Toxicological characterization of the insecticide metofluthrin and assessment of the carcinogenic risk to human health due to its chronic inhalation effect
DOI:
https://doi.org/10.26641/2307-0404.2024.3.313676Keywords:
metofluthrin, toxicological assessment, hazard criteria, carcinogenic risk, air environmentAbstract
The aim of the investigation is the toxicological characterization and analysis of the danger criteria of the insecticide metofluthrin with an assessment of the carcinogenic risk to health caused by chronic inhalation exposure to the substance at the level of the maximum possible concentrations in the air environment of human life. The analysis of scientific reports of the US Environmental Protection Agency (US EPA) and the European Chemicals Agency (ECHA) on the toxicological properties of metofluthrin was carried out. The assessment of the risk of the development of carcinogenic effects due to chronic inhalation exposure to metofluthrin was carried out taking into account the average daily dose of the substance that can enter the human body during the natural life span (LADD) and the carcinogenic potential factor (SF) in accordance with domestic guidelines. Classification of levels of carcinogenic risk was carried out using domestic and international approaches. It was established that the limiting criteria for the danger of metofluthrin are the average lethal concentration in air (LC50 =1080 mg/m³) and the size of the zone of chronic action (Zch=7.46), which characterizes the danger of occurrence of chronic intoxication due to long-term inhalation exposure. According to these indicators, metofluthrin is classified as a dangerous substance (hazard class 2). The key effects of the toxic action of metofluthrin are determined – neurotoxicity, hepatotoxicity and nephrotoxicity. The threshold non-genotoxic oncogenic potential of metofluthrin according to the phenobarbital type was established. Individual carcinogenic risk under different scenarios of chronic inhalation exposure to metofluthrin was calculated. The substance concentration of 3.54 mg/m³ leads to a high level of risk (1.5×10-3), which is considered unacceptable for production conditions and the population. At concentrations of 0.28 mg/m³ and 1.0 mg/m³, the risk is estimated as average and acceptable for production conditions (1.1-4.1×10-4). The risk of exposure to a concentration of 0.14 mg/m³ is classified as low and acceptable for the population (5.7×10-5). Thus, the results obtained in the study indicate that such concentrations of metofluthrin in the air as 0.14 – 0.28 – 1.0 mg/m³ are safe for human health, subject to compliance with medical and sanitary regulations at the stage of production and application of insecticides based on metofluthrin as prescribed.
References
Regulation (eu) no 528/2012 of the european parliament and of the council of 22 May 2012 concerning the making available on the market and use of biocidal products (Text with EEA relevance). Official Journal of the European Union [Internet]. 2012 [cited 2024 Mar 16];L167/1. EUR-Lex. Access to European Union law. Available from: https://eur-lex.europa.eu/eli/reg/2012/528/oj
Metofluthrin. Product-type 18 (Insecticides, acaricides and products to control other arthropods). Аssessment Report (UK). Finalised in the Standing Committee on Biocidal Products at its meeting in May 2010 in view of its inclusion in Annex I to Directive 98/8/EC [Internet]. 2010 [cited 2024 Mar 16]; 70 р. Available from: https://dissemination.echa.europa.eu/Biocides/ActiveSubstances/0045-18/0045-18_Assessment_Report.pdf
