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

Abstract. The establishment of a free trade zone within the framework of EU-Ukraine Association Agreement provides the necessary measures to achieve the relevant national standards regarding the level of European and international requirements. One of the important issues is the harmonization of the regulation of the circulation of chemical products, including pesticides. Particular requirements are laid down to the quality of the preclinical studies of plant protection products (PPPs) in accordance with the principles of Good Laboratory (GLP) and Good Experimental Practice (GEP) in laboratory and field conditions, the need for implementation of which is particularly relevant for the mutual recognition of PPP test results at their registration in Ukraine and European countries.
Key words: plant protection products, registration, Good Laboratory Practice, Good Experimental Practice, Good Agricultural Practice, field studies, standard operating procedures.

The globalisation of the pesticide registration process in the Organisation for Economic Cooperation and Development (OECD) member states and in the European Union, in particular, manifests itself in the unification of regulatory and methodological support for the pesticide registration system and the methods of testing plant protection products (PPPs). Only using standard unified experimental methods for determining the physiochemical properties of pesticides, parameters of their behaviour in the environment, human toxicity and ecotoxicity, reproducible and comparative data can be obtained for further classification of pesticide hazards and risk assessment [1].

In the European Union, issues related to PPPs and the active ingredients contained therein are governed by the rules laid down in Regulation (EC) of the European Parliament and of the Council No. 1107/2009 as of October 21, 2009 On the Placing on the Market of Plant Protection Products and cancellation of Council Directive 79/117/ EEC and 91/414/EEC [2]. For field pesticide studies on the determination of their residual amounts in agricultural products, food and feed for livestock production, in the environment and establishment of their maximum permissible levels of residues (MPLs) in accordance with Regulation (EC) No. 396/2005 [3], the European Union is divided into two zones (see Fig. 1) [4, 5, 6].

Fig. 1. Zones for determining residual amounts of pesticides in Europe [6].

According to the recommendations of the Directorate General for Health and Food Safety of the European Commission on comparability, extrapolation, group tolerances and data requirements for the establishment of MPLs [5], the following countries in northern and central Europe are included in the first zone: Sweden, Norway, Iceland, Finland, Denmark, Great Britain, Ireland, Northern France, Belgium, the Netherlands, Luxembourg, Germany, Poland, Czech Republic, Slovakia, Austria, Hungary, Switzerland, Estonia, Latvia, Lithuania, Romania, Slovenia. The second zone includes countries of Southern Europe and the Mediterranean: Spain, Portugal, Southern France, Italy, Greece, Malta, Croatia, Serbia, Bosnia and Herzegovina, FYR Macedonia, Turkey, Bulgaria, Cyprus.

It is important to note that the list of countries in these zones includes a number of states that are not currently EU members. Since Regulation No. 83/2013 [4] stipulates that such studies may be carried out outside the EU if they are in line with the critical Good Agricultural Practice (GAP) and production conditions (such as cultural practices, climatic conditions) are comparable.

Therefore, Ukraine may also requests the European Commission’s Directorate General for Health and Food Safety to include our country to the zone of countries for studying pesticide under field conditions for the determination of their residual amounts in agricultural products, food products and livestock feeds, in the environment and setting their maximum permissible levels of residues. At the same time, Ukraine, like France, can be attributed to two zones.

Conditions for testing pesticides in the field conditions to determine their residual amounts (for example, maximum number of proposed applications, short interval between applications, maximum rate of application and concentration, the most critical safety intervals (pre-harvest intervals — PHIs) should be defined to identify the highest residues, which can reasonably arise and must be represented in real conditions of the critical GAP in which the active ingredient is to be used [4].

It is believed that the number of necessary studies is difficult to determine in advance, before the assessment of their results. Assuming that all variables that have an impact on pesticide residue levels in field studies are commensurable, then the minimum number of tests to determine the residual amounts should be at least 4 small culture studies and at least 8 studies for the main culture in each zone.

In accordance with the recommendations on comparability, extrapolation, group tolerances and data requirements for the establishment of the MPLs [5], the criterion for determining the main agricultural crop in the EU is growing it on an area of more than 20 thousand ha and production of more than 400 thousand tons per year. However, for example, if the GAP is the same for both residue zones, 6 evenly distributed studies are sufficient for a small culture. There are other conditions in which the number of studies can be reduced (by a maximum of 40 %). To use PPPs in greenhouses, after harvesting and processing of warehouses, studies in one zone will be enough. The number of studies conducted may also be reduced if they indicate that the level of residues in plants or their products is below the limit of quantification (LOQ). The number of studies should be at least 3 for the zone of minor crops and 4 for the zone for main crops.

