Norio Ogata*

R and D Center, Taiko Pharmaceutical Co., Ltd., Seikacho, Kyoto, Japan.

*Corresponding Author: Dr. Norio Ogata

R and D Center, Taiko Pharmaceutical Co., Ltd., Seikacho, Kyoto, Japan.


The prevention of infectious diseases caused by infectious air-floating microbes in closed and semi-closed areas is strongly needed, but it is still difficult to achieve satisfactorily because of the absence of appropriate disinfection techniques. Fumigation is one of the methods to disinfect air contaminated with infectious microbes, but it absolutely requires evacuation of people from the areas to be disinfected because the gas concentration of disinfectant employed is usually very high and toxic to animals. Currently it is demonstrated that chlorine dioxide (ClO2) gas of extremely low concentrations that have no toxic effect to animals has strong anti-microbial activity against infectious microbes, such as bacteria and viruses. Disinfection using such low-concentration ClO2 gas does not require evacuation of people, and could be used to disinfect room air in the simultaneous presence of people. The use of ClO2 gas at very low concentrations may open new avenue of disinfection systems of room air without requiring evacuation of people. This review presents the details of the disinfection system of ClO2 gas.

KEYWORDS: Chlorine dioxide, ClO2, Gas, Bacteria, Virus, Disinfection.


Chlorine dioxide (ClO2) is a liquid that exhibits dark orange color below 11ºC.[1] ClO2 starts boiling above this temperature and produces yellow gas with a characteristic odor. It is a relatively stable free radical with one unpaired electron in its molecular orbital. Its molecular structure in a liquid state was demonstrated by an X-ray diffraction analysis.[2] ClO2 has long been used to disinfect tap water in place of chlorine in some countries. Contrary to chlorine disinfection, ClO2 disinfection does not produce potentially carcinogenic trihalomethane.[3] Microbes disinfected by ClO2 include bacteria, fungi, protozoa and viruses.[4] ClO2 dissolved in water and gaseous ClO2 are used to disinfect microbes. The detailed chemical dynamic mechanisms of inactivation of microbes by ClO2 are reported.[5] Currently, extremely low concentrations of ClO2 gas, on the order of 0.01- 0.05 ppm (parts per million) (volume ratio), are used to disinfect microbes in room air. The gas still possesses antimicrobial activity at these low levels.[6,7] Such extremely low levels of the gas are reported to be non-hazardous to animals,[8] and its potential use in closed and semi-closed spaces without a need of evacuation of humans is expected to open a new avenue of disinfection systems. Details of the inactivation mechanisms of microbes by ClO2 gas are also reviewed in this paper.

Chemical Characteristics and Structure of ClO2

ClO2 is reddish-yellow gas with an unpleasant odor similar to that of chlorine at room temperature.[1] ClO2 condenses to a reddish-brown liquid on cooling below 11ºC and freezes at -59ºC, producing red-orange crystals.[9] ClO2 is readily soluble in water; 3 grams can be dissolved in 1 liter of water at 25ºC.[9] ClO2 has one unpaired electron in its molecular orbital and hence is a free radical. Other chemical details of ClO2 are presented in Table 1.[1,9] Special care is needed to handle pure ClO2 gas at high concentrations due to its potential explosiveness and toxicity.[1,9] An explosion may result when high concentrations of the gas are exposed to strong light.

Table 1: Physicochemical characteristics of ClO2

The structure of ClO2 in liquid phase was observed by Xray diffraction analysis,[2] and the gas phase structure was observed by infrared spectroscopy (Table 2).[10] Of note, the ClO2 molecule is bent (C2 symmetry) with OCl- O angle of 116.1º.[2] The Cl-O bond length was 1.46 Å.[2] Nielsen and Woltz reported the infrared spectrum of ClO2 gas, revealing peaks at 290, 445 ( 2), 943.2 1), 1110, 1888 (ı ı), 2040, 2215, 2473, 2967, and 3325 cm- 1.[10] In the solid phase, ClO2 molecules dimerize, losing their paramagnetic behavior. The dimer (ClO2)2 becomes diamagnetic.[9] Shimakura et al. found that in the liquid phase, ClO2 molecules do not exhibit random orientations, but present a characteristic intermolecular orientation.[2]

