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Universal classification of protection products according to their modes of action and their chemical structures

Opening remark: Tables presented in this document are in French. Nevertheless, this explicative introduction is written in English. A full English version of this classification is under progress. We apologize for this temporary inconvenience to English-speaking readers.

Pest, disease or involves plant protection products (PPPs), of natural or synthetic origin. Independent classifications of PPPs have been proposed according to their category (: FRAC; acaricides-insecticides: IRAC; : HRAC or WSSA). They do not take into account the fact that highly different organisms may share common biochemical targets that can be inhibited by substances with the same modes of action. Furthermore, biocontrol solutions are often partially represented in these classifications, whereas many are registered in France and their use will gradually increase in the coming years. Some of them may face the adaptation of targeted pests, which justifies their inclusion in this nomenclature of PPPs. The unified classification of PPPs presented in this document takes these characteristics into account and assigns one single code to the modes of action registered against plant pathogens, pests (insects and mites) and / or weeds. It includes:

● A unified classification valid for all PPPs, showing the correlation between the R4P, RACs and WSSA group codes. ● A comprehensive list of fungicides, insecticides-acaricides and herbicides classified according to their modes of action, including their general uses, their dates of registration in France, and the resistance cases reported in France and globally ● A classification of active substances affecting the toxicity of PPPs. In these documents, active ingredients are classified according to their general mode of action, i.e. their ability to affect the following vital processes or structures:

● A – Mitochondrial respiration and energy supply ● B – Photosynthesis (chloroplasts) ● C – Carbohydrate metabolism (oses, osides or polyols) ● D – Lipid metabolism (acetogenins and derivatives) ● E – Sterol metabolism ● F – Biosynthesis of amino-acids or proteins ● G – Biosynthesis of nucleic acids or of their precursors ● H - Biosynthesis of pigments ● I – Biosynthesis of coenzymes ● K – Cell division (mitotic spindle) and cytoskeleton ● L – Hormonal regulation ● M – Cellular signalling ● N – Nervous system or muscles of arthropods ● O – Cell membrane integrity.

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In most cases, the toxicity of a PPP results from its interaction with an enzyme or a non-enzymatic protein, which is its primary target site. In some cases, for the same target site, it is possible to distinguish several classes of inhibitors, according to the interaction modalities. Resistance to PPPs often results from qualitative (and, more rarely, quantitative) changes in their target sites (i.e., target-site-based resistance). These alterations often, but not always, cause positive cross-resistance to all substances with the same primary target descriptor (R4P code, second digit), regardless of the substance chemical class. The classification of PPPs can help establishing anti-target-site-based-resistance strategies based on a rational use of the various modes of action.

However, in the case of non-target site resistance, the cross-resistance spectrum can include several different modes of action or only concern some, but not all, substances within the same mode of action group. This requires specific studies to issue recommendations adapted to each specific situation.

The PPPs distributed within the S, W and Y classes are little or not concerned by resistance phenomena. They are :

● S – Inducers of host plant response or SDP (mostly against micro-organisms) ● W – Multi-site inhibitors (interacting in a non-specific manner, in particular with - SH or -NH2 groups of respiratory enzymes, in various pests) ● Y - Microbial biopesticides.

Class X (unknown biochemical mode of action; XF: Fungicides, XA: Acaricides, XI: Insecticides, XH: Herbicides) includes old or new active substances whose mode of biochemical action remains unknown. The NC class includes unclassified novel active substances.

Finally, class Z includes compounds affecting the toxicity of PPPs (ZP: safeners and ZS: synergists). They are not concerned by resistance but can indirectly contribute to its selection by promoting the effectiveness of PPP active substances. They are therefore presented separately from the previous active substances.

Besides their classification in groups by biochemical modes of action, PPPs have been classified into subgroups according to their chemical structure. A deliberately simplified name for chemical structures was chosen. A breakdown by chemical class is proposed. When deemed necessary, a secondary subdivision per chemical subclass is also provided.

Depending on the available information on evolved resistance (in particular cross-resistance spectra), a descriptor of chemical structure is sometimes proposed within certain classes of action modes. Note that for multi-site inhibitors (Class W) and active ingredients with unknown modes of action (Class X), classification is based solely on the chemical structure of the active ingredients, pending elucidation of its mode of action.

