14698 N
HET COLLEGE VOOR DE TOELATING VAN GEWASBESCHERMINGSMIDDELEN EN BIOCIDEN
1 TOELATING Op 19 mei 2011 is van
BELCHIM Crop Protection nv/sa Technologielaan 7
B-1840 LONDERZEEL BELGIE
een aanvraag ontvangen voor toelating van het gewasbeschermingsmiddel PROMAN
op basis van de werkzame stof metobromuron.
BESLUIT HET COLLEGE tot toelating van bovenstaand middel.
Alle bijlagen vormen een onlosmakelijk onderdeel van dit besluit.
Voor nadere gegevens over deze toelating wordt verwezen naar de bijlagen:
- Bijlage I voor details van de aanvraag en toelating.
- Bijlage II voor de etikettering.
- Bijlage III voor wettelijk gebruik.
- Bijlage IV voor de onderbouwing.
1.1 Samenstelling, vorm en verpakking
De toelating geldt uitsluitend voor het middel in de samenstelling, vorm en de verpakking als waarvoor de toelating is verleend.
1.2 Gebruik
Het middel mag slechts worden gebruikt met inachtneming van hetgeen in bijlage III bij dit besluit is voorgeschreven.
1.3 Classificatie en etikettering
Mede gelet op de onder “wettelijke grondslag” vermelde wetsartikelen, dienen alle volgende aanduidingen en vermeldingen op de verpakking te worden vermeld:
- De aanduidingen, letterlijk en zonder enige aanvulling, zoals vermeld onder
“verpakkingsinformatie” in bijlage I bij dit besluit.
- De etikettering zoals opgenomen in bijlage II bij dit besluit.
14698 N
- Het wettelijk gebruiksvoorschrift, letterlijk en zonder enige aanvulling, zoals opgenomen in bijlage III bij dit besluit.
- Overige bij wettelijk voorschrift voorgeschreven aanduidingen en vermeldingen.
2 WETTELIJKE GRONDSLAG
Besluit Artikel 80, vijfde lid Verordening (EG) 1107/2009 juncto artikel 23, eerste lid, Wet gewasbeschermingsmiddelen en biociden
Classificatie en etikettering artikel 31 en artikel 65 van de Verordening (EG) 1107/2009 Gebruikt toetsingskader RGB (Hoofdstuk 2) en de Evaluation Manual 1.1.
3 BEOORDELINGEN
3.1 Fysische en chemische eigenschappen
De aard en de hoeveelheid van de werkzame stoffen en de in humaan-toxicologisch en ecotoxicologisch opzicht belangrijke onzuiverheden in de werkzame stof en de hulpstoffen zijn bepaald. De identiteit van het middel is vastgesteld. De fysische en chemische
eigenschappen van het middel zijn vastgesteld en voor juist gebruik en adequate opslag van het middel aanvaardbaar geacht.
3.2 Analysemethoden
De geleverde analysemethoden voldoen aan de vereisten om de residuen te kunnen bepalen die vanuit humaan-toxicologisch en ecotoxicologisch oogpunt van belang zijn, volgend uit geoorloofd gebruik.
3.3 Risico voor de mens
Van het middel wordt voor de toegelaten toepassingen volgens de voorschriften geen onaanvaardbaar risico voor de mens verwacht.
3.4 Risico voor het milieu
Van het middel wordt voor de toegelaten toepassingen volgens de voorschriften geen onaanvaardbaar risico voor het milieu verwacht.
3.5 Werkzaamheid
Van het middel wordt voor de toegelaten toepassingen volgens de voorschriften verwacht dat het werkzaam is.
Bezwaarmogelijkheid
Degene wiens belang rechtstreeks bij dit besluit is betrokken kan gelet op artikel 4 van Bijlage 2 bij de Algemene wet bestuursrecht 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 gewasbeschermingsmiddelen en biociden (Ctgb), Postbus 217, 6700 AE WAGENINGEN. Het Ctgb heeft niet de
mogelijkheid van het elektronisch indienen van een bezwaarschrift opengesteld.
Wageningen, 30 januari 2015
HET COLLEGE VOOR DE TOELATING VAN
GEWASBESCHERMINGSMIDDELEN EN BIOCIDEN,
Ir. J.F. de Leeuw Voorzitter
14698 N
HET COLLEGE VOOR DE TOELATING VAN GEWASBESCHERMINGSMIDDELEN EN BIOCIDEN
BIJLAGE I DETAILS VAN DE AANVRAAG EN TOELATING 1 Aanvraaginformatie
Aanvraagnummer: 20110501 TG
Type aanvraag: Aanvraag toelating gewasbeschermingsmiddel
Middelnaam: PROMAN
Formele registratiedatum: * 11 juli 2011 Datum in behandeling name: 6 maart 2014
* Datum waarop zowel de aanvraag is ontvangen als de aanvraagkosten zijn voldaan.
2 Stofinformatie
Werkzame stof Gehalte
metobromuron 500G/L
De stof metobromuron is bij Uitvoeringsverordening (EU) Nr.890/2014 van 14 augustus 2014 per 1 januari 2015 goedgekeurd overeenkomstig Verordening (EG) nr. 1107/2009 en tot wijziging van de bijlage bij Uitvoeringsverordening (EU) 540/2011 van de Commissie.
De expiratiedatum van metobromuron is 31 december 2024.
3 Toelatingsinformatie
Toelatingsnummer: 14698 N
Expiratiedatum: 31 december 2024
Afgeleide of parallel: n.v.t.
Biocide, gewasbeschermingsmiddel of toevoegingsstof:
Gewasbeschermingsmiddel
Gebruikers: Professioneel
4 Verpakkingsinformatie Aard van het preparaat:
Suspensie concentraat
14698 N
HET COLLEGE VOOR DE TOELATING VAN GEWASBESCHERMINGSMIDDELEN EN BIOCIDEN
BIJLAGE II Etikettering van het middel PROMAN Professioneel gebruik
de identiteit van alle stoffen in het mengsel die bijdragen tot de indeling van het mengsel:
Metobromuron
Pictogram GHS08
GHS09
Signaalwoord WAARSCHUWING
Gevarenaanduidingen H351 Verdacht van het veroorzaken van kanker.
H373 Kan schade aan organen <of alle betrokken organen vermelden indien bekend> veroorzaken bij langdurige of herhaalde blootstelling.
H410 Zeer giftig voor in het water levende organismen, met langdurige gevolgen.
Voorzorgsmaatregelen P260 Stof/rook/gas/nevel/damp/spuitnevel niet inademen.
P273 Voorkom lozing in het milieu.
P280 Beschermende handschoenen/beschermende kleding/oogbescherming/gelaatsbescherming dragen.
P391 Gelekte/gemorste stof opruimen.
