or alkyldimethylbenzylammonium chloride (ADBAC), a type of Quaternary Ammonium Compound. Sakkas V.A., Konstantinou I.K., Triantafyllos A.A. The results showed that the degradation rate increased with increasing temperature. Repeated dose oral toxicity Guideline : OECD 407 Species/strain : Rat, Wistar Hsd Cpb:WU Group size : 12 (6 male/6 female . SECTION 1: Identification of the substance/mixture and of the company/undertaking 1.1 Product identifier Trade name: Good Sense Breakdown UFI: RNF6-M0MS-D00F-K69J 1.2 Relevant identified uses of the substance or mixture and uses advised against SWED - Sector-specific worker exposure description : They then performed a pilot examination via bulk sample analysis of one representative product from each category labelled as containing BIT. In solutions buffered at pH 4, DCOIT degraded quickly within 30 d of observation, presenting a half-life of 6.8 d. In contrast, at pH 7, 98.4% of the dissolved DCOIT was degraded after 7 d, and the half-life was 1.2 d. At pH 9, DCOIT degraded gradually over the 30 d with an estimated half-life of 3.7 d [8]. [1] What Does Benzisothiazolinone Do in Our products? Chand R., Tulucan T., Aburlacitei M. Investigation of biocide biodegradation in wastewater under laboratory set-up in anaerobic and aerobic with substrate conditions. Therefore, over the years, several reports have been prepared illustrating their biocidal activity against a wide spectrum of industrial biological contaminants. Jeannot M.A. Biocidal Products Committee (BPC) - ECHA Cho H.J., Park D.U., Yoon J., Lee E., Yang S.I., Kim Y.H., Lee S.Y., Hong S.J. Chen L., Xu Y., Wang W., Qian P. Degradation kinetics of a potent antifouling agent, butenolide, under various environmental conditions. How does this chemical pronounce? Benzisothiazolinone, also called BIT, is an off-white to yellowish liquid antimicrobial chemical. Analysis of isothiazolinones in environmental waters by gas Fate of Microbicidal 3-Isothiazolone Compounds in the Environment: Modes and Rates of Dissipation. Todberg T., Opstrup M.S., Johansen J.D., Hald M. Occupational facial contact dermatitis caused by methylchloroisothiazolinone/methylisothiazolinone in a stainless steel aerosol spray. Sabev H.A., Handley P.S., Robson G.D. Fungal colonization of soil-buried plasticized polyvinyl chloride (pPVC) and the impact of incorporated biocides. Contact allergy to benzisothiazolinone, Author: Dr Julia Zhu, Dermatology Advanced Registrar Trainee, Greenlane Clinical Centre, New Zealand. "[10], The opinion further states: "There is no information on what may be safe levels of exposure to benzisothiazolinone in cosmetic products from the point of view of sensitisation. The principal degradative pathway involved the dissociation from CaCl2, ring opening, and loss of Cl and S, and led to N-methylmalonamic acid [70]. The NC alkyl bond cleavage of 4,5-dichloro-3-n-octylthiazolin-2-one and the oxidation of the alkyl group results in n-octanal [81]. Both compounds are degraded by UV radiation and show little adsorption by river silt but are readily absorbed and metabolized by aquatic ferns. evaluated the photodegradation of BIT by UVC irradiation and verified the influence of several parameters, including initial BIT concentration, solution pH, and HCO3 anion [75]. Inhalation Move to fresh air. Benzisothiazolinone upregulates the MUC5AC expression via ERK1/2, p38, and NF-B pathways in airway epithelial cells. Federal government websites often end in .gov or .mil. The first-order photolysis rate constant was determined to be 0.019 d1 for MCI at pH 4 [6]. Understanding labels has taken me years of practice. In this way, biocide encapsulation could be an environmentally friendly option, because the incorporation of high initial biocide concentrations to ensure long-term preservation would be avoided. In order to guarantee consumers health and ensure compliance to existing regulations, reliable methodologies must be used to identify and quantify this type of biocides. Miura Y. Electron Spin Resonance Spectroscopic Study of Cyclic Thiocarboxamidyl Radicals, 3-Oxo-1,2-Benzisothiazolin-2-Yls: Complete Evaluation of ESR Parameters by Measuring 17O and 33s Hyperfine Splittings and Comparison of the ESR Parameters with Acyclic Analog. Here is a list of potentially toxic chemicals and allergens I avoid and why. Chen L., Lam J.C.W. Aerts O., Goossens A., Lambert J., Lepoittevin J.P. Wittenberg J.B., Canas B.J., Zhou W., Wang P.G., Rua