Toelatingsnummer 12602 N

 

Sphere

 

12602 N

 

 

 

 

 

 

 

 

 

HET COLLEGE VOOR DE TOELATING VAN

BESTRIJDINGSMIDDELEN

 

1 UITBREIDING TOELATING

 

Gelet op de aanvraag d.d. 8 oktober 2004 (20040380 UG) van

 

Bayer CropScience B.V.

Energieweg 1

3641 RT MIJDRECHT

 

tot uitbreiding van de gebruiksdoeleinden van de toelating als bedoeld in artikel 2, eerste lid, van de Bestrijdingsmiddelenwet 1962 (Stb. 288) voor het schimmelbestrijdingsmiddel, op basis van de werkzame stoffen cyproconazool en trifloxystrobin

 

Sphere

 

gelet op de artikel 5, zevende lid van de Bestrijdingsmiddelenwet 1962,

 

BESLUIT HET COLLEGE VOOR DE TOELATING VAN BESTRIJDINGSMIDDELEN als volgt:

 

I Uitbreiding

Het gebruiksgebied van het bestrijdingsmiddel Sphere wordt uitgebreid met de toepassing als schimmelbestrijdingsmiddel in de teelt van triticale en suiker- en voederbieten, en in de graszaadteelt van Engels raaigras, veldbeemdgras en roodzwenkgras.

1.      Voor de gronden waarop dit besluit berust wordt verwezen naar bijlage II dezes.

2.      De toelating geldt tot 30 september 2013

 

II Samenstelling, vorm en afwerking

Onverminderd hetgeen omtrent de samenstelling, vorm en afwerking van een bestrijdingsmiddel is bepaald in de Regeling samenstelling bestrijdingsmiddelen, moeten de samenstelling, vorm en fysische toestand van het middel alsmede de chemische en fysische eigenschappen daarvan overeenkomen met de bij de aanvraag tot toelating ingediende gegevens op basis waarvan de toelating is verstrekt.

 

III Gebruik

Het bestrijdingsmiddel mag slechts worden gebruikt met inachtneming van hetgeen in bijlage I dezes onder A. is voorgeschreven.

 


IV Classificatie en etikettering

 

  1. De aanduidingen, welke ingevolge artikel 36 van de Wet milieugevaarlijke stoffen en artikelen 14, 15a, 15b, 15c en 15e van de Nadere regels verpakking en aanduiding milieugevaarlijke stoffen en preparaten op de verpakking moeten worden vermeld, worden hierbij vastgesteld als volgt:

 

Overeenkomstig artikel 15c, lid 1, onder b van de Nadere regels verpakking en aanduiding milieugevaarlijke stoffen en preparaten:

 

-          aard van het preparaat: Suspensie concentraat

 

Overeenkomstig artikel 15e, onder b van de Nadere regels verpakking en aanduiding milieugevaarlijke stoffen en preparaten:

 

- Werkzame stof:

- Gehalte:

 

 

cyproconazool

160 g/l

 

 

trifloxystrobin

375 g/l

 

 

 

Overeenkomstig artikel 14, leden 1, 2 en 3 van de Nadere regels verpakking en aanduiding milieugevaarlijke stoffen en preparaten:

 

-          andere zeer giftige, giftige, bijtende of schadelijke stof(fen):

-

 

  1. Behalve de onder 1. bedoelde en de overige bij de Wet Milieugevaarlijke Stoffen en Nadere regels verpakking en aanduiding milieugevaarlijke stoffen en preparaten voorgeschreven aanduidingen en vermeldingen moeten op de verpakking voorkomen:

 

a.      letterlijk en zonder enige aanvulling:
het wettelijk gebruiksvoorschrift
De tekst van het wettelijk gebruiksvoorschrift is opgenomen in Bijlage I, onder A.

 

b.      hetzij letterlijk, hetzij naar zakelijke inhoud:
de gebruiksaanwijzing
De tekst van de gebruiksaanwijzing is opgenomen in Bijlage I, onder B.
De tekst mag worden aangevuld met technische aanwijzingen voor een goede bestrijding mits deze niet met die tekst in strijd zijn
.

 

c.      overeenkomstig artikel 14, lid 4 tot en met lid 13 van de Nadere regels verpakking en aanduiding milieugevaarlijke stoffen en preparaten, letterlijk en zonder enige aanvulling, tenzij bij de veiligheidsaanbeveling anders is vermeld:

- Gevaarsymbool:

- Aanduiding:

 

 

Xn

Schadelijk

 

 

N

Milieugevaarlijk

 

 

-          Waarschuwingszinnen:

Zeer vergiftig voor in het water levende organismen; kan in het aquatisch milieu op lange termijn schadelijke effecten veroorzaken.

Mogelijk gevaar voor beschadiging van het ongeboren kind.

 

-          Veiligheidsaanbevelingen:

Niet roken tijdens gebruik.

Draag geschikte handschoenen en beschermende kleding.

In geval van inslikken onmiddellijk een arts raadplegen en verpakking of etiket tonen.

Deze stof en de verpakking als gevaarlijk afval afvoeren. (Deze zin hoeft niet te worden vermeld op het etiket indien u deelneemt aan het verpakkingenconvenant, en op het etiket het STORL-vignet voert, en ingevolge dit convenant de toepasselijke zin uit de volgende verwijderingszinnen op het etiket vermeldt:

1)      Deze verpakking is bedrijfsafval, mits deze is schoongespoeld, zoals wettelijk is voorgeschreven.

2)      Deze verpakking is bedrijfsafval, nadat deze volledig is geleegd.

3)      Deze verpakking dient nadat deze volledig is geleegd te worden ingeleverd bij een KCA-depot. Informeer bij uw gemeente.)

Voorkom lozing in het milieu. Vraag om speciale instructies / veiligheidsgegevenskaart.

 

d.      overeenkomstig artikel 14, lid 13 en lid 14 van de Nadere regels verpakking en aanduiding milieugevaarlijke stoffen en preparaten, letterlijk en zonder enige aanvulling:

 

-          Specifieke vermeldingen:

Bevat trifloxystrobin. Kan een allergische reactie veroorzaken.

 

e.      bij het toelatingsnummer een cirkel met daarin de aanduiding W.1.

 

f.        overeenkomstig artikel 15e, onder a van de Nadere regels verpakking en aanduiding milieugevaarlijke stoffen en preparaten, letterlijk en zonder enige aanvulling:

 

'Volg de gebruiksaanwijzing om gevaar voor mens en milieu te voorkomen.'

 

g. n.v.t.

 

h. n.v.t.

 

2 DETAILS VAN DE AANVRAAG

 

2.1 Aanvraag

Het betreft een aanvraag tot wijziging van de samenstelling en uitbreiding van het gebruiksgebied van het middel Sphere (12602 N), een middel op basis van de werkzame stoffencyproconazool en trifloxystrobin. Het middel is bij besluit van 5 november 2004 reeds toegelaten als schimmelbestrijdingsmiddel in de teelt van wintertarwe en zomertarwe. Het middel is bij dit besluit toegelaten tot 30 september 2013. Met onderliggende aanvraag wordt toelating als schimmelbestrijdingsmiddel in de teelt van winter- en zomertarwe, triticale en suiker- en voederbieten, en in de graszaadteelt van Engels raaigras, veldbeemdgras en roodzwenkgras gevraagd.

 

2.2 Informatie met betrekking tot de stof

De werkzame stof trifloxystrobin is op 1 mei 2003 geplaatst op annex 1 van richtlijn 91/414/EEG.

 

De werkzame stof cyproconazool is een bestaande werkzame stof, en is aangemeld voor plaatsing op annex 1 van richtlijn 91/414/EEG. Er is een dar (draft assessment report) voor deze stof beschikbaar (RMS is Ierland).

 

2.3 Karakterisering van het middel

Sphere is een suspensie concentraat op basis van 375 g/l trifloxystrobin en 160 g/l cyproconazool. Het middel wordt ingezet als fungicide en werkt op aanwezige sporen en groeiend mycelium. Trifloxystrobin behoort tot de groep van strobilurinen. Het remt de mitochondrische ademhaling, waardoor de schimmelsporenkieming en de groei van de kiembuis op het bladoppervlak worden geremd. Trifloxystrobin dringt slechts matig door in het blad en wordt nauwelijks in de plant verspreid. Het heeft daardoor voornamelijk een preventieve contactwerking.

Cyproconazool behoort tot de groep van de triazolen. Het heeft een systemische, preventieve en curatieve werking. Het werkingsmechanisme van triazolen valt onder de zogenaamde demythelatie inhibitors of wel DMI-fungiciden.

 

2.4 Voorgeschiedenis

De aanvraag is op 12 oktober 2004 ontvangen; op 15 oktober 2004 zijn de verschuldigde aanvraagkosten ontvangen. Op 3 mei 2005 was de aanvraag inhoudelijk onvolledig en op
16 februari 2006 zijn ontbrekende gegevens geleverd. De aanvraag is op 1 maart 2006 in behandeling genomen. Op 7 maart 2006 werden de verschuldigde beoordelingskosten ontvangen. Op 12 juli 2006 zijn door het College aanvullende gegevens gevraagd; deze zijn geleverd op 6 december 2006.

 

 

3 RISICOBEOORDELINGEN 

 

3.1 Fysische en chemische eigenschappen

De geleverde gegevens geven in voldoende mate de mogelijkheid om op basis daarvan de identiteit van het middel vast te stellen, te specificeren en te karakteriseren. Er is vastgesteld dat de standaardgegevens voor milieu, toxicologische aspecten en risicos met betrekking tot de fysisch-chemische eigenschappen beschikbaar zijn (artikel 3, lid 1, sub d Bmw 1962).

De beoordeling van de evaluatie van het middel en de stof staat beschreven in Bijlage II, Hoofdstuk 2. Physical and chemical properties behorende bij dit besluit.

 

3.2 Analysemethoden

De geleverde analysemethoden voldoen aan de vereisten. De residuanalysemethoden zijn specifiek en gevoelig genoeg om te kunnen worden gebruikt voor het controleren van de betreffende plantaardige en dierlijke producten op het maximaal toegestane gehalte, en het monitoren van de verspreiding van de residuen in het milieu (artikel 3, lid 1, sub b en c Bmw 1962).

De beoordeling van de evaluatie van de analysemethoden staat beschreven in Bijlage II, Hoofdstuk 3. Methods of analysis behorende bij dit besluit.

 

3.3 Humane Toxicologie

Er is vastgesteld dat het middel en zijn omzettingsproducten, wanneer het overeenkomstig het bepaalde bij of krachtens de Bestrijdingsmiddelenwet 1962 wordt gebruikt:

-        de gezondheid niet schaadt of de veiligheid niet in gevaar brengt van degene die het middel toepast, en

-        de gezondheid niet schaadt of de veiligheid niet in gevaar brengt van diegenen, die na toepassing van het middel door verrichten van werkzaamheden daarmee of met de residuen daarvan in aanraking komen (artikel 3, lid 1, sub a, onderdelen 5 en 6 Bmw 1962).

Het profiel humane toxicologie inclusief de beoordeling van het risico voor de toepasser staat beschreven in Bijlage II, Hoofdstuk 4. Mammalian toxicology behorende bij dit besluit.


3.4 Residuen en risico voor de volksgezondheid

Er is vastgesteld dat het middel en zijn omzettingsproducten, wanneer het overeenkomstig het bepaalde bij of krachtens de Bestrijdingsmiddelenwet 1962 wordt gebruikt geen schadelijke uitwerking heeft op de gezondheid van de mens (artikel 3, lid 1, sub a, onderdeel 3 Bmw 1962).

De vastgestelde maximum residuniveaus en de beoordeling van het risico voor de volksgezondheid staan beschreven in Bijlage II, Hoofdstuk 5. Residues behorende bij dit besluit.

 

3.5 Gedrag in bodem, water en lucht

Er is vastgesteld dat het middel en zijn omzettingsproducten, wanneer het overeenkomstig het bepaalde bij of krachtens de Bestrijdingsmiddelenwet 1962 wordt gebruikt

-        geen schadelijke uitwerking heeft op het grondwater en)

-        geen voor het milieu onaanvaardbaar effect heeft, waarbij in het bijzonder rekening wordt gehouden met:

       de plaats waar het bestrijdingsmiddel in het milieu terecht komt en wordt verspreid, met name voor wat betreft besmetting van het water, met inbegrip van drink- en grondwater en belasting van de bodem;

       de gevolgen voor niet doel-soorten

(artikel 3, lid 1, sub a, onderdelen 9 en 10 Bmw 1962).

Het profiel milieu inclusief de beoordeling van het risico voor het milieu staat beschreven in Bijlage II, Hoofdstuk 6. Environmental fate and behaviour behorende bij dit besluit.

 

3.6 Ecotoxicologie

Er is vastgesteld dat het middel en zijn omzettingsproducten, wanneer het overeenkomstig het bepaalde bij of krachtens de Bestrijdingsmiddelenwet 1962 wordt gebruikt

-        geen voor het milieu onaanvaardbaar effect heeft, waarbij in het bijzonder rekening wordt gehouden met:

       de plaats waar het bestrijdingsmiddel in het milieu terecht komt en wordt verspreid, met name voor wat betreft besmetting van het water, met inbegrip van drink- en grondwater en belasting van de bodem;

       de gevolgen voor niet doel-soorten (artikel 3, lid 1, sub a, onderdeel 10 Bmw 1962).

Het profiel ecotoxicologie inclusief de beoordeling van het risico voor niet-doelwit soorten staat beschreven in Bijlage II, Hoofdstuk 7. Ecotoxicology behorende bij dit besluit.

 

3.7 Werkzaamheid

Er is vastgesteld dat het middel en zijn omzettingsproducten, wanneer het overeenkomstig het bepaalde bij of krachtens de Bestrijdingsmiddelenwet 1962 wordt gebruikt:

-        voldoende werkzaam is en

-        geen onaanvaardbare uitwerking heeft op planten of plantaardige producten (artikel 3, lid 1, sub a, onderdelen 1 en 2 Bmw 1962).

De beoordeling van het aspect werkzaamheid staat beschreven in Bijlage II, Hoofddstuk 8. Efficacy behorende bij dit besluit.

 

3.8 Eindconclusie

Bij gebruik volgens het gewijzigde Wettelijk Gebruiksvoorschrift/Gebruiksaanwijzing is de uitbreiding voor de gevraagde doeleinden van het middel Sphere op basis van de werkzame stoffencyproconazool en trifloxystrobin voldoende werkzaam en heeft het geen schadelijke uitwerking op de gezondheid van de mens en het milieu (artikel 3 Bestrijdingsmiddelenwet 1962).

