{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T14:26:27Z","timestamp":1761920787874,"version":"build-2065373602"},"reference-count":47,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,9,22]],"date-time":"2020-09-22T00:00:00Z","timestamp":1600732800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxics"],"abstract":"<jats:p>The toxicity profiles of the widely used guanidine-based chemicals have not been fully elucidated. Herein, we evaluated the in vitro and in vivo toxicity of eight guanidine-based chemicals, focusing on inhalation toxicity. Among the eight chemicals, dodecylguanidine hydrochloride (DGH) was found to be the most cytotoxic (IC50: 0.39 \u03bcg\/mL), as determined by the water soluble tetrazolium salts (WST) assay. An acute inhalation study for DGH was conducted using Sprague-Dawley rats at 8.6 \u00b1 0.41, 21.3 \u00b1 0.83, 68.0 \u00b1 3.46 mg\/m3 for low, middle, and high exposure groups, respectively. The levels of lactate dehydrogenase, polymorphonuclear leukocytes, and cytokines (MIP-2, TGF-\u03b21, IL-1\u03b2, TNF-\u03b1, and IL-6) in the bronchoalveolar lavage fluid increased in a concentration-dependent manner. Histopathological examination revealed acute inflammation with necrosis in the nasal cavity and inflammation around terminal bronchioles and alveolar ducts in the lungs after DGH inhalation. The LC50 of DGH in rats after exposure for 4 h was estimated to be &gt;68 mg\/m3. Results from the inhalation studies showed that DGH was more toxic in male rats than in female rats. Overall, DGH was found to be the most cytotoxic chemical among guanidine-based chemicals. Exposure to aerosols of DGH could induce harmful pulmonary effects on human health.<\/jats:p>","DOI":"10.3390\/toxics8030076","type":"journal-article","created":{"date-parts":[[2020,9,24]],"date-time":"2020-09-24T03:09:51Z","timestamp":1600916991000},"page":"76","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["In Vitro and In Vivo Evaluation of the Toxic Effects of Dodecylguanidine Hydrochloride"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7431-9685","authenticated-orcid":false,"given":"Yeon-Mi","family":"Lim","sequence":"first","affiliation":[{"name":"Environmental Health Research Department, National Institute of Environmental Research, Incheon 22689, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haewon","family":"Kim","sequence":"additional","affiliation":[{"name":"Environmental Health Research Department, National Institute of Environmental Research, Incheon 22689, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seong Kwang","family":"Lim","sequence":"additional","affiliation":[{"name":"Environmental Health Research Department, National Institute of Environmental Research, Incheon 22689, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean","family":"Yoo","sequence":"additional","affiliation":[{"name":"Environmental Health Research Department, National Institute of Environmental Research, Incheon 22689, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji-Young","family":"Lee","sequence":"additional","affiliation":[{"name":"Environmental Health Research Department, National Institute of Environmental Research, Incheon 22689, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ig-Chun","family":"Eom","sequence":"additional","affiliation":[{"name":"Environmental Health Research Department, National Institute of Environmental Research, Incheon 22689, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Byung-Il","family":"Yoon","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon 24341, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pilje","family":"Kim","sequence":"additional","affiliation":[{"name":"Environmental Health Research Department, National Institute of Environmental Research, Incheon 22689, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seung-Do","family":"Yu","sequence":"additional","affiliation":[{"name":"Environmental Health Research Department, National Institute of Environmental Research, Incheon 22689, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4010-4886","authenticated-orcid":false,"given":"Ilseob","family":"Shim","sequence":"additional","affiliation":[{"name":"Environmental Health Research Department, National Institute of Environmental Research, Incheon 22689, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"161","DOI":"10.3389\/fphar.2018.00161","article-title":"Potentiation of sodium metabisulfite toxicity by propylene glycol in both in vitro and in vivo systems","volume":"9","author":"Yoo","year":"2018","journal-title":"Front. Pharm."