The application for approval of the active ingredient shall be submitted by the manufacturer to the member state (rapporteur member state) together with a short or complete dossier as provided in Article 8 of Regulation (EU) No 1107/2009. It should be noted that in the EU, in the presence of two zones for the study of pesticides under field conditions for the determination of residues, for the registration of plant protection products for commercial purposes within the Community, three zones of groups of member states have been established [2]: North, Centre and South (see Fig. 2), in accordance with Annex I, specified by the regulation. In order to obtain a permit for the placing of plant protection products on the market of EU countries, in accordance with Article 33 of the above-mentioned regulation, the applicant submits an application to each member state proposing which member state of the zone is planned to evaluate its application.  At the same time, a list of intended applications of PPP in the zone and in the member states where the product is intended to be supplied should be specified.

Fig. 2. Zones for issuing permits for plant protection products [6].

At the request of the member state reviewing the application, other member states of the application should cooperate in order to ensure an equitable distribution of the workload for the assessment of the plant protection product (Article 35 of Regulation (EC) No. 1107/2009). At the same time, the member state reviewing the application must make an independent, objective and transparent assessment of the applied product in the light of current scientific and technical knowledge, using the regulatory documents available at the time of submitting the application. In this respect, indicative, in terms of understanding the work of internal procedures in the EU registration zones, is “Regulatory document on the division of labour in the Northern zone for the issuance of permits for plant protection products” [7]. It describes the procedure for submitting and evaluating applications for authorisation and renewal authorisation on plant protection products, after approval of the active ingredient in accordance with Regulation (EU) No. 1107/2009 in the Northern zone.

Regulatory document of the Northern zone, agreed by the relevant competent authorities of Denmark, Estonia, Finland, Iceland, Latvia, Lithuania, Norway and Sweden, is based on the rates for assessing zone and mutual recognition of permits in accordance with Articles 40–43 of Regulation (EC) No 1107/2009. It is anticipated that it should be used in the context of a zonal assessment of applications for registration of plant protection products in order to reduce the workload of applicants and government authorities and promote harmonisation in the Northern zone. For general coordination of work among the member states of the zone, a zonal steering committee was set up consisting of representatives of the competent authorities of each member state in the zone and non-EU countries of European Free Trade Association (Norway, Iceland).

The government of our country, based on current practice of the European Community, in pursuing measures to harmonise its legislation on the basis of the EU-Ukraine Association Agreement, and in order to unify the processes of registration of plant protection products, in our opinion, may raise the question on the inclusion of representatives of its competent authorities to the steering committee of the Central zone of the EU. This area is the closest to us regarding the agroclimatic and geographical conditions. Certainly, the condition for this should be the harmonisation of the legislation of Ukraine and the EU, as well as the implementation of the relevant scientific and technical standards and norms in the practice of conducting official or officially recognized studies and analyses of PPPs in agricultural, phytosanitary and ecological conditions. An important part of assessing applications for registration of plant protection products for obtaining official registration for commercial purposes is the study of their biological efficiency in various agroclimatic conditions. Biological studies should be conducted in accordance with the relevant standards of EPPO — European and Mediterranean Plant Protection Organisation [2,6,8]. For pests and crops where there are no EPPO standards, national guidelines may be applied if they have at least the same level of requirements as the EPPO standards.

EPPO standards for assessing the efficiency of plant protection products (series — PP1) describe the detailed principles of conducting studies that are performed to assess the efficiency of plant protection products against specific harmful objects. Four agroclimatic zones of commensurable studies and mutual recognition of their data are identified, and Ukraine is allocated to one of them (see Fig. 3). They are intended for all institutions, official registration authorities, public institutions or private companies that carry out such studies. Currently, more than 280 standards of the specified series have been approved by the EPPO and included in the electronic database (paper brochures are no longer available).

Fig. 3. Zones for PPP biological assessment [6,8].

These standards can be divided into two parts:

- 26 standards (including such well-known standards as PP1/181, PP1/152, PP1/135) that describe the general aspects and principles of experimental work (free access).
- More than 250 special guidelines for studying the efficiency of drug action (paywall).

Therefore, in the European Union currently there are three different types of geographical zones associated with the registration of pesticides and the mutual recognition of the study results — zones for the determination of residual amounts (Fig. 1), the registration zone (Fig. 2) and PPP biological assessment zones (Fig. 3). This situation suggests that, with zoning, along with scientifically grounded approaches, political decisions also exists. Regulatory policy in the field of PPP circulation in the European Union has been evolving over the years and has a significant impact on the development of agriculture, leading to the accelerated introduction of innovative approaches in practice. There is the possibility of studying new drugs in the early stages of pre-registration, which allows manufacturers of PPPs to make informed decisions about the feasibility of further registration. Pre-registration tests are performed by officially accredited organisations in accordance with the requirements of Good Laboratory Practice (GLP) and Good Experimental Practice (GEP), as well as procedures adopted at EU or individual countries. Performance of field experiments, starting from the early stages of development, allows to completely characterise new PPPs, which increases the efficiency of their use in practice [9]. Another important aspect is the availability of legislating permits for early-stage testing PPPs, including field experiments. This will allow taking measures more quickly in case of new harmful objects appear.