P501 Inhoud/verpakking afvoeren naar inzamelpunt voor gevaarlijk of bijzonder afval.
SP 1 Zorg ervoor dat u met het product of zijn verpakking geen water verontreinigt.
Aanvullende etiketelementen
EUH208 Bevat metobromuron en 1,2-benzisothiazolin-3-one.
Kan een allergische reactie veroorzaken.
EUH401 Volg de gebruiksaanwijzing om gevaar voor de menselijke gezondheid en het milieu te voorkomen.
Kinderveilige sluiting verplicht Nee Voelbare gevaarsaanduiding verplicht Nee
14698 N
HET COLLEGE VOOR DE TOELATING VAN GEWASBESCHERMINGSMIDDELEN EN BIOCIDEN Wettelijk Gebruiksvoorschrift
Toegestaan is uitsluitend het professionele gebruik als onkruidbestrijdingsmiddel door middel van een voor opkomst behandeling in de volgende toepassingsgebieden (volgens Definitielijst toepassingsgebieden versie 2.0, Ctgb juni 2011) onder de vermelde toepassingsvoorwaarden
Toepassings- gebied
Te bestrijden organisme Dosering
(middel) per toepassing
Maximaal aantal toepassingen per teeltcyclus
Aardappelen Eenjarige breedbladige onkruiden, Straatgras1, Hanepoot2
3-4 l/ha 1
1 Straatgras (Poa annua)
2 Hanepoot (Echinochloa crus-galli)
Toepassingsvoorwaarden
In verband met residuen in volggewassen mogen direct na het mislukken van de teelt alleen wortelgewassen en bladgewassen geteeld worden. In de eerstvolgende 6 maanden na toepassen mogen geen granen worden geteeld. Een jaar na toepassen mogen alle gewassen worden geteeld.
Om niet tot de doelsoorten behorende geleedpotigen en terrestrische planten te beschermen is toepassing van het middel in de teelt van aardappels uitsluitend toegestaan wanneer gebruik gemaakt wordt van 50% driftreducerende spuitdoppen in combinatie met een kantdop.
Mocht de behandelde teelt in het voorjaar mislukken dan wordt een kerende grondbewerking d.m.v. ploegen aangeraden.
Resistentiemanagement
Dit middel bevat de werkzame stof metobromuron. Metobromuron behoort tot de Ureum verbindingen. De Hrac code is C2.
Bij dit product bestaat er kans op resistentieontwikkeling. In het kader van resistentiemanagement dient u de adviezen die gegeven worden in de voorlichtingsboodschappen, op te volgen.
14698 N
HET COLLEGE VOOR DE TOELATING VAN GEWASBESCHERMINGSMIDDELEN EN BIOCIDEN
BIJLAGE IV
RISKMANAGEMENT
Contents
1 Identity of the plant protection product...2
2 Physical and chemical properties ...1
3 Methods of analysis...6
4 Mammalian toxicology ...8
5 Residues ...17
6 Environmental fate and behaviour ...22
7 Ecotoxicology ...40
8 Efficacy ...93
9 Conclusion ...102
10 Classification and labelling...102
14698 N
1 Identity of the plant protection product 1.1 Applicant
BELCHIM Crop Protection nv/sa Technologielaan 7
B-1840 LONDERZEEL BELGIE
1.2 Identity of the active substance Common name Metobromuron Name in Dutch Metobromuron
Chemical name 3-(4-bromophenyl)-1-methoxy-1-methylurea [IUPAC]
CAS no 3060-89-7
EC no 221-301-5
The new active substance metobromuron is not approved under Reg. (EC) No 1107/2009. A DAR is available (RMS: France). An EFSA peer-review conclusion is available (EFSA Journal 2014;12(2):3541).
1.3 Identity of the plant protection product
Name PROMAN
Formulation type SC
Content active substance 500g/L pure active substance
The formulation is identical to that assessed for the approval of metobromuron under Reg.
(EC) No 1107/2009.
1.4 Function Herbicide.
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1.5 Uses applied for
The use in Lamb’s lettuce is withdrawn by applicant.
PROMAN
1.6 Background to the application
Application for the authorisation of the plant protection product PROMAN.
1.7 Packaging details 1.7.1 Packaging description
Material: Professional use:
HDPE or HDPE/PA Capacity: Professional use:
1L, 5L and 10L Type of closure and size
of opening:
49.6mm to 67.5mm opening with screw cap Other information Bottles may be rectangular or round.
UN/ADR compliant 1.7.2 Detailed instructions for safe disposal No particular recommendations
2 Physical and chemical properties 2.1 Active substance: metobromuron
The final List of Endpoints presented below is taken from the EFSA Journal 2014;12(2):3541.
Where relevant, some additional remarks/information are given in italics.
Identity
Active substance (ISO Common Name)
Metobromuron
Chemical name (IUPAC) 3-(4-bromophenyl)-1-methoxy-1-methylurea Chemical name (CA) N’-(4-bromophenyl)-N-methoxy-N-methylurea
CIPAC No 168
CAS No 3060-89-7
EEC No (EINECS or ELINCS) 221-301-5 FAO Specification (including year of publication)
not available Minimum purity of the active
substance as manufactured (g/kg)
978 g/kg (purity was based on commercial scale production of 5 batches)
Identity of relevant impurities (of toxicological, environmental and/or other significance) in the active substance as manufactured (g/kg)
no relevant impurities
Molecular formula C9H11BrN2O2
Molecular mass 259.1
PROMAN
Structural formula
Physical-chemical properties
Melting point (state purity) 95.6°C – 97.5°C (98.48%)
Boiling point (state purity) Decomposition at 173.2°C (98.48%) Temperature of decomposition 173.2°C (98.48%)
Appearance (state purity) Very light yellow crystalline solid with a musty, naphthalenic odour (98.48%)
Relative density (state purity) D420=1.52 (98.48%)
Surface tension 72.2 mN/m (90% solution of water solubility) (98.48%) Vapour pressure (in Pa, state
temperature) 2.19 x 10-4 Pa at 25°; 1.44x10-4 Pa at 20°C (98.48%) Henry’s law constant (in Pa·m3·mol-1) 1.14 x 10-4 Pa · m3 · mol-1 at 20°C
Solubility in water (in g/l or mg/l, state
temperature) 0.328 g/L at 20°C
(Due to high pKa of 12.0 and the solubility < 1 g/L effect of pH was not investigated)
Solubility in organic solvents (in g/l or mg/l, state temperature)
(98.48%) solubility at 20°C Heptane: <10g/L
Dichloromethane: >250g/L Methanol: >250g/L
Acetone: >250g/L Xylene: 50 - 57g/L Ethyl Acetate: >250g/L Partition co-efficient (log Pow) (state
pH and temperature) Log Po/w = 2.48 at 20°C and pH 7.3 (98.48%) (effect of pH was not investigated, not required) Dissociation constant pKa=12.0 at 20°C
UV/VIS absorption (max.) (if absorption >290 nm state
ε
at wavelength)λ Max: 245 nm (all pH ranges) No significant absorption > 290nm
Flammability Not highly flammable
Auto-flammability Not self-igniting Oxidising properties Not oxidising Explosive properties Not explosive 2.2 Plant protection product: PROMAN
The range of the application concentration of the plant protection product is 0.75%.