 


 

 

Degene wiens belang rechtstreeks bij dit besluit is betrokken kan gelet op artikel 8 van de Bestrijdingsmiddelenwet 1962 en artikel 7:1, eerste lid, van de Algemene wet bestuursrecht, binnen zes weken na de dag waarop dit besluit bekend is gemaakt een bezwaarschrift indienen bij: het College voor de Toelating van Bestrijdingsmiddelen (Ctb), Postbus 217, 6700 AE WAGENINGEN. Het Ctb heeft niet de mogelijkheid van het elektronisch indienen van een bezwaarschrift opengesteld.

 

 

Wageningen, 27 april 2007

 

 

HET COLLEGE VOOR DE TOELATING VAN BESTRIJDINGSMIDDELEN,





(voorzitter)

 

 



HET COLLEGE VOOR DE TOELATING VAN BESTRIJDINGSMIDDELEN

 

BIJLAGE I bij het besluit d.d. 27 april 2007 tot uitbreiding van de toelating van het middel Sphere, toelatingnummer 12602 N

 

A.

WETTELIJK GEBRUIKSVOORSCHRIFT

 

Toegestaan is uitsluitend het gebruik als schimmelbestrijdingsmiddel door middel van een gewasbehandeling in:

  1. winter- en zomertarwe en triticale;
  2. graszaadteelt van Engels raaigras, veldbeemdgras en roodzwenkgras;
  3. suiker- en voederbieten.

 

 

Om in het water levende organismen te beschermen is de toepassing middels een luchtvaartuig niet toegestaan op percelen die grenzen aan oppervlaktewater.

 

Om resistentieopbouw te voorkomen mag u dit product of andere producten die trifloxystrobin of een andere strobilurine-achtige werkzame stof bevatten niet vaker gebruiken dan 2 maal per teeltseizoen.

 

In verband met residuen in volggewassen mogen na gebruik in de teelt van granen in het hetzelfde teeltseizoen geen snelgroeiende bladgewassen geteeld worden.

 

Behandelde percelen mogen niet tijdens en binnen 45 dagen na toepassing worden beweid of gemaaid ten behoeve van voederdoeleinden

 

Dit middel is uitsluitend bestemd voor beroepsmatig gebruik.

 

Veiligheidstermijnen

De termijn tussen de laatste toepassing en de oogst mag niet korter zijn dan:

45 dagen: voor winter- en zomertarwe en triticale

21 dagen: voor bieten

 

 

B.

GEBRUIKSAANWIJZING

 

Algemeen

Sphere is een fungicide op basis van de werkzame stoffen trifloxystrobin en cyproconazool. Trifloxystrobin behoort tot de groep van de strobilurinen, cyproconazool behoort tot de groep van de triazolen.

 

Resistentiemanagement

Indien nodig Sphere afwisselen met middelen met een ander werkingsmechanisme, die een werking hebben tegen de geclaimde organismen, om resistentie of kruisresistentie tegen te gaan.

 

Volggewassen

Onder snelgroeiende bladgewassen worden verstaan sla-achtigen en spinazie met een korte groeiperiode, zoals geclassificeerd in appendix 2 van RIVM rapport 613340006.

 

 

 

 

Toepassingen

 

Winter- en zomertarwe en triticale, ter voorkoming van aantasting door blad- en aarziekten, veroorzaakt door bruine roest (Puccinia recondita), meeldauw (Erysiphe graminis) en bladvlekkenziekte (Septoria tritici en Septoria nodorum).

Een behandeling uitvoeren in de periode vanaf het verschijnen van het vlagblad tot het in de aar komen (BBCH 39-59). Het kan echter noodzakelijk zijn om, afhankelijk van de ziektedruk, een eerdere bespuiting uit te voeren in de periode vanaf het begin van het schieten van het gewas tot het verschijnen van het vlagblad (BBCH 32-39).

Dosering: 0,5 liter per ha

 

Graszaadteelt van Engels raaigras, veldbeemdgras en roodzwenkgras, ter voorkoming van aantasting door roestschimmels (Puccinia spp.).

Een behandeling uitvoeren kort voor de bloeiperiode van het gewas.

Dosering: 0,5 liter per ha

 

Suiker- en voederbieten, ter voorkoming van aantasting door bladvlekkenziekte (Cercospora beticola en Ramularia betae), roest (Uromyces beticola) en echte meeldauw (Erysiphe betae).

Bij de eerste symptomen een behandeling uitvoeren. Indien nodig de toepassing herhalen met een toepassingsinterval van 21 dagen.

Dosering: 0,35 liter per ha

 

 


HET COLLEGE VOOR DE TOELATING VAN BESTRIJDINGSMIDDELEN

 

BIJLAGE II bij het besluit d.d. 27 april 2007 tot uitbreiding van de toelating van het middel Sphere, toelatingnummer 12602 N

 

RISKMANAGEMENT

 

 

 

Contents Page

 

 

1. Identity of the plant protection product 2

 

2. Physical and chemical properties 4

 

3. Methods of analysis 11

 

4. Mammalian toxicology 16

 

5. Residues 27

 

6. Environmental fate and behaviour 39

 

7. Ecotoxicology 58

 

8. Efficacy 83

 

9. Conclusion 85

 

10. Classification and labelling 85

 


1. Identity of the plant protection product

 

1.1 Applicant

Bayer Crop science

Energieweg 1

3641 RT MIJDRECHT

 

 

1.2 Identity of the active substance

Common name

Trifloxystrobin

Name in Dutch

Trifloxystrobin

Chemical name

methyl (E)-methoxyimino-{(E)-α-[1-(α,α,α-trifluoro-m-tolyl)ethylideneaminooxy]-o-tolyl}acetate [IUPAC]

CAS nr

141517-21-7

EEG nr

Not allocated

 

The active substance was included on May 1st 2003 into Annex 1 of directive 91/414/EEC.

 

Common name

Cyproconazole

Name in Dutch

Cyproconazool

Chemical name

(2RS,3RS;2RS,3SR)-2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol [IUPAC]

CAS nr

94361-06-5

EEG nr

Not allocated

 

The active substance was submitted for placement on Annex 1 of directive 91/414/EEC (RMS Ireland). A Draft Assessment Report (DAR) is available.

 

1.3 Identity of the plant protection product

Name

Sphere

Formulation type

SC

Content active substance

Trifloxystrobin: 375 g/L (32.3%) pure a.s.

Cyproconazole: 160 g/L (13.8%) pure a.s.

 

The formulation is not part of the DARs concerning the placement on Annex 1 of 91/414/EEC.

 

1.4 Function

The product is a fungicide.

 

1.5              Uses applied for

Sphere is proposed to control leaf rust (Puccinia recondita), powdery mildew (Erysiphe graminis), and septoria leaf spot and glume blotch (Septoria tritici and Septoria nodorum) in winter wheat, spring wheat, and triticale. Also proposed is the use for the control of various rusts (Puccinia spp.) in perennial rye grass, smooth stalked meadow grass, and red fescue. In sugar beet and fodder beet the proposed use is for the control of leaf spot disease (Cercospora beticola en Ramularia beticola), rust (Uromyces betae) and powdery mildew (Erysiphe betae).

 


Trifloxystrobin

Uses

Dose a.s.

(Kg a.s./ha)

Number of applications

Interval between applications

Pre harvest interval

Application time (growth stage and season)

Winter wheat, spring wheat, and triticale

0.1875

2

7-12 days

45 days

April-June

Grass seed production: perennial ryegrass, red fescue, smooth stalked meadow grass

0.1875

1

-

 

April-June

sugar beet, fodder beet

0.1313

2

21 days

21 days

July-September

 

Cyproconazole

Uses

Dose a.s.

(Kg a.s./ha)

Number of applications

Interval between applications

Pre harvest interval

Application time (growth stage and season)

Winter wheat, spring wheat, and triticale

0.080

2

7-12 days

45 days

April-June

Grass seed production: perennial ryegrass, red fescue, smooth stalked meadow grass

0.080

1

-

 

April-June

sugar beet, fodder beet

0.056

2

21 days

21 days

July-September

 

1.6              Background to the application

The application concerns an extension of the authorisation and a major change in the formulation of the plant protection product Sphere (SC), a fungicide based on the active substances trifloxystrobin and cyproconazole, in the cultivation of winter wheat, spring wheat, triticale, perennial ryegrass, smooth-stalked meadow grass, red fescue, sugar and fodder beet.

Sphere (in EC formulation)is currently authorised in The Netherlands for use in winter wheat and spring wheat.

 

1.7              Packaging details

1.7.1 Packaging description

Material:

HDPE

Capacity:

1, 5 or 10L bottle or canister

Type of closure and size of opening:

50-63mm screwcap with HF seal or internal wad (ECPA One Trip Container Guidelines or DIN 6063

Other information

1L bottles are packed in sets of 12 pieces

5L bottles are packed in sets of 4 pieces

10L bottles are packed in sets of 2 pieces

 

1.7.2 Detailed instructions for safe disposal

See application form and MSDS.

 

 

2. Physical and chemical properties

 

2.1              Active substance: trifloxystrobin and cyproconazole

 

Identity (trifloxystrobin)

Data about the identity and the physical and chemical properties are taken from the List of Endpoints (monograph, January 2003). Changes and/or additions are taken up in italics.

Active substance (ISO Common Name)

Trifloxystrobin

Chemical name (IUPAC)

methyl (E)-methoxyimino-{(E)-α-[1-(α,α,α-trifluoro-m-tolyl)ethylideneaminooxy]-o-tolyl}acetate

 

Chemical name (CA)

methyl (αE)-α-(methoxyimino)-2-[[[(E)-[1-[3-(trifluoromethyl)phenyl]ethylidene]amino]oxy]methyl]benzeneacetate

CIPAC No

617

CAS No

141517-21-7

EEC No (EINECS or ELINCS)

not allocated

FAO Specification (including year of publication)

an FAO Specification does not yet exist

Minimum purity of the active substance as manufactured (g/kg)

960 g / kg

Identity of relevant impurities (of toxicological, environmental and/or other significance) in the active substance as manufactured (g/kg)

CGA 321113 (of environmental significance)

 

Molecular formula

C20H19F3N2O4

Molecular mass

408.4

Structural formula

 

 

Physical-chemical properties

Melting point (state purity)

72.9C (99.7%)

Boiling point (state purity)

approx. 312C at 101.325 kPa (99.7%)
(thermal decomposition starts at about 285C)

Temperature of decomposition

thermal decomposition starts at about 285C

Appearance (state purity)

Pure: white powder (99.7%)

Technical material (974 g/kg) off-white powder

Relative density (state purity)

1.36 (99.7%)

Surface tension

d = 65.3 - 66.4 mN/m (purity: 974 g/kg; 0.1 g/L suspension) at 20C. Not surface active. *

Vapour pressure (in Pa, state temperature)

3.4 10-6 Pa at 25C Essentially non-volatile.

Henrys law constant (in Pam3mol-1)

2.3 x 10-3 Pa m mol-1 at 25C

Solubility in water (in g/l or mg/l, state temperature)

0.61 mg / l at 25C, without pH dependence
(CGA 279202 has no dissociation constant in an accessible pH range)

Solubility in organic solvents (in g/l or

mg/l, state temperature)

all results at 25C
acetone >500 g / l
dichloromethane >500 g / l
ethyl acetate >500 g / l
hexane 11 g / l
methanol 76 g / l
octanol 18 g / l
toluene 500 g / l

Partition co-efficient (log Pow) (state pH and temperature)

log Pow at 25C : 4.5 (0.0094).

no pH dependence

Hydrolytic stability (DT50) (state pH and temperature)

pH 5 at 20C: 8.6 years

pH 7 at 20C: 11.4 weeks

pH 9 at 20C : 27.1 hours

Dissociation constant

CGA 279202 does not have a dissociation constant within the range 2 to 12 **

UV/VIS absorption (max.) (if absorption >290 nm state ε at wavelength)

For the absorption maximum at 250.7 nm the molar extinction coefficient was determined to be 17500 l / mol cm
No absorption maximum between 340 nm and 750 nm was observed.

Photostability (DT50) (aqueous, sunlight, state pH)

1.1 and 1.7 days at pH 5 and pH 7, respectively (natural summer sunlight at geographical latitude of 40N). Photolytically unstable.

Quantum yield of direct photo-

transformation in water at λ > 290 nm

F = 0.0639 (decay of CGA 279202 plus isomers)
F = 0.2272 (disappearance of CGA 279202)

Photochemical oxidative degradation in air

DT50 is estimated at 18 to 24 hours (Atkinson calculation).

Flammability

CGA 279202 is not considered highly flammable

Auto-flammability

Not self-igniting

Oxidative properties

Not oxidising

Explosive properties

CGA 279202 is not considered an explosive

* The surface tension of a 0.1 g/L suspension was determined, where the solubility of the active substance in water is only 0.61 mg/L. For a solubility of the active substance below 1mg/L a determination of the surface tension is not a requirement and therefore this endpoint can be accepted.

** The monograph does not state a unit. It is assumed that the values 2 to 12 are pKa values and not Ka values.

 

Identity (cyproconazole)

The identity of the active substance is unclear at this point. The active substance is currently under evaluation for inclusion on the Annex 1 list of 91/414/EC. During this evaluation it is expected the identity issue is resolved.

 

For this assessment the following assumption is made:

 

Cyproconazole possesses 2 chiral carbon atoms. The structure exists in 4 stereoisomeric forms: 2 diastereoisomeric pairs of enantiomers. Cyproconazole is an about 1:1 mixture of the 2 diastereoisomers, each of which is exactly a 1:1 mixture of the enantiomers. Meaning all four stereo isomers are present in similar amounts.

 

Based on this assumption it is expected the CAS no. of cyproconazole is 113096-99-4 (unstated stereochemistry), but this is 94361-06-5 ((2RS, 3RS)-isomers) according to ISO1750 documents.

 

The data in the list below is taken from studies submitted by the applicant.

Active substance (ISO Common Name)

Cyproconazole

Chemical name (IUPAC)

(2RS,3RS;2RS,3SR)-2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Chemical name (CA)

α-(4-chlorophenyl)- α-(1-cyclopropylethyl)-1H-1,2,4-triazol-1-ethanol

CIPAC No

600

CAS No

113096-99-4 unstated stereochemistry

94361-06-5 for (2RS, 3RS)-isomers (cyproconazole)*

94361-07-6 for (2RS, 3SR)-isomers

EEC No (EINECS or ELINCS)

Not allocated

FAO Specification (including year of publication)

Not available

Minimum purity of the active substance as manufactured (g/kg)

940 g/kg

Identity of relevant impurities (of toxicological, environmental and/or other significance) in the active substance as manufactured (g/kg)

none

Molecular formula

C15H18ClN3O

Molecular mass

291.8

Structural formula

 

5-batch analysis

Analytical closure > 98

* Apparently the CAS registry number 94361-06-5 belongs to cyproconazole (ISO 1750), which is confusing since the assumption is, based on specifications and the submitted IUPAC name, cyproconazole has an unstated stereo chemistry.