It should be noted that at the legislative level Ukraine also provides conducting such works for scientific and technological studies and testing of pesticides. However, foreign companies are required to document their registration in the manufacturing country [10], which in our opinion is incorrect, as it leads to a delay in the introduction of modern plant protection products into the market of Ukraine. For example, a rice protection product can be produced at a plant in England or Switzerland where its cultivation is not available, and therefore there is no need for its registration by the manufacturer in that country. Or another situation when a manufacturing company wants to register and bring a new promising product to the market both in the country of manufacture and in Ukraine.

Accredited organisations can develop measures to control new harmful objects, which involve the use of already registered products, and — in emergencies — new and not yet registered drugs.

Pre-registration studies allow obtaining more complete and reliable data on the characteristics of PPPs, the specifics of action. Such studies are fundamentally important for the development of PPPs and the regulations for their application and can not be replaced by extrapolation of the results obtained in the early stages of laboratory studies, including experiments in greenhouses. Checking the efficiency of PPs before submitting registration documents is very important in the EU. Efficiency, along with toxicological and environmental properties, behaviour in the environment, etc., is a regulatory requirement, which has no less importance than the other.

In Ukraine, as in the EU, the most important elements in the registration of pesticides are toxicological and hygienic studies to assess the drug, safety of the drug application in the field conditions, development of maximum permissible levels (MPLs) based on the determination of residual amounts of active ingredients and their metabolites in field tests, making appropriate recommendations on the possibilities and conditions for product registration, which include safety for human health and environment [10, 11, 12]. At the same time, Ukraine has no clear regulatory framework for organising and conducting field studies of pesticides that meet generally accepted world standards for mutual recognition of their results and the involvement of Ukrainian scientific institutions in the processes of international food safety control. The majority of scientific studies is based on methods and standards of the Soviet period [13].

In Ukraine, the requirements of Good Laboratory Practice at the state level are set out in Orders of the MoH of Ukraine as of February 16, 2009. No. 95 “On Approval of Documents for Provision of Quality of Medicinal Products” and as of December 14, 2009 No. 944 “On Approval of Procedure for Conducting Preclinical Studies of the Medicinal Products and Expert Evaluation of Preclinical Studies of the Medicinal Products” that cover different aspects of medicinal product safety [14, 15]. In matters relating to toxicological and hygienic studies of pesticides and assessment of their safety in the field conditions, no such holistic regulations are available. It should be also mentioned that the State Enterprise “L. I. Medvedev’s Research Centre of Preventive Toxicology, Food and Chemical Safety” of the MoH of Ukraine is accredited for compliance with the principles of GLP on studies in the field of toxicology, toxicokinetics, mutagenesis, physicochemical studies since 2011 and for field studies — from 2015.

The availability of accreditation gives prospects for further work on the recognition of studies in these fields, conducted by the Centre in the OECD and EU countries as well. Given the above, we consider it necessary for Ukraine to implement a number of legislative, organisational and methodological initiatives and measures aimed at achieving compliance with the EU technical regulations and the introduction of modern principles and practices in regulating the circulation of chemical products, and in particular concerning plant protection products. First of all, this requires the corresponding changes and/or preparation of a new edition of Laws of Ukraine “On Pesticides and Agrochemicals” and “On Provision of Sanitary and Epidemiological Safety of the Population” in order to harmonize the relevant statutory acts on the placing on the market of plant protection products in line with the requirements of the EU and other international organisations such as the OECD and EPPO.

The Cabinet of Ministers of Ukraine commenced work in this direction. For example, by Decree as of February 24, 2016, No. 228-p, Government approved a comprehensive strategy for the implementation of legislation in the area of sanitary and phytosanitary measures. In particular, implementation of Chapter IV, section IV “Trade and issues associated with trade” of the Association Agreement between Ukraine, for one part, and the European Union, the European Atomic Energy Community and their Member States, as part of the second part.” The document approved by the Government defines a schedule of systematic statutory alignment of domestic legislation in the area of sanitary and phytosanitary measures with the legislation of the European Union. A comprehensive strategy was developed with the support of experts from the EU project “Improvement of the Food Safety Control System in Ukraine” in pursuance of the Plan of Implementation of the EU-Ukraine Association Agreement for 2014–2017 [16].

