Application for approval of Grizly® Max

Melanie Gengos Regulatory Affairs Manager

Andrew Horsfield General Manager – Technical & Development

Chris Lee-Steere Director – Australian Environment Agency

19 July 2016

Agenda

2

• Adama overview

• Product development

• Grizly® Max

• Registration submission

• Efficacy summary

• Refined Grizly ® Max risk assessment

Adama overview

Adama – Global Overview

More than 4,500

employees

4,500120 active ingredients

120US $3.2 billion annual

revenue 2015

US$3.2

More than 50 Subsidiaries

across the globe

50The world leading manufacturer

and distributor of branded off-

patent crop protection products

No. 1The seventh largest

agrochemical company

in the world

7

4

5

1940/50Agan Chemical Manufacturers founded in 1945

Makhteshim Chemical Works founded in 1952

1970’sChemistry andtechnology

1980’sBuilt regulatory capabilities

Expanded global presence

1990’sExpansion in key European countries and Latin America

Merged Makhteshim and Agan in 1997, with a public listing in 1998

2000’sBroadened product portfolio through acquisitions

Expanded market access: Latin America, Europe, US, APAC

Entered the Non-Crop market segments

Established Agronica 2004

TodayCreating a new future and business model

Merger with

Market oriented business

Differentiation and Innovation

A true global brand

Adama New Zealand

Dedicated staff

10 209

NZ registrations

83

6

Years staff experience

in NZ agriculture &

horticulture

23Unique actives &

formulations under

development in NZ

Adama NZ Geographical Coverage

• Head Office/Customer Service: Nelson

• Commercial Team

• Warehousing: Wellington & Christchurch

• Devanning & Toll packing: Wellington

• Development Manager: Manawatu

• Regulatory Support: Sydney, AUS

7

Our portfolio spread

56%

19%

22%

1%2%

Sales by product group

37.1%

41.4%

18.0%

3.5%

Insecticides

Fungicides Herbicides

Non Agro

Europe

Americas

Asia

Pacific

Africa

Israel

Regional spread

Seed dressing

8

Development and

registration center

Chemical R&D centre

Switzerland

Germany

Israel

Brazil

Colombia

US

India

Israel India

Global development & registration network

9

7 development and

registration hubs

72 chemistry

R&D centres

2Local registration capabilities

in over 100 countries

100

China

July 18, 2016

Product Development

Crop protection in New Zealand

11

• Crop protection products are vital to farmers, safeguarding crop yields, securing food supply and contributing to New Zealand’s valuable export industry

~NZ$285 M agchem sales at wholesale level, with exports generating >NZ$35 B1

Supports >68,000 businesses and employment of >115,000 people in New Zealand

across broader agricultural industry2

Without crop protection products, nearly 50% of New Zealand’s harvest would be

lost to insect pests, weeds and diseases3

1Agcarm New Zealand, 20142Statistics New Zealand, February 20153Oerke et. al., Crop Production and Crop Protection, Elsevier, Amsterdam, 1994

Adama Product Development

12

• Our goal – develop solutions for farmers to maintain/improve productivity

• Our products need to meet regulatory and trade requirements

• Broad development objectives include:

Strong and reliable efficacy

Cost-effective and provide a return on investment for growers

Safe to the user and the environment

Resistance management

Replacement of active ingredients under regulatory pressure

Product Development Process in Adama

13

• All Adama products are tested according to OECD guidelines, satisfying

ACVM, NZ EPA & other leading regulator requirements

• Products can be in development & testing phase for 3-8 years before

registration submission:

Chemistry – a.i., formulation development, production & packaging

Biology – laboratory & field research

Human Health

Environmental Fate

Ecotoxicity

Efficacy and Residues

• Registration submissions can take 2+ years for regulatory authority evaluation

Grizly® Max

What is Grizly® Max?

15

• A unique insecticide co-formulation

• Contains175 g/L imidacloprid, 30 g/L novaluron and 20 g/L bifenthrin

• Key attributes

Three modes of action: Group 4A (neonic) + 15 (benzoylurea) + 3A (synthetic pyrethroid)

Strong activity on thrips, aphids and tomato potato psyllid (TPP)

Provides growers with a new option for resistance management

• Suspension Concentrate formulation

Are there new active ingredients in Grizly® Max?