Section (Annex point)
Study Guidelines and GLP
Findings Evaluation and
conclusion NH N
O O
CH3
CH3
Br
PROMAN
Section (Annex point)
Study Guidelines and GLP
Findings Evaluation and
conclusion B.2.2.1
(IIIA 2.1)
Appearance:
physical state
GLP Visual
Liquid at 20°C Acceptable
B.2.2.2 (IIIA 2.1)
Appearance:
colour
GLP Visual
Off-white at 20°C Acceptable B.2.2.3
(IIIA 2.1)
Appearance:
odour
GLP Olfactory
Faint aromatic at 20°C Acceptable B.2.2.4
(IIIA 2.2)
Explosive properties
GLP DSC screening
Not explosive (decomposition energy < 500 J/g)
Acceptable
B.2.2.5 (IIIA 2.2)
Oxidising properties
Theoretical assessment
Not oxidising Acceptable
B.2.2.6 (IIIA 2.3)
Flammability Not applicable
B.2.2.7 (IIIA 2.3)
Auto-
flammability
GLP EC A15
The auto-ignition temperature is > 800°C
Acceptable B.2.2.8
(IIIA 2.3)
Flash point GLP EC A9
>100°C Acceptable
B.2.2.9 (IIIA 2.4)
Acidity / alkalinity
Not required B.2.2.10
(IIIA 2.4)
pH GLP
CIPAC MT75.3
Neat: 7.9
in deionised water (pH 6.0):
0.12% 7.0 1.0% 9.0 4.0% 9.4
in CIPAC D water (pH 6.8):
0.12% 7.3 1.0% 7.4 4.0% 7.8
Acceptable
B.2.2.11 (IIIA 2.5)
Surface tension
GLP OECD 115
At 20°C
0.12% 42.5 mN/m 1.0% 40.9 mN/m 4.0% 39.2 mN/m
Acceptable
B.2.2.12 (IIIA 2.5)
Viscosity GLP OECD 114
At 20°C
10 s-1 315 mPa.s 100 s-1 111 mPa.s
Acceptable
B.2.2.13 (IIIA 2.6)
Relative density
GLP
EC A3 1.4.4
D420 = 1.219 Acceptable
B.2.2.14 (IIIA 2.6)
Bulk (tap) density
Not applicable B.2.2.15
(IIIA 2.7)
Storage stability
GLP CIPAC MT46
Stable for 8 weeks at 40°C in HDPE
Properties determined before and after storage: a.s. content, density, pH, appearance, foam persistence, suspensibility, spontaneity of dispersion, wet sieve residue, particle size distribution.
Acceptable The study
mentioned that the pack was damaged when stored for 2 weeks at 54°C.
After 8 weeks at 40°C the pack remained stable.
GLP Stable for 2 weeks at 54°C in Acceptable
PROMAN
Section (Annex point)
Study Guidelines and GLP
Findings Evaluation and
conclusion CIPAC
MT46
HDPE/PA
Properties determined before and after storage: a.s. content, density, pH, appearance, foam persistence, suspensibility, spontaneity of dispersion, wet sieve residue, particle size distribution.
GLP CIPAC MT39.3
Stable for 7 days at 0°C.
Properties determined before and after storage:
appearance, suspensibility, spontaneity of dispersion, wet sieve residue.
Acceptable
B.2.2.16 (IIIA 2.7)
Shelf life GLP Stable for 2 years at 23°C in 1L HDPE bottles.
Properties determined before and after storage: a.s. content, density, pH, appearance, foam persistence, suspensibility, spontaneity of dispersion, wet sieve residue, particle size distribution, viscosity, foam persistence, pourability.
Acceptable
B.2.2.17 (IIIA 2.8)
Wettability Not applicable
B.2.2.18 (IIIA 2.8)
Persistent foaming
GLP CIPAC MT47.2
In CIPAC D water, foam after 1 minute:
0.12% 24 mL 1.0% 22 mL 4.0% 22 mL
Acceptable
B.2.2.19 (IIIA 2.8)
Suspensibility GLP CIPAC MT161
In CIPAC D water (assay):
0.12% 98%
1.0% 99%
4.0% 100%
Acceptable
B.2.2.20 (IIIA 2.8)
Spontaneity of dispersion
GLP CIPAC MT160
In CIPAC A water (assay):
0.12% 99%
1.0% 95%
4.0% 99%
In CIPAC D water:
0.12% 94%
1.0% 96%
4.0% 100%
Acceptable
B.2.2.21 (IIIA 2.8)
Dilution stability
Not applicable B.2.2.22
(IIIA 2.8)
Dry sieve test Not applicable
B.2.2.23 Wet sieve test GLP 0.01% residue on a 75µm Acceptable
PROMAN
Section (Annex point)
Study Guidelines and GLP
Findings Evaluation and
conclusion
(IIIA 2.8) CIPAC
MT185
sieve B.2.2.24
(IIIA 2.8)
Particle size distribution
GLP CIPAC MT187
D(90) < 5.4µm D(50) < 2.3µm D(10) < 0.9µm
Acceptable
B.2.2.25 (IIIA 2.8)
Content of dust/fines
Not applicable B.2.2.26
(IIIA 2.8)
Attrition and friability
Not applicable B.2.2.27
(IIIA 2.8)
Emulsifiability, re-
emulsifiability and emulsion stability
Not applicable
B.2.2.28 (IIIA 2.8)
Stability of dilute emulsion
Not applicable
B.2.2.29 (IIIA 2.8)
Flowability Not applicable
B.2.2.30 (IIIA 2.8)
Pourability (rinsibility)
GLP CIPAC MT148
Residue: 1.53%
Rinsed residue: 0.08%
Acceptable
B.2.2.31 (IIIA 2.8)
Dustability Not applicable
B.2.2.32 (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
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.
The shelf-life of the product is 2 years in HDPE and HDPE/PA.
In the GAP/instructions for use the following has to be stated:
None.
2.3 Data requirements None.
3 Methods of analysis
The final List of Endpoints presented below is taken from the EFSA Journal 2014;12(2):3541.
Where relevant, some additional remarks/information are given in italics.
