Introduction

The BCAs (biocontrol agents) market accounts for 3.6 billion euros worldwide and 900 million euros in Europe. In France, 8% of the plant protection market deals with BCAs. This represents 170 million of euros (IBMA 2018). With a 20% annual growth and the current steady increase of market demand for BCAs products, BCAs are a now very attractive and growing business sector (Ravensberg 2015).

Although the notion of BCAs is clearly defined at the European and national levels, currently no obvious definition of this concept is observed within the European plant protection products (PPP) regulatory process (Pavela 2016). For example, the Article L253–6 of the rural French code “Code Rural et de la Pêche maritime” defines the BCAs as “agents and products that use natural mechanisms in the context of a holistic fight against pests”. In the European Union, BCAs are listed under 4 pillars, namely, macroorganisms, microorganisms, semiochemicals and substances of natural origin including botanicals. All are active substances established under the (EC) No 1107/2009 regulation and listed under the (EC) No 540/2011 regulation except macroorganisms that are not regulated at the European level (Robin 2018; Robin and Marchand 2020). Also, four types of active substances are listed under the European PPP regulation, respectively, candidates for substitution, active, low-risk and basic substances. All these substances are defined based on criteria of articles 24, 4, 22 and 23, respectively, of the (EC) No 1107/2009 regulation. Basic substances benefit from a simplified procedure and an unlimited time of approval (Marchand 2015). They are listed under Annex IV of the (EC) No 396/2005 regulation. This means that no MRL (maximum residue limit) is attached to them (Marchand 2016). Due to these characteristics, they are playing an increasingly important role in the implementation of BCAs (Robin 2018). Currently, 20/21 of the approved basic substances fit the BCAs definition, and the use of 18 of them is approved for organic agriculture (Marchand 2017).

Committed by the desire to develop substances, as they are perceived as less toxic than synthetic phytosanitary chemical substances, different stakeholders such as the IBMA (International Biocontrol Manufacturers Association) and some institutes such as ITAB (the Organic Food and Farming Institute) support the evolution of BCAs at the European level (Villaverde et al. 2014).

However, even though Charon et al. (2019) showed that the demand for products devoid of MRLs (like most BCAs) has steadily increased, the number of biocontrol substances approved has increased at a much slower pace. Previous studies have described the fate of BCAs and the process of approval of these substances (Robin and Marchand 2019a; Robin and Marchand 2019b). The present paper aims at pointing out the hurdles observed within the European approval process, even though the public demand for BCAs is high and rapidly increasing.

An increasing public demand for BCAs

The current awareness of environmental issues related to phytosanitary products (PPP) and residues testifies a crucial need for less toxic substances and devoid of MRLs, as defined by the European Chemical Agency (ECHA). This should necessarily translate into an increase of the use of BCAs. Indeed, generally, the lower the MRL, the higher is the toxicity. Nevertheless, some substances without MRLs including most BCAs are listed (133 out of 200) under Annex IV of the regulation (EC) No 396/2005 (i.e. substances with no MRL). Briefly this means that residues are not a concern. Thus, they are not investigated. To obtain an approval, a special request needs to be made. Indeed, these substances are temporarily listed under Annex V of the same regulation (MRL by default) after approval (Robin and Marchand 2019a). Following approval of the substance an additional report is required to obtain the inclusion under the Annex IV (no MRL). Then, a vote on the MRL is performed during the same PAFF Committee as is the case for synthetic agrochemical protectants meeting (Standing Committee on Plants, Animals, Food and Feed). Yet, some substances are directly included under Annex IV during approval. For example, most of the substances from animal and plant origin benefit from this bypass (Charon et al. 2019).

The present regulation has a negative impact on progress

The BCAs’ concept is not clearly defined or described within the European PPP regulations. All active substances are regulated at the European level by Regulation (EC) No 1107/2009, which grants market approval on phytosanitary products. As opposed to Directive No 91/414/EEC, the implementation of this regulation is favourable to BCAs because of their eco-toxicological criteria, and the fact that the depth of the evaluation of these products was strengthened (Robin 2018).