Committee for Risk Assessment (RAC). Opinion proposing harmonised classification and labelling at EU level of 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl (1R,3R)-2,2-dimethyl-3-[(1Z)-prop-1-en-1-yl] cyclopropanecarboxylate; Epsilon-metofluthrin. CLH-O-0000001412-86-111/F. ECHA [Internet]. 2016 [cited 2024 Mar 16]. Available from: https://www.echa.europa.eu/documents/10162/7d6db581-36a4-7a2a-a21e-5c3a5d39be4c
Biocidal Active Substances. Information on biocides. ECHA. European Chemicals Agency [Internet]. 2024 [cited 2024 Mar 16]. Available from: https://echa.europa.eu/fr/information-on-chemicals/biocidal-active-substances
Bibbs CS, Tsikolia M, Bernier UR, Bloomquist JB, Xue RD, Kaufman PE. Vapor toxicity of five volatile pyrethroids against Aedes aegypti, Ae. albopictus, Culex quinquefasciatus, and Anopheles quadrimaculatus (Diptera:Culicidae). Pest Manag Sci. 2018 Dec;74(12):2699-706. doi: https://doi.org/10.1002/ps.5088
Parker C, Ramirez D, Connelly CR. State-wide survey of Aedes aegypti and Aedes albopictus (Dip-tera:Culicidae) in Florida. J Vector Ecol. 2019;44(2):210-5. doi: https://doi.org/10.1111/jvec.12351
Tian N, Zheng JX, Guo ZY, Li LH, Xia S, Lv S, et al. Dengue incidence trends and its burden in major endemic regions from 1990 to 2019. Trop Med Infect Dis. 2022 Aug;7(8):180. doi: https://doi.org/10.3390/tropicalmed7080180
reuters.com [Internet]. [cited 2024 Mar 16]. Available from: https://www.reuters.com/business/healthcare-pharmaceuticals/who-warns-dengue-risk-global-warming-pushes-cases-near-historic-highs-2023-07-21
Sugano M, Ishiwatari T. The biological activity of a novel pyrethroid: metofluthrin. Top Curr Chem. 2012:314:203-20. doi: https://doi.org/10.1007/128_2011_259
Zarella O, Ekwomadu U, Romer Y, Kirstein OD, CheMendoza A, Gonzaґlez-Olvera G, et al. Experimental evaluation of a metofluthrin passive emanator against Aedes albopictus. PLoS ONE. 2022;17(5):e0267278. doi: https://doi.org/10.1371/journal.pone.0267278
Kim D-Y, Leepasert T, Bangs MJ, Chareonvi-riyaphap T. Dose–Response Assay for Synthetic Mosquito (Diptera: Culicidae) Attractant Using a High-Throughput Screening System. Insects. 2021;12:355. doi: https://doi.org/10.3390/insects12040355
Sukkanon C, Bangs MJ, Nararak J, Hii J, Cha-reonviriyaphap T. Discriminating lethal concentrations for transfluthrin, a volatile pyrethroid compound for mosquito control in Thailand. J Am Mosq Control Assoc. 2019 Dec;35(4):258-66. doi: https://doi.org/10.2987/19-6832.1
World Health Organization. Manual for Monitoring Insecticide Resistance in Mosquito Vectors and Selecting Appropriate Interventions [Internet]. World Health Organization: Geneva, Switzerland; 2022 [cited 2024 Mar 16]. Available from: https://www.who.int/publications/i/item/9789240051089
Pesticide Fact Sheet. Metofluthrin. U.S. Environmental Protection Agency. [Internet]. 2006 [cited 2024 Mar 16]. 29 p. Available from: https://www3.epa.gov/pesticides/chem_search/reg_actions/registration/fs_PC-109709_01-Sep-06.pdf
Metofluthrin: Exposure and Risk Assessment for Use as a Mosquito Repellent Strip and as a Personal Outdoor Insect Repellent. PC Code: 109709, Memorandum. U.S. Environmental Protection Agency. [Internet]. [cited 2024 Mar 16]. Available from: https://www3.epa.gov/pesticides/chem_search/cleared_reviews/csr_PC-109709_14-Sep-06_a.pdf
Kim D-Y, Hii J, Chareonviriyaphap T. Transfluthrin and Metofluthrin as Effective Repellents against Pyrethroid-Susceptible and Pyrethroid-Resistant Aedes aegypti (L.) (Diptera: Culicidae). Insects. 2023;14(9):767. doi: https://doi.org/10.3390/insects14090767
World Health Organization. Determining Discriminating Concentrations of Insecticides for Monitoring Resistance in Mosquitoes: Report of a Multi-Centre Laboratory Study and WHO Expert Consultations. World Health Organization: Geneva, Switzerland; 2023. p. 58-59.