 

Physical-chemical properties

Melting point (state purity)

106-109 C (99.8 %)

99-106 C (96%)

Boiling point (state purity)

Decomposition starts at 115 oC (99.7%)

Decomposition takes place before the boiling point is reached.

Temperature of decomposition

At about 115 oC (99.7%) weak oxidative decomposition takes place under air

At 230 oC cyproconazole decomposes under a nitrogen atmosphere (99.7%)

Appearance (state purity)

Light beige solid with a faint colour (96 %)

Colourless and odourless solid (99.9%)

Relative density (state purity)

1.259 (99.8 %)

1.245 (96%)

(OECD 109)

Surface tension

59.7 mN/m at 20 C (90% of saturation; 96.6% pure)

Vapour pressure (in Pa, state temperature)

3 x 10-5 Pa at 20C

12 x 10-5 Pa at 30C

(OECD 104)

2.6 x 10-5 Pa at 25 C

(OECD 104)

Henrys law constant (in Pam3mol-1)

9.41 x 10-5 Pam3mol-1 (at water solubility of 93 mg/l)

(CTB calculation)

Solubility in water (in g/l or mg/l, state temperature)

140 mg/l (22.0 C/pH 6.7)

(OECD 105)

108 mg/l (22.0 C/pH 4.1)

93 mg/l (22.0 C/pH 7.1)

109 mg/l (22.0 C/pH 10.0)

(CIPAC MT 157)

Solubility in organic solvents (in g/l or

mg/l, state temperature)

At 25 C :

n-hexane: 2 g/l

toluene: 109 g/l

xylene: 112 g/l

diisopropyl ether: 22 g/l

ethyl acetate, dichloromethane, acetone, methanol, ethanol, acetonitrile, dimethyl sulfoxide, polyethylene glycol: > 200 g/l

Partition co-efficient (log Pow) (state pH and temperature)

2.90 at 22C at pH about 7; no pH dependence

(OECD 107)

Hydrolytic stability (DT50) (state pH and temperature)

Stable in buffered solutions of pH 1,5,7,and 9 at 50 and 80C.

Dissociation constant

Cyproconazole does not dissociate in water under normal conditions

UV/VIS absorption (max.) (if absorption >290 nm state ε at wavelength)

197 nm (molar extinction coefficient 38933)

222 nm (molar extinction coefficient 11550)

No absorption between 310-400 nm

Photostability (DT50) (aqueous, sunlight, state pH)

Cyproconazole,dissolved at 1 ppm in an aqueous buffer of pH 7 is stable at 25 C when exposed to natural sun light during 40 days.

Quantum yield of direct photo-

transformation in water at λ > 290 nm

Not required

Photochemical oxidative degradation in air

A maximum photolysis half life of cyproconazole in the atmosphere is calculated at 0.661 days ( 16 hours)

Flammability

Not flammable (Method A10)

Auto-flammability

Not auto-flammable (Method A16)

Oxidative properties

No oxidizing properties (method A17)

Explosive properties

Not explosive (Method A14)

 

 

2.2              Plant protection product: Sphere

Data about plant protection product are taken from reports submitted by the applicant.

 

The range of the application concentration of the plant protection product is 0.0875-0.25 %

Section

(Annex point)

Study

Guidelines and GLP

Findings

Evaluation and conclusion

B.2.2.1 (IIIA 2.1)

Appearance: physical state

Visual

GLP: yes

Liquid suspension

Acceptable

B.2.2.2 (IIIA 2.1)

Appearance: colour

Visual

GLP: yes

Beige

Acceptable

B.2.2.3 (IIIA 2.1)

Appearance: odour

Organoleptic

GLP: yes

Slightly paint-like

Acceptable

B.2.2.4 (IIIA 2.2)

Explosive properties

EC A14

GLP: yes

Not explosive

Acceptable

B.2.2.5 (IIIA 2.2)

Oxidising properties

 

Not oxidising

Acceptable (statement)

B.2.2.6 (IIIA 2.3)

Flammability

 

Not applicable

 

B.2.2.7 (IIIA 2.3)

Auto-flammability

EC A15

GLP: yes

355 oC

Acceptable

B.2.2.8 (IIIA 2.3)

Flash point

DIN EN 22719

GLP: yes

> 105 oC (boiling point)

Acceptable

B.2.2.9 (IIIA 2.4)

Acidity / alkalinity

 

Not applicable

 

B.2.2.10 (IIIA 2.4)

pH

CIPAC MT75.2

GLP: yes

1% dispersion: 6.5

undiluted product: 6.9

Acceptable

B.2.2.11 (IIIA 2.5)

Surface tension

OECD 115

GLP: yes

43.4 mN/m (40 oC; undiluted product)

Acceptable

B.2.2.12 (IIIA 2.5)

Viscosity

OECD 114

GLP: yes

Measurements at 40 oC

Dynamic viscosity: 0.0689 Pa.s

Kinematic viscosity: 6.1x10-5 m2/s

 

Only one measurement was performed, but this is accepted based on the composition of the product; viscosity will not influence product labelling.

Acceptable

B.2.2.13 (IIIA 2.6)

Relative density

OECD 109

GLP: yes

D420 = 1.140

D440 = 1.134

Acceptable

B.2.2.14

(IIIA 2.6)

Bulk (tap) density

 

Not applicable

 

B.2.2.14 (IIIA 2.7)

Storage stability

CIPAC MT 46.3

GLP: no

 

 

Stable for 14 days at 54 oC

Stable for 8 weeks at 40 oC

 

The product was stable for 14 days at 54 oC and 8 weeks at 40 oC in HDPE packaging.

 

The suspensibility test was not performed at the exact minimum proposed concentration for use. However, based on very good suspensibility, extrapolation is deemed acceptable. No further testing is required.

Acceptable

B.2.2.14 (IIIA 2.7)

Storage stability

CIPAC MT39.3

GLP: no

Stable for 7 days at 0 oC

After storage for 7 days the following technical properties were determined: suspensibility and wet sieving.

 

The suspensibility test was not performed at the exact minimum proposed concentration for use. However, based on very good suspensibility, extrapolation is deemed acceptable. No further testing is required.

Acceptable

B.2.2.15 (IIIA 2.7)

Shelf life

GLP: no

CIPAC MT75.3

CIPAC MT160

CIPAC MT184

CIPAC MT185

CIPAC MT148

CIPAC MT47.2

CIPAC MT 46.3

CIPAC MT 39.3

Chemical stability

The content of active substances did not change significantly after 2 years storage in HDPE packaging.

 

Method used for determination of the active substances: 2001-0051901-01

 

The determinations of the pH of the formulation and 1% dispersion were not performed according to GLP guidelines. However, a separate report was provided with pH before storage. Since the difference in values found in the GLP report and in the shelf-life study, these values are accepted. No significant difference in pH was found after 2 years storage.

 

Physical stability

The following properties were determined before and after storage: pH, spontaneity of dispersion, suspensibility, wet sieving, pourability, persistence of foam.

 

No significant changes in the products technical properties were observed.

 

The suspensibility test was not performed at the exact minimum proposed concentration for use. However, based on very good suspensibility, extrapolation is deemed acceptable. No further testing is required.

 

Acceptable

 

 

 

Packaging

The product was stored in HDPE bottles. For the Dutch market HDPE bottles are proposed. No deterioration of the packaging was observed after 2 years storage. The packaging is therefore considered suitable for its content according to GIFAP monograph No. 17.

 

B.2.2.16

(IIIA 2.8)

Wettability

 

Not applicable

 

B.2.2.17 (IIIA 2.8)

Persistent foaming

CIPAC MT47.2

GLP: yes

0.5% dispersion in CIPAC D water

Acceptable

B.2.2.18

(IIIA 2.8)

Suspensibility

CIPAC MT 161

GLP: yes

0.2% dispersion in CIPAC D water

Trifloxystrobin: 100.2%

Cyproconazole: 101.5%

0.5% dispersion in CIPAC D water

Trifloxystrobin: 93.1%

Cyproconazole 94.5%

 

The maximum and minimum concentration at which the product is used for spraying are 0.0875% and 0.25%, based on the GAP provided for trifloxystrobin. The suspensibility test was not performed at the exact minimum proposed concentration for use, nor in CIPAC A water. However, based on very good suspensibility, extrapolation is deemed acceptable. No further testing is required.

 

Acceptable

B.2.2.19

(IIIA 2.8)

Spontaneity of dispersion

CIPAC MT160

GLP: yes

5%v/v dispersion in CIPAC D water

Trifloxystrobin: 98.0%

Cyproconazole: 98.8%

Acceptable

B.2.2.20

(IIIA 2.8)

Dilution stability

 

Not applicable

 

B.2.2.21

(IIIA 2.8)

Dry sieve test

 

Not applicable

 

B.2.2.22

(IIIA 2.8)

Wet sieve test

CIPAC MT185

GLP: yes

< 0.01% residue on a 75 micron sieve

Acceptable

B.2.2.23

(IIIA 2.8)

Particle size distribution

 

Not applicable

 

B.2.2.24

(IIIA 2.8)

Content of dust/fines

 

Not applicable

 

B.2.2.25

(IIIA 2.8)

Attrition and friability

 

Not applicable

 

B.2.2.26 (IIIA 2.8)

Emulsifiability, re-emulsifiability and emulsion stability

 

Not applicable

 

B.2.2.27

(IIIA 2.8)

Stability of dilute emulsion

 

Not applicable

 

B.2.2.28

(IIIA 2.8)

Flowability

 

Not applicable

 

B.2.2.29

(IIIA 2.8)

Pourability (rinsibility)

CIPAC MT148

GLP: yes

Residue: 2.02%

Poured residue: 0.12%

Acceptable

B.2.2.30

(IIIA 2.8)

Dustability

 

Not applicable

 

B.2.2.31

(IIIA 2.8)

Adherence and distribution to seeds

 

Not applicable

 

2.9.1

Physical compatibility with other products

 

Not applicable

 

2.9.2

Chemical compatibility with other products

 

Not applicable

 

 

No mixing with other plant protection products or adjuvants is proposed. No information is available on the behaviour of this product when mixed. Mixing with another product or adjuvant can therefore result in unexpected behaviour.

 

Conclusion

The physical and chemical properties of the active substance and the plant protection product are sufficiently described by the available data. Neither the active substance nor the product has any physical or chemical properties, which would adversely affect the use according to the proposed use and label instructions.

 

2.3 Data requirements

No further data required.

 

 

3. Methods of analysis

Description and data about the analytical methods for trifloxystrobin are taken from the List of Endpoints included in the monograph (January 2003). Changes and/or additions are taken up in italics.

 

For cyproconazole, data concerning the analytical methods was taken from reports, submitted by the applicant.

 


3.1. Analytical methods in technical material and plant protection product

Technical as (principle of method)

Trifloxystrobin

GC-FID, SE-54 wide bore capillary column

IR spectroscopy for confirmation of identity.

 

Cyproconazole

Reversed phase HPLC with UV detection at 220 nm, external standard.

(method AW-209/1)

Impurities in technical as (principle of method)

Trifloxystrobin

HPLC-UV (organic by-products, including relevant impurity CGA321113), Nucleosil C 18 column.

GC-FID (solvent), Poropak Q column

GC-TEA (nitrosamines)

GC-MS for confirmation of identity.

 

Cyproconazole

Reversed phase HPLC with UV detection at 220 nm, external standard.

And GC-FID, internal standard

(Method AK-209/1)

Preparation (principle of method)

GC-FID method 2001-0051901-01 for the determination of the active substances in SC formulations.

 

Conclusion

The analytical methods concerning the trifloxystrobin technical material have been assessed in the monograph and are considered to be acceptable.

 

For cyproconazole and the analytical method for determination of both active substances in the preparation the applicant submitted acceptable methods.

 

3.2 Residue analytical methods

Food/feed of plant origin (principle of method and LOQ for methods for monitoring purposes)

Trifloxystrobin

HPLC-UV, LOQ 0.02 mg/kg (apples, potatoes, grape), LOQ 0.01 mg/L (grape: wine, juice)

determined: parent.

Confirmatory method: GC-ECD

ILV: unknown *

 

GC-ECD, LOQ 0.02 mg/kg (wheat, barley, bananas), LOQ 0.05 mg/kg (straw), determined: parent and metabolite CGA 321113.

Confirmatory method: GC-MS

ILV: unknown *

 

GC-NPD, LOQ 0.02 mg/kg (fruit, vegetables, peanut hay), determined parent and metabolite CGA 321113

Confirmatory method: GC-MS

ILV: available

 

DFG method S 19 (extended revision) was validated for high water content, fat, acid and dry matrices. It was not capable of analysing hops but in general it is acceptable for the purposes of monitoring parent compound.

 

Cyproconazole

GC-MSD (method BS 8058) for determination of cyproconazole

LOQ: 0.01 mg/kg (apples, beans, cereal grains, rape seed)

Confirmatory method: 3 mass fragments

ILV: yes

 

HPLC-MS/MS (method RAM 397/01) for determination of cyproconazole

LOQ: 0.01 mg/kg (grain and straw)

Confirmatory method: not required for HPLC-MS/MS

ILV: not available **

Food/feed of animal origin (principle of method and LOQ for methods for monitoring purposes)

Trifloxystrobin

GC-NPD, LOQ 0.02 mg/kg (ruminant and poultry muscle, fat, liver, kidney and eggs); LOQ 0.01 mg/l (milk), determined: parent and metabolite CGA 321113.

Conformatory method: GC-MS

ILV: available

 

Cyproconazole

GC-MSD (method BS 8058) for determination of cyproconazole

LOQ: 0.01 mg/kg (eggs and meat)

LOQ: 0.003 mg/kg (milk)

Confirmatory method: 3 mass fragments

ILV: yes

Soil (principle of method and LOQ)

Trifloxystrobin

HPLC-UV, LOQ 0.01 mg/kg (soil), determined: parent and soil metabolites CGA 321113, 357261, 357262, 331409, 373466.