However, even though with the full implementation of Directive (EC) No 2009/128, the European Union is currently interested in taking actions to support the sustainable use of phytosanitary products; the PPP regulation is not encouraging the use or uptake of BCAs (Charon et al. 2019). For instance, since 2018, only 5 new biocontrol substances were approved. Indeed, the former Directive (EC) No 91/414/EEC, aiming at standardizing the phytosanitary products, has impeded the uptake of substances from natural origin because the rate of return and approval fees is too high for applicants (Matyjaszczyk 2011). Moreover, the decision criteria mainly focus on chemical substances, including criteria for low-risk substance in Annex II (European Commission 2017a). As a consequence, BCAs, such as microorganisms, were not approved as frequently as might have been expected (Alabouvette et al. 2006). Fortunately, different guidelines, such as SANCO/12545/2014-rev.2 concerning the microorganisms and SANCO/11470/2012-rev.8 concerning botanicals, were established recently to make their approval easier (European Commission 2014). Finally, the European parliament published the PEST report giving an injunction to the Commission to modify the regulation in order to facilitate the market access to BCAs (European Parliament 2018).

Amongst all these hurdles, one major concern is the approval process for substances, which is very cumbersome. First, a file is compiled for each substance according to the requirements defined by the regulation (EU) No 283/2013. Then, this is transmitted to the Rapporteur Member State (RMS) to each national agency that then reports on the file to the EFSA after first evaluation. Since new EU rules published 24th November 2009 in the official journal of the European Union, a co-rapporteur is also required (European Parliament 2009). After the approval of a substance, the European Member States (MS) can deliver a market authorisation for their national market. This process appears smooth; however, in practice it frequently meets with misunderstanding, generates misinterpretations and leads to over prevention due to the great number of molecules contained in these botanicals. As a result, it leads to a non-approval of biocontrol substances, even though they are safe and a very strong demand for them by the public exists (Robin and Marchand 2019a), and are in line with other overarching EU objectives for achieving a more sustainable form agriculture. This paper aims to reveal the hurdles encountered during the regulation process in order to improve its effectiveness and encourage the design of a novel framework to support the development, implementation and use of botanical BCAs.

Material and methods

Material and data

European pesticides database

The raw data were retrieved from the European pesticides database. This database lists all the substances approved as well as those not approved and those where an approval is pending (European Commission 2020a).

Review and draft assessment reports on substances

The toxicological data and the EFSA outcomes on substances applications were retrieved from reports made by the EFSA and those submitted by the rapporteurs (European Commission 2008; European Food and Safety Authority 2008; Marrone Bio Innovations 2009; European Food and Safety Authority 2013; European Commission 2014; European Food and Safety Authority 2015; Azab et al. 2017; European Food and Safety Authority 2017; ITAB 2017, 2018; European Food and Safety Authority 2018a, b, c; European Commission 2019a; European Food and Safety Authority 2019).

Implementing regulation decisions

The implementing regulations decisions of five substances, namely, Reynoutria sachalinensis (Chemical Abstracts Service (CAS) number attached to five key components: Resveratrol: 501-36-0, Resveratrol glucoside: 65914-17-2, Emodin: 518-82-1, Emodin glucoside: 38840-23-2, Physcion: 521-61-9), beer (CAS* number: 8029-31-0), grape Vitis vinifera cane tannins (CAS* number: 84929-27-1), pyrethrins (CAS* number: 8003-34-7) and mefentrifluconazole (CAS* number: 1417782-03-6) were retrieved (European Commission 2013, 2018a, b, 2019b, 2020b). These regulations detail the conclusion concerning the approval or non-approval of each substance. Beer, pyrethrins and mefentrifluconazole were approved, whereas grape cane tannins (Vitis vinifera) and knotweed extract (Reynoutria sachalinensis) were not. All the implementing regulation decisions are delivered and signed by the European Commission. Each implementing regulation decision comes with a summary of the evaluation process (review report). The summary starts with the statement of the RMS (Rapporteur Member States) and the applicant. The outcome evaluation of other member states and the EFSA follows. It ends by two articles that specify the approval or non-approval of the substance as well as the date of entry into force of the regulation.