D., Krynitsky A.J. Oil drilling is catastrophic for the environment. developed a GC-MS method for the determination of five isothiazolinones in environmental samples [83]. Danger from the workplace: Allergic contact dermatitis from the first exposure to isothiazolinones. Neisius U., Brand P., Plochmann S., Saloga J., Knop J., Becker D. Detection of increased tyrosine phosphorylation in murine Langerhans cells after stimulation with contact sensitizers. Kwon M, Park JB, Kwon M, Song J, Yeo CS, Bae SH. The https:// ensures that you are connecting to the Benzisothiazolinone as a useful template for the design of new - PubMed Considering the relevance and importance of isothiazolinone biocides, the present review describes the state-of-the-art knowledge regarding their synthesis, antibacterial components, toxicity. Other products along the degradative pathway were tentatively identified as 5-chloro-2-methyl-4-isothiazolin-1-oxide, N-methylglyoxylamide, ethylene glycol, and urea (Scheme 9) [70]. McKibben M., McClelland E.W. Schwensen J.F., Menn T., Veien N.K., Funding A.T., Avnstorp C., sterballe M., Andersen K.E., Paulsen E., Mrtz C.G., Sommerlund M., et al. 2015;10:e0124610. The biocide containing the mixture of MCI:MI was capable of inhibiting Legionella film formation below the assay detection levels at concentrations as low as 50 ppm of formulation, whereas BIT needed concentrations above 200 ppm to present a similar effect. Unspecific systemic Although a slight decrease in the MCI concentration (7%35%) was observed in the hydrolysis test at pH 9 and in the phototransformation test at pH 4 and 9, no noticeable decrease of MI concentration was observed under any test conditions [6]. They are used to kill or control insects, fungi, animals and bacteria. The isothiazolinones degraded rapidly with half-lives below 10 days (MI 0.28 days, BIT 0.52 days, DCOIT 4.8 days, and OIT 9.3 days). As they remain on the fabric they can sometimes cause skin irritation. Shade W.D., Hurt S.S., Jacobson A.H., Reinert K.H. In a recent study, Gerholds group also alerted for the potential neurotoxic effect of OIT after observation of the negative impact of this biocide on the intracellular ATP levels of three neuronal cellular lines [58]. Barman B.N., Preston H.G. Chemically, isothiazole (1,2-thiazole) is a five-membered heteroaromatic that is considered to be derived from thiophene, in which the second position is occupied by a nitrogen atom (Figure 1) [2]. Combinations of these procedures with chromatographic techniques, coupled with different selective detectors, have been proposed as powerful tools to successfully analyze and determine the presence of isothiazolinones in different samples. The biggest concern with this ingredient came to light when researchers conducted two recent laboratory studies on rat brain cells, and found that MIT caused damage to those cells. Wu T., Wang C., Wang X., Ma Q. Water-soluble biocides are prone to excessive leaching, and high concentrations are therefore required for the successful protection of products. They evaporate easily at room temperature and release harmful gases into the indoor air. Arning J., Dringen R., Schmidt M., Thiessen A., Stolte S., Matzke M., Bottin-Weber U., Caesar-Geertz B., Jastorff B., Ranke J. Structure-activity relationships for the impact of selected isothiazol-3-one biocides on glutathione metabolism and glutathione reductase of the human liver cell line Hep G2. evaluated the biodegradation of OIT in raw wastewater [77]. ECHA Seeks Comments on Benzisothiazolinone Labeling endstream endobj startxref In addition to 3-octylthiazol-2(3H)-one, resulting from OIT photoisomerization, the break of the NS-bond led to the stepwise degradation of the ring originating the attainment of N-octyl malonamic acid, N-octylprop-2-enamide, N-octylacetamide, and N-octylformamide, as well as octylamine as a final product (Scheme 11) [76]. Triclosan is a biocide that is used to kill bacteria; it is often found in antibacterial liquid soaps, although has been banned from them in the US. In-depth information on the synthesis of the most frequently isothiazolinone biocides used in consumer products and on biological/toxicity profile is presented. [9], In 2012, the Scientific Committee on Consumer Safety in Europe found BIT's "sensitising potential is of concernSensitisation from related isothiazolinones is an important problem in consumers. doi:10.1111/cod.12570. Process Development of 