CDS is chlorine dioxide without sodium chlorite content (NaClO₂) in aqueous solution and therefore toxicity must be re-evaluated in this regard.

Chlorine dioxide (ClO2) is a compound used since the early 1944th century, when it was first used in a spa in Ostend, Belgium. Since XNUMX, the ClO2 It is used as a powerful disinfectant used in the purification of water for human supply and consumption, disinfection of hemodialysis equipment, reduction of dentobacterial plaque, gingivitis, keratosis, oral cleaning, cleaning of medical equipment and sterilization of bags for blood transfusion . It is a greenish-yellow gas and at temperatures below -59ºC they are bright orange crystals. It is extremely soluble in water giving it a characteristic yellow to golden color and its evaporation point is from 11ºC. For this reason, it must be kept refrigerated to maintain its activity for a long term.

The density of ClO2  it is 3,01 g / cm3, its melting point is -59ºC, the boiling point 11ºC, its decomposition from 45ºC and its molar mass is 67,45 g / mol. The stability of ClO2 in aqueous solution it is due to its structure that is similar to water. The angulation of its three atoms is 117,6º compared to 104,45º of H2O. Their bonds create clusters of water molecules to form larger molecular networks. Upon contact with protons in the human body, it decomposes into sodium chloride (NaCl) and oxygen (O2).

Chlorine dioxide is called the ideal antimicrobial. It is a compound capable of destroying bacteria, viruses, fungi or other pathogens. Its wide spectrum is due to the fact that its 5-electron charge is capable of damaging the vital functions of microorganisms due to their size and through the oxidation of the sulfhydryl or thiol (SH) groups, of the essential proteins of the microorganism with proton charge . 

Its action is similar to that carried out by neutrophils for the lysis of pathogens for millions of years. It is carried out through a chlorinated oxidation process (myeloperoxidase cycle), which is a thermal reaction that reduces or eliminates resistance by pathogenic organisms.

It is important to emphasize that in many publications confused with chlorine dioxide gas (ClO2) in aqueous solution with other chlorinated substances that contain other different characteristics such as: 

1. Ion Hypochlorite (ClO^-) 

It is an ion (oxoanion) with a chlorine atom in oxidation +1, derived from hypochlorous acid with a molar mass of 51.4521g / mol.

2.  Sodium Hypochlorite or Bleach (NaClO) 

It is a strongly oxidizing chemical pentahydrate that contains chlorine in oxidation state +1. Its molar mass is 74.44 g / mol, its density is 1.11 g / cm3, its boiling point is 101ºC and its acidity is <7.5 pKa .

3. Hypochlorous Acid (HClO) 

It is an acid that forms when chlorine dissolves in water. Its molar mass is 52,46 g / mol. It is a weak acid. However, due to its strong oxidation effect, it can continue to irritate the skin and even cause burns. Its decomposition produces highly corrosive substances such as hydrochloric acid and this can generate significant tissue damage and even necrosis in a very short period of time.

4. Sodium Chlorite (NaClO2) 

It is a chemical compound in the form of salt used in the manufacture of paper. Its molar mass is 90.44 g / mol, its density 2.5 g / cm3, its melting point of 170ºC and its solubility in water is 39 g / 100 ml (17ºC). It is the precursor to make ClO gas2, when mixed with an acid.

5. Chloric Acid or Chlorate (HClO3) 

It is the precursor of chlorate salts and contains chlorine in oxidation state +5. It is a strong and very unstable oxidant. The colorless solution is used as a strong oxidizing agent, especially in the paper industry as a bleach.

6. Sodium Chloride (common salt)

It is the sodium salt of hydrochloric acid with the chemical formula NaCl the molar mass of 58,44 g / mol, which should not be confused with sodium chlorite (NaClO2), the sodium salt of chlorous acid. Sodium chloride is the most important mineral for humans and animals. The body of an adult human contains around 150-300 g.

7. Chlorine (Cl²) or Chlorine Gas 

In nature it is not found in its pure state as it reacts quickly with many elements, forming chlorides and trihalomethanes (THMs) that can be carcinogenic. Its density is 3,214 kg / m3, its melting point of -102ºC and its boiling point of -34ºC. Hypochlorous acid (HClO) contains its chlorine in the oxidation state + 1; and it is highly unstable and reactive. It is one of the strongest halogenates. Its molar mass is 52.46 g / mol, its acidity is 7.4 pKa and it is soluble in water.

