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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
20
• 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
25
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
28
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
29
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
31
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
c
a
bcbc
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
bc
c
bc
a
d
ab
bcd
abc
abc
cd
abc
a
0
2
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
36
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