1,2-Benzisothiazolin-3(2H)-one by Replacing of the Toxic Materials. Abstract Humans are continuously exposed to benzisothiazolinone (BIT), which is used as a preservative, through multiple routes. Methylisothiazolinone is commonly used in wastewater treatment processes [4], cosmetics, paints, and detergents [5], and in combination with MCI (in proportions of 3:1) as an active ingredient of the commercial biocide, Kathon [6]. Its definitely not something I want in the house now I have children. Bethesda, MD 20894, Web Policies Benzisothiazolinone is an preservative chemical used in a wide variety of applications, such as cleaning and building products. Baranowska I., Wojciechowska I., Solarz N., Krutysza E. Determination of Preservatives in Cosmetics, Cleaning Agents and Pharmaceuticals Using Fast Liquid Chromatography. On the other hand, MCI displayed the lowest MIC values of the tested compounds, 2.6 g/mL and 0.5 g/mL for S. pombe and E. coli, respectively. Heo J.J., Kim U., Oh J. Krzeminski S.F., Brackett C.K., Fisher J.D., Spinnler J.F. The results obtained are in accordance with the literature available for MI and DCOIT. Benzisothiazolinone (BIT) has been described as being hydrolytically stable, presenting a half-life of more than 30 days in the environment [73]. Isothiazolone Biocides in Water Treatment Applications. The synthesis of DCOIT was described by Weiler and collaborators in 1977 (Scheme 3) [16]. studied whether biocidal compounds are easily degradable or persistent in a loamy sand soil, as typical for urban regions in Northern Europe. BIT is known to be a sensitizer; in particular, dermal contact or aerosol inhalation could affect the local toxicity. Therefore, UPLC-MS/MS has been used as a powerful analytical technique for the determination of isothiazolinones in different matrices [85,88,90,95]. Benzisothiazolinone has been widely used to control bacterial and fungal diseases in various agricultural crops by destroying the nuclear structure and interfering with the metabolism of microbial cells. The biocide containing the mixture of MCI:MI was capable of inhibiting film formation below the assay detection levels at concentrations as low as 50 ppm of formulation, whereas BIT needed concentrations above 200 ppm to present a similar effect. Despite this, anyone Ive seen selling it as a disinfectant says it is fine around animals and children. Lopinavir/ritonavir: a review of its use in the management of HIV infection. Indeed, only in 2003, Clerici et al. Eye contact Rinse thoroughly with plenty of water for at least 15 minutes, lifting lower and upper eyelids. SeaNine 211 as antifouling biocide: A coastal pollutant of emerging concern. In addition, Robsons group reported that OIT was able to protect plasticized polyvinyl chloride (pPVC) samples from the colonization of some fungus present in forest and grassland soil [35], and in another study, Hus group demonstrated that leather samples pre-treated with OIT were protected from Staphylococcus aureus contamination [36]. Their findings showed all BIT concentrations well below the derived NESIL, with 0.0009% and 0.0027% for sunscreen and dish soap, respectively, and no detection in the laundry detergent and spray cleaner products, meaning the concentration was at or below the limit of detection of 0.0006%.[11]. A number of reports linked allergic contact dermatitis derived from isothiazolinones exposure to the activation of inflammatory mediators in skin cells [51,52,53]. In another study, Chand et al. MI, which is less potent than MCI, is biologically degraded in river water or a simulated sewage treatment plant faster than MCI. [2], Given sufficient dose and duration, dermal exposure can produce skin sensitization and allergic contact dermatitis,[8] and is classified as an irritant for skin and eyes. Two cases of chloromethylisothiazolinone and methylisothiazolinone-associated toxic lung injury. Environ. It may be present in: Mainstream cleaning brands tend to use them still whereas eco-friendly brands avoid them. Would you like email updates of new search results? The .gov means its official. Other known sensitisers from this class include methylisothiazolinone (MI) and octylisothiazolinone. Tong Z.B., Hogberg H., Kuo D., Sakamuru S., Xia M., Smirnova L., Hartung T., Gerhold D. Characterization of three human cell line models for high-throughput neuronal cytotoxicity screening. For the analysis of isothiazolinones, different SPE stationary phases