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"937","DOI":"10.2131\/jts.38.937","article-title":"Inhalation exposure to chloramine T induces DNA damage and inflammation in lung of Sprague-Dawley rats","volume":"38","author":"Shim","year":"2013","journal-title":"J. Toxicol. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1016\/j.envint.2018.12.033","article-title":"Health risks of chemicals in consumer products: A review","volume":"123","author":"Li","year":"2019","journal-title":"Environ. Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"711","DOI":"10.2131\/jts.41.711","article-title":"Adverse health effects of humidifier disinfectants in Korea: Lung toxicity of polyhexamethylene guanidine phosphate","volume":"41","author":"Kim","year":"2016","journal-title":"J. Toxicol. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1007\/s00204-020-02657-x","article-title":"Integration of transcriptomics, proteomics and metabolomics identifies biomarkers for pulmonary injury by polyhexamethylene guanidine phosphate (PHMG-p), a humidifier disinfectant, in rats","volume":"94","author":"Lee","year":"2020","journal-title":"Arch. Toxicol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Park, D.-U., Choi, Y.-Y., Ahn, J.-J., Lim, H.-K., Kim, S.-K., Roh, H.-S., Cheong, H.-K., Leem, J.-H., Koh, H.-S., and Jung, H.-J. (2015). Relationship between exposure to household humidifier disinfectants and risk of lung injury: A family-based study. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0124610"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1513\/AnnalsATS.201504-221OC","article-title":"Nationwide study of humidifier disinfectant lung injury in South Korea, 1994\u20132011. Incidence and dose\u2013response relationships","volume":"12","author":"Paek","year":"2015","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.jcis.2008.10.047","article-title":"Effect of amidoalkyl group as spacer on aggregation properties of guanidine-type surfactants","volume":"330","author":"Miyake","year":"2009","journal-title":"J. Colloid Interface Sci."},{"key":"ref_9","first-page":"82","article-title":"Guanidine: Studies on the reaction with ethyl N-(2-amino-1, 2-dicyanovinyl) formimidate","volume":"2010","author":"Marinho","year":"2009","journal-title":"Arch. Orgainc Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"11016","DOI":"10.1039\/C7NJ02497E","article-title":"Substituent effects on the basicity (pKa) of aryl guanidines and 2-(arylimino) imidazolidines: Correlations of pH-metric and UV-metric values with predictions from gas-phase ab initio bond lengths","volume":"41","author":"Dardonville","year":"2017","journal-title":"New J. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Luo, X., Jiang, Z., Zhang, N., Yang, Z., and Zhou, Z. (2017). Interactions of biocidal polyhexamethylene guanidine hydrochloride and its analogs with POPC model membranes. Polymers, 9.","DOI":"10.3390\/polym9100517"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1111\/j.1365-2672.2009.04482.x","article-title":"Damage of Escherichia coli membrane by bactericidal agent polyhexamethylene guanidine hydrochloride: Micrographic evidences","volume":"108","author":"Zhou","year":"2010","journal-title":"J. Appl. Microbiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1093\/abbs\/gmr067","article-title":"Interactions of biocidal guanidine hydrochloride polymer analogs with model membranes: A comparative biophysical study","volume":"43","author":"Zhou","year":"2011","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"10960","DOI":"10.1002\/chem.201500789","article-title":"The guanidinium unit in the catalysis of phosphoryl transfer reactions: From molecular spacers to nanostructured supports","volume":"21","author":"Salvio","year":"2015","journal-title":"Chem. A Eur. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5856","DOI":"10.1002\/chem.201406526","article-title":"Guanidine-based polymer brushes grafted onto silica nanoparticles as efficient artificial phosphodiesterases","volume":"21","author":"Savelli","year":"2015","journal-title":"Chem. A Eur. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2315","DOI":"10.1038\/nprot.2006.339","article-title":"Clonogenic assay of cells in vitro","volume":"1","author":"Franken","year":"2006","journal-title":"Nat. Protoc."