Dióxido de Cloro (ClO2) - La Oveja de Van Gogh

Dióxido de Cloro (ClO2)





El dióxido de cloro (ClO2), ahora comercialmente importante, no es de reciente descubrimiento. El gas fue producido por primera vez por Humphrey Davy en 1811


Informe de Gobierno de EE.UU, sobre la eficacia del dióxido de cloro.

Evaluación de la eficacia y la seguridad de una solución de dióxido de cloro 

Resumen 
En este estudio, se produjo una solución de dióxido de cloro (UC-1) compuesta de dióxido de cloro mediante un método electrolítico y posteriormente se purificó mediante una membrana. 
Se determinó que el UC-1 contenía 2000 ppm de dióxido de cloro gaseoso en el agua. 
Se evaluó la eficacia y la seguridad del UC-1. 
La actividad antimicrobiana fue de más del 98,2% de reducción cuando las concentraciones de UC-1 fueron de 5 y 20 ppm para las bacterias y los hongos, respectivamente. 
Las concentraciones inhibidoras máximas a la mitad (IC50) del H1N1, el virus de la gripe B/TW/71718/04, y el EV71 fueron 84,65 ± 0,64, 95,91 ± 11,61, y 46,39 ± 1,97 ppm, respectivamente. Una prueba de bromuro de 3-(4,5-Dimetiltiazol-2-il)-2,5-difeniltetrazolio (MTT) reveló que la viabilidad celular de las células de fibroblasto pulmonar de ratón L929 era del 93,7% a una concentración de 200 ppm de UC-1 que supera la prevista en el uso rutinario. 
Además, 50 ppm de UC-1 no mostraron ningún síntoma significativo en una prueba de irritación ocular de conejo. 
En una prueba de toxicidad por inhalación, el tratamiento con 20 ppm de UC-1 durante 24 h no mostró ninguna anormalidad ni mortalidad en los síntomas clínicos y el funcionamiento normal del pulmón y otros órganos. 
Una concentración de ClO2 de hasta 40 ppm en el agua potable no mostró ninguna toxicidad en una prueba de toxicidad oral subcrónica. Aquí, el UC-1 mostró una actividad de desinfección favorable y una tendencia de perfil de seguridad más alta que en informes anteriores. 




Palabras clave: dióxido de cloro (PubChem CID: 24870), eficacia antimicrobiana, ensayo antiviral, toxicidad por inhalación, toxicidad oral subcrónica 

Fuente: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5369164/ Artículo original Efficacy and Safety Evaluation of a Chlorine Dioxide Solution Jui-Wen Ma,1,2 Bin-Syuan Huang,1 Chu-Wei Hsu,1 Chun-Wei Peng,1 Ming-Long Cheng,1 Jung-Yie Kao,2 Tzong-Der Way,2,3,4 Hao-Chang Yin,1,* and Shan-Shue Wang5,* Miklas Scholz, Academic Editor Author information Article notes Copyright and License information Disclaimer This article has been cited by other articles in PMC. Go to: Abstract In this study, a chlorine dioxide solution (UC-1) composed of chlorine dioxide was produced using an electrolytic method and subsequently purified using a membrane. UC-1 was determined to contain 2000 ppm of gaseous chlorine dioxide in water. The efficacy and safety of UC-1 were evaluated. The antimicrobial activity was more than 98.2% reduction when UC-1 concentrations were 5 and 20 ppm for bacteria and fungi, respectively. The half maximal inhibitory concentrations (IC50) of H1N1, influenza virus B/TW/71718/04, and EV71 were 84.65 ± 0.64, 95.91 ± 11.61, and 46.39 ± 1.97 ppm, respectively. A 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test revealed that the cell viability of mouse lung fibroblast L929 cells was 93.7% at a 200 ppm UC-1 concentration that is over that anticipated in routine use. Moreover, 50 ppm UC-1 showed no significant symptoms in a rabbit ocular irritation test. In an inhalation toxicity test, treatment with 20 ppm UC-1 for 24 h showed no abnormality and no mortality in clinical symptoms and normal functioning of the lung and other organs. A ClO2 concentration of up to 40 ppm in drinking water did not show any toxicity in a subchronic oral toxicity test. Herein, UC-1 showed favorable disinfection activity and a higher safety profile tendency than in previous reports. Keywords: chlorine dioxide (PubChem CID: 24870), antimicrobial efficacy, antiviral assay, inhalation toxicity, subchronic oral toxicity Go to: 1. Introduction Chlorine dioxide, a strong oxidant, can inhibit or