Table 2: Chemical Structure of ClO2

Generation of ClO2 Gas

Numerous methods are available to generate ClO2 gas. Given that the gas is potentially explosive at high concentrations, it is generally not transported but is generated onsite for use. The most frequently used method of ClO2 generation involves mixing sodium chlorite (NaClO2) with acids or oxidizing agents.[3] Sodium chlorite is typically employed as an aqueous solution, and acid is mixed with the solution. ClO2 generated in the solution is bubbled by air to release it from the solution. For example, the chemical reaction involved in the use of HCl as the acid is 5NaClO2 + 4HCl 2 + 2H2O + 5NaCl. When ClO2 is generated from chlorine gas (Cl2) as a starting material, the chemical reaction is 2NaClO2 + Cl2 2 + 2NaCl.[3] ClO2 is also generated by mixing sodium chlorite with hypochlorous acid (HOCl) following the reaction of 2NaClO2 2. In this reaction, hypochlorous acid is generated by mixing chlorine with water in the reaction of Cl2 + H2O[3]

Electrochemical systems are also employed to generate ClO2 in situ for use.[11-13] In this method, aqueous solution of sodium chlorite is placed in an electrolytic cell, where ClO2 – becomes ClO2 in an anode and H2O becomes hydrogen and OH- in a cathode.[3] The overall reaction is 2NaClO2 + 2H2 2 + NaOH + H2. ClO2 in the aqueous solution is stripped from the solution by introducing air into the solution.[3] Bai et al. reported a sophisticated method to release ClO2 gas in a controlled manner.[14] ClO2 gas was generated by adhering two films together. One film is acrylate-based film loaded with sodium chlorite, and the other film is polyvinyl alcohol polymer loaded with tartaric acid. The rate of ClO2 gas release can be controlled by tailoring film composition and its thickness. The rate of ClO2 release is accelerated by moisture.[14] The researchers noted the usefulness of their system for food packaging. ClO2 is also generated by exposure of a solution of sodium chlorite to ultraviolet light.[15,16] ClO2 is generated in acidic conditions (pH 3.0-5.0), whereas hypochlorite is generated at alkaline conditions (pH 8.9-10.7).[15] Quantum yield of this photochemical reaction irradiated by 253.7 nm ultraviolet light is 0.43 to 0.94 and is maximal at pH 6.[16]

Chemical Reactions and Fate of ClO2

Whether it is an aqueous solution or gas, ClO2 can react with numerous organic compounds. It is known to react with some free amino acids and amino acid residues in proteins.[5,17] For instance, tryptophan and tyrosine, as residues in bovine serum albumin and glucose-6-ast Saccharomyces cerevisiae, were oxidatively modified by an aqueous solution of ClO2.[5] Furthermore, tryptophan becomes N-formylkynurenine, and tyrosine forms 3,4- dihydroxyphenylalanine (DOPA) and 2,4,5- trihyroxyphenylalanine (TOPA).[5] Oxygen atoms of ClO2 were incorporated in the products.[5]

Napolitano et al. found that tyrosine, N-acetyltyrosine and DOPA react with an aqueous solution of ClO2, consuming two molecules of ClO2 for each reaction.[17] In the reaction of tyrosine and N-acetyltyrosine, phenoxyl radicals are first generated. Next, a short-lived adduct with a C-OClO bond at the 3 position of the aromatic ring is generated, ultimately forming dopaquinone and N-acetyldopaquinone.[17]

The mechanism of the oxidation of tryptophan is proposed as follows.[18] Two molecules of ClO2 react with each molecule of tryptophan. The first molecule forms a tryptophan radical, ClO2 – and H+. The second molecule reacts with the tryptophan radical and forms a tryptophan-OClO adduct. Finally the adduct becomes stable N-formylkynurenine.[18] The oxygen atoms of ClO2 are incorporated in the product in this reaction. The amino acid cysteine also reacts with ClO2.[19] It is proposed that the reaction involves electron transfer from cysteine anion to ClO2 with a subsequent reaction of cysteine radical and ClO2 to form a cysteinyl-ClO2 adduct. The adduct finally forms pH-dependent products: cysteic acid at low pH and cystine at high pH. The tripeptide glutathione (Glu-Cys-Gly) also reacts with ClO2.[19] ClO2 decomposes in basic aqueous solution via three different pathways.[20] One pathway forms ClO2 – and O2. The other two pathways form ClO2 – and ClO3 -. All pathways exhibit a first-order dependence of the reaction with regard to OH-. All the reactions are proposed to proceed by base-assisted electron-transfer mechanisms.[20]