},{"key":"ref_17","unstructured":"Kim, H.-M., Kwon, J.-T., Shim, I.-S., Kwon, D.-Y., Lim, Y.-M., Kim, E.-J., Kim, P.-J., and Choi, K. (2016). Inhalation toxicity of ethylene glycol in rat. J. Vet. Sci. Technol., 7."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.21873\/invivo.11631","article-title":"Acute and 28-day repeated inhalation toxicity study of glycolic acid in male sprague-dawley rats","volume":"33","author":"Lim","year":"2019","journal-title":"In Vivo"},{"key":"ref_19","unstructured":"OECD (2020, July 13). Test No 403: Acute Inhalation Toxicity 2009. Available online: https:\/\/www.oecd-ilibrary.org\/environment\/test-no-403-acute-inhalation-toxicity_9789264070608-en."},{"key":"ref_20","first-page":"216","article-title":"Respiratory toxicity biomarkers","volume":"2014","author":"Gupta","year":"2014","journal-title":"Biomark. Toxicol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1093\/toxsci\/kfm018","article-title":"Assessing toxicity of fine and nanoparticles: Comparing in vitro measurements to in vivo pulmonary toxicity profiles","volume":"97","author":"Sayes","year":"2007","journal-title":"Toxicol. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.eurpolymj.2018.06.014","article-title":"New guanidine-containing polyelectrolytes as advanced antibacterial materials","volume":"105","author":"Gorbunova","year":"2018","journal-title":"Eur. Polym. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.molcel.2016.11.019","article-title":"Metabolism of free guanidine in bacteria is regulated by a widespread riboswitch class","volume":"65","author":"Nelson","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_24","first-page":"1026","article-title":"Guanidine group: Definition and pharmaceutical applications","volume":"7","author":"Khalaf","year":"2016","journal-title":"Res. J. Pharm. Biol. Chem. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.bioorg.2015.01.006","article-title":"Guanidines from \u2018toxic substances\u2019 to compounds with multiple biological applications\u2013Detailed outlook on synthetic procedures employed for the synthesis of guanidines","volume":"59","author":"Tahir","year":"2015","journal-title":"Bioorg. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.1016\/j.polymer.2008.03.042","article-title":"Modified guanidine polymers: Synthesis and antimicrobial mechanism revealed by AFM","volume":"49","author":"Qian","year":"2008","journal-title":"Polymer"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Saeed, A., Bosch, A., Bettiol, M., Gonz\u00e1lez, D.L.N., Erbe, M.F., and Lamberti, Y. (2018). Novel guanidine compound against multidrug-resistant cystic fibrosis-associated bacterial species. Molecules, 23.","DOI":"10.3390\/molecules23051158"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2334","DOI":"10.1002\/maco.201911072","article-title":"Electrochemical and theoretical assessment of the effect of two biocides on the corrosion of petroleum steel in sulfur-polluted Black Sea water","volume":"70","author":"Hasanzade","year":"2019","journal-title":"Mater. Corros."},{"key":"ref_29","unstructured":"US EPA (2020, July 13). Reregistratin Eligibility Decision for Dodine, Available online: https:\/\/archive.epa.gov\/pesticides\/reregistration\/web\/html\/index-104.html."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"227","DOI":"10.3839\/jabc.2017.036","article-title":"Anti-inflammatory and apoptosis improving effects of sulfasalazine and Cinnamomi cortex and Bupleuri radix mixture in TNBS-induced colitis mouse model","volume":"60","author":"Kim","year":"2017","journal-title":"J. Appl. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1093\/toxsci\/kfh064","article-title":"Comparison of inflammatory and cytotoxic lung responses in mice after intratracheal exposure to spores of two different Stachybotrys chartarum strains","volume":"78","author":"Flemming","year":"2004","journal-title":"Toxicol. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1736","DOI":"10.1183\/09031936.96.09081736","article-title":"Usefulness of lactate dehydrogenase and its isoenzymes as indicators of lung damage or inflammation","volume":"9","author":"Drent","year":"1996","journal-title":"Eur. Respir. J."