16

• NO – all 3 active ingredients are already approved for use in New Zealand

Active

ingredient

Registration

year in NZ

No.

brandsRegistered crops

Maximum use

rate/ha/yr

Grizly Max

proposed rate

Imidacloprid 1992 26

Arable crops, pastures,

vegetables, grapevines,

animal health

2400 g 2 × 158 g

Novaluron 2005 1 Pipfruit 2 × 150 g 2 × 27 g

Bifenthrin 1995 4Vegetables,

ornamentals, kiwifruit 100 g 2 × 18 g

Grizly® Max

Registration Submission

Background on Grizly® Max registration application

18

•Formulation development – existing active ingredients

2010

•Overseas efficacy & residue studies commence

•Chemistry & toxicology studies commence

2011

•Overseas efficacy & residue studies finalised

•Chemistry & toxicology studies finalised

•Provisional registration granted NZ – local efficacy & residue trials commence

2012/13

•Local NZ efficacy & residue trials finalised

•Submission preparation commences

2014

•Application submitted to ACVM (February) & EPA (March)

•Public consultation – submissions received

2016

•Public Hearing 19 July 2016

•Consideration and decision

2009

Proposed Use Pattern

19

Crop Pest Rates Critical Comments

Potatoes Aphid 600 mL/ha Apply at first appearance.

If required, apply a second application of GRIZLY® MAX after a minimum spray interval of

7 days. Apply in 400-600L/ha of water and ensure good coverage of all foliage. Addition of

a suitable non-ionic wetting agent at label rates is recommended.

Tomato

Potato

Psyllid

600 – 900 mL/ha

Note: DO NOT

exceed 900 mL

GRIZLY® MAX per

hectare per spray.

Apply up to two applications of GRIZLY® MAX with a minimum spray interval of 7 days as

part of a season-long psyllid spray programme. Apply in 400-600L/ha of water and ensure

good coverage of all foliage. Addition of a suitable non-ionic wetting agent at label rates is

recommended.

Use the higher application rate under high Tomato Potato Psyllid pressure where

significant yield losses are likely to occur from feeding or disease transmission.

Onions Onion

Thrips

900 mL/ha Apply up to two applications of GRIZLY® MAX once thresholds have been reached.

Applications should be made with a minimum spray interval of 7 days as part of a

programme. Apply in 500-600L/ha water and ensure good coverage of all foliage.

Addition of a suitable non-ionic wetting agent at label rates is recommended.

Comments from EPA and submitters

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• EPA identified chronic risk to soil organisms (i.e. predatory mite & collembola)

Revised use pattern & solutions to address this risk

• EPA & NBA identified potential risk to pollinators of onion seed crops

Accept label restriction for use on crops for seed production

• NBA concerns for bees foraging in treated areas

Accept 10 day no-spray window prior to flowering

• Potential synergistic effects of the three actives raised by NBA & Ngāi Tahu

EPA compared toxicity of individual actives & formulation no evidence

• Ngāi Tahu highlighted several issues including potential risks to taonga/native species & access to ‘key [commercially sensitive] data’

Accept 12 m no-spray zone for protection of aquatic environments for highest use rate

High soil disturbance EPA stated native earthworm species unlikely to be present

EPA proposed controls “use unlikely to breach the principles of the Treaty of Waitangi”

Industry Support for Grizly® Max

21July 18, 2016

Grizly® Max

Efficacy Summary

Andrew Horsfield General Manager – Technical and Development Adama ANZ

23

Grizly Max : Efficacy Overview

• Developed by Adama (Makhteshim Chemical Works)

• Used in vegetable crops overseas, i.e. tomatoes; for >7 years

• Patented insecticidal mixture (NZ patent 605538)

• Key features:

Wide pest spectrum

Knockdown + residual activity

Short PHI

IPM option

Resistance management

Reduces need for tank mixes/more simplicity for farmers

Less burden of non-active ingredients on the environment

24

Grizly Max : Efficacy Overview

• Proposed uses for Grizly Max in New Zealand:

Potatoes – control of TPP (tomato/potato psyllid – Bactericera cockerelli) & aphids

Onions – control of onion thrips (Thrips tabaci)

• Evaluated over three seasons in NZ by independent trial contractors

• Strong performance on target pests

• Significant yield and quality improvements in potatoes

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Grizly Max : Tomato/potato psyllid

