L.I. Medved’s Research Center of Preventive Toxicology, Food and Chemical Safety, Ministry of Health, Ukraine (State Enterprise), Kyiv, Ukraine

ABSTRACT. Fluoxapiproline is a new active substance of pesticides from the chemical class of piperidinyle thiazole isoxazoline. Fluoxapiproline demonstrates biological activity against plant pathogenic oomycetes with mechanisms of action involving oxysterol binding protein inhibition. It is proposed to control late blight in tomato and potato, downy mildew in onions and grapes crops.

Aim. Generalization and analysis of data on the toxic and hygienic properties of fluoxapiproline.

Materials and Methods. Systematization and evaluation of scientific literature according to the PubMed and Google Scholar databases.

Results. Results of our analysis of literature data showed that in according to accepted in Ukraine approaches (the Hygienic classification of pesticides by hazard) fluoxapiproline belongs to the pesticides of hazard class 4 (acute oral and dermal toxicity, primary skin irritation, sensitization effect, mutagenicity, carcinogenicity and reproductive toxicity). to pesticides hazard class 3 (primary eye irritation), to pesticides hazard class 2 (acute inhalation toxicity). Toxicity class limit for fluoxapiproline – 2. Fluoxapiproline (repeated dose toxicity: rats, mice and dogs) has a general toxic effect (by a decrease in feed consumption and body weight gain.).

Conclusions. According to stability in water fluoxapiproline belongs to the hazard class 1, stability in soil to the pesticides hazard class 2. Based on the conducted research, the health standards of fluoxapiproline (maximum residue limits (MRLs) preharvest interval (PHI) etc.) for safety use in Ukraine will be set and recommended.

Keywords: Fluoxapiproline, plant protection products, toxic and hygienic properties.

СПИСОК ВИКОРИСТАНИХ ДЖЕРЕЛ/REFERENCES

1. Державний реєстр пестицидів та агрохімікатів, дозволених до використання в Україні. [Електронний ресурс]. (дата оновлення 23.01.25) Режим доступу: URL: https://mepr.gov.ua/upravlinnya-vidhodamy/derzhavnyjreyestr-pestytsydiv-i-agrohimikativ-dozvolenyh-do-vykorystannya-v-ukrayini. [State Register of Pesticides and Agrochemicals Allowed for Use in Ukraine. [Electronic resource]. (updated on 01/23/25) Access mode: URL: https://mepr.gov.ua/upravlinnya-vidhodamy/derzhavnyjreyestr-pestytsydiv-i-agrohimikativ-dozvolenyh-do-vykorystannya-v-ukrayini].

2. Наказ Міністерства охорони здоров’я України 07 червня 2024 року № 992. ЗМІНИ до Гігієнічних нормативів і регламентів безпечного застосування пестицидів і агрохімікатів, затверджених наказом Міністерства охорони здоров’я України від 02 лютого 2016 року № 55. Електронний ресурс. Режим доступу: https://moz.gov.ua/storage/uploads/3b84e156-47d4-402e-910a-203b3b62a1d5/dn_992_07062024_dod.pdf. [Order of the Ministry of Health of Ukraine dated June 7, 2024 No. 992. AMENDMENTS to the Hygienic Standards and Regulations for the Safe Use of Pesticides and Agrochemicals, approved by Order of the Ministry of Health of Ukraine dated February 2, 2016 No. 55. Electronic resource. Access mode: https://moz.gov.ua/storage/uploads/3b84e156-47d4-402e-910a-203b3b62a1d5/dn_992_07062024_dod.pdf].

3. Public Release Summary on the evaluation of the new active constituent fluoxapiprolin in the product Xivana Prime 20 SC Fungicide. Australian Pesticides and Veterinary Medicines Authority. 2022 (APVMA website) [Electronic resource]. URL: https://www.apvma.gov.au/sites/default/files/publication/98651-ublic_release_summary_on_the_evaluation_of_the_new_active_constituent_fluoxapiprolin_in_the_product_xivana_prime_20_sc_fungicide.pdf.

4. Acute reference doses (ARfD) for agricultural and veterinary chemicals used in food producing crops or animals. Edition 2/2024. Australian Pesticides and Veterinary Medicines Authority [Electronic resource]. URL: https://www.apvma.gov.au/sites/default/files/2024.pdf.

5. New Zealand Food Safety Discussion Paper No: 2023/03. Proposals to Amend the New Zealand (Maximum Residue Levels for Agricultural Compounds). Food Notice [Electronic resource]. URL: http://www.mpi.govt.nz/newsand-resources/publications.

6. Food Notice: Maximum Residue Levels for Agricultural Compounds. Ministry for Primary Industries (MPI) New Zealand Food Safety. 2023 [Electronic resource]. URL: https://www.mpi.govt.nz/dmsdocument/19550-maximumresidue-levels-foragricultural-compounds.