3.1 Analytical methods in technical material and plant protection product
Technical as (principle of method) High Performance Liquid Chromatography (HPLC), equipped with UV-DAD detector
Impurities in technical as (principle of method)
High Performance Liquid Chromatography (HPLC) equipped with UV detector, Gas Chromatography equipped with Mass Detector (MS), GC ECD and Thermal Energy Analyser (TEA)
Preparation (principle of method) High Performance Liquid Chromatography (HPLC), equipped with UV-DAD detector
Conclusion
The analytical methods regarding the technical active substance and the preparation have been assessed in the DAR and are considered to be acceptable.
3.2 Residue analytical methods Food/feed of plant origin (principle of method and LOQ for methods for monitoring purposes)
High Performance Liquid Chromatography (HPLC), equipped with tandem Mass Detector (MS/MS) [QuECheRS multiresidue method]
The LOQ is 0.005 mg/kg for potato The LOQ is 0.01 mg/kg for lamb’s lettuce
Data/justification to address the verification of the
extraction efficiency of the enforcement method provided for high water content matrix are required.
Validated method(s) for analysis of residues in dry, high acid content and high oil content matrices is required.
Food/feed of animal origin (principle of method and LOQ for methods for monitoring purposes)
None, not triggered
Soil (principle of method and LOQ) High Performance Liquid Chromatography (HPLC), equipped with tandem Mass Detector (MS/MS) The LOQ is 0.01 mg/kg for soil
Water (principle of method and
LOQ) High Performance Liquid Chromatography (HPLC),
equipped with tandem Mass Detector (MS/MS) The LOQ is 0.05 µg/L for drinking, ground and surface water
Air (principle of method and LOQ) High Performance Liquid Chromatography (HPLC), equipped with tandem Mass Detector (MS/MS) The LOQ is 2.0 µg/m3 for air
Body fluids and tissues (principle of method and LOQ)
None, not triggered
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 matrices with a high water content (potatoes).
Definition of the residue and MRLs for metobromuron Matrix Definition of the residue for
monitoring
MRL Food/feed of plant
origin
4-Bromophenylurea 0.01 mg/kg (potato)
Food/feed of animal origin
No definition of the residue is proposed.
No relevant residues are expected to occur in food/feed of animal origin.
Required LOQ
Soil Metobromuron 0.05 mg/kg
Drinking water Metobromuron 0.1 µg/L (drinking water
guideline)
Surface water Metobromuron 0.1 µg/L
Air Metobromuron 4.8 µg/m3 (derived from
the AOEL (0.016 mg/kg bw/day) 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.
The residue analytical methods, included in the abovementioned List of Endpoints, are suitable for monitoring of the MRLs.
According to the EFSA peer-review conclusion, the following data is required:
• Validated methods for analysis of residues in dry, high acid content and high oil content matrices of plant origin and verification of the extraction efficiency of the proposed enforcement method for high water content plant matrices (relevant for all representative uses evaluated; submission date proposed by the applicant: unknown; see section 1) The data gap set by EFSA was based on the requirements of SANCO/825/00 rev 8.1. The methods included in the dossier comply with SANCO/825/00 rev 7, which is considered sufficient for this application.
The residue analytical methods for water, soil and air, evaluated in the DAR, 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 None.
4 Mammalian toxicology List of Endpoints
The final List of Endpoints presented below is taken from the EFSA Scientific Report on metobromuron (EFSA Journal 2014; 12(2):3541 (d.d. 4 February 2014). Where relevant, some additional remarks/information are given in italics.
Absorption, distribution, excretion and metabolism (toxicokinetics) (Annex IIA, point 5.1) Rate and extent of oral absorption ‡ > 80%, based on urinary excretion, cage wash,
carcass and tissues residues within 24h
Distribution ‡ Widely distributed, highest value in blood.
Metobromuron seems to associate with blood cellular component
Potential for accumulation ‡ No evidence for accumulation
Rate and extent of excretion ‡ Rapid and extensive > 90% within 72h, mainly via urine (75%) within 24 h, 10% via faeces
Metabolism in animals ‡ Complete degradation, N-demethylation/N-
demethoxylation, phenyl ring hydroxylation and conjugation
Toxicologically relevant compounds ‡ (animals and plants)
Metobromuron Toxicologically relevant compounds ‡
(environment)
Metobromuron
Acute toxicity (Annex IIA, point 5.2)
Rat LD50 oral ‡ 1000-2000 mg/kg bw (female rat) 1290-2150 mg/kg bw (male mice)
Acute tox 4, H302
Rat LD50 dermal ‡ > 3000 mg/kg bw
Rat LC50 inhalation ‡ > 1.6 mg/L air/4h, nose only exposure (highest attainable concentration)
Skin irritation ‡ Non-irritant
Eye irritation ‡ Non-irritant
Skin sensitisation ‡ Sensitiser (Magnusson & Kligman) Skin sens, H317
Short term toxicity (Annex IIA, point 5.3)
Target / critical effect ‡ Blood system: regenerative haemolytic anemia, body weight effects (all species)
Rat: spleen, bone marrow Mouse: spleen
Dog: liver, kidney, spleen, bone marrow
Relevant oral NOAEL ‡ 28-day, rat: < 2.7 mg/kg bw per day 28-day, mouse: < 13.8 mg/kg bw per day
1-year, dog: 1.59 mg/kg bw per day
STOT RE 2, H373
Relevant dermal NOAEL ‡ 28-day, rat: 40 mg/kg bw per day Relevant inhalation NOAEL ‡ No data – not required
Genotoxicity ‡ (Annex IIA, point 5.4)
Metobromuron is unlikely to be genotoxic
Long term toxicity and carcinogenicity (Annex IIA, point 5.5)
Target/critical effect ‡ Rat: Blood system, mammary gland, adrenals Mouse: Blood system
Relevant NOAEL ‡ 2.6 mg/kg bw per day;2-year, rat 0.8 mg/kg bw per day; 2-year, mouse Carcinogenicity ‡ Increased incidence of mammary gland
fibrosarcoma in female and pheochromocytomas in male rat.
