“Evaluación de productos fitosanitarios: de la sustancia activa al uso autorizado”

Cristina Adalid Coordinadora del Grupo de Estrategia Reglamentaria de AEPLA

40ª Jornadas de Productos Fitosanitarios IQS, 6 de Noviembre de 2019

Requerimientos actuales para un producto fitosanitario

Eficacia probadaSelectivo – tolerado por el cultivo y respetuoso con los organismosbeneficiososPropiedades toxicológicas adecuadasRápida degradación pero con la persistencia y acción necesariasDe fácil manejo. Seguro. Con valor añadido para productoresy usuarios.

Plazos para el desarrollo de un nuevo producto

El camino para la selección y desarrollo de una nueva sustancia activa conlleva:

– Seleccionar y discriminar entre numerosas moléculas potenciales– Dar respuesta a más de 800 requerimientos diferentes mediante la realización de los ensayos

oportunos– Anticipar requerimientos futuros y diseñar los ensayos de forma acorde

100140,000 20,000 1,000-2,000 1 a.i.Prescreening Microtest Field trialGreenhouse

Tiempos 9 – 10 años

Significant Cost Increase to Launch a single A.I.

Source: PMD R&D study 2016 (survey result of 14 AgChem companies, including BCS, SYN, BASF, Dow, DuPont, Monsanto, Amvac, ISK, Belchim, Nufarm )

Incremento de costes para llevar una sustancia activa al mercado

El coste de la innovación se ha incrementado en los últimos años. Los riesgos se incrementan por los tiempos de registro cada vez más largos.

Source: PMD R&D study 2016

Longer Discovery & Development Timelines

Gestion de Proyectos – Implementación

5

Launch

Registration Granted

-1 Year 0-2-3-5-6-7 -4-8-10 -9

Feasibility & GAP refinement trials

Dossier Submission

Registration & residues trials

Opportunity Finding trials

Phase 1

OpportiunityIdentification

Phase 2 Phase 3

APROVEDGAP

Registration Granted

Phase 1 Phase 2 Phase 3

Registrable GAP Approved GAP Dossier GAP Submitted

GAPRegistered

GAPLABELS

-1 Year 0-2-3-5-6-7 -4-8-10 -9Opportunity Identification

Proceso de definición de GAP

140,000

Desarrollo de un producto fitosanitario

7

costs per active

incredient

300 million euros

Years 1 2 3 4 5 6 7 8 9 10

Active Ingredient

Chemistry

Formulation

Research

Biology

Development

Degradation& residues

Toxicology

Ecotoxicology

Small-plot trials

Registration

Kilo lab scale

Process development

Synthesis

Production

Process development

Development

Field trials (worldwide)

Plant, animal, soil, water, air

Algae, daphnia, fish, birds,microorganisms, bees, beneficials

Acute and chronic toxicity, carcinogenicity, mutagenicity, teratogenicity, reproduction

ScreeningLaboratory/greenhouse

Source: Industrieverband Agrar

Evaluación de los productos fitosanitarios

Antes de permitir su utilización en los cultivos, Autoridades independientesevalúan la seguridad de los fitosanitarios.

Áreas de Evaluación:AnalíticaFitoterapéuticaEcotoxicología y Medio ambienteToxicología humanaSeguridad del aplicadorResiduos

Expertos evalúan según principios uniformes para dar una autorización.Todos los estudios se realizan de acuerdo con estándares científicosinternacionales, conocidos como Buenas Prácticas de Laboratorio (BPL/GLP),que garantizan la calidad, integridad y trazabilidad de los datos.

Legislación aplicable

Díptico legislativo: 66 normas

Junto con los medicamentos, los fitosanitarios son los productos más regulados del mundo.