Unlike ClO2Many of the chlorinated substances mentioned above can produce trihalomethanes in aqueous solutions and be harmful to humans. Chlorine dioxide does not generate trihalomethanes, or reduces their production by at least> 97%. It is because of this characteristic that its use as a water disinfectant is preferred and that it allows to achieve the levels of safety and purity of the water, suggested by the US Environmental Protection Agency (EPA).

There are many ways to produce chlorine dioxide. Some may contain impurities such as 10% sulfuric acid (H2SO4), nitrate salts and products derived from the reaction such as Cl2 and the chlorine anion. The salts contain unknown impurities between 90 and 85%, respectively. This type of Chlorine Dioxide is not suitable for therapeutic treatments.

However, when production is carried out using hydrochloric acid (HCl) and sodium chlorite (NaClO2), with distilled water, through the gas scrubbing process, or through NaClO electrolysis2 , the mixture is very safe, without impurities and the production of harmful metabolites is reduced. It is recommended that production be in the place where it is going to be used, to avoid contamination and guarantee its refrigeration status preferably at 4ºC.

The way in which ClO is produced2 determines its composition and purity. The ClO2 It is a very stable compound at a pH greater than 5. At a pH between 6 and 10, the chlorite and chlorate ions will be in a very stable state. At the pH of the human body, it can be assumed that only ClO2 it will be the only chlorinated species that produces electron transfer, giving it security in its use. With the two processes mentioned above it does not cause a secondary reaction in the stomach unlike the mixture of sodium chlorite (Naclo2) with an acid or react with stomach HCL.

Another of the main characteristics of ClO2 it is your biosecurity. Due to its properties, at high concentrations it could be harmful to all cells. However, in aqueous solution at low concentrations, no harm is observed in the human body. Due to its physicochemical characteristics and its size, it reacts first selectively with the protons of microorganisms or with other acids in the interstitium.  

Due to the larger size of cells in the human body, a higher concentration of chlorine dioxide is required to cause damage since cells have a greater antioxidant capacity than microorganisms. Cell groups are organized in tissues with a greater capacity for electrophysiological dissipation and together they have an even greater antioxidant capacity. As a result, the human body has a much higher endurance capacity; in addition to containing redundancy of enzymatic and non-enzymatic antioxidant systems, vitamins and compartmentalization.

Chlorine dioxide reacts only with a select group of amino acids, while other macromolecules are only oxidized to a lesser extent depending on their pH according to the Nernst equation. Due to this the penetration of ClO2 in human cells it is low and the concentration required for its bactericidal effect is much lower than the toxic concentration for the cells of the human body.

On the other hand, there is a protection of the human body that resides in glutathione (deposit of SH groups) which is one of the most important non-enzymatic antioxidants in the human body. Glutathione exerts a protective effect on living cells of the body since the reaction of glutathione with ClO2 it is faster than the oxidation of cysteine. Because of this, the concentrations of ClO2 in living organisms it is very small and prevents the protein residues of cysteine, tyrosine and tryptophan in cells from being attacked by it in the cytoplasm. The cells of the body continuously produce glutathione, exerting its protective effect despite the continuous consumption of ClO2.

Human cells contain glutathione as the main antioxidant factor, but they also contain other systems that exert their protective effect. Due to the functioning of these systems within the body cells and their regeneration capacity, the effect of ClO2 on cells is much less than the effect exerted on individual microorganisms that do not have protective antioxidant systems. Furthermore, because the cells of the body are found in tissues capable of electrical dissipation, the amounts of antioxidant substances are several orders of magnitude higher than microorganisms. A human being can consume a solution of ClO2 with 24 mg / L in a liter of in a day, without any harmful effects.

 In a study conducted to determine the toxicity of chlorine dioxide, no symptoms were observed in the eye irritation test in rabbits using ClO2 at 50 ppm. In mice that drank 40 ppm water for 90 consecutive days, no toxicity was observed in the test. Animal tests showing toxicity are performed at much higher doses (> 100 or 200 mg / L).