NOAEL carcinogenicity: 2.6 and 3.4 mg/kg bw per day in males and females No carcinogenicity potential in mouse
Carc.
cat 2, H351
Reproductive toxicity (Annex IIA, point 5.6) Reproduction toxicity
Reproduction target / critical effect ‡ Parental toxicity: haemolytic regenerative anemia
Offspring’s and reproductive toxicity: no effects
Relevant parental NOAEL ‡ 1.38 mg/kg bw per day
Relevant reproductive NOAEL ‡ 16.03 mg/kg bw per day (highest dose tested)
Relevant offspring NOAEL ‡ 16.03 mg/kg bw per day (highest dose tested)
Developmental toxicity
Developmental target / critical effect ‡ Parental toxicity: reduced bw gain and feed consumption (rats and rabbits) and mortality (rabbits)
Developmental toxicity: Delayed
ossification (rats) and post-implantation losses (rabbits)
Relevant maternal NOAEL ‡ Rats: 10 mg/kg bw per day (30 mg/kg bw per day for acute effects)
Rabbits: 30 mg/kg bw per day Relevant developmental NOAEL ‡ Rats: 10 mg/kg bw per day
Rabbits: 30 mg/kg bw per day
Neurotoxicity (Annex IIA, point 5.7)
Acute neurotoxicity ‡ No data – not required Repeated neurotoxicity ‡ No data – not required Delayed neurotoxicity ‡ No data – not required Other toxicological studies (Annex IIA, point 5.8)
Mechanism studies ‡ 4-weeks oral feeding study in rat + 9 weeks recovery
- reversibility of haemolytic effects - no sperm effects
LOAEL 3.3 mg/kg bw per day (heamatological changes)
Hershberger assay
No androgenic or anti-androgenic potential seen up to 100 mg/kg bw per day
In vitro assays (T47D-Luc Reporter gene assay (stable transfection) and prostate specific antigen (PSA) expresssion assay) indicate that metabromuron may inhibit
dihydroxytestosterone (DHT) expression, either as decreased luciferase activity or decreased PSA formation; quantitative comparison among several analogues of phenyl ureas was not conclusive and no correlated effects were found in vivo.
CGA 18236 (desmethoxy-metobromuron):
Rat oral LD50 > 2000 mg/kg bw Negative Ames test
Toxicological profile similar to metobromuron in QSAR models – further data required to
address consumer exposure Studies performed on metabolites or
impurities ‡
CGA 18237 (4-bromophenylurea):
Rat oral LD50 between 300 and 2000 mg/kg bw (Acute tox 4, H302)
Negative Ames test
Toxicological profile similar to metobromuron in QSAR models – further data required to
address consumer exposure
CGA 18238 (desmethyl-metobromuron):
Rat oral LD50 oral > 2000 mg/kg bw Negative Ames test
Toxicological profile similar to metobromuron in QSAR models – further data required to
address consumer exposure
4-bromoaniline: publicly available information indicate that this environmental metabolite should be regarded as toxic in contact with skin – data required
Metobromuron is not yet approved under Regulation (EC) No 1107/2009 according to Reg. (EU) 540/2011, and the following is stated in the EFSA conclusion on the peer review of metobromuron: “A data gap was identified to assess the relative toxicity of the three metabolites included in the plant residue definition, CGA 18236
(desmethoxy-metobromuron), CGA 18237 (4-bromophenylurea) and CGA 18238 (desmethyl-metobromuron) in comparison with the parent metobromuron. Acute oral toxicity studies, Ames tests and QSAR analysis were provided for the three metabolites that were found at low concentrations in the rat metabolism studies (< 1% of the administered dose for CGA 18238 and CGA 18237) or postulated to be intermediate in the rat metabolism (CGA 18236). These data are insufficient to conclude whether the reference values of the parent are applicable to the metabolites or if new reference values should apply and therefore a data gap was identified to address the consumer exposure to these metabolites. A further data gap was identified to address the toxicity of the metabolite 4-bromoaniline that was found at low levels in the environment (see section 4) as publicly available information indicate that the metabolite should be regarded as toxic in contact with skin.”.
These data gaps are related to the residue and environmental evaluations and are not relevant for the this section on mammalian toxicology.
Medical data ‡ (Annex IIA, point 5.9)
Limited data on medical surveillance of manufacturing plant personnel (commercial scale production of 5 batches) did not indicate abnormal behaviour, health complaints or change in the health status of the workers linked to metobromuron production.
Summary (Annex IIA, point 5.10) Value Study Safety factor
ADI ‡ 0.008 mg/kg
bw per day
mouse, 2-year study
100
AOEL ‡ 0.016 mg/kg
bw per day
dog, 1-year, supported by the rat
multigeneration study
100*
ARfD ‡ 0.3 mg/kg bw rat and rabbit,
developmental studies
100
*no correction needed regarding oral absorption Dermal absorption ‡ (Annex IIIA, point 7.3)
Formulation Metobromuron 500 SC (suspension concentrate containing 500 g metobromuron/L, e.g. BCP 222 H)
Concentrate: 0.5%
In-use spray dilution (1:50): 6.3%
In vitro study through human skin
Local effects
Metobromuron produces skin effects in a sensitisation study. However, the formulation PROMAN does not have skin sensitising properties. Metobromuron does not produce local effects after repeated exposure.
Data requirements active substance
Metobromuron is not yet approved under Regulation (EC) No 1107/2009 according to Reg.
(EU) 540/2011, however, no direct data requirements for mammalian toxicology are mentioned in the EFSA conclusion.
4.1 Toxicity of the formulated product (IIIA 7.1)
The formulation PROMAN does not need to be classified on the basis of its acute oral (LD50 rat >2000 mg/kg bw), dermal (LD50 rat >2000 mg/kg bw), and inhalation toxicology (no study, not required).
The formulation PROMAN is considered not irritating to skin and eyes.
The formulation PROMAN does not have sensitising properties in a Maximisation test.
4.1.1 Data requirements formulated product No additional data requirements are identified.
4.2 Dermal absorption (IIIA 7.3)
See List of endpoints. The in vitro dermal absorption studies were performed with the formulation BCP 222 H (= PROMAN). Therefore, the dermal absorption value for the concentrate (0.5%) can be directly used for PROMAN. The maximum dilution of the 1:133 spray dilution of PROMAN is 3.75 g/L, while the value of the in-use spray dilution in the List of endpoints (6.3%) is determined with a 1:50 dilution. Since these concentrations differ only a factor 2.7, the value of 6.3% is acceptable to be used for the filed dilution of PROMAN in the present request.
Therefore, the dermal absorption of metobromuron in the formulation PROMAN is 0.5% for the concentrate and 6.3% for the spray dilution.
4.3 Available toxicological data relating to non-active substances (IIIA 7.4)
The available toxicological data relating to non-active substances will be taken into account in the classification and labelling of the formulated product.
4.4 Exposure/risk assessments Overview of the intended uses
An application has been submitted for registration of the plant protection product PROMAN, a herbicide based on the active substance metobromuron.
PROMAN is a SC formulation and contains 500 g/L metobromuron.
4.4.1 Operator exposure/risk
According to the Dutch Plant Protection Products and Biocides Regulations the risk assessment is performed according to a tiered approach. There are four possible tiers:
Tier 1: Risk assessment using the EU-AOEL without the use of PPE Tier 2: Risk assessment using the NL-AOEL without the use of PPE
Tier 3: Refinement of the risk assessment using new dermal absorption data Tier 4: Prescription of PPE
Tier 1
Calculation of the EU-AOEL / Tolerable Limit Value (TLV)
For metobromuron no TLV has been set. The AOEL will be used for the risk assessment.
