Herbicide Registration What s the Process? Fred Fishel Professor, UF Agronomy

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1 Herbicide Registration What s the Process? Fred Fishel Professor, UF Agronomy

2 Objectives Pesticide registration process in general Aquatic herbicide registration New active ingredient Existing active ingredient for aquatic use

3 Who decides if a pesticide is acceptable to go to market?

4 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?

5 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?

6 The product to meet tomorrow s Better efficacy demands must offer Compatibility with current pest management practices Nonleaching tendencies Less persistence in the environment Reduced residues in food Lower risks to workers and bystanders

7 Start Synthesis in a test tube Registration package compiled Patent review Chemical research Toxicology screening Market research Field development & product performance, Laboratory & field testing Secondary screening Advanced toxicology The decision to commercialize Applicant submits data package to EPA (about 150 various tests) EPA product manager reviews with their technical support group Commercial label accepted

8 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

9 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?

10 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 The Innovative Product 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

11 What Does it Cost to Get a Pesticide Labeled? The cost is now estimated at $250M

12 New product development cost Chemistry 22.3 Biology 23.9 Tox/environmental chemistry Percentage of total cost 23.4 Developmental chemistry 10.8 Field trials 13.6 Registration 6.0 Source: The cost of new agrochemical product discovery, development, and registration in 1995 and Phillips-McDougall

13 Who Pays the Cost to Get a Pesticide Labeled? The cost is on the manufacturer s shoulders

14 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!!!

15 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

16 Goal Register at least one product in as many MOA s as possible for resistance management

17 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

18 Currently.. Full EPA aquatic registration: Section : One : Eight

19 Currently.. Herbicide Mode of action Herbicide Mode of action Endothall Imazamox Not classified Copper Penoxsulam ALS inhibitor Diquat PS I Bispyribac 2,4-D Imazapyr Synthetic auxin Triclopyr Flumioxazin PPO inhibitor Fluridone PDS inhibitor Carfentrazone Glyphosate EPSP inhibitor Topramezone 4-HPPD inhibitor

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21 Number of Species Number of Resistant Species for Several Herbicide Sites of Action (HRAC Codes) ACCase Inhibitors (A) ALS Inhibitors (B) EPSP Synthase Inhibitors (G) Synthetic Auxins (O) PSI Electron Diverter (D) Microtubule Inhibitors (K1) 160 HPPD Inhibitors (F2) PSII Inhibitors (C1,C2,C5) Note: PSII Inibitors Combined B C A 40 D22 O 20 G K1 0 F Year Dr. Ian Heap, WeedScience.org 2015

22 Herbicide Resistance Terrestrial/cropland weeds So many Aquatics A handful so far

23 Only labeled if: New aquatic herbicides 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

24 Development and registration process for new active ingredient for aquatic use

25 Development and registration process for new active ingredient for aquatic use Three big areas of concern for EPA: Mammalian toxicology Ecotoxicology Environmental fate

26 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

27 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

28 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

29 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

30 Aquatic herbicide screening Experimental Use Permit Hydrilla: EC90 Pickerelweed: EC50 Ornamentals: EC10

31 The Development of Sonar : Discovery : Environmental fate studies : C 14 nature in plants : Acute toxicology : Subchronic toxicology : Efficacy and use patterns for aquatics : C 14 soil metabolism studies : Chronic toxicity/oncogenicity studies : Residue studies in plants and irrigated crops : C 14 animal metabolism studies : Residue studies in fish, livestock, poultry, milk, and eggs : Avian, aquatic, and nontarget organism toxicity : Reproduction/teratology studies : Residue in potable water and mutagenicity studies EUP granted in 1980 and fully registered in 1985!

32 Addition of aquatic use to existing herbicide product label

33 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

34 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

35 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

36 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 possibilities

37 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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