Through a prospective, randomized and double-blind study, the chronic administration of water treated by ClO was evaluated.2 in humans. It was a study in three phases.

1. Phase I studied the acute effects of single increasing doses in healthy adult volunteers. 
2. In Phase II, the impact on normal subjects of the daily intake of concentrations of 5 mg / L was considered for twelve consecutive weeks.
3. In Phase III, chlorine dioxide concentrations of 5 mg / L daily for 12 weeks were administered to a person with glucose-6-phosphate dehydrogenase deficiency. No undesirable clinical sequelae were observed in any of the participants. Ingestion of chlorine dioxide and its metabolites is considered safe within the parameters of this study.

 The lethal dose (LD50) for oral ingestion is 292 milligrams per kilogram of body weight for 14 consecutive days (= 15,000 mg in a 50 kg person). However, cases of ClO inhalation toxicity have been reported.2 , where the concentration is usually higher than 3000 mg inhaled in a few minutes.

In the three phases of the toxicity study mentioned above, no adverse effects were found. The medical evaluation team did not observe undesirable clinical sequelae in any of the participants. In some cases variations were found in some biochemical and physiological parameters, but none caused physiological consequences. A period longer than the continuous intake of twelve weeks would be required to determine if the variations could be statistically significant. Therefore, oral ingestion of chlorine dioxide and its metabolites was considered safe.

In a study conducted by the Department of Health and Human Services of the US Department of Health and Human Services - Agency for Toxic Substances and Disease Registry published in September 2004, it was reported Several interesting results related to the intake of chlorine dioxide, in humans:

1. It is a reddish-yellow gas, with a molecular weight of 67.452th g / mol. Its boiling point is at 11ºC and has a density of 1.640 g / mL (0ºC). Its odor is sour and it is very soluble in water (3.01 g / L at 25ºC and 34.5 mmHg.
2. About 5% of US water purification units use chlorine dioxide to produce drinking water. It is estimated that around 12 million people drink drinking water where chlorine dioxide is applied.
3. The Environmental Protection Agency (EPA) determined that the maximum concentration for drinking water was 0.8 milligrams per liter.
4. Animal studies have indicated that the lowest level of adverse effect (Lowest Observed Adverse Effect Level - LOAEL) is 5 mg / kg / day for repeated exposures.
5. No death was observed in rats after 90-day ingestion at concentrations of 11.5 mg / kg / day in males and 14.9 mg / kg / day in females.
6. The lethal dose 50 (LD50) has been reported to be> 10,000 mg / kg in mice.
7. No deaths were found in rats at doses of 56 mg / kg / day
8. No statistical difference was found in mortality in control rats compared to rats with daily intake for two years at concentrations of 13 mg / kg / day.
9. No toxic effects on cardiovascular system, skeletal muscle, skin, eye and metabolic effects have been reported in humans and animals.
10. No adverse respiratory effects were observed in human adults after ingestion with doses up to 0.34 mg / kg / day for 16 days.
11. No association of cancer with human intake has been reported.
12. No deaths have been reported in humans or animals after dermal exposure.
13. Respiratory, cardiovascular, hematological, musculoskeletal, liver, kidney, endocrine toxicities have not been reported.

ocular or by weight; associated with dermal exposure

14. There are no reports that relate the intake with genotoxicity; has no mutagenic effects
15. The mean absorption rate was 0.198 / hour and the half-life was 3.5 hours.
16. The main pharmacokinetic mechanisms are related to redox reactions in tissue compartments. Because it exerts its functions through oxidative reactions rather than chlorination, the formation of chlorinated organic compounds is limited
17. The main route of elimination after oral administration is the urinary route, mostly in the form of chloride ion.
18. There are no specific biomarkers
19. There is no information related to interactions with other chemical substances
20. People most susceptible to toxicity are those with glucose-6-phosphate dehydrogenase (G6PD) deficiency.
21. In the event of severe exposures, especially in children, well above the recommended levels, methemoglobinemia may occur (especially in patients with G6PD deficiency). Treatment is the use of methylene blue intravenously. 