• TPP are the major insect pest of potatoes in NZ

• Ngāi Tahu confirmed TPP as a serious threat (APP201955)

• Damage crops and reduce profitability for growers via: Nymph/adults secreting toxins during feeding, causing “psyllid yellows” symptoms

Stunting crops and reducing marketable tuber yield

Transmitting bacterial disease Candidatus Liberibacter solanacearum

Bacteria reduces tuber marketability due to “zebra chip” disorder

• Insecticides the main tool for managing TPP

• Spray programmes target multiple life stages of psyllids

• Limited systemic options for TPP control limited/banning older MOA’s

26

Tomato/potato psyllid : Life stages and crop damage

Adults, eggs and nymphs Clockwise from top left: Psyllid yellows, tuber discolouration, zebra chip

symptoms on potato chips and fries

Photo credits: A.Shreiber & A. Hensen: S.I. Rondon

27

Why are there three active ingredients in Grizly® Max?

• There are a range of reasons for combining active ingredients (AI):

Improve efficacy on a specific pest

Reduce the effective dose required of each AI

Broaden the spectrum i.e. control a suite of pests

Manage/reduce selection for insecticide resistance

Convenience of single application

• Grizly® Max has been developed to deliver these benefits for

farmers

• More effective due to additive effects of three active ingredients

• Tank mixing already common practice in many crops

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Grizly® Max : Comparison of activity × TPP life stage

Product Active IngredientTPP life stage

Eggs Nymphs Adults

Grizly® Max

Imidacloprid

Novaluron

Bifenthrin

Movento Spirotetramat

Karate Zeon Lambda-cyhalothrin

ProteusThiacloprid

Deltamethrin

Sparta Spinetoram

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Grizly® Max : Mode of action × active ingredientImidacloprid

• Registered in NZ on sucking pests in horticultural crops

Thrips in onions – 315 g ai/ha/crop (4 × 78 g ai/ha)

Aphids in brassicas – 126 g ai/100L

Aphids in lettuce – 420 g ai/100L

Mealybug in grapes – >2000 g/ha

• Systemic with anti-feeding activity (key for managing zebra chip)

• Less residual via foliar applications

• Extensively used for TPP control in US, particularly mixtures with SP’s

• Maximum dose per ha equivalent to existing rate in onions

30

ab a

bc cd

d

b

b

abb

a

0

2

4

6

8

10

Untreated Karate Zeon 50 g ai/ha 100 g ai/ha 150 g ai/ha

Rimon 100 SC

Psyllid yellows rating (0-10) Yield score (0-10)

Grizly® Max : Mode of action × active ingredientNovaluron

• MOA is a chitin synthesis inhibitor

• Chitin a component of insect cuticle

• Interrupts moulting & development

• Slow acting

• Activity on eggs, larvae/nymphs

• Favourable IPM profile

• More effective in mixtures

• Max rate in GM much lower than solo

Evaluation of Rimon (novaluron 100 SC) in potatoesHawkes Bay 2010

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Grizly® Max : Mode of action × active ingredientBifenthrin

0

50

100

150

200

250

300

350

400

450

0 1 2 4 6TP

P n

ymp

hs

pe

r p

lan

t (±

SEM

)

Weeks after application

Bifenthrin 8 g ai/100L Untreated Spinetoram 2.5 g ai/100L

Bioassay on TPP on capsicumsWeir et al (NZPPS 2011)• Synthetic pyrethroid

• Non-systemic activity

• Highly active on TPP & thrips

• Low dose applied in Grizly Max

• Knockdown adults & nymphs

• Good residual activity

• Used in mixtures with systemics

• Max rate in GM much lower than

solo use rate

32

• Screening trials conducted in 2011/12

• Three formulations compared

CMT 101 (“Grizly®”) – imidacloprid 175 g/L + novaluron 30 g/L SC

CMT 105 (“Galil”) – imidacloprid 250 g/L + bifenthrin 50 g/L SC

Grizly® Max

• Tested on TPP and onion thrips

• Compared dose responses at similar imidacloprid doses

• Registration trials conducted in 2012 to 2014

Grizly® Max : NZ Trial Results

33

Grizly® Max : Industry Screening Trial, TPP in PotatoesAgrivet, Hawkes Bay 2011/12

a

cc c

c

b

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a

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bcbc bc

bc

a

bcd cdcd

bcd

b

cd

0

50

100

150

200

250

300

350

400

Untreated Benevia Bifenthrin 50b Bifenthrin 72b CMT 101105i+18n

CMT 105105i+21b

Grizly Max105i+18n+12b

TPP

nym

ph

s p

er

25

leav

es

(7D

AA

3)