destroy microbes [1,2,3,4,5]. Studies have investigated the application of chlorine dioxide in numerous fields such as water or wastewater treatment, environment and food disinfection, and medicine [6,7,8,9,10,11,12,13]. Typically, chlorine dioxide is produced using either an acid-based or an electrolytic method [7,8,10,12]. In the acid-based method, chlorine dioxide is produced by mixing starting materials, such as sodium chlorite and hydrochloric acid, sodium chlorite and ferric trichloride, or sodium chlorite and chlorine gas. In the electrolytic method, the reactants are aqueous sodium chloride or saturated saline and sodium hypochlorite. According to the disinfectants and disinfection byproducts rule (DBPR) of the United States Environmental Protection Agency Microbial and Disinfection Byproduct Rules Simultaneous Compliance Guidance Manual [14], the maximum residual disinfectant level goals (MRDLG) and maximum residual disinfectant levels (MRDL) of chlorine dioxide are 0.8 mg/L [14]. The permissible exposure limits (PELs) for chlorine dioxide defined by the Occupational Safety and Health Administration are as follows: (a) General industry: 0.1 ppm and 0.3 mg/m3; (b) Construction industry: 0.1 ppm and 0.3 mg/m3 time weighted average (TWA); (c) American Conference of Governmental Industrial Hygienists threshold limit value: 0.1 ppm and 0.28 mg/m3 TWA; 0.3 ppm and 0.83 mg/m3 short term exposure limit (STEL); (d) National Institute for Occupational Safety and Health recommended exposure limit: 0.1 ppm TWA; 0.3 ppm STEL. The application of chlorine dioxide products or their contact with food or the human body is a serious issue if the products contain high levels of impurities. Impurities are mainly caused by impure reactants such as 10% H2SO4 and 15% NaClO2 or reaction byproducts such as Cl2 and chloroxy anion. For example, 10% H2SO4 and 15% NaClO2 contain 90% and 85% unknown impurities, respectively. The chlorine dioxide product obtained from a mixture of 10% H2SO4 and 15% NaClO2 is highly impure. The Cl2 product can react with organic matter to form trihalomethane, which is a carcinogen. Chloroxy anions, such as ClO2− or ClO3−, can be harmful to human health [15]. The domestic and industrial use of chlorine dioxide should be assessed according to product purity, for which the preparation method is an essential step. Low purity starting materials (e.g., 5% HCl and 10% NaClO2) have a high impurity content. If the product of these reactions is not further purified, then the chlorine dioxide products produced, which also contain high levels of impurities, are useful only for wastewater treatment and are unsuitable for contact with humans or food because of the harmful impurities. Therefore, a higher percentage of chlorine dioxide gas molecules must be obtained through further chlorine dioxide gas molecule purification. To increase the safety of chlorine dioxide solution, eliminating or reducing the impurities and increasing the gas chlorine dioxide concentration in a solution is a reasonable approach. Herein, a clean and concentrated process for chlorine dioxide gas production was designed and implemented. We produced a chlorine dioxide solution (UC-1) containing 2000 ppm chlorine dioxide gas in water through the electrolytic method. The solution was further purified with a film membrane, and subsequently dissolved in reverse osmosis (RO) water. UC-1 was investigated to determine its efficacy, and safety issues such as the antimicrobial activity, in vitro cytotoxicity, in vivo rabbit ocular irritation, in vivo inhalation toxicity, and in vivo subchronic oral toxicity were assessed. Go to: 2. Materials and Methods 2.1. Electrolytic Method for Gas Chlorine Dioxide Production The UC-1 solution is produced in an apparatus, the technical details of which will be published later in the form of a patent application (PCT applied PCT/CN2016/080198; PCT applied PCT/CN2016/080199; PCT applied PCT/CN2015/099515; DE202016103175) by an electrochemical method. Briefly, sodium chloride solution was made from 99% (food grade) sodium