Since the formulation is applied once during the period March - June, a semi-chronic
exposure duration is applicable for the operator (including contract workers). A semi-chronic AOEL is therefore derived.
The semi-chronic EU-AOEL of 0.016 mg/kg bw/day (= 1.12 mg/day for a 70-kg operator), based on the 1-year study in dog and supported by the rat multi-generation study is used for the risk assessment (see List of Endpoints).
Exposure/risk
Exposure to metobromuron during mixing and loading and application of PROMAN is estimated with models. The exposure is estimated for the unprotected operator. 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.
In the Table below the estimated internal exposure is compared with the systemic EU-AOEL.
Table T.1 Internal operator exposure to metobromuron and risk assessment for the use of PROMAN
Route Estimated internal exposure a (mg /day)
Systemic EU-AOEL
(mg/day)
Risk-index b
Mechanical downward spraying on potato (uncovered, 2 kg a.s./ha)
Respiratory 0.10 1.12 0.09
Mixing/
Loadingc Dermal 2.00 1.12 1.79
Respiratory 0.16 1.12 0.14
Applicationc
Dermal 2.90 1.12 2.59
Total 5.16 1.12 4.61
a Internal exposure was calculated with:
• biological availability via the dermal route: 0.5% (concentrate) and 6.3% (spray dilution) (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.
c External exposure is estimated with EUROPOEM.
Since the EU-AOEL is exceeded without the use of PPE, a tier 2 assessment has to be performed using the NL-AOEL.
Tier 2
Calculation of the NL-AOEL
The risk index calculated with the EU-AOEL is >1. Therefore, the Plant Protection Products and Biocides Regulations (NL: Rgb) prescribes the calculation of the risk with an AOEL based on allometric extrapolation (known as the NL-AOEL). This method takes into account the caloric demand of the species studied 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 2.6 mg/kg bw/day in the 2-year study with the rat. The chronic 2-year exposure study is used in this case as no semi-chronic 90-day study is available. A 28-day study is available,
however, these are generally not appropriate to derive reference values due to the limited number of animals tested in these studies. Calculations from other studies result in higher AOELs.
Safety factors are used to compensate for the uncertainties, which arise, for example, from 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→ human on basis of caloric demand 4
• other interspecies differences: 3
• intraspecies differences: (professional use) 3
• biological availability via oral route: 100%*
• weight of professional operator/worker: 70 kg
* If the absorbed dose is significantly lower (<80%) than the administered dose, this is adjusted by a correction factor equal to the percentage absorption.
AOELsystemic: 2.6 x 1 x 70 / (4 x 3 x 3) = 5.06 mg/day Exposure/risk
Table T.2 Internal operator exposure to metobromuron and risk assessment for the use of PROMAN
Route Estimated internal exposure a (mg /day)
Systemic NL-AOEL
(mg/day)
Risk-index b
Mechanical downward spraying on potato (uncovered, 2 kg a.s./ha)
Respiratory 0.10 5.06 0.02
Mixing/
Loadingc Dermal 2.00 5.06 0.40
Respiratory 0.16 5.06 0.03
Applicationc
Dermal 2.90 5.06 0.57
Total 5.16 5.06 1.02
a Internal exposure was calculated with:
• biological availability via the dermal route: 0.5% (concentrate) and 6.3% (spray dilution) (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.
c External exposure is estimated with EUROPOEM.
Since the NL-AOEL is exceeded without the use of PPE, a higher tier assessment is required.
Tier 3
Since the results of acceptable dermal absorption studies were already used in tier 1 and 2, a further refinement with additional dermal absorption data is not considered relevant and a tier 4 assessment will be performed.
Tier 4
The NL-AOEL is exceeded without the use of PPE and dermal absorption data have already been taken into account in the risk assessment. Therefore, in Tier 4 a risk assessment is performed with and without the use of PPE.
Table T.3 Internal operator exposure to metobromuron and risk assessment for the use of PROMAN
Estimated internal exposure a (mg /day)
Risk-index b Route
without PPE
with PPE
Systemic NL-AOEL
(mg/day) without PPE
with PPE
Estimated internal exposure a (mg /day)
Risk-index b Route
without PPE
with PPE
Systemic NL-AOEL
(mg/day) without PPE
with PPE Mechanical downward spraying on potato (uncovered, 2 kg a.s./ha)
Respiratory 0.10 (0.10) 5.06 0.02 (0.02)
Mixing/
Loadingc Dermal 2.00 0.2 5.06 0.40 0.04
Respiratory 0.16 (0.16) 5.06 0.03 (0.03)
Applicationc
Dermal 2.90 (2.90) 5.06 0.57 (0.57)
Total 5.16 3.36 5.06 1.02 0.66d
a Internal exposure was calculated with:
• biological availability via the dermal route: 0.5% (concentrate) and 6.3% (spray dilution) (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.
c External exposure is estimated with EUROPOEM.
d PPE: gloves and coverall during mixing and loading
4.4.2 Bystander exposure/risk
The exposure is estimated for the unprotected bystander. In Table T.4 the estimated internal exposure is compared with the systemic EU-AOEL.
Table T.4 Internal bystander exposure to metobromuron and risk assessment during application of PROMAN
Route Estimated internal exposure a (mg /day)
Systemic EU-AOEL
(mg/day)
Risk-index b
Mechanical downward/upward spraying on potato (uncovered, 2 kg a.s./ha, 200 L/ha)
Respiratory 0.38 1.12 0.34
Dermal 0.13 1.12 0.11
Total 0.50 1.12 0.45
a External exposure was estimated with EUROPOEM II. Internal exposure was calculated with:
• biological availability via the dermal route: 6.3% (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.
Bystanders and residents may be exposed via the dermal route to spray drift deposits or by inhalation of vapour drift within or directly adjacent to an application area (bystander), or in the vicinity of the application (resident). The internal bystander and resident exposure is calculated in addition to the internal bystander exposure and risk assessment calculated with EUROPOEM II above, which is intended to estimate the work-related bystander exposure.
Two different methods are used: 1) the German model which calculates the total exposure for adults, and children, and considers for the latter also the oral exposure via hand-to-mouth or object-to-mouth transfer; and 2) the UK method which calculates the total bystander exposure for adults, and separately the respiratory and dermal/oral route for resident children. In the table below the estimated internal exposure values from these methods are compared with the systemic AEL.