Confirmatory method: trifloxystrobin and CGA357262: column switching method

 

Cyproconazole

GC-MSD (method BS 8058) for determination of cyproconazole

LOQ: 0.01 mg/kg soil (2 types)

Confirmatory method: 3 mass fragments

 

HPLC-MS/MS (RAM 369/01) for determination of cyproconazole

LOQ: 0.01 mg/kg (4 types)

Confirmatory method: not required for HPLC-MS/MS

Water (principle of method and LOQ)

Trifloxystrobin

HPLC-UV, LOQ 0.05 mg/L, determined: parent and metabolite CGA 321113 in potable water

Confirmatory method: REM 177.07

 

GC-ECD (REM 177.07), LOQ 1.0 mg/L (surface water), 0.05 mg/L (potable water), determined: parent and metabolite CGA 321113

Confirmatory method: GC-MS

 

Cyproconazole

GC-MSD (method REM 200.01) for determination of cyproconazole

LOQ: 0.05 μg/l drinking water

LOQ: 0.1 μg/l surface water

Confirmatory method: 3 mass fragments

Air (principle of method and LOQ)

Trifloxystrobin

GC-ECD, LOQ 2 mg/m3, determined: parent

Confirmatory method: GC-MS

 

Cyproconazole

GC-NSD (TENAX adsorbent/extracted by toluene)

(method BS 3786) for determination of cyproconazole

LOQ: 2 μg/m3

Confirmatory method: method for determination of cyproconazole in water

Body fluids and tissues (principle of method and LOQ)

Trifloxystrobin

Not required; non (very) toxic compound

 

Cyproconazole

Not required; non (very) toxic compound

* from the data, included in the monograph, it was unclear whether an ILV was performed for this method. This method is not considered acceptable as a method for monitoring purposes.

** no ILV was submitted for this method, but a GC-MS method was fully validated, including ILV for food/feed of plant origin

 

Based on the proposed use of the plant protection product analytical methods for determination of residues in food/feed of plant origin are required for dry and watery matrices (cereals, sugar beets). Because the evaluation of the dossier started before September 2006, sugar beets are still regarded as a watery matrix.

 

Definition of the residue and proposed MRLs for trifloxystrobin

Matrix

Definition of the residue for monitoring

MRL

Food/feed of plant origin

CGA 279202 (parent EE isomer)

The Dutch Pesticide Law states the following MRLs:

Rye, wheat, triticale: 0.05 mg/kg

Sugar beets (other): 0.02 mg/kg

Food/feed of animal origin

CGA 279202 (parent EE isomer) and CGA 321113

All: 0.02 mg/kg (source: monograph)

 

Required LOQ

Soil

Trifloxystrobin

0.05 mg/kg

Drinking water

Trifloxystrobin

0.1 g/L (Dutch drinking water guideline)

Surface water

Trifloxystrobin

2,7 g/L (NOEC for Daphnia Magna)

Air

Trifloxystrobin

0.018 mg/m3 (derived from the AOEL according to SANCO/825/00)

Body fluids and tissues

The active substance is not classified as (very) toxic thus no definition of the residue is proposed.

Not applicable

 

 

Definition of the residue and proposed MRLs for cyproconazole

Matrix

Proposed definition of the residue for monitoring

Proposed MRL

Food/feed of plant origin

Cyproconazole

0.05 mg/kg for all products

Food/feed of animal origin

Cyproconazole

0.05 mg/kg for all products

 

Required LOQ

Soil

Cyproconazole

0.05 mg/kg

Drinking water

Cyproconazole

0.1 g/L (Dutch drinking water guideline)

Surface water

Cyproconazole

77 g/L (EC50 for algae)

Air

Cyproconazole

0.01 mg/m3 (derived from the AOEL according to SANCO/825/00)

Body fluids and tissues

The active substance is not classified as (very) toxic thus no definition of the residue is proposed.

Not applicable

 

The residue analytical methods, included in the abovementioned List of Endpoints, are suitable for monitoring of the (proposed) MRLs.

 

The residue analytical methods for water, soil and air are acceptable and suitable for monitoring of residues in the environment.

 

Conclusion

The submitted analytical methods meet the requirements. The methods are specific and sufficiently sensitive to enable their use for enforcement of the MRLs and for monitoring of residues in the environment.

 

3.3 Data requirements

No data requirements.

 

3.4 Physical-chemical classification and Labelling

 

Proposal for the classification of the active ingredient trifloxystrobin (symbols and R phrases)
(EU classification) concerning physical chemical properties

Symbol(s):

-

Indication(s) of danger: -

 

Risk phrase(s)

-

-

 

Proposal for the classification of the active ingredient cyproconazole (symbols and R phrases)
(EU classification) concerning physical chemical properties

 

Symbol(s):

-

Indication(s) of danger: -

 

Risk phrase(s)

-

-

 


Proposal for the classification and labeling of the formulation concerning physical chemical properties

Based on the profile of the substance, the provided toxicology of the preparation, the characteristics of the co-formulants, the method of application, the following labeling of the preparation is proposed:

 

Substances, present in the formulation, which should be mentioned on the label by their chemical name (other very toxic, toxic, corrosive or harmful substances):

-

Symbol:

-

Indication of danger:

-

R phrases

-

-

 

 

 

S phrases

21

When using do not smoke.

 

 

 

Special provisions:
DPD-phrases

-

-

 

 

 

Child-resistant fastening obligatory?

Not applicable

Tactile warning of danger obligatory?

Not applicable

 

Explanation:

Hazard symbol:

-

Risk phrases:

-

Safety phrases:

S21 is assigned to products containing halogenated compounds, which can form toxic fumes when burned or incinerated.

Other:

-

 

 

4. Mammalian toxicology

 

Trifloxystrobin

Trifloxystrobin is a new active substance, included in Annex I of 91/414/EEC. The final list of endpoints presented below is copied from the final review report on trifloxystrobin (SANCO/4339/2000 final, d.d. 7 April 2003). When relevant, some additional remarks/information is given in italics.

 

List of End-points trifloxystrobin

 

Absorption, distribution, excretion and metabolism in mammals

Rate and extent of absorption:

60% oral absorption based on urinary and biliary excretion and

tissue residues after 48 hours.

Distribution:

Widely distributed.

Potential for accumulation:

No potential for accumulation.

Rate and extent of excretion:

Within 48 hours 72-96% of the administered dose eliminated in

the urine and faeces.

Toxicologically significant compounds:

Parent compound and metabolites.

Metabolism in animals:

Extensive: hydrolysis, O-demethylation, oxidation and

conjugation.

 


Acute toxicity

Rat LD50 oral:

>5000 mg/kg

Rat LD50 dermal:

>2000 mg/kg

Rat LC50 inhalation:

>4.6 mg/litre

Skin irritation:

Not irritant.

Eye irritation:

Not irritant.

Skin sensitization (test method used and result):

Sensitiser (M&K) (R43).

 

Short term toxicity

Target / critical effect:

Decreased bodyweight & food consumption

Liver: increased weight, hepatocellular hypertrophy and necrosis..

Kidney: increased weight and acute tubular lesions.

Pancreas: atrophy.

Lowest relevant oral NOAEL / NOEL:

90-day rat: 100 ppm (6.4 mg/kg bw/day)

Lowest relevant dermal NOAEL / NOEL:

28-day rat: 100 mg/kg bw/day

Lowest relevant inhalation NOAEL / NOEL:

No study - not required

 

Genotoxicity

 

No genotoxic potential

The genotoxic potential of trifloxystrobin was investigated in 4 in vitro studies (Ames test, mammalian cell gene mutation test in Chinese hamster lung fibroblasts V79, mammalian cytogenetic test in Chinese hamster ovary cells, mammalian cell DNA repair test) and in 1 in vivo study (micronucleus test in mouse bone marrow). All studies were negative for genotoxicity.

 

Long term toxicity and carcinogenicity

Target / critical effect:

Decreased bodyweight & food consumption.

Liver: increased weight, hepatocellular hypertrophy, fatty change and necrosis.

Kidney: increased weight.

Lowest relevant NOAEL:

2-yr rat: 250 ppm (9.8 mg/kg bw/day)

Carcinogenicity:

No carcinogenic potential

 

Reproductive toxicity

Target / critical effect - Reproduction:

Decreased bodyweight gain of pups and delayed eye opening at parental toxic doses.

Lowest relevant reproductive NOAEL / NOEL:

50 ppm(2.3 mg/kg bw/day)*

Target / critical effect - Developmental toxicity:

Enlarged thymus (rat) and skeletal effects (rabbit) at maternally toxic dose levels.

Lowest relevant developmental NOAEL / NOEL:

50 mg/kg bw/day (rabbit)*

* reproduction:

Parental NOAEL: 50 ppm (2.3 mg/kg bw/day)

Developmental NOAEL: 50 ppm (2.3 mg/kg bw/day)

No reproductive effects

**developmental:

Maternal NOAEL: 50 mg/kg bw/day

Developmetal NOAEL: 50 mg/kg bw/day

 


Neurotoxicity

Acute and 90-day neurotoxicity study, rat:

No evidence of neurotoxicity

 

Other toxicological studies

Investigations into replicative DNA synthesis:

No evidence of replicative DNA synthesis in rat or mouse heptocytes following 3-months administration in diet.

Investigations into mitochondrial function:

In vitro studies in isolated rat liver mitochondria indicated trifloxystrobin caused a significant concentration dependant inhibition of mitochondrial respiration.

Studies performed with metabolites:

CGA 373466, NOA 413161, NOA 413163, CGA 357261 and NOA 414412 were of low acute oral toxicity (LD50 values >2000 mg/kg bw) and there was no evidence of genotoxic activity (each tested in 1-3 in vitro assays, including Ames test).

For metabolites CGA 373466 and NOA 413163 data requirements were set in C-123.3.7 In addendum III to the monograph dated December 2002, new studies have been evaluated. CGA 373466 and NOA 413163 were both negative in a gene mutation test with mammalian cells in Chinese hamster lung fibroblasts V79. With these data the data requirements on the genotoxicity of CGA 373466 en NOA 413163 set in C-123.3.7 have been fulfilled.

 

Medical data

 

New active substance. Limited data. Some evidence of skin and eye irritation in 3 people during field trials (but 120 people without effects).

 

Summary

 

Value

Study

Safety factor

ADI:

0.1 mg/kg bw/day

2-year rat study

100

AOEL

0.06 mg/kg bw/day

2-year rat study (adjusted for 60% oral absorption)

100

ARfD (acute reference dose):

Not allocated - not necessary due to low acute toxicity of trifloxystrobin.

 

Dermal absorption

 

In-vivo and in-vitro data submitted. In vivo rat: 38% (low dose, 48 h), 16% (high dose, 48 h)

In vitro rat/human: human epidermis was shown to be at least 10-fold less permeable than rat epidermis. Therefore dermal absorption for risk assessment will be 1.6% for the concentrate and 3.8% for the in-use dilutions. Individual Members to decide on precise dermal absorption value to use.

 

Data requirements trifloxystrobin

There are no data requirements. In the final review report SANCO/4339/2000 no particular conditions to be taken into account by Member States in relation to the granting of authorisations of plant protection products containing trifloxystrobin were reported.

 

Cyproconazole

Cyproconazole is an existing active substance. The EU-dossier is complete, however the Draft assessment report (DAR) did only become available very recently and was not used for the assessment. Ireland is RMS. The toxicological profile presented below is based on the RIVM report 91/679107/011 dated 1991 and the addenda 91/679107/011 (1992) and 08138A00 (2000) to these reports. Since the active substance is still in the process of evaluation/discussion, the toxicological profile below should be regarded as provisional.

 

Toxicokinetics

 

Oral intake

After oral intake cyproconazole is well absorbed in rat (>86%). Seven days after exposure, 30-40% of the dose administered was excreted in urine and 45-60% was excreted in faeces. The faecal excretion was mainly originating from bile. The half-time value for excretion from blood was 25 to 30 hours. The highest levels were found in kidneys, adrenal glands, kidney fat and liver. The levels detected in female animals were higher than the levels in male animals.

A large number of degradation products of cyproconazole were isolated and partly identified in urine and faeces. The identified route of degradation is the removal of the triazole-group and hydroxylation of the central butanol-chain, followed by partial oxidation to the carboxylic acid.

For risk-assessment the values for oral absorption used is 86% (i.e. females 60% bile, 27% urine and 1% carcass, male 75% bile, 10% urine en 0,6% carcass).

 

Toxicodynamics

 

Acute toxicity

Technical grade cyproconazole is harmful (R22) via the oral route (LD50 200-1330 mg/kg bw in the rat, mouse and rabbit). The substance is not toxic via de dermal (LD50 > 2000 mg/kg bw in rat and rabbit) or inhalatory (LC50 > 5,650 mg/l) route and was not irritating for skin and eyes and does not have sensitizing properties.

Sub-acute and semi-chronic toxicity/carcinogenicity

From sub-acute, semi-chronic and chronic studies with technical grade cyproconazole in rats and dogs, the liver was identified as the target organ (increased weight, histopathological and clinical-chemical changes). At higher doses, cyproconazole caused a reduction of body-weight gain. In the rat, no carcinogenic potential during lifelong exposure to technical grade cyproconazole was observed.

 

Tabel T.1 Relevant NOAELs/LOAELs and toxicological effects

Study

NOAEL

LOAEL

Toxicological effects

 

(mg/kg bw/day)

 

21-days dermal rabbit

50

250

Slight increase ASAT and increased adrenal gland weight

28-days oral rat

8,1

25

Reduction of body-weight gain, liver weight

28-days oral mouse mechanistic study

-

2,2

Increased Iiver weight, vacuolisation of the Iiver, Iiver cell proliferation

28-days dermal rat

10

100

Increased thyroid gland and Iiver weight

16-days inhalation rat

<0,017

0,017

Increased Iiver weight

90-days oral rat

1,4

25

Increased Iiver, adrenal gland, spleen and pituitary weight

13-weeks diet rat

1,5

6,4

Slight reduction of body-weight gain, piloerection, increased liver weight, slight decrease of haematocrit value

13-weeks diet dog

0,8

4

Increase ALAT, alkalic phosphatase and gamma-GT (F), , increased liver weight (M) and hepatocytomegalia (furthermore non dose-related increases of cortisol and testosterone(M))

1-year diet dog

1

3

Increases in the platelet count and alkalic phosphatase and in the liver an increased P450-level and histopathological changes (in 1/4 M)

carcinogenicity oral mouse

0,7

1,8

Iiver adenomas and l-carcinomas increased from doses >13 mg/kg Ig/d)

121 -weeks diet rat

1

2,2

Increased gamma-GT and slight increase of liver weight (F)

No increased tumor incidence

2-generation reproduction diet rat

matern: 0,2

matern: 1

Duration of pregnancy somewhat elongated (F0 only)

 

foetus: 0,2

foetus: 1

Slight increase of peri- en postnatal death of pups (F1 only)

teratogenicity oral rat

matern: 12

matern: 24

Reduction of body-weight gain and reduced food consumption, increased implantation loss

 

develop: 12

develop: 24

Decreased bodyweight foetuses, incomplete ossification, at 24 and 48 mg/kg bw/day structural defects.

teratogenicity oral rabbit

matern: 10

matern: 50

Reduction of body-weight gain and reduced food consumption, increased post-implantation loss

 

develop: 50

develop: >50

Some non dose-related defects in all dose groups (supposedly non related to cyproconazole)

teratogenicity oral rabbit

10 (matern)

50

 

Reduction of body-weight gain and reduced food and water consumption

 

10 (develop)

50

Malformations, irreversible structural effects from doses >50 mg/kg bw/day

 

Genotoxicity

The substance was not mutagenic in bacteria (Ames test with and without metabolic activation), and yeast cells and did not induce an increase of revertants in a in vitro gene mutation test in mammalian cells (with and without metabolic activation).