Comisión Europea – Documentos Guía

https://ec.europa.eu/food/plant/pesticides/approval_active_substances/guidance_documents_en

https://ec.europa.eu/food/plant/pesticides/authorisation_of_ppp/application_procedure_en

2020 2021 2022Posible Entry into

force DateComment

Mandate 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12Standing Committee Dates 19-20 15-16 10-11 9-10 11-12 26-27 20 28-29 13-14 8-9 10-11 28-29 7-8 18-19 11-12 6-7 6-7 23-24 22-23 17-18 19-20 5-6 12-13 25-26 22 24-25 19-20 23-24 12-13 24-25 21-22 11 20-21 16-17 21-22 5-6

Guidance and Scientific OpinionsHuman Health

Scientific Opinion on pesticides in food for infants and young children M-2015-0243 28Systematic literature review on the adverse outcome pathway (AOPS) involved in Parkinson's disease and childhood leukaemia M-2014-0161 14

vestigation into experimental toxicological properties of plant protection products having a potential link to Parkinson’s disease and childhood leukaemia M-2014-0161 16 follow-up of the findings of the External Scientific Report 'Literature review of epidemiological studies linking exposure to pesticides and health effects' M-2014-0162 31

Guidance on the assessment of exposure of operators, workers, residents and bystanders in risk assessment for plant protection products M-2011-0309 23 29 1 24 The risk assessment on residents and bystanders cannot Review of the published non-dietary exposure data to pesticides for residents and bystanders and for environmental risk assessment M-2015-0189 4

Revision of the OPEX Guidance Document M-2017-0216 PC Sept. 2022?Guidance Document on Residue definition to be used for dietary risk assessment M-2013-0350 22 ? Not noted yet in SCoPAFF

EFSA scientific report on the assessment of the quality and scientific relevance of dermal absorption studies submitted to EFSA M-2015-0027 12Guidance Document on Dermal Absorption M-2015-0027 30

Applicability of in silico tools for the prediction of dermal absorption for pesticides 16External Scientific report on exposure assessment for pesticides on acute effects on the nervous system M-2014-0247 31

Reports on CAGs for specific effects on the nervous system, the liver, the eyes, the adrenals, the reproduction and the development M-2013-0171 ?External Scientific report on exposure assessment for pesticides on chronic effects on the thyroid M-2014-0247 31

Cumulative Assessment Groups and Cumulative Risk Assessments for the effects of pesticides on the thyroid and the nervous system M-2014-0247 31Cumulative Exposure Assessments with SAS for 2 acute effects on the nervous system and 2 chronic effects on the thyroid system M-2014-0247

Technical report: Assessment of endocrine disrupting properties in EFSA conclusions on pesticides M-2012-0276 21 6Guidance for the implementation of the hazard based criteria to identify endocrine disruptors M-2016-0234 7 To be revised when experience is gained

R Panel for developing Integrated Approaches to Testing and Assessment (IATA) case studies on Developmental Neurotoxicity (DNT) risk assessment M-2015-0264 JuneEnvironment

Guidance on tiered RA for aquatic organisms in edge-of-field surface waters M-2009-0001 5 15Scientific Opinion of the PPR Panel on the effect assessment for pesticides on sediment organisms in edge-of-field surface waters M-2009-0001 16

n the state of Toxicokinetic/Toxicodynamic and Simple Food Chain effect modelling for regulatory risk assessment of pesticides for aquatic organisms M-2009-0001 1 Likely expansion to other areas than PPPsFOCUS surface water repair action M-2016-0124 ?

edicting environmental concentrations of active substances of plant protection products and transformation products of these active substances in soil M-2012-0252 28 29 19 April 2015 for annual crops Link / end 2017 for permanen Development of software models for predicting environmental concentrations of plant protection products in soil M-2012-0252 12 31 Tools are available now. Info session in June 2019 for sta

fic Opinion about the CRD Guidance on how aged sorption studies for pesticides should be conducted, analysed and used in regulatory assessments M-2017-0152 13 27 and transformation products of these AS from protected crops (greenhouses and crops grown under cover) to relevant environmental compartments M-2012-0252 13 26-27 1

ation studies to obtain DegT50 values of active substances of plant protection products and transformation products of these active substances in soil M-2012-0252 8 11-12 1Scientific Opinion and Guidance document on In soil risk assessment M-2009-0002 PC ?