chloride and RO water and pumped into the electrobath equipment. The electrolysis was operated by 6–12 V and 40–80 A current. After electrolysis, the ClO2 gas was mixed with water using a water-ClO2 mixer which was designed based on the Venturi effect. Mixing of water with ClO2 gas was continued by the cycle till the concentration of ClO2 in water was over 2000 ppm (Figure 1) and pH value was 2.2. The chlorine dioxide solution produced by this process is named as UC-1. An external file that holds a picture, illustration, etc. Object name is ijerph-14-00329-g001.jpg Figure 1 Flowchart of chlorine dioxide solution production. The chemical composition of the UC1 solution was determined according to a standard method [16]. The following data were obtained: ClO2: 2120 ppm, free chlorine (Cl2): 882 ppm, and total chlorine (Cl2 + HOCl + OCl−): 900 ppm. The total chlorine concentration is somewhat higher than in the case of other ClO2 generators because the electrolyte applied by us does not contain any NaClO2. The UC-1 solution was produced by using only 25% NaCl solution, with no other additive, which is an obvious advantage. At the same time, despite the higher total chlorine content (which is present in the diluted UC-1 solutions mostly as HOCl), no detectable adverse effects were observed on the test animals or animal tissues. 2.2. Antimicrobial Efficacy Test The test was performed following U.S. Pharmacopeia 34 NF29 Microbiological Tests/<51> [17]. Antimicrobial Effectiveness Testing. The test organisms were as follows: Escherichia coli (BCRC 11634/ATCC 8739), Staphylococcus aureus (BCRC 10451/ATCC 6538P), Pseudomonas aeruginosa (BCRC 11633/ATCC 9027), S. aureus subsp. aureus (BCRC 15211/ATCC 33591), Bacillus subtilis subspecies. (BCRC 10447/ATCC 6633), Listeria monocytogenes (BCRC 14848/ATCC 19114), Acinetobacter baumannii (BCRC 10591/ATCC 19606), Salmonella enterica subspecies. (BCRC 12947/ATCC 13311), Klebsiella pneumoniae (BCRC 16082/ATCC 4352), Penicillium funiculosum (BCRC 30438/ATCC 11797), and Candida albicans (BCRC 21538/ATCC10231). 2.3. Antiviral Assay Viruses were amplified in MDCK/RD cells. MDCK/RD cells were cultured in 10% fetal bovine serum Dulbecco’s modified Eagle’s medium (FBS DMEM). When the cells reached 90% confluence, they were washed with phosphate-buffered saline (PBS) and infected at a multiplicity of infection of 0.01. Following the infection, 0% FBS DMEM was added, and the cells were incubated at 35 °C in a 5% CO2 incubator for 48 h. A 1-mL cell suspension (6 × 105 cells) was loaded into each well of a 6-well plate, which was incubated at 37 °C for 18–24 h. PBS was used to dilute UC-1 to final concentrations of 0, 25, 50, 100, and 200 ppm in wells reacted with cells and viruses for 2 min at 37 °C. Following the reaction, the total reaction mixture was diluted to 10−8. Subsequently, the 10−8 dilution mixture was incubated at 37 °C for 48–64 h. The cells were fixed with 10% formalin for 1 h and stained with 0.1% crystal violet for 5 min. The virus-formed plaque number was counted and compared between the test and control groups. The antiviral activity is shown as the percentage of virus control = plaques in the test group/plaques in the control group × 100. The virus control is defined as infected virus with cells without the testing agent and is considered as 100%. 2.4. In Vitro Cytotoxicity Test (MTT Assay) Mouse lung fibroblast L929 cells were cultured in complete Eagle minimum essential medium (MEM) and incubated at 37 °C ± 1 °C in 5% ± 1% CO2. Furthermore, 100 μL of L929 cell suspension (1 × 105 cells/mL) was transferred into each well of a 96-well cell culture plate. The cells were subsequently incubated at 37 °C ± 1 °C for 24 h ± 2 h. The culture medium was replaced with 100 μL of the test solution or blank, positive, or negative control. The test solutions contained 0 (control), 200, 400, 600, and 800 ppm UC-1 in MEM. The blank control medium contained 10% horse serum. The cells were incubated for another 24 h. The cells were treated with the solutions in triplicate. After the MTT solution was added to each well, the plate was incubated for 2 h ± 10 min at 37 °C ± 1 °C. The MTT solution was replaced with 100 μL of dimethyl sulfoxide and subsequently subjected to a microplate reader equipped with a 570-nm filter for colorimetric measurement (reference, 650 nm). The triplicate results of the MTT assay are presented as mean ± standard deviation (SD). Cell viability (%) = optical density of the test group/optical density of the control group × 100. 