Two UDS-tests in rat Iiver cells in vitro were negative.

In an in vitro cytogenetic test, cyproconazole was weakly clastogenic, in the presence as well as in the absence of metabolic activation.

The substance did not induce DNA repair in rat hepatocytes. In an in vivo micronucleus test in mice no effects were observed. Based on the submitted mutagenicity tests, cyproconazole is not considered as mutagenic.

 

Neurotoxicity

Neurotoxicity was not observed in any of the available toxicity studies.

 

Reproduction toxicity

Based on the 2-generation reproduction study in rats (see table), submitted for the original registration of Sphere, a slight increase in the peri-and postnatal death of pups was observed in F1 animals. This effect cannot be explained by the somewhat elongated duration of pregnancy in F0 animals, hence cyproconazole needs to be classified with R63.

 

Moreover, cyproconazole causes irreversible structural defects in rats at and above dose levels of 24 mg/kg bw/d.

 

Other toxicological studies

Studies on the toxicity of cyproconazole plants and soil metabolites have not been performed. It is assumed that the plant metabolism is similar to the metabolism in the rat.

 

Four mechanistic studies were provided. In this study the main subject was (the difference in) liver effects in rat and mouse.

In the fourth study the influence of cyproconazole on hepatic cell proliferation was studied in male rats and mice for four weeks. A clear interspecies-difference was recorded: in the rat the increased liver weight was supported by increased centrilobulairy hepatocyt size and vacuolisation and in the mouse the increased liver weight was histopathologically supported by increased centrilobulairy hepatocyt size and vacuolisation and cell proliferation.

The LOAEL for the mouse for hepatic cell proliferation, increased liver weight and vacuolisation was set at 15 mg/kg feed (2,2 mg/kg bw./day). The NOAEL was 20 mg/kg feed in the rat (1,5

mg/kg bw./day), based on liver effects at 350 mg/kg feed (25 mg/kg bw./day).

In a different study, the inhibition and induction of liver enzymes in rats and mice was compared. This study showed that the rat liver has a larger capacity to metabolise and eliminate cyproconazole than the mouse, as in rats a higher induction of Cyt P450, Cyt P450IIB mediated enzymatic activity, UDPGT and GST was observed.

Possibly different metabolites were formed in the rat than in the mouse. A comparable study showed similar results.

In another study histopathological evaluation was performed to compare the effect on the liver of male rats when exposed sub-chronically to cyproconazole and propiconazole. The study showed that in (male) mice a similar pattern of histopathological changes affected the liver with exposure to cyproconazole or propiconazole.

The mechanistic studies show that in the rat the metabolic pathway of cyproconazole is different from the pathway in the mouse. In the mouse cell proliferation occurs, where this is not observed in the rat; this might explain the increased tumour incidence in mouse in comparison to the rat. Whether cyproconazole is a possible human carcinogenic substance cannot be excluded based on these studies available.

 

Data requirements active substance

No additional data requirements are identified. The data requirements identified in the EU-assessment are also applicable to the Dutch assessment.

 

4.1 Toxicity of the formulated product (IIIA 7.1)

As a major change in the formulation of Sphere was requested, a new set of acute toxicity studies was provided.

The formulation Sphere does not need to be classified on the basis of its acute oral (LD50 rat >5000 mg/kg bw), dermal (LD50 rat >4000 mg/kg bw), and inhalation toxicology (LC50 rat >1.96 mg/l, highest attainable level).

The formulation Sphere does not need to be classified for dermal irritation, eye irritation or skin sensitisation (maximisation).

 

4.1.1 Data requirements formulated product

No additional data requirements are identified.

 

4.2 Dermal absorption (IIIA 7.3)

Trifloxystrobin

The dermal absorption studies were performed with a 125 EC formulation. A major change in the formulation of Sphere is requested from an EC formulation, containing 187.5 g trifloxystrobin/l to a SC formulation, containing 375 g trifloxystrobin/l.

In the in vivo and in vitro studies in the monograph, dose rates of 24 g/cm2-1.14 mg/cm2 and 15 g/cm2-10.27 mg/cm2 were applied, respectively.

As the studies in the DAR are comparable, EC formulation vs. SC formulation, the dermal absorption rates from the list of end points will be used for the risk assessment.

 

Cyproconazole

Both in vitro and in vivo dermale absorption studies were conducted with SL formulations with cyproconazole as active substance.

In the in vivo studie in rat, a dermal absorption of 9.5% was demonstrated at a dose of 14 mg/cm2 after 10 hours of occluded exposure. 20% of the dose remained present in the skin after removal of the gauze. After seven days, 2% was still detected in the skin and approximately 20% had been excreted. Based on this study, the total dermal penetration amounted to 30%.

In the in vitro study a comparison was made between the absorption by human and rat skin samples (concentrations 1, 2, 10 en 641 g cyproconazole/cm2). At the highest dose, the permeation rate was shown to be 25-fold slower en at the lowest dose 3-fold slower. At the lowest dose, 49.2% penetrated the human skin and 72.4% the rat skin. At this dose, 22.8% and 17.5% remained in the skin samples, respectively. This indicates a dermal absorption of 72% for humans and of 90% for rat.

It should be mentioned that in the in vivo studies 10 hours after exposure, 48% of the administered dose was still present in the gauzes and were therefore not/no longer available for dermal penetration.

The dermal absorption might therefore be significantly higher in real life, than the 30% reported in the in vivo study. Therefore, the absorption rate from the in vitro study are used.

A major change in the formulation of Sphere is requested from an EC formulation, containing 80 g cyproconazole/l to a SC formulation, containing 160 g cyproconazole/l.

As the formulations used in the available studies are comparable, i.e. SL formulation vs. SC formulation, the dermal absorption rates of 72% will be used for the risk assessment.

 

4.3 Available toxicological data relating to non-active substances (IIIA 7.4)

Other formulants: no reason for toxicological concern.

 

4.4 Exposure/risk assessments

 

Overview of the intended uses

The formulation Sphere is applied by mechanical downward spraying in the cultivation of winter wheat, spring wheat, triticale, perennial ryegrass, smooth-stalked meadow grass, red fescue, sugar and fodder beet. The formulation is applied twice in the cultivation of winter wheat, spring wheat and triticale during the period April June with a maximum dose of 0.5 L formulation / ha. Sphere is applied twice in the cultivation of sugar and fodder beet during the period July-September with a maximum dose of 0.35 L formulation / ha, and once in the cultivation of perennial ryegrass, smooth-stalked meadow grass and red fescue during the period April June with a maximum dose of 0.5 L formulation / ha. Therefore, as the formulation is applied with an interval of 21-30 days and twice per cultivation, a semi-chronic exposure duration is applicable for the operator (contract workers included).

 

Calculation of the AOEL

Trifloxystrobin

Trifloxystrobin is included in Annex I of 91/414/EEC. Therefore, the AOEL established in the list of end points is used.

 

AOELsystemic: 0.06x 70 = 4.2 mg/day

 

Cyproconazole

Cyproconazole is not yet included in Annex I of 91/414/EEC. This means that The Netherlands may calculate the AOEL according to the Dutch method. This method takes into account the caloric need of the studied species and results in a more specific value than the EU-AOEL for which a standard factor of 100 is applied.

 

The calculation of the systemic AOEL for semi-chronic exposure is based on the NOAEL of 1.5 mg/kg bw/d in the 90-day study in rats as the starting point for the calculation of the semi-chronic AOEL, instead of the NOAEL in the 13-week toxicity study in rats as was used in C-171.3.13 of July 12th 2006.

The NOAEL from this study would lead to a lower AOEL, however, the effects found in this study where identified to be less relevant than the effect found in the 90-day rat study. The latter study is considered to be the study with the most relevant effects.

 

Safety factors are used to compensate for the uncertainties, which arise from for example extrapolation from the tested species to humans and the differences between experimental circumstances, and to ensure that at the acceptable exposure level no adverse health effects will occur.

 

Used factors are:

       extrapolation rat man on basis of caloric need: 4

       other interspecies differences: 3

       intraspecies differences: (professional use) 3

       biological availability via oral route: 86%

       weight of professional operator/worker: 70 kg

 

AOELsystemic: 1.5 x 0.86 x 70 / (4 x 3 x 3) = 2.51 mg/day

 

4.4.1 Operator exposure/risk

Exposure to trifloxystrobin and cyproconazole during mixing and loading and application of Sphere is estimated with models. The exposure is estimated for the unprotected operator. In the Tables T.2 and T.3 below the estimated internal exposure is compared with the systemic AOEL. In general, mixing and loading and application is performed by the same person. Therefore, for the total exposure, the respiratory and dermal exposure during mixing/loading and application have to be combined.

The maximum dose in the field is 0.094 kg/ha trifloxystrobin and 0.04 kg/ha cyproconazole.

 

Table T.2 Internal operator exposure to trifloxystrobin and risk assessment for the use of Sphere

 

Route

Estimated internal exposure a (mg /day)

Systemic

AOEL

(mg/day)

Risk-index b

Mechanical downward spraying on winter wheat, spring wheat, triticale, perennial ryegrass, smooth-stalked meadow grass and red fescue

Mixing/

Loading

Respiratory

<0.01

4.2

<0.01

Dermal

0.60

4.2

0.14

Application

Respiratory

0.02

4.2

<0.01

Dermal

0.21

4.2

0.05

 

Total

0.84

4.2

0.20

a External exposure was estimated by EUROPOEM. Internal exposure was calculated with:

       biological availability via the dermal route: 3.8%(dilution) (see 4.2)

1.6 % (concentrate)

       biological availability via the respiratory route: 100% (worst case)

b The risk-index is calculated by dividing the internal exposure by the systemic AOEL.

 

Table T.3 Internal operator exposure to cyproconazole and risk assessment for the use of Sphere

 

Route

Estimated internal exposure a (mg /day)

Systemic

AOEL

(mg/day)

Risk-index b

Mechanical downward spraying on winter wheat, spring wheat, triticale, perennial ryegrass, smooth-stalked meadow grass and red fescue

Mixing/

Loading

Respiratory

<0.01

2.51

<0.01

Dermal

11.5

2.51

4.59

Application

Respiratory

<0.01

2.51

<0.01

Dermal

1.73

2.51

0.69

 

Total

13.2

2.51

5.28

Mechanical downward spraying on sugar and fodder beets

Mixing/

Loading

Respiratory

<0.01

2.51

<0.01

Dermal

8.06

2.51

3.21

Application

Respiratory

<0.01

2.51

0.01

Dermal

1.21

2.51

0.48

 

Total

9.28

2.51

3.70

a External exposure was estimated by EUROPOEM. Internal exposure was calculated with:

       biological availability via the dermal route: 72% (see 4.2)

       biological availability via the respiratory route: 100% (worst case)

b The risk-index is calculated by dividing the internal exposure by the systemic AOEL.

 

4.4.2 Bystander exposure/risk

The bystander exposure is only a fraction of the operator exposure. Based on the low risk-index for trifloxystrobin for the operator, no exposure calculations are performed for bystanders. For the exposure to cyproconazole, a considerable risk for the unprotected operator is calculated; therefore, the bystander exposure is estimated with EUROPOEM II.

The highest dose of cyproconazole based on the intended use of Sphere is 80 g/ha, i.e. 8.0 mg/m2. Considering a body surface of 2 m2, the estimated exposure is 16 mg/person/day. A standard surrogate exposure value 5% for downward spraying is used, leading to an estimated exposure of 0.08 mg/person/day. Considering the dermal absorption of 72%, the final estimated exposure is 0.058 mg/person/day.

The AELsystemic for non-professional users is 2.15 mg/person/day (bodyweight of 60 kg). Therefore the systemic exposure of unprotected bystanders is 2.7% of the AELsystemic for cyproconazole

 

4.4.3 Worker exposure/risk

Re-entry activities in these crops are normally performed by tractor mounted devices and therefore, no worker exposure is expected.

 

4.4.4 Re-entry

See 4.4.3 Worker exposure/risk.

 

Overall conclusion of the exposure/risk assessments of operator, bystander, and worker

The product complies with the Uniform Principles.

 


Operator exposure

Trifloxystrobin

Based on the risk assessment it can be concluded that no adverse health effects are expected for the unprotected operator after dermal and respiratory exposure to trifloxystrobin as a result of the application of Sphere in the cultivation of wheat, triticale, sugar and fodder beets and grass seed.

 

Cyproconazole

Based on the risk assessment, it can be concluded that no adverse health effects are expected for the unprotected operator after respiratory exposure to cyproconazole as a result of the application of Sphere in wheat, triticale, sugar and fodder beets and grass seed.

For the unprotected operator, adverse health effects after dermal exposure to cyproconazole as a result of the application of Sphere in wheat, triticale, sugar and fodder beets and grass seed cannot be excluded. Correct use of personal protective equipment can reduce the dermal exposure by a factor of 10. This results in a sufficient reduction of the exposure to cyproconazole for the application of Sphere in wheat, triticale, sugar and fodder beets and grass seed.

 

Bystander exposure

Based on the risk assessment it can be concluded that no adverse health effects are expected for the unprotected bystander due to exposure to trifloxystrobin and cyproconazole during application of Sphere in the cultivation of wheat, triticale, sugar and fodder beets and grass seed.

 

Worker exposure

No risk assessment was performed as no exposure to cyproconazole and trifloxystrobin after application of Sphere is expected for workers. It can therefore be concluded that no adverse health effects are expected for the unprotected worker after dermal and respiratory exposure during re-entry activities in the cultivation of wheat, triticale, sugar and fodder beets and grass seed due to exposure to cyproconazole and trifloxystrobin after application of Sphere.