In a study conducted to determine the efficacy and safety of a chlorine dioxide solution, the solution with 5 ppm (bacteria) and 20 ppm (fungi) had an antimicrobial efficacy of 98.2%. The mean maximum inhibitory concentration (IC50) for H1N1, influenza virus B / TW / 71718704 and EV71 was 84.65 ± 0.64, 95.91 ± 11.6 and 46.39 ± 1.97 ppm, respectively. In a test on mouse lung L929 fibroblasts, cell viability was observed to be 93.7% at concentrations of 200 ppm. Neither eye irritation was observed in rabbits when applying a 50 ppm solution. In the inhalation test at 20 ppm for 24 hours, no symptoms were observed, no mortality or impairment of respiratory function tests. This confirms that it has an antimicrobial activity and greater safety than previously reported.

Due to its benefits as an antimicrobial agent and its biosecurity, its use has been proposed for the neutralization of viral agents. In 1986 the inactivation of the virus was tested by its reaction with the proteins of the virus capsid. They found that cysteine, tyrosine, and tryptophan react with ClO2 quickly. Its antiviral activity has been reported to reside in attacking viral nucleic acids and proteins and in oxidizing amino acids such as cysteine, tryptophan, and tyrosine. It was found that cysteine ​​reacted faster and that histidine, hydroxyproline, and proline also reacted, but at a slower rate.

The antiviral activity of the gas in chlorine dioxide solution was evaluated on a variety of viruses. It was shown to have a high antiviral activity (99.99%) with concentrations between 1 and 10 ppm at 180 seconds. Its antiviral capacity is less affected by pH than chlorine, it has a more pleasant odor and is more stable when stored. 

It was also found that ClO2 It inactivates the influenza virus by oxidizing tryptophan residues in the hemagglutinin of the virus capsid protein, abolishing its ability to bind to the receptor. The capsid protein of SARS-CoV-2 contains 54 residues of tyrosine, 12 of tryptophan and 40 of cysteine, which allows the ClO2 can inactivate SARS-CoV-2 in an extremely short time and at a low concentration calculated as up to 0.1mg / L.

In a previous work, Z. Noszticzius, found that the time it takes for ClO2 to kill a living organism is proportional to the square of its diameter. Therefore, the smallest organisms will die much faster. In his calculation, he found that a bacteria 1 micron in diameter would die in a 300 mg / L solution in 3 milliseconds; and one of 0.25 mg / L in 3.6 seconds. At this time, the ClO2 it would reach all parts of the cell, destroying proteins that contain cysteine, tyrosine and tryptophan. The SARS-CoV-2 virus has a diameter of 60-140 nm.[.https://www.ncbi.nlm.nih.gov/books/NBK554776/] 

Cascella M, Rajnik M, Cuomo A, et al. Features, Evaluation and Treatment Coronavirus (COVID-19) [Updated 2020 Jul 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-.Available from: https://www.ncbi.nlm.nih.gov/books/NBK554776/

The time required to activate it would be 1-2 orders of magnitude faster than bacteria. The ClO2 it does not need to penetrate the virus to inactivate it. Inactivation is due to degradation of the virus capsid and its genome. The ClO2 It reacts with cysteine, tyrosine or tryptophan residues to exert its effect and affect the capsid, and on proline and hydroxyproline at the level of the binding receptor domain (RBD) and the ACE2 receptor. 

Through different studies it has been shown that ClO2 inactivates several types of viruses, including: human rotavirus, human norovirus, feline calicivirus, polio virus and echovirus (SARS), influenza, and parainfluenza. It also does so in adenovirus type 40, Feline Calicivirus, Canine Parvovirus, Hantavirus, Hepatitis virus, Human Coronavirus, mouse minute virus, Newcastle, Norwalk, Theiler encephalitis, Vaccinia and HIV. 

Fact Sheet, National Agricultural Biosecurity Center, Kansas State University.

influenza virus [https://benthamopen.com/ABSTRACT/TOANTIMJ-2-71]. 

Adenovirus Type 40  Inactivation of Enteric Adenovirus and Feline Calicivirus by Chlorine Dioxide, Thurston-Enriquez, JA, APPLIED AND ENVIRONMENTAL MICROBIOLOGY, June 2005, p. 3100-3105.

calicivirus Inactivation of Waterborne Emerging Pathogens by Selected Disinfectants, J. Jacangelo, pg 23.

