“Evaluación de productos fitosanitarios: de la sustancia activa al … · “Evaluación de...
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“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/