Chen CD, Chin AC, Lau KW, Low VL, Lee HL, Lee PKY, et al. Bioefficacy evaluation of commercial mosquito coils containing metofluthrin, d-allethrin, d-trans allethrin, and prallethrin against Aedes albopictus (Diptera: Culicidae) in Malaysia. J Med Entomol. 2018 Oct 25;55(6):1651-5. doi: https://doi.org/10.1093/jme/tjy130
Ujihara K, Mori T, Iwasaki T, Sugano M, Shono Y, Matsuo N. Metofluthrin: a potent new synthetic pyrethroid with high vapor activity against mosquitoes. Biosci Biotechnol Biochem. 2004 Jan;68(1):170-4. doi: https://doi.org/10.1271/bbb.68.170
Bibbs CS, Kaufman PE, Xue R-D. Comparative Evaluation of Metofluthrin as an Outdoor Residual Treatment for Barriers and Harborage Against Aedes albopictus (Diptera: Culicidae). Environmental Entomo-logy. 2020;49(2):435-43. doi: https://doi.org/10.1093/ee/nvz170
Soderlund DM. Molecular mechanisms of pyrethroid insecticide neurotoxicity: Recent advances. Arch Toxicol. 2012 Feb;86(2):165-81. doi: https://doi:10.1007/s00204-011-0726-x
Yastrub T. [Identification of the hazard to workers from complex exposure to pyrethroid insecticides based on alpha-cypermethrin using new toxicological data]. Ukrainskyi zhurnal medytsyny pratsi. 2022;1:52-62. Ukrainian. doi: https://doi.org/10.33573/ujoh2022.01.052
Zhu Q, Yang Y, Zhong Y, Lao Z, O'Neill P, Hong D, et al. Synthesis, insecticidal activity, resistance, photodegradation and toxicity of pyrethroids (A review). Chemosphere. 2020 Sep:254:126779. doi: https://doi.org/10.1016/j.chemosphere.2020.126779
SCJ-14-210857 (metofluthrin). U.S. Environmental Protection Agency [Internet]. 2015 [cited 2024 Mar 16]. 127 p. Available from: https://www.epa.govt.nz/assets/FileAPI/hsnoar/APP202155/20d0ec9a58/APP202155-APP202155-decision-Final.pdf
Devine GJ, Vazquez-Prokopec GM, Bibiano-Marin W, Pavia-Ruz N, Che-Mendoza A, Medina-Barreiro A, et al. The entomological impact of passive metofluthrin emanators against indoor Aedes aegypti: A randomized field trial. PLoS Negl Trop Dis. 2021;15(1):e0009036. doi: https://doi.org/10.1371/journal.pntd.0009036
Serdiuk AM, Chernychenko IO, Lytvychenko OM, Babii VF, Kondratenko OYe, Hlavachek DO. Carcinogenic substances in the atmospheric air of Dnipro and the risk to the population. Medicni perspektivi. 2021;1:226-31. Ukrainian. doi: https://doi.org/10.26641/2307-0404.2021.1.228020
Serdyuk AM, Gushchuk IV, Chernichenko IA, Litvichenko ON. Features of atmospheric air pollution in a non-industrial city: risk for the population. Medicni perspectivi. 2019;4:154-9. doi: https://doi.org/10.26641/2307-0404.2019.4.189609
Committee for Risk Assessment (RAC). Opinion proposing harmonised classification and labelling at EU level of 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl (1R,3R)-2,2-dimethyl-3-[(1Z)-prop-1-en-1-yl] cyclopro-panecarboxylate; Epsilon-metofluthrin. EC Number: - CAS Number: 240494-71-7 [Internet]. 2016 [cited 2024 Mar 16]. Available from: https://echa.europa.eu/documents/10162/fa5dc212-bfdb-8a9b-a2a9-489168fa1d67
Preliminary considerations for ECHA’s guidance on the “Methodology to assess the risk to bees and other non-target arthropod pollinators from the use of biocides”. Summary of consultation feedback. ECHA-20-H-24-EN [Internet]. 2020 [cited 2024 Mar 16]. р. 1-65. Available from: https://op.europa.eu/ga/publication-detail/-/publication/6bbc9246-15ca-11ec-b4fe-01aa75ed71a1/language-en
CLH report Proposal for Harmonised Classifi-cation and Labelling Based on Regulation (EC) No 1272/2008 (CLP Regulation), Annex VI, Part 2. Substance Name: Epsilon-metofluthrin. ECHA [Internet]. 2015 [cited 2024 Mar 16]. Available from: https://echa.europa.eu/documents/10162/213dc625-4121-e5e9-81e7-70c2f2435b6c
Pesticide Properties Data Base (PPDB) Epsilon-metofluthrin (Ref: S-1264) [Internet]. [cited 2024 Mar 16]. Available from: https://sitem.herts.ac.uk/aeru/ppdb/en/Reports/3175.htm
Guidelines for Carcinogen Risk Assessment. 70 FR 17765-17817. U.S. Environmental Protection Agency [Internet]. 2005. [cited 2024 Mar 16]. Available from: https://www.epa.gov/risk/guidelines-carcinogen-risk-assessment