All PPPs, whatever their target (weed, pest or fungi) are thus grouped in one single, homogeneous classification, primarily according to their biochemical action mode of action, and secondarily according to their chemical class. This last indication can be useful for reasoning cross resistances within the same mode of action. To avoid confusion of this new nomenclature with existing ones, the letter "U" (for “Universal” nomenclature) is added in front of all codes. This is exemplified below.

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In this example, the code A1b corresponds to inhibitors of mitochondrial respiration and energy supply (A) which bind to the mitochondrial complex I (ubiquinone binding zone essentially involving the PSST subunit) (1), represented chemically by rings containing two nitrogens (b). These active ingredients can be fungicides (code FRAC C1 / 39) or insecticides (code IRAC 21A).

Acknowledgments: R4P warmly thanks Pierre Leroux, Christian Gauvrit, Jean-Philippe Guillemin, Bruno Chauvel, Laurent Thibault, Hélène Tombette and Véronique Mironet for their invaluable help in the design and development of this classification and the research of the characteristics associated with active substances.

As errors or gaps in these summaries may persist, readers are strongly encouraged to report them at [email protected].

Sources :

- FRAC classification : http://www.frac.info/ - IRAC classification : http://www.irac-online.org/ - HRAC classification : http://www.hracglobal.com/ - WSSA classification : http://wssa.net/ - E-Phy database : https://ephy.anses.fr/ - Index phytosanitaire ACTA 2017, Ed. ACTA : http://acta-publications.com/index-phytosanitaire- acta-2017.html - The Compendium of Common Names: http://www.alanwood.net/pesticides/index.html - MatPhyto Database : http://matphyto.acta-informatique.fr/Accueil - Compendium of Common Names: http://www.alanwood.net/pesticides/index.html - The Pesticide Manual 17th Edition, Ed. British Production Council : https://www.bcpc.org/product/bcpc-online-pesticide-manual-latest-version

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Table legends

Unified classification of PPPs:

- Columns “Abbreviations”, “Chemical classes”. - : no particular abbreviation is used for this group of inhibitors.

Classifications according to PPP category (fungicides, herbicides, insecticides-acaricides):

- Columns “Abbreviations”, “Chemical classes”. - : no known element. - Columns « Codes ». - : no known code because no active ingredients with this mode of action are known for this class of PPPs; NC : unclassified ; U or UN : unknown mode of action. . - Column « Use ». + : yes ; (+) : limited use ; - : no ; Columns « Use/Others ». A : acaricide ; B : bactericides ; F : ; G : turf ; I : insecticide ; H : ; M : medical fungicide ; N : nematicide ; R : plant growth regulator ; X : algae or moss killers ; - : none. - For fungicides only: Column « Use ». E : take-all ; F : head-blight ; H : helminthosporiums ; O : powdery mildews ; P : rice blast ; R : rhizoctonia. - Column « Registration in France ». - : no ; + : yes. - Column « Registration year in France ». First date of registration of the molecule in France, whatever the use, the crop and the target pest. - Column « Date of first use ». First year of use of the active ingredient in France, whatever the use, the crop and the targeted pest. This date may regularly differ from the previous one for regulatory reasons or crop timing. - Column « Removal date ». Last year of withdrawal of the active ingredient, whatever the use, the crop and the target pest (final withdrawal from the market). - Column “Resistance in France”. - : No resistance reported in France; + : at least one resistance case reported in France. - Column “Resistance outside of France”. - : no resistance reported in a country other than France,; + : at least one resistance case reported in a country other than France. - “Resistance Mechanism” columns: For each mode of action, the numbers indicate the associated resistance mechanism, as described in the diagram and table below. Category of mechanism not detected for this mode of action, in France or in the world. - “Positive cross-resistance" columns. For each mode of action for which resistance has been described, this column indicates the resistance spectrum generally observable with other modes of action (mentioned by their code). Some exceptions may occur for specific active ingredients within a mode of action. If several resistance mechanisms are observed, their respective resistance spectra are separated by /. - “Negative cross-resistance" columns. For each mode of action for which resistance has been described, this column indicates the modes of action for which increased sensitivity was observed. If several resistance mechanisms are observed, their respective resistance spectra are separated by /. - “Unknown resistance mechanism" columns. The number 13 indicates that a resistance has been validated in at least one organism but that the mechanism is not characterized, whether or not it is linked to the target.

