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

Article Receivedon20/06/2017 ArticleRevisedon10/07/2017 ArticleAcceptedon31/07/2017


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.


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.


Molecular weight67.45
Melting point-59ºC
Boiling point11ºC
Density of liquid1.642 g/cm3
Solubility in water at 25ºC3.01 g/L
Oxidation state of chlorine+4
Dissociation energy of first Cl-O bond273 kJ/mol
Dissociation energy of second Cl-O bond270 kJ/mol
Standard enthalpy of formation (Hf)102.6 kJ/mol

The structure of ClO2 in liquid phase was observed by X-

cell, where ClO becomes ClO2 in an anode and H2O

ray diffraction analysis,[2] and the gas phase structure was observed by infrared spectroscopy (Table 2).[10] Of note, the ClO2 molecule is bent (C2ϖ symmetry) with O- Cl-O angle of 116.1º.[2] The Cl-O bond length was 1.46 Å.[2] Nielsen and Woltz reported the infrared spectrum of

 ClO   gas, revealing peaks  at 290, 445 (ϖ ), 943.2  ϖ ),

becomes hydrogen and OH in a cathode.[3] The overall reaction is 2NaClO2 + 2H2O → 2ClO2 + 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

2 2 1

1110, 1888 (2ϖ1), 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]


Cl-O bond length in liquid phase1.46 Å
Cl-O bond length in gas phase1.491± 0.014 Å
O-Cl-O bond angle in liquid phase116.1º
O-Cl-O bond angle in gas phase116.5 ± 2.5º


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 → 4ClO2 + 2H2O + 5NaCl. When ClO2 is generated from chlorine gas (Cl2) as a starting material, the chemical reaction is 2NaClO2 + Cl2 → 2ClO2 +

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]


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- phosphate dehydrogenase of baker’s yeast 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 ClO ,

2NaCl.[3]  ClO2  is  also  generated  by  mixing  sodium

chlorite with hypochlorous acid (HOCl) following the

consuming two molecules of ClO2


for each reaction.[17]

reaction of 2NaClO2 + HOCl → NaCl + NaOH + 2ClO2. In this reaction, hypochlorous acid is generated by mixing chlorine with water in the reaction of Cl2 + H2O

→ HOCl + HCl.[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

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, ClO 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 ClO and O2. The other two pathways form ClO and ClO .

(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

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 (ClO ) and chlorite (ClO ) ions, which

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  ClO   are  elicited  as  a  gas.  For  instance,  Bacillus

3 2 2

   are further converted to chloride (Cl) ion.[21-26] Kaur et al demonstrated that Cl and ClO 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 ClO per gram of rind. They detected 8.1 ± 1.0  g of Cl and no ClO per gram of flesh. Given that Cl is non- toxic, 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 (Escherichiacoli, 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, ClO was found in apples. In addition, Cl,

subtilis, S. enterica, B. anthracis, Francisella tularensis, Yersiniapestis, E.coliO157:H7, and Staphylococcusaureus 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.monocytogenesspot-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. subtilisvar. 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



 and ClO

above  control  values  were  noted  in

pre-humidification   treatment   of   the   test   pieces.[69]

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.


ClO2 has strong oxidizing activity presumably due to its

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.subtilisspores and S.albusinoculated

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

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. subtilisspores, the rate constant kis 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.enteritidisinoculated 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]


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.typhimuriumand L.monocytogenesinoculated on spinach leaves and tomato surfaces were inactivated by 5 or  10  ppm  (28   g/L)  ClO2  gas.[33]  S. entericaE. 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.anthracisand Mycobacteriumsmegmatis. The reduction of viability was greater than 6 log10.[34]


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]


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.


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 notfumigation. 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



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.


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


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