Methodology

The chosen substances for this study are either basic or active substance, of chemical or plant origin. From the five considered, three were approved and two were not. Data analyses enabled us to produce two comparative tables summarizing all the substance characteristics. These tables highlight the similarities and differences between the approved and non-approved substances. Although the natural substances are all botanical BCAs, the chemical substance was chosen by criteria: recently approved (2019) and with fungicide properties as some botanicals. The results of this study are summarized in two tables. These tables were produced using all information available on the substances. Only some data are collected and listed in the Tables 2 and 3. In order to make interpretation and comparison easier, two parts were produced focusing either on the identification (composition, use, application) or the hazard evaluation (residues, toxicology, ecotoxicology, persistence) with corresponding abbreviations in Table 1. More explanations are provided in the following paragraphs.

Table 1 Abbreviations
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Primarily, four substances from plant origin were studied. The Grape Vitis vinifera cane tannins is a substance used in nutraceuticals (VINEATROL 30) and for oenological purpose (VineTAn). It is a mixture based on proanthocyanidic (natural pigments) tannins extracted from vine wood, in accordance with the International Oenological Codex (International Organisation of Vine and Wine 2019). The main active component in the mixture is resveratrol. It is currently used as a food ingredient (International Organisation of Vine and Wine 2019). The second substance is beer. The major component is water, and the alcoholic degree is usually around 4% to 8%, although it may vary between 0.5 and 20%. The production of beer (brewing), involves the fermentation of starches. Beer mainly derived from either malted barley, wheat or maize, and hops. The brewing industry is an important business (ITAB 2017). The third substance, Reynoutria sachalinensis extract, derives from a plant stem from the Polygonaceae family composed of perennial, grasses and rhizomatous plants. The active mixture is a green, brown and cream powder manufactured according to food and pharmaceutical standards. For example, it is used as a food supplement and as a pharmaceutical product (Marrone Bio Innovations 2009). Finally, the last biocontrol substances are the pyrethrins. Pyrethrin insecticides naturally occur in Chrysanthemum cinerariifolium flowers, a plant commonly found in Europe. The active substance targets the neural system of insects. They have been used as natural insecticide for thousand years even though their toxic effects on humans are high.

Secondly, to study the general framework of the evaluation process, an approved synthetic chemical substance was used as an internal control during this study. To compare the toxicity of these 5 substances, a pairwise analysis was performed. Ratings of potential danger used in the table derive from the GHS protocol (Globally Harmonized System of Classification and Labelling of Chemicals) (United Nations 2017a, b).

Results

Tables 2 and 3 show the results of the comparative evaluation. The worst candidate in each row of Table 2 is underlined in red when possible (notable values or level of toxicity/eco toxicity). At first glance, red marks are not equally distributed in Table 2. Some of the substance’s column, although corresponding to approved active substance at PPP Reg. contain more red than certain non-approved substances (active or basic).

Table 2 Comparison of approved and non-approved BCAs substances under the regulation 1107/2009
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Table 3 Characteristic of a chemical substance approved under the regulation 1107/2009
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Discussion

Basic substances

Beer and cane tannins are basic substances. However, they are respectively approved and non-approved. But both substances have similar ecotoxicological data. Both derive from the production of alcoholic drinks, namely, beer and wine. The oenological tannins presented as a fungicide derive from the cane. Their antioxidant properties are well known. It protects the wine from its ageing process and against some toxic bacteria. However, during the evaluation process of this file, EFSA and other member states requested supplementary data regarding the impact of this substance on the environment, the mammals, the birds and the aquatic species, although such data were not requested for beer. In addition, the EFSA underlined the possible toxicity of cane tannins on children’s health in particular with regard to its presumed carcinogenic potential. Yet, this property is well known for beer, even though beer was approved (European Commission 2017c). As shown in the table, both substances show a similar toxicity/ecotoxicity (or even higher for beer (European Food and Safety Authority 2017)); the grape cane (Vitis vinifera) tannin substance was not approved because of its supposed toxicity (European Food and Safety Authority 2018b; European Commission 2020b). As a matter of fact, grape cane (Vitis vinifera) tannins are allowed as feed additive for mammals, whereas beer is of concern, although risk management measures may reduce exposures.