Small (1-3 instar) Large (4-5 instar) Total (1-5 instar)

34

Grizly® Max : Effect on Zebra chip symptoms in potatoesHawkes Bay 2013

Untreated Grizly Max

35

Grizly® Max : Potato tuber yield × grade from TPP controlAgrivet, Hawkes Bay 2012/13

c

b

c

bc

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bc

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d

ab

bcd

abc

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0

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4

6

8

10

12

14

Untreated MoventoOD

Proteus Sparta Avid 300 mL 600 mL 1200 mL

Grizly Max

Tu

be

r yie

ld (

t/h

a)

Table size Seed size Under size

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Grizly® Max : Onion thrips

• Onion thrips are a major pest of onions in NZ

• Key quarantine pest for export markets

• Insecticides the main tool for managing thrips

• Current options include:

Imidacloprid (solo), Proteus (thiacloprid + deltamethrin)

Fipronil i.e. Regent

Spinetoram i.e. Sparta

• Insecticide resistance an issue, limited modes of action available

37

Grizly Max : Onion thrip controlPeracto NZ, 2012/13

a

c

a

ab

a

bc

cabab b

a

abb b

0

5

10

15

20

25

30

Untreated Pyrinex Proteus Kohinor 450 mL 900 mL 1800 mL

Grizly Max

On

ion

th

rip

ad

ult

s p

er

pla

nt

(6D

AA

2)

Pukekohe Hawkes Bay

38

Efficacy summary

• Grizly® Max is a highly effective new insecticide for NZ farming

• Controls key pests and improves yield and quality

• Reduces the need for high rates of individual products

• Patented & complementary combination of active ingredients

• Easy to use, simple solution for farmers

Grizly® Max

Refined Risk Assessment

Chris Lee-Steere Director – Australian Environment Agency

0

50

100

150

200

250

300

350

Effe

ctiv

e ap

plic

atio

n r

ate,

g a

c/h

a

Effective application rates, imidacloprid to onions

Grizly Max, 2 sprays,7 day intervalGrizly Max, 14 dinterval, 2 spraysImidacloprid, onion, 4sprays, 7 day interval

Imidacloprid in onions – Grizly Max and current situation in New Zealand

Grizly MaxKohinor

Confidor

Single application rate 900 225 mL product/ha

Single application rate 158 78.8 g ac/ha

Soil half-life (NZ EPA) 90.5 90.5 days

Spray interval 7 14 7 days

Number of

sprays 2 2 4

Multiple application

factor (MAF) 1.947 1.898 3.698

Effective total

rate 307 299 291 g ac/ha

PECsoil, 5 cm, no

interception 0.41 0.40 0.39

The difference in maximum application rates and worst case predicted soil concentrations between Grizly Max and currently registered imidacloprid use pattern in onions is 2.6-5.3%.

Refinement of PECsoil – consideration of soil depth

• EPA assessed for top 5 cm only;• It is suggested that 10 cm could be applied and be justified as follows:

The risk is identified for chronic exposure, not acute; For soils under conventional and reduced tillage, it is defensible to assume that the soil is

perfectly mixed up to 20 cm depth periodically in long-term calculations (EFSA, 2010); Imidacloprid is a relatively mobile chemical; Long term field studies in Europe with sampling to 50 cm showed:

Relatively clear that residues remained in the top 10 cm; There was movement into the 10-20 cm layer which indicates restriction to the

top 5 cm may be conservative; Other international methodology allow for consideration of residues in the top 10 cm

in the initial assessment where substances are not strongly bound (SCEW, 2009).