Table T.5 Internal bystander and resident exposure to metobromuron and risk assessment for the application of PROMAN
Route Estimated internal
exposure a (mg /day)
Systemic AEL (mg/day)b
Risk-index c
Bystander exposure during application in representative uses according to the German model
Route Estimated internal exposure a (mg /day)
Systemic AEL (mg/day)b
Risk-index c
Child Total 0.07 0.26 0.28
Adult Total 0.35 0.96 0.36
Resident exposure during application in all representative uses according to the German model
Child Total 0.03 0.26 0.12
Adult Total 0.04 0.96 0.04
Bystander exposure during application in representative uses according to the UK method
Adult Total 0.07 0.96 0.07
Resident exposure during application in representative uses according to the UK method
Child Respiratory 0.01 0.24 0.03
Dermal+Oral 0.01 0.24 0.05
a External exposure was estimated according to 1) the German guidance paper for exposure and risk
assessment for bystanders and residents (Martin et al. 2008, J. Verbr. Lebensm. 3: 272-281), and 2) the UK method. Internal exposure was calculated with:
• biological availability via the respiratory route: 100% (worst case)
• biological availability via the dermal route: 6.3% (see 4.2)
• biological availability via the oral route: 100% (see List of EndPoints)
b From the systemic AOEL of 0.016 mg/kg bw/day a specific AEL is derived assuming a body weight of 16.15 or 15 kg for children in the German model or UK method, respectively, and of 60 kg for adults.
c The risk-index is calculated by dividing the internal exposure by the systemic AEL.
Based on the calculated risk indexes, the resident exposure of children and adults living next to a field treated with PROMAN is considered to be safe.
4.4.3 Worker exposure/risk
PROMAN is a pre-emergency application. Shortly after application it is not necessary to perform any re-entry activities, including crop inspection tasks. Therefore no worker exposure is calculated.
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
For the unprotected operator, adverse health effects after dermal/respiratory exposure to metobromuron as a result of the application of PROMAN in potatoes cannot be excluded.
Correct use of personal protective equipment will reduce the dermal exposure and results in a sufficient reduction of the exposure to metobromuron for the application of PROMAN in potatoes.
Bystander exposure
Based on the risk assessment, it can be concluded that no adverse health effects are expected for the unprotected bystander, nor for nearby non-work related bystanders and residents, due to exposure to metobromuron during application of PROMAN in potato.
Worker exposure
Shortly after application it is not necessary to perform any re-entry activities including crop inspection tasks. Therefore no adverse health effects to workers are expected.
4.5 Appropriate mammalian toxicology and operator exposure end-points relating to
the product and approved uses See List of Endpoints.
4.6 Data requirements
Based on this evaluation, no additional data requirements are identified.
4.7 Combination toxicology
PROMAN contains only one active substance and it is not described that it should be used in combination with other formulations.
5 Residues List of Endpoints
The List of Endpoints for metobromuron presented below is obtained from the EFSA Conclusion on the peer review of the pesticide risk assessment of the active substance metobromuron (EFSA Journal 2014;12(2):3541).
Metabolism in plants (Annex IIA, point 6.1 and 6.7, Annex IIIA, point 8.1 and 8.6)
Plant groups covered Potato
Rotational crops Lettuce (30 and 365 days), wheat (180 days), sugar beet (365 days), corn (365 days) Metabolism in rotational crops similar to
metabolism in primary crops?
Yes
Processed commodities Not necessary
Residue pattern in processed commodities similar to residue pattern in raw
commodities?
Not relevant
Plant residue definition for monitoring 4-bromophenylurea
Plant residue definition for risk assessment total hydrolysable residue analyzed as 4- bromoaniline and expressed as parent metobromuron
Conversion factor (monitoring to risk assessment)
3.4
Metabolism in livestock (Annex IIA, point 6.2 and 6.7, Annex IIIA, point 8.1 and 8.6)
Animals covered Not required
Time needed to reach a plateau concentration in milk and eggs
Not relevant Animal residue definition for monitoring Not required Animal residue definition for risk
assessment
Not required Conversion factor (monitoring to risk
assessment)
Not relevant
Metabolism in rat and ruminant similar (yes/no)
Not required Fat soluble residue: (yes/no) No
Residues in succeeding crops (Annex IIA, point 6.6, Annex IIIA, point 8.5)
Lettuce (30 and 365 days), wheat (180 days), sugar beet (365 days), corn (380) –
Metobromuron of metabolite never detected except traces in mature lettuce at the 29 replanting interval. In case of crop failure, only potatoes (or another root crop) and lettuce (or another leafy crop) can be grown in the treated plot. For rotational crops, it is possible to estimate that cereals can be grown 6 months after application and one year after application no quantifiable residues are expected whatever the crop grown.
Stability of residues (Annex IIA, point 6 introduction, Annex IIIA, point 8 Introduction) Residues of metobromuron, desmethyl-
metobromuron, desmethoxy-metobromuron and 4-bromophenylurea have been shown to be stable in potato and lamb’s lettuce when stored deep frozen at <-18°C for at least 12 months.
Residues from livestock feeding studies (Annex IIA, point 6.4, Annex IIIA, point 8.3)
Ruminant Poultry Pig
Conditions of requirement of feeding studies Expected intakes by livestock ≥ 0.1 mg/kg
diet (dry weight basis) (yes/no - If yes, specify the level)
no no no
Potential for accumulation (yes/no) no no no
Metabolism studies indicate potential level of residues ≥ 0.01 mg/kg in edible tissues (yes/no)
NA NA NA
Feeding studies (Specify the feeding rate in cattle and poultry studies considered as relevant)
Residue levels in matrices : Mean (max) mg/kg
Muscle Not required Not required Not required
Liver Not required Not required Not required
Kidney Not required Not required Not required
Fat Not required Not required Not required
Milk Not required - -
Eggs - Not required -
Processing factors (Annex IIA, point 6.5, Annex IIIA, point 8.4) Not applicable, no residues
Comments on/additions to List of Endpoints No comments
5.1 Summary of residue data
The following assessment is based on the Draft Assessment Report (July 2012) prepared by Rapporteur Member State France and on the EFSA’s peer review (EFSA Journal
2014;12(2):3541).
5.1.1 Metabolism in plants
Metabolism in plants was investigated in potatoes using metobromuron radiolabelled with 14C in the phenyl ring. At harvest metobromuron was neither detected in tubers nor in the foliage.
TRR of metabolites in the tubers amounted to 18.2 % 4-bromophenylurea (0.017 mg/kg eq.), 1.3 % desmethoxy-metobromuron (0.0012 mg/kg eq.) and 0.6 % desmethyl-metobromuron (0.0006 mg/kg eq.) and in foliage 10.3 % 4-bromophenylurea (0.018 mg/kg eq.), 7.1 % desmethoxy-metobromuron (0.012 mg/kg eq.) and 13.8 % desmethyl-metobromuron (0.024 mg/kg eq.) were detected. Non-extractable residues represented the major part of the radioactivity in tubers and consisted mainly of radioactivity incorporated into the starch fraction. A smaller amount of radioactivity was found in the protein fraction. It has been demonstrated that in strong acidic or basic conditions metobromuron and the identified metabolites with 4-bromoaniline moiety (desmethoxy-metobromuron, desmethyl- metobromuron and 4-bromophenylurea) hydrolyse to 4-bromoaniline.