7. EPA Staff Report. Application for approval to import or manufacture Xivana for release APP204042. 2022 [Electronic resource]. URL: https://www.epa.govt.nz/assets/FileAPI/hsnoar/APP204042/APP204042_Staff_Report.pdf.

8. Marchand PA. EU Chemical Plant Protection Products in 2023: Current State and Perspectives. Agrochemicals. 2023;2(1):106–17. [Electronic resource]. URL:https://DOI.org/10.3390/agrochemicals2010008.

9. Priority list of pesticides for evaluation by joint FAO/WHO food standards programme. Codex Alimentarius commission report of the 54th session of the codex committee on pesticide residues. 2023 [Electronic resource]. URL: https://www.fao.org/fao-who-codexalimentarius/shproxy/en/?lnk=1&url=https%253A%252F%252Fworkspace.fao.org%252Fsites%252Fcodex%252FMeetings%252FCX-718-54%252FREPORT%252FFINAL%2BREPORT%2BCORRIGENDUM%252FREP23_PR54e_CORR.pdf.

10. FEDERAL REGISTER, US. Environmental Protection Agency. Pesticide Product Registration; Receipt of Applications for New Active Ingredients. Federal Register / Vol. 88, № 121 on 06/26/2023 [Electronic resource]. URL: https://www.federalregister.gov/documents/2023/06/26/2023-13426/pesticide-product-registrationreceipt-of-applications-for-new-active-ingredients-may-2023

11. Miao J, Li C, Liu X, Zhang X, Li G, Xu W, et al. Activity and Resistance-Related Point Mutations in Target Protein PcORP1 Fluoxapiprolin in Phytophthora capsici. J Agric Food Chem. 2021;69(13): 3827–35. DOI:10.1021/acs.jafc.0c05119.

12. Cohen Y, Rubin AE, Galperin M. Effective control of two genotypes of Phytophthora infestans in the field by three oxathiapiprolin fungicidal mixtures. PLoS ONE. 2021;16(10):e0258280 [Electronic resource]. URL: https:journals.plos.org/plosone/article?id=10.1371/journal.pone.0258280.

13. Bian Q, Zhao RQ, Peng XJ, Gao LJ, Zhou GN, Yu SJ, et al. Design, Synthesis, and Fungicidal Activities of Novel Piperidyl Thiazole Derivatives Containing Oxime Ether or Oxime Ester Moieties. J Agric Food Chem. 2021;69(13):3848–58. DOI: 10.1021/acs.jafc.0c07581.

14. Li C, Liu X, Liu Z, Hu S, Xue Z, Fu Y, et al. Resistance Risk and Novel Resistance-Related Point Mutations in Target Protein PiORP1 of Fluoxapiprolin in Phytophthora infestans. J Agric Food Chem. 2022;70(16):4881–8. DOI: 10.1021/acs.jafc.1c08199.

15. Chauhan NR, Parmar CR, Patel MS, Kalsariya RL, Parmar KD. Determination of Fluoxapiprolin+Fluopicolide Residue and Its Dissipation Kinetics in/on Tomato by Liquid Chromatographic Technique OP (S10) 23. J Mycol Pl Pathol. 2023;2(53):202–3.

16. Bhardwaj AK, Mandal K, Sharma S, Kang BK. Method validation and residue analysis of fluoxapiprolin and its metabolites on tomato by QuEChERS method combination with liquid chromatography tandem mass spectrometry (LC-MS/MS). International Journal of Environmental Analytical Chemistry. 2024;16:1–16. https://DOI.org/10.1080/03067319.2024.2344710.

17. Litoriya NS, Kalasariya RL, Parmar KD, Patel JH, Patel SH, Chaudhary NN, et al. Dissipation and dietary risk assessment of fluoxapiprolin (and its metabolites) residues in cucumber and tomato samples under field conditions. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2024;41:1–13. DOI: 10.1080/19440049.2024.2380918.

18. Wei Sun, Anjing Liao, Li Lei, Xu Tang, Ya Wang, Jian Wu. Research progress on piperidine-containing compounds as agrochemicals. Chinese Chemical Letters. 2024. https://doi.org/10.1016/j.cclet.2024.109855 [Electronic resource]. URL: https://www.sciencedirect.com/science/article/pii/S1001841724003747).

19. Li C, Tian S, Fu Y, Li Y, Miao J, Peng Q, et al. Activity of OSBPI fungicide fluoxapiprolin against plant-pathogenic oomycetes and its systemic translocation in plants, Pesticide Biochemistry and Physiology. 2024;204:106085. [Electronic resource]. URL: https://doi.org/10.1016/j.pestbp.2024.106085.(https://www.sciencedirect.com/science/article/pii/S0048357524003183).