were used [83,86,87,88,89,90,91]. Simulated solar irradiation for 30 h resulted in a 97%, 92%, 87%, and 77% decline of Sea-Nine 211 concentration, respectively. Association of the biocide 5-chloro-2-methylisothiazol-3-one with Pseudomonas aeruginosa and Pseudomonas fluorescens. Currently, a rather limited number of studies regarding isothiazolinones encapsulation have been published, but the relatively recent launch on the market of antifouling products based on encapsulation technologies is an encouraging reason for further research on this field. Technically tallow is not toxic, but I personally do not believe animals should be killed to be used in cleaning products. The antibacterial and antifungal activity of isothiazolinones is highly valued by a number of industries. Health A Toxic Hazard. On Google, type in the name of the brand, products and the word ingredients, (adding quotes can give you a more accurate search). In 2003, Jin et al. Chiyoda T., Iida K., Takatori K., Kajiwara M. Convenient Synthesis of 1,2-Benzisothiazol-3(2H)-ones by Cyclization Reaction of Acyl Azide. Isothiazolinones are used in cosmetic and as chemical additives for occupational and industrial usage due to their bacteriostatic and fungiostatic activity. Benzisothiazolinone is known to be a sensitiser in man and has induced sensitisation at circa 20 ppm in gloves. When used as a spray tiny droplets in the air get inhaled and can cause respiratory symptoms. The importance of a minimum amount of the right biocide to maintain long-term microbiological quality as well as the high cost of biocides makes accurate biocide quantification in the final product necessary. Methylchloroisothiazolinone and methylisothiazolinone contact allergy: An occupational perspective. In cleaning products they are commonly used to stabilise synthetic fragrances. There have been no independent safety tests to prove that these methods are safe on humans. The https:// ensures that you are connecting to the This may be found on the manufacturers website or by contacting the manufacturer directly. In their work, the authors initially obtained the sulfoxide derivative (2.2) from the corresponding (Z)-3-(benzylsulfinyl)-N-methylpropenamide (2.1). ), 2CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal; tp.pu.cf@seraos.aitac (C.S. My body felt constantly itchy and I suffered from recurring sinusitis and out-of-control asthma. The site is secure. published the first and only synthesis of MI that, unlike most of the previously described routes, did not rely on SO2Cl2 to induce the formation of the isothiazol-3-one ring (Scheme 2) [15]. EWG's Guide to Healthy Cleaning | BENZISOTHIAZOLINONE | Substance These algae often grow in such great numbers that the water becomes starved of light and oxygen, killing fish and plant life. evaluated the biocidal activity of MI, MCI, and BIT against Schizosacchurornyces pombe and Escherichia coli (Table 1) [30]. Furthermore, isothiazoles have been described to act as inhibitors of proteases for the treatment of anxiety and depression, as inhibitors of aldose reductase, and as 5-hydroxytryptamine receptor antagonists [1]. Taubert L., Kraus S., Schulze B. Isothiazol-3(2H)-ones, Part I: Synthesis, Reactions and Biological Activity. Wang et al. They are usually included in fabric softeners as they make clothes feel softer. Later, the same group compared the toxicological effect and the ecotoxicological effect of the same biocides using the HepG2 cell line, marine bacterium Vibrio fischeri cells, and green algae Scenedesmus Vacuolatus. The fraction in adhesives, sealants, plasters and fillers was shown at that time as 25%. FUSE, focused ultrasound-assisted extraction; SLE, solid-liquid extraction; SPE, solid-phase extraction; SBSE, stir bar sorptive extraction; TD, thermal desorption system; UAE, ultrasonic-assisted extraction; ASE, accelerated solvent extraction; LLE, liquidliquid extraction; HF-LPME, three-phase hollow-fiber liquid-phase microextraction; MSPD, matrix solid-phase dispersion. Genetically modified organisms are now being added to cleaning products, instead of palm oil. They are biocides and commonly used as disinfectants. The exact incidence of allergic contact dermatitis due to benzisothiazolinone is not known. official website and that any information you provide is encrypted Eye Contact In the case of contact with eyes, rinse immediately with plenty of water and seek medical advice Skin Contact Wash off immediately