Residues after the treatment of objects with ClO2 are a particular concern. Basically, ClO2 gas is rapidly broken down to chlorate (ClO3 -) and chlorite (ClO2 -) ions, which are further converted to chloride (Cl-) ion.[21-26] Kaur et al demonstrated that Cl- and ClO3 – were formed after the treatment of cantaloupes with 36Cl-labeled ClO2 gas.[22] They treated cantaloupes with 5.1 ± 0.7 mg/L (1850 ± 254 ppm) ClO2 gas for 10 min for fumigation. Then, they measured residues from the rind and flesh of this fruit. They detected 19.3 ± 8.0 g of Cl- and 4.8 ± 2.3 g of ClO3 – per gram of rind. They detected 8.1 ± 1.0 g of Cland no ClO3 – per gram of flesh. Given that Cl- is nontoxic, they concluded that fumigation of edible flesh would not pose a health concern.[22] Trinetta et al. treated vegetables and fruits with 0.5 mg/L (180 ppm) ClO2 gas with 90 to 95% relative humidity for 10 min to disinfected pathological bacteria (Escherichia coli, Listeria monocytogenes and Salmonella enterica). They next rinsed the food surfaces immediately with water to remove any remaining ClO2 and byproducts and analyzed the after-rinse water. At 24 h post treatment with ClO2 gas, no differences in ClO2 residues were noted between control (no ClO2 gas treatment) and treated foods such as tomatoes and navel oranges. However, ClO3 – was found in apples. In addition, Cl-, ClO2 – and ClO3 – above control values were noted in lettuce.[23] Thus, these anions may remain on the surfaces of some agricultural foods treated with ClO2 gas if the treatment concentration of the gas is high.

Mechanism of Kinetics of Antimicrobial Activity of ClO2

ClO2 has strong oxidizing activity presumably due to its free radical properties.[9] For instance, ClO2 oxidizes tryptophan and tyrosine residues of protein and denatures proteins.[5,17,27] In this reaction, oxygen atoms of ClO2 are incorporated in the above amino acid residues of proteins, and proteins are denatured.[5] The denaturation of proteins and inactivation of enzymes are demonstrated.[5,28,29] Finnegan et al. reported degradation (fragmentation) of bovine serum albumin and aldolase by ClO2.[28]

Benarde et al. demonstrated that ClO2 kills bacteria by blocking the biosynthesis of bacterial proteins.[30] Cho et al. found that ClO2 oxidizes bacterial membrane lipids and consequently increases the permeability of the membrane.[31] On the other hand, Berg et al. reported that ClO2 causes a loss of control of the permeability of K+ ion and oxidative damage of the bacterial outer membrane. They concluded that E. coli is inactivated by these effects.[32] Roller et al. found that dehydrogenase enzymes of E. coli are completely inhibited by ClO2, but this effect does not exclusively explain the inactivation mechanism of the bacteria. They suggested that inhibition of protein synthesis might have a contributory lethal effect on the bacteria.[29]

Many microorganisms are inactivated by ClO2. Bacteria,[33-54] fungi,[55-58] viruses[59-68] and protozoa[56-58] are inactivated. ClO2 dissolved in water has long been used to disinfect tap water.[3] The antimicrobial activities of ClO2 are elicited as a gas. For instance, Bacillus subtilis, S. enterica, B. anthracis, Francisella tularensis, Yersinia pestis, E. coli O157:H7, and Staphylococcus aureus are inactivated by ClO2 gas.[4,7,36,37,39,44-46,50,54,69] Bhagat et al. demonstrated that S. enterica inoculated on navel orange surfaces were inactivated to a level of 3.5 log10 reduction of viability with 0.1 mg/L (36 ppm) ClO2 gas for 12 min at 22ºC with 90-95 % relative humidity.[50] A mixture of S. enterica, E. coli and L. monocytogenes spot-inoculated on the surface of tomatoes, cantaloupes and strawberries were treated with 10 mg/L ClO2 (3600 ppm) gas for 180 s, and a 3-5 log10 reduction of viability was reported.[35]

The inactivation activity of the ClO2 gas is elicited against the bacteria not only in their floating state in the air, but also in their attachment state on solid objects.[69] Li et al. found that spore-forming bacteria, B. subtilis var. niger attached to pieces of metal, plastic, and glass were inactivated by 800 ppm (2.2 mg/L) ClO2 gas for 3 h to levels of 1.8 to 6.64 log10 reduction.[69] The results clearly indicated sporicidal activity of the gas. Interestingly, the inactivation activity is dependent on pre-humidification treatment of the test pieces.[69] Viruses are also inactivated by the gas. For instance, influenza virus, feline calicivirus, human herpesvirus, and canine distemper virus are inactivated by ClO2 gas.[6,27,64,70,71]