 

4.5 Appropriate mammalian toxicology and operator exposure end-points relating to the product and approved uses

See List of end-points for trifloxystrobin and the toxicological profile for cyproconazole.

 

4.6 Data requirements

Based on this evaluation no additional data requirements are identified. The data requirements identified in the EU-assessment are also applicable to the Dutch assessment.

 

4.7 Combination toxicology

The formulation Sphere is a mixture of two active substances, i.e. cyproconazole and trifloxystrobin. The combined toxicological effect of these two active substances has not been investigated with regard to repeated dose toxicity.

It is possible that the combined exposure to the active substances in Sphere may lead to a different toxicological profile, than the profile that is based on the individual substances due to influences on each others effects.

Trifloxystrobin and cyproconazole both induce effects on the liver. The working mechanism of these effects has not been studied any further.

 


4.8 Mammalian toxicology classification and labelling

 

Proposal for the classification of the active ingredient trifloxystrobin (symbols and R phrases)

(EU classification)

Symbol:

Xi

Indication of danger: Irritant

 

Risk phrases

R43

May cause sensitisation by skin contact.

 

Proposal for the classification of the active ingredient cyproconazole (symbols and R phrases)
(EU classification)

Symbol:

Xn

Indication of danger: Harmful

 

Risk phrases

R22

Harmful if swallowed.

 

R63

Possible risk of harm to the unborn child.

 

Proposal for the classification and labelling of the formulation concerning health

Based on the profile of the substance, the provided toxicology of the preparation, the characteristics of the co-formulants, the method of application and the risk assessment for the operator, as mentioned above, the following labelling of the preparation is proposed:

 

Substances, present in the formulation, which should be mentioned on the label by their chemical name (other very toxic, toxic, corrosive or harmful substances):

-

Symbol:

Xn

Indication of danger:

Harmful

R phrases

63

Possible risk of harm to the unborn child.

 

 

 

S phrases

36/37

Wear suitable protective clothing and gloves.

 

46

If swallowed, seek medical advice immediately and show this container or label.

Special provisions:
DPD-phrases3

DPD-11

Contains trifloxystrobin. May produce an allergic reaction.

 

 

 

Plant protection products phrase:
DPD-phrase

DPD01

To avoid risk for man and the environment, comply with the instructions for use

Child-resistant fastening obligatory?

n.a.

Tactile warning of danger obligatory?

n.a.

 

Explanation:

Hazard symbol:

-

Risk phrases:

R41 is no longer assigned, based on acute eye-irritation study with the formulation.

R63 is assigned as the active substance cyproconazole is present in a concentration larger than the concentration limit for R63.

Safety phrases:

S46 is invariably assigned to formulations assigned with the mentioned R-phrase(s), intended for professional use only when this does not lead to more than six safety-phrases.

S26 and S39a are no longer assigned, as R41 is deemed as redundant.

Other:

DPD-11 is assigned as the formulation was negative in a skin sensitisation study, whilst the active substance trifloxystrobin is present in a concentration larger than > 0.1%

 

 

5. Residues

 

Trifloxystrobin

Trifloxystrobin is a new active substance, included on Annex I of 91/414/EEC. The final list of end points presented below is copied from the final review report on trifloxystrobin (SANCO/4339/2000 final, d.d. 7 April 2003). When relevant, some additional remarks/information is given in italics.

 

List of End-points

 

Metabolism in plants (Annex IIA, point 6.1 and 6.7, Annex IIIA, point 8.1 and 8.6)

Plant groups covered

wheat (cereals), apple (fruits) and cucumber (fruiting vegetable).
No qualitative metabolism differences between the crops.

Rotational crops

lettuce, radish, winter wheat, spring wheat

Plant residue definition for monitoring

CGA 279202 (parent EE isomer)

Plant residue definition for risk assessment

CGA 279202 (parent EE isomer)

Conversion factor (monitoring to risk assessment)

--

 

Metabolism in livestock (Annex IIA, point 6.2 and 6.7, Annex IIIA, point 8.1 and 8.6)

Animals covered

Goat, Hen

Animal residue definition for monitoring

CGA 279202 (parent EE isomer) and CGA 321113

Animal residue definition for risk assessment

CGA 279202 (parent EE isomer) and CGA 321113

Conversion factor (monitoring to risk assessment)

--

Metabolism in rat and ruminant similar (yes/no)

yes

Fat soluble residue: (yes/no)

Yes

 

Residues in succeeding crops (Annex IIA, point 6.6, Annex IIIA, point 8.5)

 

 

Metabolism studies in rotational crops conducted at >2N rate (in relation to all proposed GAPs) indicated total radioactive residues to be <0.08 mg/kg, of which only <15% was identified as parent (the residue definition). Therefore no further data on residues in rotational crops are required.

 

Stability of residues (Annex IIA, point 6 introduction, Annex IIIA, point 8 introduction)

 

Stable in grapes cucumber, potatoes, wheat up to 12 months (interim report).

Stable in pomme fruit, grape juice up to six months (interim report).

 

Residues from livestock feeding studies (Annex IIA, point 6.4, Annex IIIA, point 8.3)

Intakes by livestock 0.1 mg/kg diet/day:

Ruminant:

yes

Poultry:

no

Pig:

no

Muscle

<0.02

 

 

Liver

<0.02

 

 

Kidney

<0.02

 

 

Fat

<0.02

 

 

Milk

<0.01

 

 

Eggs

<0.02 (theoretical expected)

 

 

 

Processing factors (Annex IIA, point 6.5, Annex IIIA, point 8.4)

Crop/processed crop

 

Number of studies

Transfer factor

% Transference

Apple/Pear

Washed fruit

Pomace

Juice

Puree

Dried fruit

 

8

7

7

2

2

 

0.64 1.21

2.75 18.6

0.06 0.28

0.33 0.15

0.17 - 0.31

It was not possible to calculate % transference from the data submitted.

Grape

Must

Wine

 

17

17

 

0.06 1.17

0.01 0.2

See above.

 

Comments on/additions to List of End-points

There are mo comments to the List of End-Points.

 

5.1 Summary of residue data

Cyproconazole

Cyproconazole is an existing active substance. The EU-dossier is complete, however the Draft assessment report (DAR) did become available only very recently, and was not used in the assessment. Ireland is RMS. The residue profile presented below is based on the NOTOX report 405563/140508, dated 22 March 2004 and RIVM reports 09556A01 (November 2004) and 10292A00 (17 February 2006). Since the active substance is still in the process of evaluation/discussion, the residue profile below should be regarded as provisional.

 

5.1.1 Metabolism in plants

Cyproconazole

One additional metabolism study for sugar beets was submitted. Parts of the text from decision of the board of 23 December 2005 (Board meeting C-164.3.18, of 14 December 2005) for admission of the product Priori Xtra and from the decision of the board of 5 November 2004 (Board meeting C-150.3.1, d.d. 13 October 2004) for the authorisation of SPHERE were translated and adapted for the present evaluation.

 

Metabolism in plants was studied in three crop categories: fruits (grapes), root and tubers (sugarbeets) and cereals (wheat). Plant metabolism was studied with cyproconazole labelled at three different positions in the molecule: at the central alpha-carbon atom, uniformly 14C-labelled at the phenyl ring or uniformly labelled at the triazole ring.

 

The metabolite profile in grapes (fruits, leaves), wheat (forage, straw) and sugarbeets (leaves, roots) is similar, although cyproconazole in sugarbeets (leaves/roots) is metabolised for a smaller part (15%-20% TRR). The parent compound is the major component of the total radioactive residue (24%-80% TRR). The main metabolic pathway is hydroxylation of the parent compound and subsequent conjugation.

The metabolic profile for wheat grains is variable and in some studies the metabolic profile in grains deviates from other plant parts (forage, straw). The amount of parent compound ranges between 2.6%-46% TRR. The main metabolic pathway in wheat grains is cleavage of the triazole ring or hydroxylation of the parent compound followed by conjugation.

All plant metabolites, except triazolylalanine, were also found in rat. The presence of triazolylalanine was, however, not verified in rat. Triazolylalanine is considered toxicologically not relevant for humans. The metabolism in the plant passes partly through the same pathways as in the rat en livestock, although conjugation between plant and rat/livestock is different (glucose versus sulphate conjugation).

 

Trifloxystrobin

Additional metabolism studies for sugar beets were submitted. Parts of the text from
C-150.3.13 is translated and adapted for the present evaluation.

 

Metabolism in plants was studied in three crop categories: fruits (apples, cucumber), root and tubers (sugar beets) and cereals (wheat). Plant metabolism was studied with trifloxystrobin uniformly 14C-labelled at the trifluoromethyl-phenyl ring or at the at the glyoxyl-phenyl ring.

 

In metabolism studies in apples, trifloxystrobin was the major component of the residue (90% TRR). Metabolic reactions involved cis/trans isomerization, methyl ester cleavage (hydrolysis) and subsequent hydroxylation (oxidation) at the trifluoromethyl-phenyl ring followed by conjugation, methyl ester cleavage (hydrolysis) and subsequent cleavage (hydrolysis) of the ethylideneaminooxy-methyl bridge.

 

In metabolism studies in cucumbers, trifloxystrobin was the major component of the residue (80%-90% TRR). Metabolites formed were only minor components. Metabolism in cucumbers proceeded along a similar pathway as apples, except that cleavage (hydrolysis) of the ethylideneamino-oxymethyl bridge was not observed, while hydroxylation (oxidation) at the methyl group of the ethylidenenaminooxy-methyl group was observed. Next to parent, CGA 321113 ((E,E)-methoxyimino-{2-[1-(3-trifluoro-methyl-phenyl)-ethylideneamino-oxymethyl]-phenyl}-acetic acid) was the major metabolite (3.5% TRR).

 

In metabolism studies in sugarbeets, trifloxystrobin (parent and isomers) was the major component of the residue (21%-95% TRR in leaves or roots at DAT = 0, 21 or 45). Metabolism in sugarbeets proceeded along a similar pathway as cucumbers, except that further hydroxylation (oxidation) at the trifluromethyl-phenyl ring was observed. Next to parent, metabolites CGA 321113 ((E,E)-methoxyimino-{2-[1-(3-trifluoromethyl-phenyl)-ethylideneamino-oxymethyl]-phenyl}-acetic acid) and II19a ({2-[1-(2,3-dihydroxy-5-methyl-phenyl)-2-hydroxy-ethylideneamino-oxymethyl]-phenyl}-methoxy-imino-acetic acid) were the major metabolites: 11% TRR in roots at DAT = 21 or 45 or 15%-19% TRR in roots at DAT= 0 or 45, respectively.

 

In wheat, trifloxystrobin is effectively metabolised. Trifloxystrobin (parent and isomers) only take up 1.5%-5.7% TRR in wheat stems, 3% TRR in grains and 3.5% TRR in straw. Metabolism in wheat proceeded along a similar pathway as cucumbers, except that further oxidation at the methyl group of the ethylideneaminooxymethylgroup was observed. The metabolic profile was complex due to cis/trans isomerisation of parent and metabolites. About 47% TRR in grain and 46% TRR in straw could not be extracted.

 

Metabolite patterns in leaves with tops and roots in an overdose experiment were identical to the normal dose experiment regarding the qualitative distribution of the radioactivity. However, the qualitative distribution of radioactivity showed significant higher parent contents.

 

All metabolites found in apple, cucumber, sugarbeets and wheat were also found in rat, goat and hens.

 

5.1.2 Metabolism in livestock

Cyproconazool

Distribution, excretion and metabolism of cyproconazole were studied in goats and in laying hens.

The goats were exposed for 3, 4 or 12 days to 1, 0.4 or 0.048 mg/kg bw/day, respectively (comparable to 30, 10 and 1 mg/kg diet). In milk a steady state level is reached within one day.

The excretion in the urine was 51-81%, the excretion in the faeces was 10-28%. In milk 0.19-1.09% of the dose was recovered, in organs/tissues 1.06-0.5% was recovered; the majority of this amount was present in the liver.

Parent cyproconazole amounted to 8.5% of the TRR in urine and 20.4% TRR in faeces. Five metabolites were identified in urine and faeces (approximately 20% of TRR in urine and faeces). 9.1% of TRR in milk was parent cyproconazole. Two metabolites, 5-(4-chlorophenyl)-3,5-dihydroxy-4-methyl-6-(1 H-1,2,4-triazole-1 -yl)-1 -hexaneacid en 5-(4-chlorophenyl)-5 hydroxy-4-methyl-6-(1H-1,2,4-triazole-1-yl)-2-hexeneacid, were present for 46.9% and 31.5%, respectively, and were the major residues in milk.

In liver, kidneys, muscle and fat, parent cyproconazole were the major components detected, amounting to 19-47% of the TRR, reduced parent substance (up to 36% as M38), OH-derivates of parent cyproconazole (up to 27% as M9/M14 and up to 16% as M11/M18) and a metabolite with an opened cyclopropane-ring (up to 12% as M36).

The major metabolite in milk, 5-(4-chlorophenyl)-3,5-dihydroxy-4-methyl-6-(1H-1,2,4-triazole-1-yl)-1 -hexaneacid, was only recovered in the goat, but was proposed as an intermediate in the rat.

The metabolite pattems in milk appear inconsistent for the three goat metabolism studies. This can be explained by the age of one of the studies. This study was performed several years ago, when the techniques then available could not identify certain metabolites, which were recovered in the other two metabolism studies in the goat, performed some years later.

It was therefore concluded, that the metabolic pathway in the three studies is consistent.

 

Hens were exposed to 100 and 1 mg a.s./kg bw/day (the latter is equivalent to ca. 30 mg/kg feed) for 1 or 3 days respectively or 4 days to 8,1 mg a.s./kg bw/day (corresponding to 114 mg a.s./kg feed). The metabolism studies were to short in duration to establish a plateau level in eggs. Highest residue levels were found in liver or in fat. The residue levels in egg yolk are higher than in egg white.

 

The metabolite pattern in goats is different from the one in hens. Furthermore, the metabolite pattern in milk, eggs and chicken fat deviates from the metabolic pattern in other tissues from the same animal.

In the chicken metabolism studies the metabolite pattems in tissues and eggs depend on the dose levels. Relatively large amounts of parent cyproconazole were present at the high dose levels, while at the low dose levels parent substance was metabolised to a large extend. In fat relatively high levels of parent substance were present.