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Resistance mechanisms towards pesticides

- Adapted from: R4P. (2016) "Trends and Challenges in Pesticide Resistance Detection." Trends in Plant Science 21(10): 834-853.

1 Behavioral resistance 2 Physical barrier 3 Increased efflux / Altered translocation 4 Intracellular sequestration 5 Molecular sequestration 6 Detoxification : enhanced activity 7 Detoxification : overexpression 8 Target overexpression 9 Target modification 10 Compensation 11 Protection against cytotoxic effects 12 Other mechanism (including reduced absorption or reduced activation) 13 Mechanism not elucidated

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Abbreviations (inhibitors and others)

A – Mitochondrial respiration and energy supply NDHI: NADH dehydrogenase inhibitor (Complex I) METI (IRAC): Mitochondrial complex I electron transport inhibitor SDHI: Complex II or succinate dehydrogenase inhibitor QiI: Quinone inside inhibitor of complex III – site of quinone reduction within cytochrome b QoI-D: Quinone outside inhibitor of complex III – site of quinol oxidation within cytochrome b, in the heme bl distal domain QoSI (FRAC): Quinone outside inhibitor of complex III – site of quinol oxidation within cytochrome b, binding site of stigmatellin inhibitor → synonymous to QoI-D QoI-P: Quinone outside inhibitor of complex III – site of quinol oxidation within cytochrome b, in the heme bl proximal domain QoI (FRAC): synonymous to QoI-P QioI: Quinone inside and outside inhibitor of complex III site of quinone reduction and quinol oxidation within cytochrome b QxI: Quinone inhibitor of complex III – binding site to cytochrome b unknown (x) COXI: cytochrome c oxidase inhibitor ATPSI: Adenosine triphosphate synthase inhibitor OPUC: Oxidative phosphorylation uncoupler

B – Photosynthesis (chloroplasts)

C – Carbohydrate metabolism (oses, osides and polyols) CAA (FRAC): Carboxylic acid amide CESI: Cellulose synthase inhibitor CHSI: Chitin synthase inhibitor DOPSI: 1-deoxy-D-xylulose-5-phosphate synthase inhibitor THAI: Trehalase inhibitor

D – Lipid metabolism (acetogenins and derivatives) ACCase: Acetyl CoA carboxylase ACCI: Acetyl CoA carboxylase inhibitor FOP: Herbicides ACCI – phenoxypropionates. Ex: dichlofop-methyl DEN: Herbicides ACCI - pyrazolinones. Ex: pinoxaden DIM: Herbicides ACCI - cyclohexanedione-oximes. Ex: alloxydim LCEI: Lipid chain elongation inhibitor MTFI: Methyl transferase inhibitor (fungicides preventing phospholipid biosynthesis) SPIRO: Acaricides or insecticides ACCI. Ex : spirodiclofen VLCFAI (HRAC): Very long chain fatty acids inhibitor (syn. LCEI)

E – Sterol metabolism SBI: Sterol biosynthesis inhibitor SBI-SE: Sterol biosynthesis inhibitor of squalene epoxidase Sterol biosynthesis inhibitor

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SBI-DM: Sterol biosynthesis inhibitor of 14α-demethylase DMI (FRAC): synonymous to SBI-DM SBI-IR: Sterol biosynthesis inhibitor of Δ8→Δ7 isomerase and/or Δ14 reductase SBI-KR: Sterol biosynthesis inhibitor of 3-ketoreductase OSBP: Oxydo-sterol binding protein

F – Biosynthesis of amino-acids or proteins EPSPSI: 5-enolpyruvyl-shikimate-3-phosphate synthase inhibitor AHASI: Acetohydroxy acid synthase inhibitor ALSI: Acetolactate synthase inhibitor GSI: Glutamine synthase inhibitor ASI: Asparagine synthase inhibitor IGPDI: glycerol phosphate dehydratase inhibitor AP (FRAC): Anilinopyrimidine

G – Biosynthesis of nucleic acids and of their precursors ADAI: Adenosine deaminase inhibitor DNAGI: DNA gyrase inhibitor RNAPI: RNA polymerase inhibitor PA (FRAC): Phenylamide