with plenty of water Inhalation Remove to fresh air. CAS No. Additionally, in the same paper, the authors also described obtaining MCI as a side product of the cyclization reaction that gave MI. Careers. Furthermore, in the same study, the authors observed that MI/MCI led to the release of pro-inflammatory cytokines such as TNF- and IL-1 through the upregulation of the mitogen-activated protein kinases (MAPK) signaling pathway [54]. Analysis of isothiazolinone preservatives in polyvinyl alcohol cooling towels used in Japan. Before COLIPA has requested the inclusion of benzisothiazolinone in Annex VI in order . An official website of the United States government. Benzisothiazolinone allergy is more likely to be due to occupational exposure given the products that it is found in. Park S.-K., Kwon J.-H. No obvious biodegradation was observed for DCOIT after incubation for 4 d in natural seawater. MIC and minimum biocidal concentration (MBC) values for MI, MCI, MCI/MI, OIT, and DCOIT against Aspergillus niger and Saccharomyces cerevisiae. 2020;31(2):e13e14. Benzoisothiazolinone, also known as 1,2-Benzisothiazolin-3-one, is an established contact allergen and belongs to a class of molecules called isothiazolinones. PLoS ONE. Lundov M., Kolarik B., Bossi R., Gunnarsen L., Johansen J. Until safe levels of exposure have been established, the use of benzisothiazolinone in cosmetic products as a preservative or for other functions cannot be considered safe in relation to sensitisation. It was found that these biocides are stable in acidic media. Isothiazolone itself is of limited interest, but several of its derivatives are widely used preservatives and antimicrobials. Analytical Method Development of Benzisothiazolinone, a Biocide - MDPI It is the active ingredient in antibacterial cleaners, like Zoflora. Calculated IC50 for MI, MCI, OIT, and DCOIT using glutathione reductase (GR) inhibition assay. Baranowska I., Wojciechowska I. In 1993, Green compared the efficacy of BIT and a commercial formulation containing a mixture of MCI:MI (4:1) against an autofluorescent species of Legionella bozemanii [31]. Schoenig GP, Hartnagel RE Jr, Osimitz TG, Llanso S. Drug Metab Dispos. so most of them dont. Safety Data Sheet - Hp Benzisothiazolinone is a skin sensitiser in animal models with potency similar to methylisothiazolinone. The mice were housed in polycarbonate cages under . Boonstra M.B., Christoffers W.A., Coenraads P.J., Schuttelaar M.L.A. Actually, many recent developments in LLE have been focused on new techniques, which greatly reduce the amount of solvent used (cost and environmental factors) and facilitate automation of the process in conjunction with chromatographic analysis [84]. Octylisothiazolinone (OIT) is hydrolytically stable, showing a half-life time exceeding 40 days at 25 C and pH 7.4 [57]. We also provide new information on the structural requirements for MAGL inhibition by these compounds. VOCs are the most common air pollutants at home. Existing active substance. Tanji Y., Nishihara T., Miyanaga K. Iron dependent degradation of an isothiazolone biocide (5-chloro-2-methyl-4-isothiazolin-3-one). Contact allergy caused by isothiazolinone derivatives: an overview of non-cosmetic and unusual cosmetic sources. Paul L.D.S., Nicolas M., Quivet E. Development of quantification methods for studying the emissions of isothiazolinones from building and consumer products into indoor environments. The determination of preservatives in Cosmetics and environmental waters by HPLC. In this study, we evaluated the pharmacokinetic properties of BIT in rats following various routes of administration. EWG Skin Deep | What is BENZISOTHIAZOLINONE The isothiazolinones most commonly found in commercial applications, alone or in combination, are methylisothiazolinone (MI), methylchloroisothiazolinone (MCI), benzisothiazolinone (BIT), octylisothiazolione (OIT), and dichlorocthylisothiazolinone (DCOIT) (Figure 1). Arning J., Matzke M., Stolte S., Nehen F., Bottin-Weber U., Bschen A., Abdulkarim S., Jastorff B., Ranke J. Analyzing cytotoxic effects of selected isothiazol-3-one biocides using the toxic ratio concept and structure-activity relationship considerations. Lee J., Lee H., Jang S., Hong S.-H., Kim W.J., Ryu S.M., Park S.-M., Lee K.-H., Cho S.-J., Yang S.