EFSA Guidance Document on the Risk Assessment of Plant Protection Products on Bees M-2011-0185 4 Partial ? 31-12-19 Partial implementation e suitability of the BEEHAVE model for its potential use in a regulatory context and for the RA on multiple stressors in honeybees at the landscape level M-2014-0331 25 3

Revision of the EFSA Bee Guidance Document M-2019-100 PC

Scientific Opinion and Guidance Document on Non-target terrestrial plants M-2009-0002 21 PC ? 2022?

Scientific Opinion and Guidance Document on Non-Target Arthropods M-2009-0002 12 PC ? 2022?

tive effects) observed in studies with amphibians and reptiles in view of population level impacts on amphibians and reptiles. OC/EFSA/PRAS/2015/01 M-2009-0002 19Scientific Opinion and Guidance Document on Amphibians and reptiles M-2009-0002 23 PC ? 2022?

Revision of the EFSA Guidance document on risk assessment for birds and mammals from plant protection products M-2016-0124 PC ? 2021?Data collection for the estimation of ecological data and residues level and decline of AS to be used in RA for birds and mammals M-2016-0124 20

Scientific Statement on the coverage of bats by the current pesticide risk assessment for birds and mammals ?

ment for active substances of plant protection products that have isomers and for transformation products of active substances that may have isomers M-2016-0124 ?Guidances or Opinions from EFSA Scientific Comittee

Guidance Document to define protection goals for environmental risk assessment in relation to biodiversity and ecosystem services M-2013-0098 16Scientific Opinion on Addressing temporal/spatial recovery of non-target organisms in environmental risk assessment M-2013-0098 3

Scientific Opinion on Coverage of endangered species as non-target organisms in environmental risk assessment M-2013-0098 3

Guidance Document on Uncertainty Analysis in Scientific Assessment M-2013-0261 20 24Guidance on the use of the Weight of Evidence Approach in Scientific Assessments M-2015-0007 3

Guidance for the identification of biological relevance of adverse positive health effects from experimental & human studies M-2014-0294 30 pulation dynamics of aquatic and terrestrial organisms using Dynamic Energy Budget Models: application to the risk assessment of chemical mixtures M-2014-0235 31

External literature review of nonmonotonic dose-responses of substances for human risk assessment M-2013-0206 3xTox: Harmonisation of risk assessment methodologies for human health and ecological risk assessment of combined exposure to multiple chemicals M-2016-0095 25

Scientific guidance on appraising and integrating evidence from epidemiological studies for use in EFSA’s scientific assessments M-2019-0073 cience behind the development of an integrated holistic approach for the risk assessment of multiple stressors in managed honey bees (Apis mellifera) M-2018-0155 Dec.

Guidance on the human and animal risk assessment of the application of nanoscience and nanotechnologies in agro/food/feed M-2016-0082 4 Health GD in 2018, ENVI to be developed in 2019Guidance on the use of the TTC approach in food safety M-2017-0103 6

Possible Future MandateMedRice?

Aneugenicity? M-2019-0091Transition metals ?