2.5. White Rabbit Ocular Irritation Test Six 2–3-kg female New Zealand white rabbits were purchased from the Taiwan Livestock Research Institute (Xinhua, Tainan, Taiwan); the rabbits were quarantined and acclimatized before treatment. The animals were fed ad libitum and maintained at 20–26 °C under 30%–70% humidity. Furthermore, 0.1 mL of 50 ppm UC-1 (test solution) was administered to the left eye of the rabbits, and 0.1 mL of 0.9% normal saline (control solution) was administered to the right eye. Subsequently, the eyelids were held together for 1 s for instillation. Each treatment was repeated three times. Ocular irritations were observed for at the 1st, 24th, 48th, and 72nd hour using an ophthalmoscope (Welch Allyn, Skaneateles Falls, NY, USA). Extended observation was necessary in case of persistent lesions to determine the progression or reversal of the lesions. Ocular irritation scores were based on the system for grading ocular lesions (ISO 10993-10). When more than one animal in the test group showed a positive result at any stage of the observations, the test component was considered an eye irritant and further testing was not required or performed. When only one of the test groups showed a mild or moderate reaction that was equivocal, the procedure was conducted on three additional animals. When more than half of the eyes showed a positive result at any stage of the observation, the test component was considered an eye irritant. A severe reaction in only one animal was considered sufficient to label the test component as an eye irritant. 2.6. Inhalation Toxicity Test Fifteen 4-week-old BALB/c male mice were purchased from the National Laboratory Animal Center (Taipei, Taiwan); they were quarantined and acclimatized before treatment in an animal room at China Medical University, Taiwan. The animals were fed ad libitum and maintained at 20–25 °C and 65%–80% humidity. Five mice were housed in one cage and fed with 0 (PBS) and 10 or 20 ppm UC-1 (test solution), which was administered as mist by using a humidifier in an airtight box for 24 h. The clinical symptoms and body weight of the animals were observed; they were subsequently sacrificed to examine their lung sections and organ weight. The experimental animals were observed, and their clinical symptoms were recorded as abnormality (%), defined as the animals behaving abnormally compared with normal animals, and mortality (%), defined as animal death. 2.6.1. Evaluation of the Organ Weight During the experiment, the animals were immediately dissected on death, and a record was made. All surviving animals were sacrificed and autopsied to observe their appearance and all organs in the mouth, chest, and cranial and abdominal cavities. Subsequently, the organs, including the liver, adrenal glands, kidneys, and gonads, were removed, weighed, and recorded. 2.6.2. Hematoxylin and Eosin Staining of Mouse Lung Sections Tissue sections frozen in the optimal cutting temperature compound were fixed in acetone and chloroform; the sections were immersed in filtered Harris hematoxylin (Leica Biosystems Richmond, Inc., Richmond, IL, USA) for 1 min. The slides were rewashed with Tris-buffered saline and Tween 20 (Biokit Biotechnology Inc., Miaoli, Taiwan), and the sections were counterstained with eosin (Leica Biosystems Richmond, Inc., Richmond, IL, USA) for 1–2 min. The sections were dehydrated in ascending alcohol solutions and cleared with xylene. The prepared slides were examined through light microscopy. 