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Herbicide Registration – What’s the Process?
Fred Fishel
Professor, UF Agronomy
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Objectives
• Pesticide registration process in general
• Aquatic herbicide registration
– New active ingredient
– Existing active ingredient for aquatic use
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Who decides if a pesticide is acceptable to go to market?
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What does a manufacturer have to consider before developing a new active ingredient?
• Is it biologically active?
• Is it a new mode of action?
• Is the tox profile acceptable?
• Can it be patented?
• Will cost of production be reasonable?
• Can it be registered in other countries?
• Will use restrictions be acceptable to customers?
• Will it control multiple pests on multiple crops?
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What does a manufacturer have to consider before developing a new active ingredient?
• Will it be efficacious and reliable?
• Will it be safe to crops?
• Can it be competitively priced?
• Will it be easy to handle?
• Will it offer significant advantages over competing products?
• What are the projected returns?
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The product to meet tomorrow’s demands must offer…
• Better efficacy
• Compatibility with current pest management practices
• Nonleaching tendencies
• Less persistence in the environment
• Reduced residues in food
• Lower risks to workers and bystanders
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Synthesis in
a test tube
Patent review
Chemical research
Toxicology screening
Market research
Secondary screening
Advanced toxicology
The decision to
commercialize
Field development &
product performance,
Laboratory & field testing
Registration
package
compiled
Applicant submits data
package to EPA (about
150 various tests)
EPA product manager
reviews with their
technical support group
Start
Commercial label
accepted
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Many molecules don’t make it past initial greenhouse screening
• Activity observed during initial screening is not present in greenhouse studies
• Control is limited to a very narrow range of pests or a poor pest spectrum
• Phytotoxicity occurs in the crop species• Control rates are too high; the product would not be
economically viable• Low water solubility or other undesirable chemical
characteristics make the product difficult for applicators to use
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The decision to commercialize• What will the customer pay for the product? • What kind of short- and long-term market share can we expect
from the product? • How much sales revenue will the product generate? • What will be our expenses, including promotion, advertisement,
and demonstrations? • What will be the dose rates by country, crop, and pest? • What quantity of active ingredient will be needed? • Are there unique manufacturing problems associated with the
product? • What will be the cost per unit to manufacture the product? • How much will the manufacturing plant cost to build and
maintain? • What will it cost to develop the molecule globally?
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Testing Requirements for Registration
Efficacy:• High degree of biological
efficacy• Broad spectrum of efficacy• Good plant compatibility• Low risk for resistance
development
User friendly:• Low acute and chronic toxicity• Good formulation qualities• Easy to handle• Low application rate• Good storage stability
Environmental profile:• Low toxicity to non-target
organisms• Sufficient degradation in soil• Low leaching• No significant residues in food
and animal feed
Economy:• Favorable cost/benefit ratio• Competitiveness• Broad spectrum of uses• Patentability
The Innovative
Product
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What Does it Cost to Get a Pesticide Labeled?
• The cost is now estimated at $250M
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New product development cost
Percentage of total cost
Chemistry 22.3
Biology 23.9
Tox/environmental chemistry
23.4
Developmental chemistry 10.8
Field trials 13.6
Registration 6.0Source: The cost of new agrochemical product discovery, development, and registration in 1995 and 2000. Phillips-McDougall. 2003.
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Who Pays the Cost to Get a Pesticide Labeled?
• The cost is on the manufacturer’s shoulders
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What are the odds of a chemical ever reaching the marketplace as a pesticide?
?????A Purdue University publication states that 1 in 140,000 tested chemicals will ever reach the market as a registered pesticide
WOW!!!
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Registering a new aquatic use herbicide - two possible approaches
• Development and EPA registration of new active ingredient for aquatic use
• Addition of aquatic use to existing herbicide product
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Goal
• Register at least one product in as many MOA’s as possible for resistance management
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Currently…..
• Endothall, copper, diquat, 2,4-D – 1950s
• Glyphosate – 1978
• Fluridone – 1985
• Imazapyr – 1999
• Triclopyr – 2002
• Carfentrazone – 2004
• Penoxsulam – 2007
• Imazamox – 2008
• Flumioxazin – 2010
• Bispyribac – 2011
• Topramezone - 2013
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Currently…..
• Full EPA aquatic registration: Section 3
• 1979-1998: One
• 1999-2013: Eight
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Currently…..