In addition, it is necessary to review the procedure and requirements for the registration tests of pesticides and their state registration in order to obtain mutual international recognition of the results of these studies, to exclude their duplication, to revise and adapt the criteria for assessing PPP hazard, with regard to national proper agricultural practices, diet and other conditions of our country. For field and laboratory pesticide studies, it is necessary to adopt the European regulations for the principles of Good Laboratory Practice and Good Experimental Practice in the form of relevant national standards or technical guidelines.

Implementation of GLP and GEP in the experimental practice of the study sites of Ukraine should be preceded by significant preparatory work on their development and preparation under the auspices, such as the Ministry of Agrarian Policy and Food or the Ministry of Ecology and Natural Resources, as well as the appropriate accreditation procedure for the compliance of these sites. At the same time, it is necessary to prepare the service of inspectors (auditors) of GLP and GEP for control and monitoring to confirm the principles of the compliance of the study sites. The next step is to train and prepare administrations, study directors, investigators and executives, as well as independent quality assurance personnel. For this purpose, it is advisable to establish a national training centre based on the principles of GLP and GEP. Priority is given to justifying approaches to the allocation of national zones for the determination of residues of pesticides, PPP biological assessment and their harmonisation with European regulations for the mutual recognition of the results of relevant studies.

Conclusion

Therefore, in order to achieve compliance with the EU technical regulations and standards, metrology, accreditation, conformity assessment and market surveillance measures, on the basis of the principles and practices set out in current EU Decisions and Regulations in the field of safety control of the use of plant protection products, Ukraine needs to develop and implement a program of work involving the scientific and public institutions. These works should be started with a detailed step-by-step plan of actions within a clear time frame, as well as a determination of specific performers.

REFERENCES

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3. REGULATION (EC) No 1107/2009 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of February 23, 2005 concerning the maximum level of residues of pesticides in food products and feed of plant and animal origin, amending Council Directive 91/414/EEC. Electronic resource. – Available at: http://www.milkiland.nl/upload/pdf/laws/es/ES_396-005_rus.PDF.

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5.  EUROPEAN COMMISSION DIRECTORATE-GENERAL FOR HEALTH AND FOOD SAFETY. SANCO 7525/VI/95  Rev. 10.3 13 June 2017. Guidelines on comparability, extrapolation, group tolerances and data requirements for setting MRLs. Electronic resource. – Available at: https://ec.europa.eu/food/sites/food/files/plant/docs/pesticides_mrl_guidelines_app-d.pdf

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7. Northern zone, 2017. Guidance document on work-sharing in the Northern zone in the authorisation of plant protection products. Version 6, May 2017. 4.5 Environmental fate and behaviour expert group. 1 November 2017. 4.6 Ecotoxicology expert group.  Electronic resource. – Available at: www.pma.agri.ee/download.php?getfile2=8006

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11. On Approval of the Procedure for Conducting State Tests, State Registration and Re-Registration, Publication of Lists of Pesticides and Agrochemicals Authorized for Use in Ukraine. / Decree of the Cabinet of Ministers of Ukraine as of 04.03.1996 No. 295.  Electronic resource. – Available at: http://zakon5.rada.gov.ua/laws/show/295-96-%D0%BF.

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13. Chmil V. D. On the issue of compliance of domestic standards regulating the state testing of plant protection products, their registration and use in agriculture, to the requirements of the European Union / V. D. Chmil // Current topics of toxicology, food and chemical safety, 2014 – No. 1/2. – P. 10–26. 

14. MINISTRY OF HEALTH OF UKRAINE. Order No. 95 as of February 26, 2009 “On Approval of Documents for Provision of Quality of Medicinal Products”.  Electronic resource. – Available at: http://search.ligazakon.ua/l_doc2.nsf/link1/MOZ9538.html.

15. MINISTRY OF HEALTH OF UKRAINE. Order No. 944 as of December 14, 2009 “On Approval of Procedure for Conducting Preclinical Studies of the Medicinal Products and Expert Evaluation of Preclinical Studies of the Medicinal Products”. Electronic resource. – Available at: https://docs.dtkt.ua/download/pdf/1194.32.1.

16. Cabinet of Ministers of Ukraine. Decree as of February 24, 2016 No. 228-p  “On Approval of Comprehensive Strategy of Implementation of Chapter IV (Sanitary and Phytosanitary Measures), section IV “Trade and issues associated with trade” of the Association Agreement between Ukraine, for one part, and the European Union, the European Atomic Energy Community and their Member States, as part of the second part.”  Electronic resource. – Available at: https://www.kmu.gov.ua/ua/npas/248928183.

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