2.7. Subchronic Oral Toxicity Test Twenty-five 4-week-old BALB/c male mice were purchased from the National Laboratory Animal Center; they were quarantined and acclimatized before treatment in an animal room at China Medical University. The animals were fed ad libitum and maintained at 20–25 °C under 65%–80% humidity. Five mice were housed in one cage and fed 0 (PBS; control), 5, 10, 20, and 40 ppm UC-1 (test solutions) continuously for 90 days. PBS or test solutions fed as drinking water were freshly prepared daily before treatments. 2.7.1. Evaluation of the Clinical Symptoms The experimental animals were observed, and their clinical symptoms were recorded as abnormality (%), defined as the animals behaving abnormally compared with normal animals, and mortality (%), defined as animal death. 2.7.2. Body Weight The body weight of the experimental animals was recorded at treatment initiation and once per week during the experimental period using an electronic balance (AND, FX-2000i, Tokyo, Japan). 2.7.3. Necropsy, Gross Examination, and Organ Weighing During the experiment, the animals were dissected immediately on death, and a record was made. All surviving animals were sacrificed and autopsied to observe their appearance, and all organs in the mouth, chest, and cranial and abdominal cavities were analyzed. Subsequently, the organs, including the liver, adrenal glands, kidneys, and gonads, were removed, weighed, and recorded. 2.8. Statistical Analysis The results were analyzed using SPSS Version 20.0 (IBM Corp., Armonk, NY, USA) with one-way analysis of variance, F-test, and Duncan’s new multiple range test for comparing more than two mean values; results with p < 0.05 indicated significant differences. The results represent at least 3 independent experiments and are shown as the mean ± SD. 2.9. Ethical Statement This research was approved by the China Medical University Laboratory Animal Service Center. Program Number: 10442699 (for the white rabbit ocular irritation test) and 10442686 (for the inhalation toxicity and subchronic oral toxicity tests). Go to: 3. Results In this study, a UC-1 containing 2000 ppm chlorine dioxide in water was produced through the electrolytic method with food-grade salt (99% NaCl) and RO water as the starting reactants. Subsequently, the chlorine dioxide was purified through a film and dissolved in RO water. Because a chlorine dioxide solution can be directly applied to food or human hygiene or preventative health measures, its safety and efficacy were investigated. 3.1. Antimicrobial Efficacy Test The in vitro antimicrobial activity of UC-1 was examined. The in vitro antimicrobial activity was more than 98.2% reduction for bacteria and fungi (Table 1); excellent antimicrobial activity was observed at low concentrations of 5 and 20 ppm UC-1 for bacteria and fungi, respectively. Table 1 Antimicrobial efficacy of UC-1. Organisms Original Inoculum (CFU/mL) Counts of UC-1 at Contact Time a (CFU/mL) Percent Reductions (R) b Escherichia coli c,* 2.55 × 105 <1>99.9 Staphylococcus aureus c,* 3.15 × 105 <1>99.9 Pseudomonas aeruginosa c,* 2.55 × 105 <1>99.9 Staphylococcus aureus subsp. Aureus c,* 2.60 × 105 <1>99.9 Bacillus subtilis subspecies c,* 3.75 × 105 1.35 × 103 99.6 Listeria monocytogenes c,* 8.20 × 105 <1>99.9 Acinetobacter baumannii c,* 5.40 × 105 <1>99.9 Salmonella enterica subspecies c,* 4.80 × 105 <1>99.9 Klebsiella pneumoniae c,* 9.30 × 105 <1>99.9 Penicillium funiculosum ,cΔ 3.70 × 105 6.70 × 103 98.2 Candida albicans c,Δ 3.20 × 105 <1>99.9 a The contact time was 10 min. b Percent reductions of <1 .="" 0.05="" 0.1="" 0.2="" 0.3="" 0.4="" 0.5="" 0.64="" 0.6="" 0.7="" 0.8="" 0.9="" 0="" 1.97="" 1.="" 10.1007="" 10.1016="" 10.1021="" 10.1099="" 10.1155="" 10.1289="" 10.4265="" 10.="" 100="" 10="" 11.61="" 11.="" 12.="" 13.="" 14.="" 15.="" 15="" 16.="" 17.="" 18="" 1970="" 1982="" 1989="" 1995.="" 1997="" 1999.="" 1999="" 19th="" 1="" 2.5="" 2.="" 2008="" 2009="" 200="" 2010="" 2014="" 2015="" 2016="" 20="" 24="" 25="" 2="" 3.2.="" 3.3.="" 3.4.="" 3.5.="" 3.6.="" 3.="" 30="" 34="" 3="" 4.="" 40.3="" 400="" 40="" 45="" 46.39="" 48="" 4="" 5.="" 50="" 5="" 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