H - Biosynthesis of pigments PDSI: Phytoene desaturase inhibitor LCI: Lycopene cyclase inhibitor PPOI: Protophorphyrinogen IX oxidase inhibitor MBI-D: Melanin biosynthesis inhibitor – dehydratase MBI-P: Melanin biosynthesis inhibitor – polyketide synthase MBI-R: Melanin biosynthesis inhibitor – reductase

I – Biosynthesis of coenzymes TTAI: Tyrosine transaminase inhibitor HPPDI: 4-hydroxyphenyl-pyruvate-dioxygenase inhibitor DHPSI: Dihydropteroate synthase inhibitor

K – Cell divisions (mitotic spindles) and cytoskeleton MBC (FRAC): Methyl benzimidazole carbamate (syn. benzimidazoles and precursors)

L – Hormonal regulation KOI: Kaurene oxidase inhibitor

M – Cell signalling AH: Aromatic hydrocarbon AZN (FRAC) : Azanaphthalene

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PP (FRAC) : Phenylpyrrole

N – Nervous and sensory system or muscles of arthropods GABA: Gamma aminobutyric acid GABA-Cl: GABA-gated chloride channel Glu-Cl: Glutamate-gated chloride channel ACHEI: Acetylcholinesterase inhibitor OP: Organophosphorous coumpounds nAChR: Nicotinic acetylcholine receptor TRPV: Transient receptor potential vanilloid

O – Cell membrane integrity

S – Induction of host plant defences BTH: Benzothiadiazole SDP: Stimulant of plant defences

W – Multi-site activity MSI: Multisite inhibitor

X – Unknown biochemical mode of action

NC – Unclassified PPPs

Y - Microbial biopesticides

Z - Compounds affecting the toxicity of PPPs

Mode d'action biochimique Classes chimiques Code RAC Usage

Code Substances actives Fonctions R4P Cibles ou sites ou biochimiques et principales secondaires Cible Code structures

mécanismes d'action Date homologation Maladies Adventices majeures inhibiteurs Homologation en France Date retrait homologation Abréviations des Insectes/Acariens pipéronyl-butoxide - - + - + 1984 - ZS1 - Synergistes Benzodioxoles - sesamex ZS1a NC - - + - - - - inhibiteurs de - sulfoxide - - + - - - - monooxygénases à P450 Dicarboximides - ENT 8184 ZS1b NC - - + - - - - Diméthoxybenzènes - MB599=verbutin ZS1c NC - + + + - - - ZS2 - Synergistes - Phosphorotrithioates tribufos=DEF ZS2 NC - - + - - - - inhibiteurs d'estérases Organo-phosphorés ZS3 - Synergistes inhibiteurs de glutathion- - Alkyl maléates - DEM ZS3 NC - - + - - - - S-transférases

ZS4 - Synergistes de mode Alkyléther halogénés - S421 ZS4 NC - - + - - - - d'action et cible inconnus

bénoxacor + 1990 - dichlormide - 2000 2013 furilazole - - - Dichloroéthanones - ZP1 NC NC - - + AD67 - - - R29148 - - - TI35 - - - cyométrinil - - - ZP1-ZP6 - Oximes - fluxofénime ZP2 NC NC - - + - - - Phytoprotecteurs ou oxabétrinil - - - safeners, entrainant cloquintocet-mexyl + 1994 - généralement une isoxadifène-éthyl + 2004 - détoxification accrue des Carboxylates - ZP3 NC NC - - + fenchlorazole - - - herbicides par les plantes cultivées méfenpyr-diéthyl + 2000 cyprosulfamide NC NC - - + - - - Z : Composés affectant la toxicité des PPP Benzamides ZP4 Carboxamides metcamifène - - + - - - - fenclorime ZP5 NC NC - - + - - - - cumyluron - - - ZP6 Benzyl-urées (Voir U- Z 17 - - + XH10) 2/10/2018 ZP1-ZP6 - Phytoprotecteurs ou safeners, entrainant généralement une détoxification accrue des herbicides par les plantes cultivées Z : Composés affectant la toxicité des PPP

ZP6 Benzyl-urées (Voir U- Z 17 - - + daimuron - - - XH10)

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