Herbicide Mode of action Herbicide Mode of action
EndothallNot classified
Imazamox
ALS inhibitorCopper Penoxsulam
Diquat PS I Bispyribac
2,4-DSynthetic auxin
Imazapyr
Triclopyr FlumioxazinPPO inhibitor
Fluridone PDS inhibitor Carfentrazone
Glyphosate EPSP inhibitor Topramezone 4-HPPD inhibitor
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0
20
40
60
80
100
120
140
160
1955 1965 1975 1985 1995 2005 2015
Nu
mb
er
of
Spe
cies
Year
ACCase Inhibitors (A) ALS Inhibitors (B) EPSP Synthase Inhibitors (G)
Synthetic Auxins (O) PSI Electron Diverter (D) Microtubule Inhibitors (K1)
HPPD Inhibitors (F2) PSII Inhibitors (C1,C2,C5)
B
C1
A
G
O
F2
K1
D22
Number of Resistant Species for Several Herbicide Sites of Action (HRAC Codes)
Dr. Ian Heap, WeedScience.org 2015
Note: PSII Inibitors Combined
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Herbicide Resistance
• Terrestrial/cropland weeds
• So many…
• Aquatics
• A handful – so far
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New aquatic herbicides
• Only labeled if:
When applied according to label instructions, will perform its intended function without unreasonable adverse effects on human health or the environment
• FIFRA still requires continuing re-registration
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Development and registration process for new active ingredient for aquatic use
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Development and registration process for new active ingredient for aquatic use
• Three big areas of concern for EPA:
– Mammalian toxicology
– Ecotoxicology
– Environmental fate
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Development and registration process for new active ingredient for aquatic use
• Toxicology- active ingredient mammalian toxicity
– Acute tox
– Chronic tox
– Mutagenicity
– Reproductive and developmental
– Oncogenicity
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Development and registration process for new active ingredient for aquatic use
• Toxicity to wildlife and aquatic organisms
– Avian acute oral (Bobwhite quail and/or mallard duck)
– Avian dietary
– Avian reproduction
– Freshwater/marine fish acute (rainbow trout, sunfish)
– Freshwater/marine invertebrate acute (Daphnia, shrimp)
– Freshwater/marine fish and invertebrate repro and life cycle
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Development and registration process for new active ingredient for aquatic use
• Environmental Fate
– Hydrolysis
– Volatility
– Photolysis in water
– Aerobic/anaerobic soil metabolism
– Leaching, Adsorption/Desorption
– Field dissipation - soil and water
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Development and registration process for new active ingredient for aquatic use
• Plant protection– Seed germination
– Seedling emergence
– Vegetation vigor
– Aquatic plant growth
• Non-target plants - endangered species concerns
• Potential injury to irrigated crops or other vegetation
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Aquatic herbicide screening• Experimental Use Permit
Hydrilla: EC90Pickerelweed: EC50Ornamentals: EC10
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The Development of Sonar
• 1974-75: Discovery
• 1975-82: Environmental fate studies
• 1975-78: C14 nature in plants
• 1975-77: Acute toxicology
• 1975-76: Subchronic toxicology
• 1976-83: Efficacy and use patterns for aquatics
• 1976-81: C14 soil metabolism studies
• 1976-81: Chronic toxicity/oncogenicity studies
• 1977-83: Residue studies in plants and irrigated crops
• 1978-79: C14 animal metabolism studies
• 1978-85: Residue studies in fish, livestock, poultry, milk, and eggs
• 1978-81: Avian, aquatic, and nontarget organism toxicity
• 1978-80: Reproduction/teratology studies
• 1979-80: Residue in potable water and mutagenicity studies
EUP granted in 1980 and fully registered in 1985!
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Addition of aquatic use to existing herbicide product label
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Aquatic products supported by crop use…
• Triclopyr– Noncrop, pasture/range, forestry, turf, rice
• Carfentrazone– Corn, soybean, cotton, sugarcane, sunflower, fruit,
vegetables, tobacco• Penoxsulam
– Rice, turf, tree nut, grapes• Flumioxazin
– Corn, soybean, cotton, peanut, fruit, vegetables, forestry• Bispyribac
– Rice, turf• Topramezone
– Turf, corn, ornamentals, noncrop
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Why so few aquatic herbicides???
• New active ingredient development and registration is a long term investment of resources
• Justification for developing an aquatic use herbicide often depends on additional (crop) uses and global utility
• Herbicidal activity especially for submersed species can not be predicted by activity on emergent or terrestrial species
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Why so few aquatic herbicides???
• Tox package must be exceptionally clean due to increased human exposure through drinking water
• Ecotox profile must be safe due to higher expected concentrations in the water resulting from direct application to water
• Difficult to achieve desired level of aquatic plant control while maintaining acceptable non-target plant selectivity
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Why so few aquatic herbicides???• Herbicide candidates
– 325 registered herbicides
– 28 families
– 100 too toxic in aquatic systems, residual
– 130 not effective
– 50 ALS inhibitors
– 15-20 possibilities
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Summary
• The modern cost of developing new herbicide active ingredients is prohibitive and require large market potentials to be justified
• Adding aquatic uses to an existing herbicide is more easily justified, but is often not a company priority
• Heightened concerns for environmental and human health effects from aquatic use products makes finding new products that can meet these requirements extremely difficult
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