-R. CMIT/MIT induce apoptosis and inflammation in alveolar epithelial cells through p38/JNK/ERK1/2 signalling pathway. They are cheap surfactants, fillers and emulsifiers. ); moc.liamtoh@seraosgh_ordep (P.S.). Rafoth A., Gabriel S., Sacher F., Brauch H. Analysis of isothiazolinones in environmental waters by gas chromatographymass spectrometry. You may not be allergic to it the first time you have contact with it but you could develop an allergy from repeated exposure. Goodier M.C., Ljungberg L., Persson C., Engfeldt M., Bruze M., Warshaw E.M. Allergic Contact Dermatitis from Methylisothiazolinone in Residential Wall Paint. 2020;82:94100. Humans are continuously exposed to benzisothiazolinone (BIT), which is used as a preservative, through multiple routes. This project was supported by FEDER funds through COMPETE2020Programa Operacional Competitividade e Internacionalizao (POCI) and by national funds through Foundation for Science and Technology (FCT) (Projects UID/QUI/00081/2019 and POCI-01-0145-FEDER-030219). The paper reflects the views of the scientists, and not the company and the authors declare no conflicts of interest. In aqueous media, the half-life values obtained ranged from less than two hours at pH 9.6 and 60 C to 46 days at room temperature and pH 8.5. Dissipation and sorption-desorption of benzisothiazolinone in [5] A later study in 2014 shows a dramatic rise in usage, to 95.8% of house paints. The overall yields obtained for MI and OIT were 33% and 96%, respectively. See this image and copyright information in PMC. Preparation and antibacterial activity of one novel leather material. Environ. Photochemical fate of organic booster biocides in the aquatic environment. PDF PREVENTOL BIT 20 N - 5.imimg.com Tsolomitis and Sandris in 1987 reported an alternative route for the synthesis of MI (Scheme 1C) [13]. Willi R., Pfab F., Zilker T., Buters J., Schalock P., Huss-Marp J., Todorova A., Ring J., Darsow U. Through the handling of the ratio between the amide precursor and the chlorinating agent (SO2Cl2), the reaction temperature and the time of reaction Clerici et al. I try my best to help, but there are so many products out there that I thought it would be helpful to give you the tools to find out yourself. Introduction With the intensified application of reverse osmosis (RO) technology for wastewater reclamation, growing attention was paid on the non-oxidizing biocides used in RO system, where biocides were used to alleviate the biofouling [1]. (A) Interaction with thiols from cellular components (e.g., GSH) and the formation of thio-acylchloride intermediates; (B) interaction of thio-acylchloride intermediates with thiols, amines, and water [29]. One of the pathways involves cleavage of the isothiazolone ring followed by subsequent dechlorination, hydroxylation, and oxidation yielding the formation of N-n-octyl malonamic acid, which is then decarboxylated to give the corresponding N-n-octyl acetamide [81]. Major pesticides are more toxic to human cells than their declared active principles. The phototransformation of Sea-Nine 211 in natural waters under natural sunlight increases following the order: lake water > river water > sea water > distilled water, showing a strong dependence on the composition of the irradiated media [80,81]. The simulated pseudo-first-order kinetic at various pH indicated that the kinetic constant increased from 0.03 min1 to 0.29 min1 with an increase of pH from 5 to 8, and then decreased to 0.17 min1 when a continuous increment of pH to 10 occurred. Consult a physician. Benzisothiazolinone: Allergic Contact Dermatitis - DermNet In summary, over the last 30 years, considerable efforts have been made to increase the diversity of the synthetic portfolio to obtain BIT and at the same time avoid the use of the very corrosive and toxic reagents employed on the most traditional reactions to obtain this compound. Synthesis of the biocides methylisothiazolinone (MI), methylchloroisothiazolinone (MCI), and octylisothiazolinone (OIT) as described in references [11,12,13]. Additionally, given the increased concern about the possible unintended side effects that isothiazolinones could have on human health and the environment, this review also covers chemical and photochemical stability issues and the analytical procedures often used for their determination. DCOIT, the biocidal ingredient in SeaNine 211, is a widely used antifouling agent to deter the undesirable biofouling phenomenon [6,7,8]. route, respiratory tract irritation for the inhalation route and stomach irritation for the oral route.
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