This observation can be extended to other non-approved plant origin substances such as the Origanum vulgare L. essential oil derived from oregano. It is commonly used as a food aroma and well known for its antioxidant, antimicrobial, immunomodulating and anti-inflammatory properties. Nevertheless, it was not approved as a basic substance. The substance was targeted for use as a fungicide, bactericide and insecticide on different crops: potatoes, lettuce, kidney bean, tomato, pear tree, apple tree, citrus tree, kiwi tree, apricot tree, quince tree and grapevine. The objective was to use it as a foliar spray on most of the crops (PHI* was not applicable). Four major components were identified in this oil: carvacrol, thymol, p-cymene and γ-terpinene. The identification of these components enabled their possible risks and effects to be specifically identified. No severe deleterious effects (genotoxicity, reprotoxicity, neurotoxicity) were encountered concerning thymol and carvacrol, the oil’s active components. As a matter of fact, thymol alone has been approved at the European level as a fungicide and is already used in eight European countries. It was granted no MRL under Annex IV, as expected for oils. Oregano essential oil is listed as a GRAS food (generally recognize as safe) in USA and Canada. In Europe it is used as a food additive for the weaned piglet (European Commission 2020c). All the information available provides an overview of the low risk of this substance (ITAB 2016). Yet, the EFSA report mentioned that requested rejection of this substance was due to the danger of thymol, which is approved at EU level. Also, some doubt was raised about the oil’s pharmaceutical effects, although these are already recognized by the World Health Organization (European Food and Safety Authority 2016). The major issue concerning the evaluation of each substance is that the evaluation process only takes into account every component of the substance, but does not take into account the fact that a mixture may have different properties than each of its constituents alone, due to interactions between them (Andersen et al. 1994). Nevertheless, this substance was not approved (European Commission 2017b).

Finally, although SANCO/11470/2012-rev.8 guideline concerning botanicals (European Commission 2014) clearly mentions basic substances as an issue for botanicals in its Article 16, 11 botanicals proposed as basic substance applications were non-approved.

Botanical active substances

Pyrethrins and Reynoutria sachalinensis extract are two botanical applicants. From the data, the toxicity of Reynoutria sachalinensis is comparable with the pyrethrins. Yet, the knotweed extract was not approved because of its aquatic toxicity, whereas pyrethrins has received one approval duration extension. Currently pyrethrins are approved in 22 European countries. Knowing that the Reynoutria sachalinensis is an invasive plant, it would have been useful to include it along with botanical BCAs. Some applicant botanical substances were also non-approved, i.e. Decision (EC) No 442/2007 (European Commission 2007). Pyrethrins were not considered by Decision (EC) No 442/2007 and were approved in 2008 (Commission Directive (EC) No2008/127), later transferred in Part A of implementing Reg. (EC) No 540/2011 during the implementation of Reg. (EC) No 1107/2009. During the last revision of the approval (SANCO/2627/08) in 2013, ADI, ARfD and AOEL were defined, and further toxicity studies were required (European Commission 2017d). Furthermore, renewal process is ongoing with an extension of the approval period granted in 2017 (European Commission 2017e) until 2022.

Chemical active substances

Unfortunately, synthetic chemical substances often make their way through this cumbersome process quite easily. Surprisingly, Table 2 shows that a toxic chemical substance, such as mefentrifluconazole, was recently approved under the current regulation (European Commission 2019b). One understands the danger of this substance with a very low MRL when one compares it with other substances in Table 1. This strongly underlines the inconsistent behaviour of the evaluation process with respect to the official desire to increase the number and boost the use of BCAs and low-risk substances. As matter of fact, the EU Parliament has already asked the EU Commission to improve and simplify the regulation process in the PEST report (European Parliament 2018).

