10-12 April 2019: The OECD Conference on RNAi based pesticides provided an overview on the current status and future possibilities for the regulation of externally applied dsRNA-based products that are proposed for use as pesticides. The event facilitated exchanges between policy makers, academia, industry on their implications in health, environment, and regulation.

1. The European perspective on regulatory
aspects and experiences with dsRNA-
based products
Achim Gathmann
Federal Office of Consumer Protection and Food Safety (BVL)

2. Outline
• Experiences in the EU
• Principles in the authorisation process of Plant Production
Products (PPP) in the EU
• What’s new? - Challenges for the
current risk assessment system of PPP
• Preliminary remark
– Perspective of the BVL
– Information is not based on survey or any other
coordinated position
– Focus is on environmental consideration
18.04.2019 2Achim Gathmann, BVL
Jagtap et al. 2011 Science
of Nature 98(6):473-92

3. Experiences in the EU
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• No dsRNA-based plant protection product is authorised in the EU
yet
• Some experiences with GMO using RNAi silencing mechanisms in
the EU
– e.g. MON87411 and carnation, but only application for import
and processing
– Therefore environmental risk assessment does not include the
full environmental risk assessment

4. Experiences in the EU
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• EFSA (GMO unit)
– organised Workshop in June 2014 (EFSA 2014, EN-705)
– Initiated a literature review (Christiaens et al. 2018, EN-1424)
– Topic on the EFSA conference Science Food Society in 2018
• My impression: ds-based RNA PPP are not really on the agenda of
many EU MS member states
• Some MSs start to address the topic e.g. NL (Techreport COGEM
2016 & 2018) or DE actively participate on the current OECD
activity
Experiences are very limited in the EU!

5. Outline
• Experiences in the EU
• Principles in the authorisation process of Plant Production
Products (PPP) in the EU
• What’s new? - Challenges for the
current risk assessment system of PPP
18.04.2019 5Achim Gathmann, BVL
Jagtap et al. 2011 Science
of Nature 98(6):473-92

6. Steps placing plant protection products
on the market
Active substances (a.s.):
Assessed on EU level
Approval for at least 10 years
Benalaxyl
Fluazinam,
Fenamidone
,
…
Product
containing one or more a.s.:
Company submits application including
a risk assessment for national (or zonal) authorization
Authorization
for specific
intended use
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Photo: „Folienserie“ BVLU

7. • Approval of a.s. in the EU under lead of EU COM
• Risk assessment a.s.: EFSA and member states (MS)
(EFSA = European Food Safety Authority)
• a.s. fulfilling following cut-off criteria are not approvable:
 Endocrine disruptors
 Mutagens
 Cancerogens
 Toxic for reproduction
 Substances with high potential for persistence, bioaccumulation and toxicity
EU-approval of active substances (a.s.)
according to regulation (EC) N0 1107/2009
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8. • Risk management and authorisation of PPP take place on national level
• Zonal cooperation: reporting member state (zRMS) assesses the application for
all MS of one of the three zones
• MS are bound on these authorisation
• MS can consider national specificities and decide
on specific risk management options
Zonal authorisation of plant protection
products according regulation EC 1107/2009
North: Denmark, Estonia, Finland, Latvia, Lithuania, Sweden
Central: Belgium, Germany, Ireland, Luxembourg, Nether
Austria, Poland, Rumania, Slovakia, Slovenia, Czech Republic,
Hungry, UK
South: Bulgaria, France, Greece, Italy, Malta, Portugal, Spain,
Cyprus
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Graphic: „Folienserie“ BVL

9. • Product chemistry
• Chemical identity
• Physical and chemical properties
• Analytical methods
• Efficacy and application
• Health
• Toxicology
• Residues in food an feed
• Maximum residues levels
• Exposure of applicants and bystander
• Environment
• Fate
• Ecotoxicology
Areas of concern
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10. • Regulation EC 1107/2009
• Data requirements are provided in law in Regulation
(EC) No 283/2013 and 284/2013 data requirements for
the approval of active substances and the authorisation
of plant protection products
• Regulation (EU) 546/2011 implementing Regulation (EC)
No 1107/2009 of the European Parliament and of the
Council as regards uniform principles for evaluation and
authorisation of plant protection products
• Noted test protocols are described in different OECD GD
and EFSA GD
• Defined set of test parameters and endpoints!
Legal framework defining
data requirements
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Photo: „Folienserie“ BVL

11. Quantitative risk assessment
= TER ≥ target value
LC50 /EC50 / NOEC
PEC
The higher the TER, the lower the risk
• According to legal authorisation criteria, the TER must at least achieve a
target value which depends on
– Organism group (e.g. aquatic organisms, birds etc.)
– Toxicity value from acute or longer-term tests
The toxicity value relevant for assessment is considered in relation to the
expected exposure (Toxicity-Exposure-Ratio, TER)
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12. • Terrestrial arthropods
• Bees
• Aphidius rhopalosiphi
• Typhlodromus pyri
Fixed set of NTO test organisms :
Example terrestrial non-vertebrates
• Soil organisms
• Earthworm
• Folsomia candida
• Hypoaspis aculeifer
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13. Legal classification
• dsRNA-base products has to be considered as any other plant
protection product at the moment
• Therefore the whole data package is needed for authorisation as
active substance and later on for plant protection products.
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14. Article 77 (EC/1107/2009)
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Guidance documents
The Commission may, in accordance with the advisory procedure
referred to in Article 79(2), adopt or amend technical and other
guidance documents such as explanatory notes or guidance
documents on the content of the application concerning micro-
organisms, pheromones and biological products, for the
implementation of this Regulation. The Commission may ask the
Authority to prepare or to contribute to such guidance documents.

