO and CDC, during the SARS-CoV-2 outbreak. The alcohol-based disinfectants are easily accessible and effective in preventing the spread of SARS-CoV-2. The iodine-based counterpart has also proven efficacious against many pathogenic microorganisms over many years. Most of its preparations demonstrated efficient virucidal activity against SARS-CoV-1, MERS-CoV, and SARS-CoV-2, suggesting its broad applicability on many viral diseases. However, a high concentration of these disinfectants in wastewater and the soil leads to environmental and aquatic toxicity and, in some cases, resistance to viruses. Notably, the residual chemical remaining on the surfaces or inhaled by individuals may have long-term effects on public health, such as reproductive disorders, COPD, cancers, skin damage, and CNS impairment. Therefore, further research on long-term preventive alternatives such as formulating disinfectants with natural products as active ingredients is necessary to mitigate the effects of alcohol-and iodine-based chemicals on humans and the environment.
Additionally, effective technologies and strategies need to be developed for minimizing these toxic effects and drug resistance. Safe, eco-friendly technologies should be used to produce safe, effective, and affordable disinfectants using nanotechnology and nanomedicine. Comprehensive guidelines for rational disinfectants are also necessary at regional, national, and international levels to reduce the toxic effects on humans and the environment.

PROFESSIONAL ANNOTATION
Disinfection pronounces a procedure that eradicates several or all infective microbes, excluding bacteriological spores, on nonliving objects (Baron et al., 1996;Basta and Annamaraju, 2020;Council, 1977;Protano et al., 2019;Rutala and Weber, 2008;Rutala and Weber, 2016). Nevertheless, sterilization labels a method that abolishes or exterminates all microbiological life forms and is regularly conducted in all sorts of healthcare facilities by physical or chemical approaches (Anderson et al., 2018;Protano et al., 2019;Rutala and Weber, 2008;Rutala and Weber, 2016). The disinfection of health professional hands is a significant avenue to transfer through healthcare providers. It was first noticed by the Hungarian Obstetrician Professor (Dr.) Ignaz Phillip Semmelweis in 1847 Haque et al., 2018). Dr. Ignaz Phillip Semmelweis is primarily known as the father of infection control (Flynn, 2020;Habboush et al., 2021 a). The essential standing of hand sanitization and other issues in managing infection control has been similarly advocated by Florence Nightingale, Oliver Wendell Holmes, Louis Pasteur, Joseph Lister, and Robert Koch (Ataman et al., 2013;Gebel et al., 2013;Görig et al., 2019;Glass, 2014;Hillier, 2020;Kampf et al., 2009;La Rochelle and Julien, 2013;Lane et al., 2010;Pitt and Aubin, 2012;Smith et al., 2012;Tulchinsky and Varavikova, 2014;Tyagi and Barwal, 2020;Worboys, 2013). After that, the importance of hand hygiene practice was validated through multiple scientific works and remains essential and pertinent Magiorakos et al., 2010;Mathur, 2011;Reichardt et al., 2013).
Healthcare-associated infections (HCAIs) and community infections remain safety concerns for health professionals and patients (Monegro et al., 2021). Thereby, it increases considerable morbidity and mortality and prolongs the hospital stay and healthcare overhead length (Badia et al., 2017;Grant et al., 2017;Jia et al., 2019;Zhou et al., 2019). Therefore, multiple studies revealed that efforts need to promote infection preventive strategies in all healthcare facilities and communities to avert infection and maximize healthcare benefits (Cheung et al., 2019;Schmid et al., 2018;Wagh and Sinha, 2018;Worth et al., 2018). Infection management denotes the strategy and measures to be implemented to curb and curtail the spreading and propagation of HCAIs infections in different types of healthcare facilities that include ambulatory surgical centers, birth centers, blood banks, clinics, and medical offices, diabetes education centers, dialysis centers, hospice homes, hospitals, primary healthcare centers, imaging and radiology centers, mental health and addiction treatment centers, nursing homes, orthopedic and other rehabilitation centers, urgent care, telehealth, and communities (Boev and Kiss, 2017;Collins, 2008;Gandra and Ellison, 2014;Guzman, 2021;Haque et al., 2018;Hsu, 2014). The infection control strategy was reported as a well-established practice in US hospitals in the early 1950s (Dixon, 2011;Habboush et al., 2021a;Monegro et al., 2021). Additionally, multiple pieces of research revealed that efficient practice infection prevention program reduces morbidity, mortality, healthcare financial overhead, and disability-adjusted life years (DALYs) and maximizes proper utilization of healthcare (De la Rosa-Zamboni et al., 2018;Friedrich, 2019;La Rochelle and Julien, 2013;Zacher et al., 2019). The health management system progressively recognizes the importance of surface disinfection (Gebel et al., 2013). Notwithstanding, several unanswered questions remain to be determined (Gebel et al., 2013).
Surface disinfection is an essential procedure in healthcare facilities and infectious diseases such as COVID-19. It is vital to curbing contagious diseases and reducing the risk of direct and indirect contact transmission from healthcare personnel to patients. This could decrease surfaces to act as reservoirs for various infectious diseases (Donskey, 2013). For many years, alcohol-based preparations have been used as low-level disinfectants in hospitals against bacteria. Recently, a combination of alcohol-based and QACs was used to disinfect surfaces against Ebola viruses and several coronaviruses. The antiseptic preparations are used due to their ability to evaporate rapidly and short contact time on the skin, therefore, less damaging the skin due to lesser exposure to the agents (Boyce, 2018). Most of these disinfectants, such as chlorine-based, are inexpensive and readily available in rural and urban areas (Gallandat et al., 2021). However, disinfections are necessary to inactive and reduce the viral load on surfaces. However, many disadvantages follow. The high amount of surface disinfectants is corrosive to the environment, especially iodine-based disinfectants. Also, most of these disinfectants cause irritation when applied in high concentrations and on stain surfaces and can be quickly inactivated by organic matter (Gallandat et al., 2021).
Moreover, some disinfecting agents have antibacterial agents in their formulation; inappropriate exposure to bacteria could cause bacterial resistance development . In some cases, prolonged exposure to these disinfectants could cause serious health problems such as cancers, respiratory problems, and genetic defects in an unborn baby (Ahmed-Lecheheb et al., 2012;Choi et al., 2020). In most cases, not all disinfectants products eradicate the coronaviruses. Therefore, further investigation on individual disinfecting agents is required to validate their merit and demerit potentials further.

DECLARATIONS
Ethics approval and consent to participate: This is a review paper. Thereby does not require Institutional Review Board's approval and consent.

ACKNOWLEDGMENT
The corresponding author is grateful to Universiti Pertahanan Nasional Malaysia (National Defence University of Malaysia), Kem Perdana Sungai Besi, 57000 Kuala Lumpur, Malaysia.

AUTHORS' CONTRIBUTION
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis, and interpretation or in all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

FUNDING
This paper was not funded.

AVAILABILITY OF DATA AND MATERIALS
All data generated or analyzed during this study are included in this published article.

CONSENT FOR PUBLICATIONS
All authors reviewed and approved the final version and have agreed to be accountable for all aspects of the work, including any issues related to accuracy or integrity.

COMPETING INTEREST
The authors declare that they have no competing interests.