Canine parvovirus. BASF Aseptrol Label

Coronavirus Chlorine Dioxide, Part 1 A Versatile, High-Value Sterilant for the Biopharmaceutical Industry, Barry Wintner, Anthony Contino, Gary O'Neill. BioProcess International DECEMBER 2005.

Feline Calici Virus Chlorine Dioxide, Part 1 A Versatile, High-Value Sterilant for the Biopharmaceutical Industry, Barry Wintner, Anthony Contino, Gary O'Neill. BioProcess International DECEMBER 2005.

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Hepatitis A, B & C Virus3,8 Chlorine Dioxide, Part 1 A Versatile, High-Value Sterilant for the Biopharmaceutical Industry, Barry Wintner, Anthony Contino, Gary O'Neill. BioProcess International DECEMBER 2005, BASF Aseptrol Label

man coronavirus BASF Aseptrol Label

Human Immunodeficiency VirusChlorine Dioxide, Part 1 A Versatile, High-Value Sterilant for the Biopharmaceutical Industry, Barry Wintner, Anthony Contino, Gary O'Neill. BioProcess International DECEMBER 2005.

Influenza a Protective effect of low-concentration chlorine dioxide gas against influenza A virus infection Norio Ogata and Takashi Shibata Journal of General Virology (2008), 89, 

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Vaccinia virus NHSRC's Systematic Decontamination Studies, Shawn P. Ryan, Joe Wood, G. Blair Martin, Vipin K. Rastogi (ECBC), Harry Stone (Battelle). 2007 Workshop on Decontamination, Cleanup, and Associated Issues for Sites Contaminated with Chemical, Biological, or Radiological Materials Sheraton Imperial Hotel, Research Triangle Park, North Carolina June 21, 2007.

In addition to its oxidizing capacity that exerts on the spikes and the RNA of the virus, ClO2 exerts an indirect benefit by restoring the neutrophil myeloperoxidase cycle to exert its virucidal activity by increasing the molecular oxygen in the interstitium and therefore the effectiveness of the mitochondria in the Krebs cycle. Neutrophils are our first defense cell line in the human body against microorganisms and other types of cell damage that acts in inflammation, repair and tissue regeneration. However, they are also implicated in tissue damage in inflammatory and autoimmune diseases, and in respiratory distress syndrome. This is linked to the ability to release a large number of compounds that can kill bacteria, viruses, normal cells, and connective tissue.

These toxins are normally used in the defense of the host against microorganisms. Around 50 toxins have been detected that are divided into two large groups; those derived from the plasma membrane or intracellular granules. In the plasma membrane, it is associated with the enzyme NADPH oxidase which generates reactive oxygen species (O2-, H2O2 and OH-). Neutrophils contain a large amount of myeloperoxidase enzyme that in combination with H2O2 can oxidize Cl-, Br- or I- towards hypochlorous acid (HOX). Myeloperoxidase oxidizes chlorine to HOCl- which has a high biological activity as an oxidant. A quantity of 2x10-7 mol of HOCl- generated by 106 neutrophils, can destroy 150 million Escherichia coli cells in milliseconds.

Due to its high reactivity, chlorine dioxide cannot accumulate in biological systems, but dissociates almost instantly in multiple reactions in the presence of protons. The myeloperoxidase system generates a certain amount of oxidants under physiological conditions without damaging the tissue.

Due to the confusion in terms of chlorine compounds and the lack of in-depth knowledge and properties of chlorine dioxide within the medical community and in general, its use as a drug for the treatment of COVID-19 has been controversial. Chlorine dioxide is a molecule (ClO2) which, when dissociated, releases bioavailable molecular oxygen into the blood. It has an important redox effect with an ORP of 0,94V under normal conditions, much more effective than the effect related to chlorine, due to its rapid conversion into common salt (NaCl) within the human body and its easy elimination through the urinary tract. . This redox effect favors the lipoperoxidation of the capsid and the RNA of the virus, promotes direct and indirect antimicrobial effects and favors the oxygenation of the tissues.