Cumulative Risk Assessment for non dietary exposure? M-2015-0204

Key

Mandate sent XX EFSA Reports/Statements/othersInternal By EFSA XX EFSA Scientific OpinionSelf task By Chair of Panel XX Guidance DocumentsExternal By EC

Opinion or Report DevelopmentGuidance Document DevelopmentDiscussion at SCoPAFFEntry into force

2017

Publication by EFSA

2014

Adoption by SCoPAFF

2018

PC

Publication by EFSA

Public consultation

Public consultation

Public consultation

Public consultationPublic consultationPublic consultation

Internal testing phase within EFSA

20192016

Protection Goals definition by Risk Managers

Public consultation

Protection Goals definition by RM

2015

PC

Public consultationPublic consultation

Reports

PCPC

Public Consultation

Public consultation

Protection Goals definition by Risk Managers

Protection Goals definition by Risk Managers

Protection Goals definition by Risk Managers

Public consultation

PC on ToRs

Protection Goals definition by Risk Managers

EFSA scientific Guidances – Opinions – Reports

Guías de Evaluación de la EFSA

FOCUS Surface Water Repair actionDelayed to end 2019

In soil organisms GuidanceBee Guidance and its revision

Non-Target Plants GuidanceNon-Target Arthropods GuidanceAmphibians & Reptiles Guidance

EFSA Statement on bats publishedIsomer Guidance published

Bird & Mammals Guidance revision

EFSA – MEDIO AMBIENTE

Framework for conducting ENVI exposure and RA for transition metals

Outcome of the Pesticides Peer Review Meeting on general recurring issues in ecotoxicology

Protection Goal Definition: DG SANTE conducted workshops with MS (June) and stakeholders (September) to present the methodology on how to derive Specific Protection Goals (based on Ecosystem Services Approach). Real discussions per topic will start in Q1 2020

OPEX Guidance Revision Public consultation on a new draft in 2020

Scientific Reports on CAGS Consultations launched (nervous system (acute) + thyroid (chronic)) mid September

Opinion on IATA cases (DNT)

Residue Definition GD not noted and without implementation date

EFSA – SALUD HUMANA

Guidance on testing and interpretation of comparative

inter-species in-vitro metabolism

Legislación que establece los requisitos para un producto fitosanitario en Europa

https://eur-lex.europa.eu/legal-content/EN/ALL/?uri=CELEX%3A32013R0284

Dossier Europeo

› Un producto tóxico es una sustancia que causa un efecto adversocuando se administra a un organismo vivo

› Se estudia la toxicologia:

- aguda

- crónica

- subcrónica

Área de Toxicología

Estudios de toxicología

Toxicological Screening

● DEREK evaluation

● Acute oral rat screen

● Genotoxicity screens

● Rat: subacute (28d)

● Embryotoxicity screen

● Family-specific screens

Small amount of test substance, rapid results,select development candidate

Toxicological Development

● Rat: 90d + oncogenicity (2y)

● Developmental toxicity rat + rabbit

● Mouse: 28d + 90d + oncogenicity

● Acute toxicity (oral, dermal, inhalation;eye / skin irritation; skin sensitization, phototox)

● Genotoxicity battery

● Dog: 28d + 90d + 1y

● Reproductive toxicity rat

● Other: neurotoxicity, immuno-toxicity, mechanistic studies, etc.

Identify hazardintrinsic toxic properties:

classification and labelling (EU)

Perform human risk assessment“Take appropriate

NOAEL, apply safety factor,

calculate AOEL, ADI, ARfD”

AOELADI ARfD

● Endocrine screen

- Good laboratory practice (GLP)- OECD test guidelines- EU data requirement: Commission Regulation 283/2013(Regulation 1107/2009 of EU Parliament and Council)

Fuente: Bayer

- Farmacodinámica

- Farmacocinética (PK)-> ADME – absorption, distribution, metabolism and excretion

- Toxicología aguda, crónica y subrónica

› Valores de referencia :

ADI – Acceptable Daily Intake - NOAEL (Life-time) / 100 = ADIARfD – Acute Reference Dose - NOAEL (short-term) / 100 = ARfDAOEL – Acceptable Operator Exposure Level - NOAEL (mid-term) * oral bioavailability / 100 = AOEL

Valores de exposición Evaluación de riesgo

Estudios de toxicología

Seguridad del producto para el operario y el trabajador

Fuente: Bayer

Seguridad del producto para el residente y transeúnte

Fuente: Bayer

Parámetros de seguridad para el consumidor

Se realiza una evaluación del riesgo para el consumidor para garantizarque la posible exposición crónica y aguda de los consumidores a losresiduos permanezca por debajo de la IDA y de la DARf, respectivamente.