Wang et al. extensively studied the kinetics of the inactivation of B. subtilis spores and S. albus inoculated on a piece of filter paper by ClO2 gas.[46] They fitted the rate of the kill of the bacteria using a first-order kinetic model using a function of log10(N/N0) = -kt, where N0 is the initial number of cells, N is the number of surviving bacteria after time t (min) of ClO2 gas exposure, and k (min-1) is the rate constant. In the case of B. subtilis spores, the rate constant k is 0.09 ± 0.01 min-1 (n = 6) at 1 mg/L gas concentration with 70% relative humidity at 22 to 24ºC, and this value increases to 0.21 ± 0.02 min-1 at 5 mg/L.[46] In the case of S. albus, k was 0.15 ± 0.01 min-1 at 2 mg/L gas with 70% relative humidity and 0.32 ± 0.02 mg/L at 5 mg/L gas.[46] Interestingly, the rate constant k decreases to 0.04 ± 0.01 min-1 at 2 mg/L gas with 30% relative humidity, whereas it increases to 0.66 ± 0.04 min-1 with 90% relative humidity. Thus, the rate of killing increases along with the increase in relative humidity. The same trend is also noted in the case of B. subtilis spores.[46] The augmentation of the inactivation activity of ClO2 gas upon the increase in relative humidity was also reported regarding S. enteritidis inoculated on eggshells.[45] Of note, the same trend of the effect of humidity was also reported regarding the inactivation of feline calicivirus. Morino et al. found that feline calicivirus placed on a glass surface and treated with 0.26 ppm (0.72 g/L) ClO2 gas for 24 h at 20ºC was inactivated to 1.0 log10 reduction (n = 4) with 45 to 55% relative humidity, whereas it was inactivated to 6.3 log10 reduction with 75 to 85% relative humidity.[70]

ClO2 Gas as a Fumigant

Previously high-concentration ClO2 gas was frequently used as a fumigant to inactivate various microbes. For instance, Park and Kang demonstrated that E. coli, S. typhimurium and L. monocytogenes inoculated on spinach leaves and tomato surfaces were inactivated by 5 or 10 ppm (28 g/L) ClO2 gas.[33] S. enterica, E. coli O157:H7 and L. monocytogenes spotted on the surface of crops (tomatoes, cantaloupes and strawberries) were treated with 10 mg/L (3600 ppm) gas of ClO2 for 180 s.[35] In this experiment, a 5-log10 reduction in colony forming unit (CFU) was noted in S. enterica in all crops. In contrast, a 3-log10 reduction in CFU was noted in E. coli and L. monocytogenes, indicating that the latter two are more resistant to ClO2 gas.[35] A 3-log10 CFU reduction of S. enterica was also reported for mung bean sprouts at 0.5 mg/L (180 ppm) ClO2 gas for 15 min.[37] Of note, the inactivation activity of ClO2 gas was also found on bacterial spores.[34,36,38,42,46,47,72,73] Jenk and Woodworth reported that spore-forming bacteria B. subtilis planted in the artificial organs were reproducibly sterilized with 30-min dwell time with 30 mg/L ClO2 gas (10900 ppm) with 80 to 85% relative humidity at 30ºC.[72] The D value (time required for 90% spore inactivation) was 4.4 min.[72] Lowe et al. found that 362 695 ppm ClO2 gas maintained at exposures of 756 ppm-hours with 65% relative humidity achieved inactivation of B. anthracis and Mycobacterium smegmatis. The reduction of viability was greater than 6 log10.[34]

Toxicity Study of ClO2 Gas

High-concentration ClO2 gas is toxic against numerous animals including human. Paulet and Desbrousses performed a toxicological study. Rats exposed to 10 ppm (28 g/L) ClO2 gas for 2 h/day for the 30-day period exhibited nasal discharge, red eyes, localized bronchopneumonia with desquamation of the alveolar epithelium and an increase in leukocytes.[74] The same group also performed other experiment using rats. They exposed rats to 1 ppm (2.8 g/L) ClO2 gas for 5 h/day for 5 days/week during a 2-month period. They found vascular congestion and peribronchiolar edema in the lungs of the rats.[75] However, Ogata et al[8] could not reproduce their pathological findings in rats exposed to the experimental conditions exactly as described in the paper of Paulet and Desbrousses.[75] They concluded that the most likely reason for this discrepancy might involve the fine controls of gas concentrations.[8] As noted by Ogata et al.,[8] fine controls of ClO2 gas concentrations at such low levels might have been quite difficult to achieve at the time of Paulet and Desbrousses[75] as a gas generator with a sophisticated control system was not available.[8]