20. Cohen Y, Galperin M. Comparative efficacy of oxathiapiprolin-based fungicides in controlling late blight in field-grown potatoes induced by mixed mefenoxam-sensitive and resistant genotypes of Phytophthora infestans, Crop Protection. 2024;179(10):106599. [Electronic resource]. URL: https://doi.org/10.1016/j.cropro.2024.106599. https://www.sciencedirect.com/science/article/pii/S0261219424000279).

21. Jeschke P. Recent developments in fluorine-containing pesticides. Pest Manag Sci. 2024;80:3065–87. https://doi.org/10.1002/ps.7921.

22. Ivanova L, Prodanchuk M, Kravchuk O, Zvarych H. Consumer risk assessment of new fungicide fluoxapiprolin residues in Ukraine. Toxicology Letters. Official Journal of EUROTOX. 58th Congress of the European Societies of Toxicology (EUROTOX 2024). Toxicology – a quest for safer chemicals and medicines, Copenhagen, Denmark. 8–11 September 2024; P. S 260

23. Іванова ЛП, Медведєв ВІ, Павленко ІП, Зварич ГВ. Розробка гранично допустимої концентрації флуоксапіпроліну у воді водойм. Матеріали науково-практичної конференції з міжнародною участю «Екологічні та гігієнічні проблеми сфери життєдіяльності людини» (Київ, 13 березня 2024 р.) За заг. ред. член-кор. НАМН України, професора С.Т. Омельчука. К.: МВЦ «Медінформ», 2024. С. 113–4. [Ivanova LP, Medvedev VI, Pavlenko IP, Zvarych GV. Development of the maximum permissible concentration of fluoxapiproline in water reservoirs. Materials of the scientific and practical conference with international participation “Ecological and hygienic problems of the sphere of human life” (Kyiv, March 13, 2024) Under the general editorship of corresponding member of the National Academy of Medical Sciences of Ukraine, professor S.T. Omelchuk. Kyiv: IEC “Medinform”, 2024. P. 113–4].

24. Пестициди. Гігієнічна класифікація пестицидів за ступенем небезпечності: ДСанПін 8.8.1.002 – 98. [затв. Постановою МОЗ України 28.09.98 №2]. Зб. Важливих офіційних матеріалів з санітарних та протиепідемічних питань. Київ. 2000;9(1):249–66. Pesticides. Hygienic classification of pesticides by degree of hazard: DSanPin 8.8.1.002 – 98. [approved by the Resolution of the Ministry of Health of Ukraine of 28.09.98 No. 2]. Collection of important official materials on sanitary and anti-epidemic issues. Kyiv. 2000;9(1):249–66].

25. Petition for Tolerance. Fluoxapiprolin, 2023 [Electronic resource]. URL: https://www.regulations.gov/document/EPA-HQ-OPP-2022-0980-0003.

26. The University of Hertfordshire Agricultural Substances Databases - Background and Support Information PPDB/BPDB/VSDB Version: April 2024 [Electronic resource]. URL: http://sitem.herts.ac.uk/aeru/ppdb/en/docs/Background_and_Support.pdf

27. Проданчук МГ, Кравчук ОП, Іванова ЛП, Гринько АП, Багацька ОМ. Розробка методичних підходів до нормування пестицидів в рослинних оліях Єдине здоров’я та проблеми харчування України. 2022;1(56):7–18. [Prodanchuk MG, Kravchuk OP, Ivanova LP, Hrynko AP, Bahatska OM. Development of methodological approaches to the regulation of pesticides in vegetable oils. Unified Health and Nutrition Problems of Ukraine. 2022;1(56):7–18].

28. Science Memorandum for application to import or manufacture Xivana for release, 2021 [Electronic resource]. URL: https://www.epa.govt.nz/assets/FileAPI/hsno-ar/APP204042/APP204042_Science_28randum.pdf.

29. OECD Guidelines for the Testing of Chemicals, Section 4 Health Effects [Electronic resource]. URL: http://www.oecdilibrary.org/ environment/oecd-guidelines-for-the-testingof-chemicals-section-4-health-effects_ 20745788 [2016/06/03 11:27:04].

30. Boesten J, Aden K, Beigel C, Beulke S, Dust M, Dyson J et al. Guidance Document on Estimating Persistence and Degradation Kinetics from Environmental Fate Studies on Pesticides in EU Registration: Report of the FOCUS Work Group on Degradation Kinetics, EC Document Reference Sanco/10058/2005 version 2.0. 2006. [Electronic resource]. URL: https://esdac.jrc.ec.europa.eu/public_path/projects_data/focus/dk/docs/finalreportFOCDegKinetics.pdf.

31. EFSA Guidance Document for evaluating laboratory and field dissipation studies to obtain DegT50 values of active substances of plant protection products and transformation products of these active substances in soil - European Food Safety Authority (EFSA). 2014;12(5):3662. URL: https://doi.org/10.2903/j.efsa.2014.3662.

The article was received by the editorial office on February 3, 2024