La autorización solo se concede si se ha comprobado que los nivelesmáximos de residuos son seguros basándose en el peor caso posible.

Evaluación Medioambiental – preguntas a contestar

Outline

Air: Does the substance

volatilize from plant and soil surfaces ?

How fast will the substance be degraded in air ?

Water: Is the degradation in water pH-

dependend ? How fast is the substance

degraded in natural water/sediment systems ?

Is the degradation influenced by light (UV) ?

Which degradation productsare formed in water and/or sediment ?

Soil and Groundwater: How fast is the substance

degraded in soil ? Which degradation products are

formed in soils ? Do different soil types influence

the degradation behaviour ? Is the dgradation on soil surface

influenced by sunlight (UV) ?

What is the degradation mechanism (microbial, photolytical, hydrolytical... ) ?

How is the degradation under anaerobic conditions (water-logged soils) ?

Does the substance accumulatein soil ?

Is there any risk for active substance or metabolites to leach into groundwater ?

Se evalúa si el producto fitosanitario es seguro para elmedio ambiente

Fuente: Bayer

Se estudia su comportamiento en el medio ambiente

Fuente: Bayer

Se estudia su transporte en el medio ambiente

Fuente: Bayer

Se realiza una evaluación de riesgos para la fauna y la flora

Fuente: Bayer

Se realizan ensayos para especies acuáticas

Fuente: Bayer

Se realizan ensayos para especies terrestres

Fuente: Bayer

Un producto sólo se registra si es

seguro (no tiene efectos

inaceptables)considerando todas las secciones de un

dossier

¿Cómo llevamos un producto al mercado? Producto formulado

Evaluación a nivel zonalSustancia activa

Evaluación a nivel europeo

Registro de un formulado –evaluación zonal

Nuevo formulado – art. 33

Reconocimiento mutuo – art. 40

Proceso segun guia SANCO - guidance document on “zonal evaluation and mutual recognition”

Timelines zonal evaluation and mutual recognition

Utilización de productos fitosanitarios

Los productos fitosanitarios solo se autorizan cuando se ha demostradoque son seguros para la salud humana, animal y del medio ambiente.

Al igual que las medicinas deben utilizarse únicamente cuando seannecesarios y conforme a las indicaciones de la etiqueta (Buenas PrácticasAgrícolas):

- Cultivos- Dosis- Momento y modo de aplicación- Plazo de seguridad- Empleo de Equipos de Protección Individual- Respeto a las medidas de mitigación medioambientales…

Evaluación del Riesgo y Gestión del riesgo: Medidas de mitigación

Evaluación del riesgo Riesgo= Exposición a un determinado peligro

Si la exposición es cero el riesgo es cero.

Las medidas de mitigación del riesgo minimizan la exposición

Leer la etiqueta para saber qué equipo de protección es la más adecuado

Lavar y secar la ropa de protección después del uso y guardarla en un armario cerrado, separadade la ropa de uso personal.

Recuerda hacer el mantenimiento de la ropa de protección y guardarla siguiendo lasinstrucciones del fabricante.

IMPORTANTE: Los guantes de protección disminuyen la exposición en más de un 85% ¡Utilízalossiempre!

Los guantes de protección, las botas y la vestimenta de protección deben ser resistentes aproductos químicos. Los guantes preferiblemente de Neopreno o Nitrilo.

Cuando se indique en la etiqueta, utilizar máscara respiratoria con gafas de protección o lamáscara completa.

Cuatro compromisos fundamentales

Nuestros alimentos son completamente seguros

Aprendamos algo más de los productos fitosanitarios

MUCHAS GRACIAShttp://www.aepla.es/