Refinement of PECsoil – Consideration of crop interception

• EFSA (2014) applies the following crop interception factors:

Crop BBCH Growth stage Cover Interception

Potatoes

0-9 No interception 0

10-19 Minimal 0.15

20-39 Intermediate 0.5

40-89 Full 0.7

Onions

(assessed as

Vegetables,

bulb crops)

0-9 No interception 0

10-19 Minimal 0.1

20-39 Intermediate 0.25

40-89 Full 0.4

• EPA calculated risk based on earthworm chronic NOEC >0.562 mg/kg soil;• For “risk” to be acceptable, a toxicity exposure ratio (TER) must exceed a value of 5;• This TER has an assessment factor of 5 applied to the PNEC value (toxicity value = PNEC X 5);• While the EPA assessment reported additional toxicity results for soil organisms (Folsomia candida;

Hyapoaspis aculeifer), these results were not considered in the risk assessment;• Reducing the assessment factor based on increased toxicity data is a valid approach to refining risk

assessments;• A recent proposal in Europe was to use the lower limit HC5 without assessment factors (ECHA,

2015);• Soil toxicity data are available for earthworms, collembolan and predatory mite;• While there are insufficient data to determine an HC5, the availability of chronic data from three

standard soil organism tests does reduce interspecies uncertainty so a reduction in the assessment factor can be argued;

• A more detailed assessment of a chronic NOEC for imidacloprid to earthworms can be made using the Confidor toxicity data reported in the European DAR, where dose response curves could be generated;

Refinement of PNECsoil

Test substance Organism NOEC/EC10reproduction

(mg ac/kg soil)

Imidacloprid active

constituent

Earthworm ≥0.562

Collembola 1.25

Predatory mite ≥2.67

Confidor Earthworm EC10 = 0.57

FS200 Earthworm EC10 = 0.40

Concentration, mg/kg soil1 10 100

%re

du

ctio

n,

rep

rod

uctio

n

0

10

20

30

40

50

60

70

80

90

100

Concentration, mg/kg soil1 10 100

%re

du

ctio

n,

rep

rod

uctio

n

-10

10

30

50

70

90

Refinement of PNECsoil

Conclusions:• Earthworms appear the most sensitive of the soil organisms tested;• There are several results with relatively good agreement;• A lower assessment factor could be considered;• The following equations apply an assessment factor of 2 (TER ≥2)

considered acceptable;• EARTHWORM GEOMEAN EC10 = 0.48 mg/kg soil is applied

FS600 formula;EC10 = 0.4 mg/kg soil

Confidor formula;EC10 = 0.57 mg/kg soil

Revised Toxicity Exposure ratios, top 10 cm, 2 X applications 7 days apart

This indicates if refinement arguments are accepted, the risk to soil organisms should be considered acceptable. Imidacloprid is already registered for use in onions at essentially the same rate so risks from imidacloprid in Grizly Max should represent no greater environmental risk than from other registered products containing this active for this use pattern.

A final thought with respect to imidacloprid exposure to soil organisms in New Zealand

Imidacloprid is currently registered in New Zealand for the following crop uses:

• Onions at a total effective rate of 291 g ac/ha; This use pattern will see crop interception and actual soil exposure will be much lower;

• Grapevines at a rate of 1.5 mL product (350 g/L imidacloprid) per tree; This is for a soil applied treatment and there will be no interception.

How do these rates compare? • In New Zealand, vineyard can have row spacing of 1.5-2.5 m. • Tree spacing can range from 0.9 to 2.0 m. • The potential range in vines per hectare is 2000-7400. The resulting application rate range for

imidacloprid direct to the soil in this case is ~1000 to 3900 g ac/ha;• The predicted soil concentration (top 10 cm) is 0.67 mg/kg to 2.6 mg/kg;• These are 3.7 to 17 times greater than the highest soil PEC for onions and 11 to 43 times higher than

the lowest soil PEC for potatoes!

The potential for risk to bees

The EPA assessment concluded:• Bees may be exposed to Grizly Max when they forage on crop pollen or nectar; BUT

Potatoes do not produce nectar, only pollen; and Onions will be harvested prior to bloom.

In addition, potatoes are not an attractive crop for honey bees (EFSA, 2013 – slightly attractive for bumble bees);

The EPA established the following controls:• No spraying after 10 days pre-flowering;• No spraying on plants in flower if they are likely to be visited by bees or other pollinators;• No spraying during daylight hours where bees are actively foraging and pollinating.

The Beekeepers Association interpreted the last point to mean night spraying only. This interpretation is not correct as spraying can occur when bees are not foraging.

The first two controls will essentially ensure bees are unlikely to be foraging and the following label statements are therefore proposed:

• DO NOT apply within 10 days of flowering commencing;• DO NOT apply when bees are actively foraging in and around the treatment area.

48