15. Adopted requirements for
according Article 77
• Microorganisms
– Guidance Document for the assessment of the equivalence of technical grade active
ingredients for identical microbial strains or isolates approved under regulation (EC) no
1107/2009 (SANCO/12823/2012 –rev. 4,12 December 2014)
• Pheromones/Straight Chain Lepidopteran Pheromones (SCLPs)
– Guidance Document on semiochemical active substances and plant protection products
(SANTE/12815/2014 rev. 5.2 May 2016)
– Guidance Document on the assessment of new substances falling into the group of Straight
Chain Lepidopteran Pheromones (SCLPs) included in Annex I of Council Directive 91/414/EEC
(SANCO/5272/2009 rev. 3 28 October 20101)
• Plant extracts/Botanicals
– Guidance document on botanical active substances used in plant protection products
(SANCO/11470/2012– rev. 8 20 March 2014)
• However for dsRNA-based products such guidance documents are not
available
• There is no initiative on preparation of such GD at the moment
Reference for documents: ttps://ec.europa.eu/food/plant/pesticides/approval_active_substances/guidance_documents_en
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16. Outline
• Experiences in the EU
• Principles in the authorisation process of Plant Production
Products (PPP) in the EU
• What’s new? - Challenges for the
current risk assessment system of PPP
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Jagtap et al. 2011 Science
of Nature 98(6):473-92

17. Why ds-RNA-based products
might be useful?
– New mode of action – high value for resistance management
– Potential for environmentally safe products
• High specificity – minor effects on NTO
• Low stability in the environment – low environmental load in
soil, surface and ground water
• Low risk for vertebrates due to existing physiological barriers
But it might depend on the formulation of the product
But some data gaps must be filled
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18. Lessons learned from GMO
• History of save use of RNAi silencing
– Many GMOs using the gene silencing mechanism like
• blue carnation,
• not browning apples
• `Flavr Savr’ tomato
• compositionally-modified soybeans and alfalfa (Lucerne),
• virus-resistant papaya, squash, plums, potatoes and beans
• bruise-resistant potatoes
Target is the metabolism of the plant (but none of them are
authorised in the EU for cultivation)
• New products with target outside of the plant
– MON87411 (construct DvSnf7; assessed for import and
processing)
– Sprayable PPP
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19. Differences an d similarities between
GMO and ds-RNA based PPP
–
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GMOs dsRNA-based PPP
NTOs by feeding of plant
material or debris
by feeding of sprayed
plant material, direct or
other exposure routes
Time of exposure continuously limited
Application of ds-RNA in tissue formulated product
Degradation balance between
degradation and
production in plant
rapid degradation in
the environment
strongly dependent on
formulation
Construct identical
Mode of action same
Specificity identical

20. Challenges – adoption of risk assessment
methods
• Methods in risk assessment may need adoption
– Are models used in risk assessment appropriate to model
exposure in soil, surface and ground water?
– Adaption of ecotoxicological testing schemes?
– Do we need additional information to support risk assessment
e.g. bioinformatics?
• Risk management
– Mechanisms of resistance evolution
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Photo: „Folienserie“ BVLScreen copy Pelmo

21. Challenges - formulation
• For efficient application RNAi must be protected from
degradation (RNAse, UV light)
– Possibly new approaches for stabilising RNAi
• Improving RNAi efficiency
– delivery/uptake of intact RNAi into cells
• Methods in discussion
– Polymeric nanoparticles e.g. chitosan (Zhang et al. 2010)
– Liposomes (Whyard et al. 2009)
– Chemical modifications e.g. adding methylgroups on specific parts
of the RNAi
– ds-RNA plus the biomass debris and spent fermentation medium
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22. Challenges – procedural issues
• Product chemistry
– Does each difference in sequence lead to a new active
substance?
– Sequence differences, but matches to the same binding site?
– Criteria for identification of the product?
– No experience about purity: Have all ds-RNAs in a product the
same sequence?
– How much variability in RNA sequence is acceptable in a
product?
– If microbial production system will be used (GMO)
– Inactivation of microorganisms might be guaranteed
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23. Summary
– New product class with new mode of action and possibly lower
environmental harm
– Risk assessment of PPP is established but might need
regulatory and methodological adoptions
– Limited experiences with this new class of products
– Data gaps need to be filled
– Some unknowns such as formulation strategies
– Some procedural aspects need to be clarified
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24. Contact:
Thank you for your attention!
Dr. Achim Gathmann
Federal Office for Consumer Protection and
Food Safety
achim.gathmann@bvl.bund.de
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