In chicken tissues the prominent residue components were parent substance (up to 78%), a metabolite where the atom with the cyclopropane-ring separated (up to 53% as M15) and OH-derivates of parent cyproconazole (up to 41% as M9/M14 and up to 13% as M11/M18).

In eggs the most prominent residue components were parent substance (up to 54%), OH-derivates of parent cyproconazole (up to 44% as M9/M14) and a metabolite where the carbon atom with the cyclopropane-ring separated (up to 23% as M15).

Chlorophenyldihydroxymethyltriazolehexeneacid (M36) and chlorophenylcyclopropylethyl-

triazole (M38) are important metabolites in goat tissues, whilst these were not detected in

chicken tissues.

However, chlorophenyldihydroxymethyltriazolehexeneacid (M36) could be an intermediate of chlorophenylhydroxymethyltriazolylhexeneacid (M21/M21a) that was identified in chicken

tissues. Chlorophenyltriazole-ethanol (M15) is a major metabolite in chicken tissues, whilst this metabolite was only present in very small concentrations.

This implies that the metabolic pathway in goat and chicken is different.

Of the metabolites recovered in the goat, the presence of chlorophenylcyclopropylethyl-triazole (M38) and chlorohydroxyfenylcyclopropyltriazolylbutanetriol (Z2) was not studied in the rat. Of the metabolites recovered in the hen, the presence of chlorophenylmethyltriazolylpentanediol (M59) was not studied in the rat. M59 was detected in a very low (0,6%) amount, therefore, the metabolite is considered to be of no toxicological relevance. All other metabolites, recovered in goat and hen, were also found in the rat.

Therefore it is assumed that the metabolism of cyproconazole in the goat is similar to the metabolism in the rat.

 

Trifloxystrobin

The excretion, distribution and metabolism of trifloxystrobin was studied in the lactating goat and the laying hen. Although differences in the metabolic rate were identified, the routes of degradation in the goat and hen were comparable to the metabolic pathway in the rat.

 

5.1.3 Residue definition (plant and animal)

Cyproconazole

Separate residue definitions for enforcement and risk assessment are proposed.

The residue in plant commodities for enforcement is proposed as:

cyproconazole (no metabolites or conjugates), expressed as cyproconazole.

The limit of quantification is 0.05 mg/kg.

 

The residue definition in plant commodities for risk assessment is proposed as:

The sum of cyproconazole, diastereomers M9[1] and M14 and diastereomers M11[2] and M18, including the conjugates of cyproconazole and the diastereomers stated, expressed as cypronozole equivalents.

The limit of quantification is 0.05 mg/kg eq.

 

To convert the residue for enforcement into the residue for risk assessment the following multiplication factors are used:

3.5 for cereal grains

1.5 for cereal straw

1.3 for cereal forage

1.0 for sugarbeets (leaves, roots)

 

The residue definition in animal commodities for enforcement is proposed as:

Cyproconazole including conjugates (no metabolites), expressed as cypronconazole equivalents.

The limit of quantification is 0.01 mg/kg in milk and 0.05 mg/kg for other animal commodities

 

The residue definition in animal commodities for risk assessment is proposed as:

The sum of cyproconazole, diastereomers M91 and M14, diastereomers M112 and M18, diastereomers M21[3] and M21a, metabolite M15[4], metabolite M36[5] and M38[6], including the conjugates of these compounds, expressed as cyproconazole equivalents.

Metabolites M14, M21a and M36 were included based on feeding studies. The other metabolites were found in the metabolism studies.

The limit of quantification is 0.01 mg/kg in milk and 0.05 mg/kg for other animal commodities.

 

To convert the residue for enforcement into the residue for risk assessment the following multiplication factors are used:

3.9 for ruminant tissues

9.7 for milk

2.2 for poultry fat

26 for other poultry tissues

5.1 for eggs

 

The residue in poultry is considered to be fat-soluble.

 

Trifloxystrobin

Additional metabolism studies for sugar beets were submitted. Text from EU-monograph (RMS UK, version April 2000) is adopted and adapted for the present evaluation.

 

No qualitative differences in metabolism were observed in apple, cucumber, sugar beets and wheat. Based on these metabolism data, residues in primary crops should be defined as parent only. Trifloxystrobin was extensively metabolised in wheat, however, metabolites were not considered to be of toxicological concern. The ratio of trifloxystrobin to its isomers is such that the levels of the isomers are not of concern. Residues in following crops should be defined as parent only as trifluoroacetic acid is not of toxicological concern at the levels present in crops as a result of trifloxystrobin being applied at rates comparable with those of proposed GAPs.

The residue in plant commodities is defined as CGA 279202 (parent EE isomer) for compliance with MRLs and for dietary intake.

 

Metabolism in livestock was studied in ruminants (goats) and poultry (laying hens). Based on these metabolism data, residues in product of animal origin should be defined as the sum of parent and metabolite CGA 321113 (acid). Metabolism was more extensive in some tissues, however metabolites were not considered to be of toxicological concern at the levels present. Residues in poultry products as a result of predicted normal rate exposure are highly unlikely to be determinable. CGA 321113 was found in the rat and is considered to be of no greater toxicological concern than the parent molecule.

The residue in animal commodities is defined as the sum of CGA 279202 (parent EE isomer) and CGA 321113 for compliance with MRLs and for dietary intake. The residue is considered to be fat-soluble.

 

5.1.4 Stability of residues

Cyproconazole

In a storage stability study of cyproconazole in frozen samples of peach, raisin, nectarine, grape, peanut (nut, husk, green forage, hay) and wheat (grain, forage, hay) no decline in the residue level was detected during a storage period of at least 38 months.

Two studies, in which no decline of cyproconazole-residues was observed in wheat, grape and apple after 36 months of storage, is seen as supporting data as data on concurrent recovery monsters is not available.

No study in the storage stability of cyproconazole residues in products of animal origin have been provided. However, in a feeding study with lactating cows, the storage stability in milk, kidney, liver and fat was demonstrated for the duration of the study.

Storage stability of wheat and sugarbeet samples from the additionally submitted trials is covered by the 42 month storage stability period for water containing crops (wheat forage, sugarbeet leaves), the 39 month storage stability period for dry crops with starch and protein (wheat grain), the 41 month storage stability period for wheat hay (wheat straw) and the 12 month storage period for sugarbeet roots.

 

Trifloxystrobin

Parent trifloxystrobin and metabolite CGA321113 were shown to be stable for at least 12 months during frozen storage in grapes, cucumbers (watery matrix), wheat (whole plant, straw and grains; dry matrix). In another study apples and applesauce were stored at 20C during 6 months. Parent trifloxystrobin as well as metabolite CGA 321113 were shown to be stable in both samples. In meat, liver, eggs and milk samples, residues of trifloxystrobin and metabolite CGA321113 were shown to be stable for 24 months storage at -20C.

Storage stability data for the special crop sugar beet roots can be derived from the storage stability tests in the metabolism study in sugarbeet. Residues were shown to be stable for at least 9 months when stored at 18C. Storage stability for sugar beet leaves + tops is covered by the 24 month storage stability period for water containing crops (grapes, cucumber).

 

5.1.5 Residue data

The product Sphere SC is intended for use on wheat, triticale, grass seeds, sugarbeet and fodder beets.

 

Cyproconazole

Wheat

For winter wheat 13 residue trials, performed in Northern-Europe, were selected at more worst case conditions than the critical GAP: a PHI of 35-46 days and 2 treatments of each 0.078-0.10 kg ai/ha at BBCH 31-49 and BBCH 61-69.

Residues in wheat grain ranged from <0.01-0.05 mg/kg, residues in wheat straw ranged from 0.09-1.6 mg/kg. Residues in wheat forage were not evaluated. All trials were carried out with winter wheat. Wheat is a major crop. Therefore at least 8 residue trials should be available. A sufficient number of residue trials is available. An STMR of <0.02 mg/kg and a HR of 0.05 mg/kg in wheat grain is proposed

Residue data for triticale can be extrapolated from wheat.

 

Grass seeds

There are no residue trials for grass seeds. Grass seeds are not fed to livestock.

Gras straw can be fed to livestock and can be extrapolated from wheat straw if the GAP is the same. The critical GAP for wheat straw is worst case when compared to the critical GAP for grass straw. Therefore residue data extrapolated from wheat straw must be considered more worst case than would be expected from GAP.

The preparation is applied in accordance with the growth-stages identified in the GAP in the cultivation of cereals. These growth stages are not identified in the GAP for grass seeds, therefore a restriction for grazing or feeding of treated grass within 45 days after application is included on the label. Grass seeds could be harvested at an earlier time point than cereals. No residue trials are available for grass grown from treated grass seeds. But because the seeds only contain very low amounts of residues (<0.01-0.05 mg/kg), residues are not expected in the grass grown from these seeds. From a metabolism study with wheat grains, treated with cyproconazole as seed dressing at an equivalent concentration of 10 mg/kg, total radioactive residues in wheat forage, wheat grains, wheat straw were < 0.001 mg/kg eq. Therefore, no STMR and HR are proposed for grass.

 

Sugar beets

For sugar beets, 4 residue trials were selected at the critical GAP: a PHI of 21 days and 2 treatments of each 0.056 kg ai/ha with an interval of 21-23 days. Residue levels in sugar beet roots were <0.02-0.03 mg/kg, while residue levels in leaves with tops ranged from 0.13 mg/kg to 0.48 mg/kg. Sugar beet is a major crop. Therefore at least 8 residue trials should be available. However, residue levels were at or about the LOD of 0.02* mg/kg, therefore the available studies are sufficient.

 

Fodder beets

There are no residue trials for fodder beets. Residue data for fodder beets can be extrapolated from sugar beets. Fodder beets are fed as whole crop (i.e. leaves and roots). Sugar beet leaves can be used as livestock feed.

 

Trifloxystrobin

Wheat

None of the additionally submitted wheat trials is considered representative for the critical NL-GAP, because the last application was too late in the growing season (growth stage BBCH 69-BBCH 83). Residue trials evaluated in the EU monograph for Northern Europe can however be used for the NL situation. Residues in wheat grain ranged from <0.02-0.02 mg/kg (8 trials), residues in wheat straw ranged from 0.06-2.3 mg/kg (8 trials) and residues in wheat forage ranged from 0.05-0.25 mg/kg (2 trials). Wheat is a major crop. Therefore at least 8 residue trials should be available. A sufficient number of residue trials is available.

Residue data for triticale can be extrapolated from wheat.

 

Grass seeds

There are no residue trials for grass seeds. Grass seeds are not fed to livestock.

Grass straw can be fed to livestock and can be extrapolated from wheat straw if the GAP is the same. The critical GAP for wheat straw is more worst case than the critical GAP for grass straw. Therefore residue data extrapolated from wheat straw must be considered more worst case than would be expected from GAP.

The preparation is applied in accordance with the growth-stages identified in the GAP in the cultivation of cereals. These growth stages are not identified in the GAP for grass seeds, therefore a restriction for grazing or feeding of treated grass within 45 days after application is included on the label. Grass seeds could be harvested at an earlier time point than cereals

No residue trials are available for grass grown from treated grass seeds. But because the seeds only contain very low amounts of residues (<0.02-0.02 mg/kg), residues are not expected in the grass grown from these seeds.

 

Sugar beets

Four trials on sugar beets were submitted which were carried out in Northern Europe. Residue levels in sugar beet roots were <0.02 mg/kg, while residue levels in leaves with tops ranged from <0.02 mg/kg to 0.44 mg/kg. Residue results for sugar beet roots are considered provisional because storage stability was not verified for this special crop. Sugar beet is a major crop. Therefore at least 8 residue trials should be available. However, residue levels were at the LOD of 0.02* mg/kg, therefore the available studies are sufficient.

 


Fodder beets

There are no residue trials for fodder beets. Residue data for fodder beets can be extrapolated from sugar beets. Fodder beets are fed as whole crop (i.e. leaves and roots). Sugar beet leaves can be used as livestock feed.

 

5.1.6 Residues in succeeding crops

Trifloxystrobin

The metabolism of cyproconazole in rotational crops was studied in lettuce, radish winter wheat and spring wheat. No residues in rotational crops due to the use of cyproconazole are expected.

 

Cyproconazole

In a greenhouse study, soil was treated with 1x 0,10 kg a.s./ha radioactively labelled

cyproconazole. Crops were planted 30 and 90 days after application.

The maximum level of total radioactive residue (TRR) amounted 0,44 mg/kg eq.

Taking the residue definition for monitoring into consideration, the following residue levels were detected: 0,024-0,029 mg/kg cyproconazole in lettuce, 0,05-0,07 mg/kg in wheat forage, 0,016-

0,036 mg/kg in sugar beet leaf and 0,016 mg/kg in lettuce roots (0,1%-6,3% TRR).

In a field study, barley or non-use land was treated with 2x 0,080 kg a.s./ha or 1x 0,10 kg a.s./ha. After 56-57, 183-192, 315-345 and 414 days, rotational crops were planted on this land (radish, carrot, rape seed and/or potatoes).

In most crops, no cyproconazole (parent) was detected (<0,01 mg/kg). In only two cases, residues were detected. In radish (sown DAT=57 and harvested DAT = 91) 0,02 mg/kg cyproconazole was detected and in carrot (sown DAT=183 and harvested DAT = 246) 0,01 mg/kg cyproconazole was detected. These residue levels are lower than the LOQ for monitoring (0,05 mg/kg).

In the field studies summarized above, only root and tuber vegetables (radish, carrot and potatoes) and pulses/oilseeds (rape seed) were studied.

No studies in leafy crops and cereals were performed, but are required. Especially studies in leafy crops, as it was evident from the studies under protected conditions, that detectable residues are expected in leafy crops. Studies with the leaves of sugar beets cannot be extrapolated to leafy crops, as the ratio root: leaves is very different in sugar beets than in leafy crops. The used dose of 1x 0,10 kg a.s./ha is, despite the GAP 2x 80 g a.s/ha, a correct dose. Depending on the crop/commodity and the growth stage of the erop, interception occurs. When SPHERE is applied in correspondence to the cGAP, 90% of the applied dose is intercepted by the erop and only 16 g cyproconazole/ha will reach the soil. The greenhouse study available represents a worst-case situation.

It can be concluded that in cereals grown as rotational erop, no residue levels higher than residue levels in primary crops are expected.

 

When cyproconazole is applied twice on cereals, residues can be expected in fast growing leafy crops, grown as rotational crops.

As only one study is available (spread unknown) and therefore in practice higher concentrations might be detected, residues at or above the LOQ of 0,05 mg/kg cannot be excluded. Therefore, fast growing leafy crops need to be excluded as rotational crops in the same season by a restrictive sentence on the product label.