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Lodovici, M., and Bigagli, E. (2011). Oxidative stress and air pollution exposure. J. Toxicol., 2011.","DOI":"10.1155\/2011\/487074"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Hiraiwa, K., and van Eeden, S.F. (2013). Contribution of lung macrophages to the inflammatory responses induced by exposure to air pollutants. Mediat. Inflamm., 2013.","DOI":"10.1155\/2013\/619523"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1172\/JCI36130","article-title":"The cytokine network in asthma and chronic obstructive pulmonary disease","volume":"118","author":"Barnes","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1042\/bj3520913","article-title":"Cross-talk between interleukin 1\u03b2 (IL-1\u03b2) and IL-6 signalling pathways: IL-1\u03b2 selectively inhibits IL-6-activated signal transducer and activator of transcription factor 1 (STAT1) by a proteasome-dependent mechanism","volume":"352","author":"Shen","year":"2000","journal-title":"Biochem. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1126\/science.1140485","article-title":"Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production","volume":"317","author":"Naugler","year":"2007","journal-title":"Science"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1097\/TA.0b013e3181650fdf","article-title":"Male gender is associated with excessive IL-6 expression following severe injury","volume":"64","author":"Sperry","year":"2008","journal-title":"J. Trauma Acute Care Surg."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1006\/jsre.2001.6325","article-title":"Role of macrophage inflammatory protein 2 in acute lung injury in murine peritonitis","volume":"103","author":"Tsujimoto","year":"2002","journal-title":"J. Surg. Res."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Konrad, F., and Reutershan, J. (2012). CXCR2 in acute lung injury. Mediat. Inflamm., 2012.","DOI":"10.1155\/2012\/740987"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3489","DOI":"10.1002\/app.39369","article-title":"Synthesis and antimicrobial properties of a guanidine-based oligomer grafted with a reactive cationic surfactant through Michael addition","volume":"130","author":"Wang","year":"2013","journal-title":"J. Appl. Polym. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-017-08749-6","article-title":"Identification, synthesis and biological activity of alkyl-guanidine oligomers as potent antibacterial agents","volume":"7","author":"Zamperini","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1099\/jmm.0.047514-0","article-title":"Akwaton, polyhexamethylene-guanidine hydrochloride-based sporicidal disinfectant: A novel tool to fight bacterial spores and nosocomial infections","volume":"61","author":"Oule","year":"2012","journal-title":"J. Med. Microbiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"24903","DOI":"10.1039\/C7RA02706K","article-title":"Development of contact-killing non-leaching antimicrobial guanidyl-functionalized polymers via click chemistry","volume":"7","author":"Peng","year":"2017","journal-title":"RSC Adv."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6867","DOI":"10.1016\/j.biomaterials.2010.05.027","article-title":"The systemic toxicity of positively charged lipid nanoparticles and the role of Toll-like receptor 4 in immune activation","volume":"31","author":"Kedmi","year":"2010","journal-title":"Biomaterials"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1007\/s11743-013-1560-3","article-title":"Biological behaviors of guanidine-based cationic surfactants","volume":"17","author":"Song","year":"2014","journal-title":"J. Surfactants Deterg."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"22343","DOI":"10.1039\/D0RA03108A","article-title":"Effects of lipid membrane composition on the distribution of biocidal guanidine oligomer with solid supported lipid membranes","volume":"10","author":"Ha","year":"2020","journal-title":"RSC Adv."}],"container-title":["Toxics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2305-6304\/8\/3\/76\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:12:29Z","timestamp":1760177549000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2305-6304\/8\/3\/76"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,22]]},"references-count":47,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["toxics8030076"],"URL":"https:\/\/doi.org\/10.3390\/toxics8030076","relation":{},"ISSN":["2305-6304"],"issn-type":[{"type":"electronic","value":"2305-6304"}],"subject":[],"published":{"date-parts":[[2020,9,22]]}}}