Akamatsu et al. demonstrated the rats exposed to 0.1 ppm ClO2 gas for 24 h/day and 7 days/week for a period of 6 months were completely healthy at the end of the experiment.[76] Dalhamn conducted ClO2 gas inhalation study on rats. Exposure to 260 ppm (720 g/L) ClO2 gas for 2 h resulted in ocular discharge, epistaxis, pulmonary edema, circulatory engorgement and death.[77] In contrast, exposure to 0.1 ppm (0.28 g/L) ClO2 gas for 5 h/day during a 10-week period did not cause any pathological effect, and he concluded that this level is NOAEL (no-observed-adverse-effect level).[77] Exposure of rats to 10 ppm (28 g/L) ClO2 gas for 4 h/day during a 2-week period caused respiratory tract irritation, and he concluded that this level is LOAEL (lowest-observed-adverse-effect level).[77]

Governmental Regulations of ClO2 Gas Concentrations

Given that high-concentration ClO2 gas and liquid are explosive and toxic to animals as mentioned above, several governmental regulations have been implemented in some countries. American OSHA (Occupational Safety and Health Administration) states that the 8-hour time-weighted average of permissible exposure level of the ClO2 gas is 0.1 ppm (0.28 g/L).[78] The American Conference of Governmental Industry Hygienist (ACGIH) also states 0.1 ppm as a permissible level for workers working 40 hours per week and 8 hours a day.[79] NIOSH (National Institute for Occupational Safety and Health) of USA states that the permissible average 10-hour exposure level is 0.1 ppm to humans.[80] Taken together, exposure to less than 0.1 ppm ClO2 gas appears to be safe for humans. Thus, it would be concluded that long-term exposure to ClO2 gas at or below 0.1 ppm would be allowable to humans.

Antimicrobial Activity of ClO2 Gas at Extremely Low Concentrations

Ogata and Shibata first reported the effect of extremely low-concentration ClO2 gas at a level of 0.03 ppm (0.084 g/L) against influenza virus in an animal experiment[6] using a sophisticated machine to generate and deliver ClO2 gas at finely controlled concentrations.[7] The gas concentration was precisely controlled and accurately monitored during the study as demonstrated by recently published paper.[81] They found that the lethal activity of influenza A virus aerosol exposed to mice was dramatically reduced when 0.03 ppm ClO2 gas was present simultaneously with the virus aerosol. All the virus-challenged mice were alive and appeared quite healthy during and after the exposure of the virus when ClO2 gas was concomitantly present.[6] This result suggests the potential usefulness of the gas to protect human diseases caused by floating microbes in a room. A crucial point of this result is that evacuation of people from the room would not be required during the exposure to the gas because the concentration of the ClO2 gas employed is extremely low, i.e., below the permissible exposure concentration to human as mentioned above.[79,80,82] Thus, the exposure is not fumigation. Currently there is no useful and reliable measure to protect humans from infection by floating microbes without requiring evacuation in closed or semi-closed spaces, such as an airplane cabin or a spacecraft. The prevention of airborne microbe infection by the extremely low-concentration of ClO2 gas will open new avenues in the field of public health, e.g., prevention of highly pathogenic and transmissible H5N1 influenza virus.[83] The use of 0.03 ppm ClO2 gas is also useful in prevention of mosquito-related infective diseases, such as malaria and dengue fever, given that this concentration of ClO2 gas has a repellent effect against mosquitoes.[84]


Exposure to extremely low concentrations of ClO2 gas, effect on animals, whereas 0.03 to 0.1 ppm still has inactivation activities against bacteria and virus. Such concentrations of ClO2 gas could be used without requiring evacuation of people to prevent infections by microbes floating in air in closed or semi-closed spaces, such as in the cabins of aircrafts, living rooms and spacecraft. This effect of ClO2 gas can be used to prevent the spread of infectious diseases, such as highly pathogenic H5N1 influenza virus, by increasing the quality of indoor air. Currently, such a disinfectant is not commercially available. To the best of our knowledge, the extremely low concentrations of ClO2 are the only measure to prevent the infection by airborne microbes in the presence of humans.


This work was supported by Taiko Pharmaceutical Co., Ltd.

Declaration of Interest

The author is an employee of Taiko Pharmaceutical Co., Ltd.


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