 

When the contribution of 0,02 mg/kg cyproconazole in radish is extrapolated to swedes/turnip and sugar/fodder beets, no extra contribution to the MRL for animal products is expected. The HR and STMR (based on the residue definition for risk assessment) for liver of ruminants, however, is increased from 0.53 to 0.56 mg/kg eq and from 0,17 to 0,24 mg/kg eq. Influence on residue levels in other tissues in negligible.

 

When the contribution of 0,02 mg/kg cyproconazole in radish is extrapolated to all other root and tuber vegetables grown in the Netherlands and when the contribution of the residues in root and tuber vegetables and in animal products is included in the NTMDI-calculation, only the contribution to the ADI for children ages 1-6-years increases from 47,3% to 49,1%. When the contribution of residues in root and tuber vegetables and in animal products is included in the NESTI-calculation, then the maximum contribution of the ARfD is not increased for the general population nor for children ages 1-6.

 

5.1.7 Residues from livestock feeding studies

Trifloxystrobin

Livestock feeding studies in hen and pig are not required as the trigger value of 0.1 mg/kg diet is not exceeded.

As the use of wheat straw and grain as livestock feed can lead to an intake of 0.2 to 0.6 mg/kg feed (dry weight) for cattle, a feeding study in dairy cattle was performed. In this study it was shown that at a residue level of 6 mg/kg feed (dry weight), no residue levels of trifloxystrobin were detectable in tissues and milk. According to the EU-monograph on trifoxystrobin, no detectable residues in products of animal origin are expected after the use of wheat and apple as livestock feed.

 

Cyproconazole

The exposure of livestock to cyproconazole was estimated using the highest residue levels found in the supervised residue trials; grain 0.05 mg/kg, straw 1.6 mg/kg, sugar/fodder beet 0.02 and sugar beet leaves 0.13 mg/kg.

Livestock feeding studies in hen and pig are not required as the trigger value of 0.1 mg/kg diet is not exceeded.

For dairy cattle the estimated intake was 0.65 mg/kg dry matter and 1.2 mg/kg dry matter for beef cattle.

 

In a feeding study, 3 lactating cows per dose group were fed a cyproconazole containing diet twice-daily for 34-37 consecutive days, at dose rates 0.01, 0.107, 0.376 en 1.01 mg/kg bw/day, corresponding to 1.25, 3.75, 12.5 en 37.5 mg/kg dry feed (hay). Cyproconazole residues in milk reached a steady state of <0.005, 0.005, 0.005 en 0.008 for the 4 dose groups.

Residues in muscle, fat and kidney were below the limit of detection of 0.05 mg/kg for al dose groups. The highest residue level in liver amounted to 0,09, 0,22, 0,60 en 0,93 mg/kg in the 4 dose groups.

The mean residue level in liver amounted to 0,082, 0,21, 0,51 en 0,75 mg/kg in the four dose groups.

 

5.1.8 Processing factors

Trifloxystrobin

Four processing studies with trifloxystrobin in barley are available. No residues in malt and beer could be detected.

 

Cyproconazole

No processing studies with cyproconazole are available. In the view of the low residue levels in sugar and fodder beets and cereals, processing studies are not required.

 

5.1.9 Calculation of the ADI and the ARfD

Trifloxystrobin

The ADI is based on the NOAEL of 10 mg/kg bw/d in the 2-year toxicity study in rat. Application of a safety factor for inter- and intraspecies differences of 100 results in an ADI of 0.1 mg/kg bw/day (see the List of Endpoints for mammalian toxicology).

No ARfD is derived, since trifloxystrobin has no acute toxic properties.

 


Cyproconazole

The ADI is based on the NOAEL of 0.7 mg/kg bw/d in the oral carcinogenicity study in the mouse. Application of a safety factor for inter- and intraspecies differences of 100 results in an ADI of 0.007 mg/kg bw/day (see the List of Endpoints for mammalian toxicology).

The ARfD is based on the NOAEL of 10 mg/kg bw/d in the rabbit teratogenicity study. Application of a safety factor for inter- and intraspecies differences of 100 results in an ARfD of 0.1 mg/kg bw/day (see the List of Endpoints for mammalian toxicology).

 

5.2 Maximum Residue Levels

Cyproconazole

MRLs, STMRs and HRs proposed are listed in the table. In the Dutch MRL directive an MRL of 0.05* mg/kg for all commodities is established.

 

Table R.1 Provisional proposals for national MRLs, STMRs and HRs for cyproconazole

Product

MRLa

(mg/kg eq)

maximum residueb

(mg/kg eq)

STMRb

(mg/kg eq)

HRb

(mg/kg eq)

wheat

0.1

0.1 x 3.5 = 0.35

0.07

0.175

triticale

0.1

0.1 x 3.5 = 0.35

0.07

0.175

meat, fat, kidney

from slaugher animals

0.05*

0.05 x 3.9 = 0.20

0.20

0.20

liver

from slaughter animals

0.2

0.2 x 3.9 = 0.78

0.20

0.43

milk

0.03

0.03 x 9.7 = 0.29

0.23

not applicable

poultry tissues

0.05*

0.05

0.05

0.05

eggs

0.05*

0.05

0.05

0.05

a based on the residue definition for enforcement

b based on the residue definition for risk assessment

 

Trifloxystrobin

MRLs, STMRs and HRs proposed are listed in the table.

Harmonised provisional EU-MRLs have been established in Directives 2005/37/EC (cereals) 2006/60/EC (plant products).

 

Crop/commodity

MRL (mg/kg)

Citrus fruit

0.3

 

Tree nuts

0.02

*

Pome fruit

0.5

 

Apricots, cherries, peaches, nectarines

1

 

Plums

0.2

 

Grapes

5

 

Strawberries

0.5

 

Currants, goose berries

1

 

Bananas

0.05

 

Tomatoes

0.5

 

Cucurbitaceae edible peel

0.2

 

Melons

0.3

 

Beans (with pods)

0.5

 

Oilseeds, tea

0.05

*

Hops

30

 

Barley

0.3

 

Rye, triticale, wheat

0.05

 

Other products plant origin

0.02

*

 

The product does not comply with the MRL Directives/Regulation. Proposals for

The MRLs for cyproconazole in liver, milk, wheat and triticale need to be notified nationally.

 

5.3 Consumer risk assessment

Cyproconazole

Risk assessment for chronic exposure through diet

Based on the proposed residue tolerances, a calculation of the National Theoretical Maximum Daily Intake (NTMDI) was carried out using the National Dutch diet. Calculation of the NTMDI shows that 45% and 160% of the ADI is used for the general population and for children, respectively.

 

Because the ADI is exceeded for children, a calculation of the national estimated daily intake (NEDI) was carried out using the National Dutch diet and the STMR values for wheat grain (0.02 mg/kg), milk (0.005*9.7) and liver (0.082*3.9). Calculation of the NEDI shows that 5.4% and 22.7% of the ADI is used for the general population and for children, respectively.

 

Risk assessment for acute exposure through diet

Based on the STMR and HR values for cyproconazole, a calculation of the National Estimate of Short Term Intake (NESTI) was carried out using the National Dutch diet. Calculation of the NESTI shows that 3.9% (turkey meat) and 11.9% (cows milk) of the ARfD is used for the general population and for children, respectively. An acute risk for the consumer from consumption of products treated with cyproconazole is therefore not expected.

 

Trifloxystrobin

Risk assessment for chronic exposure through diet

Based on the proposed residue tolerances, a calculation of the National Theoretical Maximum Daily Intake (NTMDI) was carried out using the National Dutch diet. Calculation of the NTMDI shows that 6.5% and 11% of the ADI is used for the general population and for children, respectively.

 

Risk assessment for acute exposure through diet

An ARfD for trifloxystrobin is considered not necessary, because trifloxystrobin has no acute toxic properties. An acute risk for the consumer is therefore not expected.

 

Combination toxicology

Cyproconazole and trifloxystrobin both have an effect on the liver. The mechanism of action was not investigated; a cumulative exposure cannot be excluded. As the risk assessment for cyproconazole and trifloxystrobin for chronic as well as acute exposure show that the ARfD and ADI are not used for less than 100% individually as well as combined maximally 11.9% general population and 33.7% children 1-6 for chronic exposure), a risk due to the combined exposure to trifloxystrobin and cyproconazole is not expected.

 

Conclusion

If Sphere SC is used according to GAP, a risk for the consumer is not expected.

The product complies with the Uniform Principles.

 

In the GAP/instructions for use the following has to be stated:

In het WG:

Behandelde percelen mogen niet tijdens en binnen 45 dagen na toepassing worden beweid of gemaaid ten behoeve van voederdoeleinden.

 

In verband met residuen in volggewassen mogen na gebruik in de teelt van granen in het hetzelfde teeltseizoen geen snelgroeiende bladgewassen geteeld worden.

 


In het GA:

Onder snelgroeiende bladgewassen worden verstaan sla-achtigen en spinazie met een korte groeiperiode, zoals geclassificeerd in appendix 2 van RIVM rapport 613340006.

 

5.4 Data requirements

No data requirements were identified

 

 

6. Environmental fate and behaviour

 

In the Dutch Pesticide Law the Uniform Principles are implemented in the Regulation of Uniform Principles for Plant protection products (BUBG). This Regulation is also the legal basis for the Dutch specific criteria.

 

List of Endpoints Fate/behaviour

 

Trifloxystrobin

Fate and behaviour in soil

 

Route of degradation

 

Aerobic:

 

Mineralization after 100 days:

4-64% after 105-365d [14C-GP]-label (n=8), 57% after 365 days [14C-TP]-label (n=1)

sterile conditions - negligible after 365 d (n=1)

Non-extractable residues after 100 days:

9-27% after 105-365d [14C-GP]-label (n=8), 27% after 365 days [14C-TP]-label (n=1)

sterile conditions - negligible after 365d (n=1)

Major metabolites above 10 % of applied active substance: name and/or code
% of applied rate (range and maximum)

CGA321113 85-97% at 7-28d (n=9)

[14C-GP & TP]-labels

 

 

Supplemental studies

 

Anaerobic:

Mineralisation negligible

Non-extractable residues 7% after 365d

 

Metabolites

CGA321113 97% after 90 d

(n=1, [14C-GP]-label)

Soil photolysis:

Mineralisation 2-5% after 30d

Non-extractable residues 25% after 30d

 

Metabolites

CGA321113 36-44% after 2-10d

CGA373466 42% after 18-22d

(n=2, [14C-GP & TP]-label)

 

 

Remarks:

None

 

Rate of degradation

 

Laboratory studies

 

DT50lab (20 C, aerobic):

Method of calculation 1st, 2 compartment 1st , √ 1st and 1.5st order decline

0.3-3.6d (n=10, 19-25C, 40-75%WHC, r2= 0.98-1.0);

mean first order normalised to 20C,10kPa, 0.67d

(from 11 experiments where n= 5)

CGA321113: 35->500d (n=10, 19-25C, 40-75%WHC)

CGA321113 mean first order normalised 20C,10kPa, 116d (from 11 experiments where n= 5)

NOA413161: 253 d (n=1, 20C, 40% WHC)

DT50lab (22C, photolytic): 0.7 days of 50N summer sunlight

CGA321113: 50 days of 50N summer sunlight

CGA373446: 50 days of 50N summer sunlight

DT90lab (20 C, aerobic):

ca. 39 days.

DT50lab (10 C, aerobic):

1.2d (n=1, 75%WHC, r2= 1.0

CGA321113: 380 d (n=1, 75%WHC)

DT50lab (20 C, anaerobic):

0.4d (n=1, r2= 0.98)

CGA321113: >1000d (n=1)

 

 

Field studies (country or region)

 

DT50f from soil dissipation studies:

Northern France (pre-emergence): 9d (n=1, r2=1.0, 1st order)
Southern France (pre-emergence):5d (n=1, r2=0.96, 1st order)

Switzerland (pre-emergence): 2-9d (n=5, r2=0.95-1.0, 1st, 1.5st & 1st order)

Germany (cropping details not provided): 8-12d

Italy (pre-emergence): 5d (n=1, r2=0.98, 1st order) Geometric mean 1st order value used as groundwater modelling input 6.7 d (n=6, 3 Swiss, German, French & Italian trials)

DT90f from soil dissipation studies:

Northern France (pre-emergence): 28d (n=1, r2=1.0, 1st order)
Southern France (pre-emergence): 16d (n=1, r2=0.96, 1st order)

Switzerland (pre-emergence): 17-31d (n=5, r2=0.95-1.0, 1st, 1.5st & 1st order)

Germany (cropping details not provided): 26-41d

Italy (pre-emergence): 15d (n=1, r2=0.98, 1st order)

 

DT50f and DT90f for metabolites:

CGA321113

Northern France: 0.16 mg/kg max (91d), DT50 120d, DT90 400d (r2=0.99, 1st order, n=1)
Southern France:0.12 mg/kg max (28d), DT50 88d, DT90 460d (r2=0.89, 1.5st order, n=1)

Switzerland: 0.17-0.4 mg/kg max (0-31d), DT50 8-110d, DT90 83->500d (r2=0.87-0.99, 1st, 1st order, n=5)

Germany: DT50 58d, DT90 190d (n=1)

Italy: DT50 25d, DT90 280d (r2=0.99, 1st order, n=1)

Geometric mean 1st order DT50 value used as groundwater modelling input 59.9 d (n=6, 3 Swiss, German, French & Italian trials) normalised to 20C 41.9d

CGA373466

Switzerland: 0.1-0.24 mg/kg max (2-28d), DT50 8.3-86d, DT90 92-290d (r2=0.92-0.95, 1st, 1st order, n=2)

Italy: DT50 40d, DT90 210d (r2=0.94, 1.5 order, n=1) Geometric mean 1st order DT50 value used as groundwater modelling input 52.1 d (n=3, 2 Swiss & Italian trials) ) normalised to 20C 36.1d

NOA 413161

Swiss lysimeter study, single Borstel soil 1st order DT50 97.3 d (normalised to 20C, -10kPa)

NOA 413163

Swiss lysimeter study, single Borstel soil 1st order

DT50 43.8 d (normalised to 20C, -10kPa)

Soil accumulation studies:

CGA321113 could accumulate. A plateau concentration is calculated at 0.052 mg/kg assuming a DT50 of 120 days, 50% crop interception, 50% formation and 1125g a.s/ha (total annual dose to grapes) is applied a year. An accumulation factor of ca. 1.14 is calculated.

Soil residue studies:

None. Not required.

 

 

Remarks:

e.g. effect of soil pH on degradation

rate

None