Risk Characterization Handbook. U.S. Environmental Protection Agency [Internet]. 2000 [cited 2024 Mar 16]. Available from: https://www.epa.gov/risk/risk-characterization-handbook
pubchem.ncbi [Internet]. [cited 2024 Mar 16]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Metofluthrin
oehha.ca [Internet]. [cited 2024 Mar 16]. Available from: https://oehha.ca.gov/media/downloads/crnr/101211metofluthrin.pdf
drugs.ncats [Internet]. [cited 2024 Mar 16]. Available from: https://drugs.ncats.io/substance/WZX356S299
Exposure Assessment Tools by Routes – Inhalation. U.S. Environmental Protection Agency [Internet]. 2024 [cited 2024 Mar 16]. Available from: https://www.epa.gov/expobox/exposure-assessment-tools-routes-inhalation
[Hygienic regulations for the permissible content of chemical and biological substances in the air of the working area. Order of the Ministry of Health of Ukraine dated 2020 Jul 14, No. 1596]. [Internet]. 2020 [cited 2024 Mar 16]. Ukrainian. Available from: https://zakon.rada.gov.ua/laws/show/z0741-20#Text
[Pesticides. Classification by degree of dander: DSanPin 8.8.1.002-98. Аpproved by the Ministry of Health of Ukraine on 1998 Aug 28, No. 2]. Collection of Important official materials on sanitary and anti-epidemic issues. 2000;9(1):249-66. Ukrainian.
[Assessment of the carcinogenic and non-carcinogenic risk to public health from chemical air pollution: methodological recommendations approved by the Order of the Ministry of Health of Ukraine dated 18.10.2023, No. 1811]. Kyiv: Ministry of Health of Ukraine; 2023. 24 р. Ukrainian.
Guidelines for Carcinogen Risk Assessment. 70 FR 17765-17817. U.S. Environmental Protection Agency [Internet]. 2005 [cited 2024 Mar 16]. Available from: https://www.epa.gov/risk/guidelines-carcinogen-risk-assessment
Risk Characterization Handbook. U.S. Environmental Protection Agency [Internet]. 2000 [cited 2024 Mar 16]. Available from: https://www.epa.gov/risk/risk-characterization-handbook
Lewandowska AM, et al. Environmental risk factors for cancer – review paper. Ann Agric Environ Med. 2019 Mar 22;26(1):1-7. doi: https://doi.org/10.26444/aaem/94299
Birch R, Johansen M, Skakkebæk N, Anders-son AM, Rehfeld A. In vitro investigation of endocrine disrupting effects of pesticides on Ca2+-signaling in human sperm cells through actions on the sperm-specific and steroid-activated CatSper Ca2+-channel. Environ Int. 2022;167:107399. doi: https://doi.org/10.1016/j.envint.2022.107399
Yamada Т. Case examples of an evaluation of the human relevance of the pyrethroids/pyrethrins-induced liver tumours in rodents based on the mode of action. Toxicol Res. 2018;7:681-96. doi: https://doi.org/10.1039/c7tx00288b
Elcombe CR, Peffer RC, Wolf DC, Bailey J, Bars R, Bel D, et al. Mode of action and human relevance analysis for nuclear receptor-mediated liver toxicity: a case study with phenobarbital as a model constitutive androstane receptor (CAR) activator. Crit Rev Toxicol. 2014 Jan;44(1):64-82. doi: https://doi.org/10.3109/10408444.2013.835786
Yamada T, Kikumoto H, Lake BG, Kawamura S. Lack of effect of metofluthrin and sodium phenobarbital on replicative DNA synthesis and Ki-67 mRNA expression in cultured human hepatocytes. Toxicol Res. 2015 Jul;4(4):901-13. doi: https://doi.org/10.1039/c4tx00217b
Deguchi Y, Yamada T, Hirose Y, Nagahori H, Kushida M, Sumida K, et al. Mode of action analysis for the synthetic pyrethroid metofluthrin-induced rat liver tumors: evidence for hepatic CYP2B induction and hepatocyte proliferation. Тoxicol Sci. 2009 Mar;108(1):69-80. doi: https://doi.org/10.1093/toxsci/kfp006
[On the approval of Amendments to the Hygienic Regulations of Chemical Substances in the Air of the Work Zone. Order of the Ministry of Health of Ukraine 2023 Aug 17, No. 1473]. [Internet]. 2023 [cited 2024 Mar 16]. Ukrainian. Available from: https://zakon.rada.gov.ua/laws/show/z1520-23#Text
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