Number of botanical extracts concerned by non-approval as substances (active or basic)

Basic substances

Grape (Vitis vinifera) cane tannins, propolis (water-soluble extract), Saponaria officinalis (root extract), Artemisia absinthium L., Origanum vulgare L. essential oil, Satureja montana L. essential oil, Arctium lappa L. (aerial parts), Tanacetum vulgare L., Artemisia vulgaris L., paprika extract (capsanthin, capsorubin E 160 c), Achillea millefolium L., Rheum officinale root extract and citrus pulp were non-approved, whereas extract of the wood of Quassia amara L., rhododendron honey, Castanea and Schinopsis tannins (European Food and Safety Authority 2018c) and later fermented extract from leaves of Symphytum officinale L. (comfrey) and extract from rhododendron and valerian extract were withdrawn before vote due to damaging EFSA evaluation conclusions, although some are nevertheless approved for food, feed, cosmetic or medicinal purposes.

Active substances

Citrus extract/grapefruit seed extract, conifer needle powder, extract from Menta piperita, garlic pulp, marigold extract, onion extract, mustard powder, plant oils/marjoram oil, plant oils/coconut oil, soybean extract and wheat gluten were not approved at the 4th stage for diverse reasons and more recently Reynoutria sachalinensis extract.

Conclusions

Conclusion of the study

This study aims at pointing out the drawbacks of the approval process for botanical BCAs as active substances under the European PPP regulation. It shows clearly that some chemical substances exhibiting similar toxicological data were approved, whereas other botanicals were not. But this study does not reveal all the hurdles encountered throughout the evaluation process, especially for non-single chemical molecules as botanicals. Finally, it is worth noting that no botanical low-risk substance was approved nor even considered.

Therefore, the present study emphasizes the deficiency existing at the European level regarding an important issue, namely, a strong need to expand new botanical BCAs. In fact, more than 30 applications for promising botanicals have not been approved under EU PPP regulations since 2007. These pitfalls seriously harm the development of renewable botanical BCAs. We hope this work will trigger some attempts to improve the PPP existing framework for botanicals or to develop a novel plant protection system for a better sustainable agriculture. Recent modification of low-risk substances criteria regarding natural occurring substances may be a positive signal for this (European Commission 2017a).

Possible solutions to improve the evaluation system

Although, possible ways to overcome these approval struggling are numerous (PPP regulation evolution, evaluation criteria changes, other Regulations dispositions taking in consideration…) some are already being deployed to change these negative issues (Amichot et al. 2018). However, nothing really changed through PPP regulation evolution, including “REFIT” evaluation of all EU pesticide legislation (Möhring et al. 2019). First of all, although application renewal is possible after a non-approval by regulatory provision, a few applicants took this opportunity (i.e. Capsicum (Paprika extract (capsanthin, capsorubin E 160 c)) and R. sacchalinensis extract) to finally obtain an approval for these substances. The EFSA outcome for Capsicum annuum L. var. annuum, longum group, and cayenne extract is now released. The decision about its approval or otherwise will be known soon (European Food and Safety Authority 2020).

Secondly, the evolution of evaluation criteria may be another target or approach to improve the narrow evaluation tunnel. Recent modification of low-risk substances criteria regarding natural occurring substances may be a positive signal of such developments (European Commission 2017a). Low-risk substances criteria were also adapted to consider natural substances specifically compared with chemicals in terms of stability, degradation and lifetime in soils. Moreover, some criteria are waived for naturally occurring active substances and substances emitted and used by plants, animals and other organisms.

Concerning basic substances evaluation specifically, the ongoing modification and update of the corresponding guideline (working document SANCO/10363/2012) from rev. 9 to a new revision in 2020 may be a way to progress the approval opportunities, although next botanical extract application as comfrey steeping is proposed for non-approval.

However, considering the essential point of botanicals, that is to say the almost infinite total of molecules, compared with the single molecules usually subject to approval, the system is not yet fit for purpose for this kind of application, in particular if the problem of residues and metabolites of the active substance is included. The best evidence for the capriciousness of the approval process is the approval of the PPP triterpene Mevalone® with three separate active substances (thymol, eugenol and geraniol) instead of a botanical extract with the same molecule content. Finally, if a substance such as Reynoutria sachalinensis containing physcion and resveratrol was approved as an active substance by an international company and is having several market authorizations in different countries and did not obtain approval in EU, then the approval system maybe be more deeply revised or modified.