The nature of residues in rotated crops was determined in lettuce, wheat, sugar beet and corn. In this study [Phenyl-(U)-14C]metobromuron was applied to bare soil at a rate of 2.5 kg a.s./ha. The study is not fully compliant with EU guidelines because of lack of data for all crop/plant back interval combinations (lettuce was planted 30 days and 1 year after application, wheat was sown 6 months after application, sugar beet and corn 1 year after treatment). However the available data showed that the total residues in harvest samples exceeded 0.01 mg/kg only in the lettuce replanted 29 days after treatment. The analyses of the immature lettuce extracts showed the presence of metobromuron (0.021 mg/kg) and trace amounts of 4-bromophenylurea and desmethoxy-metobromuron. No parent
metobromuron was found in any other sample.
5.1.2 Metabolism in livestock
TMDIs for domestic animals have been calculated using the HR found for 4-bromoaniline (0.032 mg/kg). The intakes calculated for pigs and beef cattle were slightly above the trigger value (0.13 vs. 0.10 mg/kg dry matter), however it was considered that the requirement for livestock metabolism study can be waived on the basis that the calculations account the worst case situation (60 % intake of potatoes for pigs and beef cattle and all compounds that can be hydrolysed to 4-bromoaniline). Consequently no livestock metabolism study is
provided and considered necessary.
5.1.3 Residue definition (plant and animal)
4-bromophenylurea was set as residue definition for monitoring. Based on the results of the residue trials it has been concluded that total hydrolysable residues analysed as 4- bromoaniline (that include the parent and the metabolites with 4-bromoaniline moiety:
desmethoxy-metobromuron, desmethyl-metobromuron and 4-bromophenylurea) and
calculated as parent metobromuron is an appropriate plant residue definition for risk assessment. A conversion factor of 3.4 is proposed in potatoes between monitoring and risk assessment residue definitions.
5.1.4 Stability of residues
Residues of metobromuron, desmethyl-metobromuron, desmethoxy-metobromuron and 4- bromophenylurea have been shown to be stable in potato when stored deep frozen at <- 18°C for at least 12 months.
5.1.5 Supervised residue trials
Potatoes (cGAP-NL: 1x 2 kg/ha, Pre-emergence)
The intended use of PRONAN in the Netherlands corresponds to the defended uses for metobromuron in the Draft Assessment Report. In the DAR a total of 20 supervised residue trials on potato, 11 in Northern Europe and 9 in Southern Europe (9 sites, 10 experiments) were evaluated. Among them, 7 Northern trials have not been considered because the analytical method was not fully validated or the maturity of tubers at harvest was not
sufficient (below 50 % of the final size of tuber, stage BBCH 41-44). Samples collected were analysed for metobromuron, its metabolites 4-bromophenylurea, desmethoxy-metobromuron and desmethyl-metobromuron as well as for the common moiety 4-bromoaniline (after basic hydrolysis). In NEU, 4 residue trials have been considered among which residue level of 4- bromoaniline was in the range 0.009 and 0.032 mg/kg. The levels of 4-bromophenylurea were below or at the LOQ level of 0.005 mg/kg with exception for one of the trials where the amount determined was 0.007 mg/kg. The remaining compounds were either not detected or detected but at levels at or below the LOQ of 0.005 mg/kg. In SEU, 9 residue trials have been considered. Residue levels of 4-bromoaniline were in the range <0.005-0.024 mg/kg.
For 4-bromophenylurea the range was <0.005-0.008 mg/kg, while metobromuron,
desmethoxy-metobromuron and desmethyl-metobromuron were not found at levels above the LOQ.
Based on the individual results for 4-bromophenylurea an MRL of 0.01 mg/kg is proposed for potatoes. The content of 4-bromophenylurea in the rejected trials (tubers collected at stage BBCH 41-44), that could be considered as worst case, is similar to that found in the rest of the NEU and SEU trials (H-test, 5%). Moreover, if the values from the rejected studies are considered in the calculations, the MRL would not be affected. Therefore it is considered that additional trials in NEU are not needed.
The residue levels selected for MRL setting and risk assessment are presented in table R1.
Table R1: Selected residue levels from trials with metobromuron
Crop Residue levels (mg/kg) STMR
(mg/kg)
HR (mg/kg) NEU, field: 2 x <0.005; 0.005; 0.007 0.005 0.007 SEU, field: 6 x <0.005; 2 x 0.005; 0.008 0.005 0.008 Potato
EU, field: 8 x <0.005; 3 x 0.005; 0.007;
0.008
0.005 0.008
5.1.6 Residues in succeeding crops
Based on the available data considered in the DAR it was concluded that in case of crop failure, only root crops and leafy crops can be grown in the treated plot, while as rotational crops, cereals can be grown 6 months after application and one year after application all types of crops can be grown. Considering the normal agricultural practice no quantifiable residues are expected to be found in rotated crops. The following label restriction is required:
“In case of crop failure, only root crops and leafy crops can be grown in the treated plot, while as rotational crops, cereals can be grown 6 months after application and one year after application all types of crops can be grown”.
“In verband met residuen in volggewassen mogen direct na het mislukken van de teelt alleen wortelgewassen en bladgewassen geteeld worden. In de eerstvolgende 6 maanden na toepassen mogen geen granen worden geteeld. Een jaar na toepassen mogen alle gewassen worden geteeld.”
5.1.7 Residues from livestock feeding studies
It was concluded that the use of metobromuron 500 SC in potatoes used as animal feed will not lead to detectable residues in food of animal origin. Consequently it is considered that there is no need to conduct livestock metabolism and feeding studies.
5.1.8 Processing factors
As the total residues in field trials were significantly below the trigger value of 0.1 mg/kg, no processing study is required.
5.1.9 Calculation of the ADI and the ARfD Calculation of the ADI
The ADI is based on the NOAEL of 0.8 mg/kg bw/d from the 2-year study in mouse.
Application of a safety factor for inter- and intraspecies differences of 100 results in an ADI of 0.008 mg/kg bw/day (see the List of Endpoints for mammalian toxicology).
Calculation of the ARfD
The ARfD is based on the NOAEL of 30 mg/kg bw/d in the rat and rabbit developmental studies. Application of a safety factor for inter- and intraspecies differences of 100 results in an ARfD of 0.3 mg/kg bw/day (see the List of Endpoints for mammalian toxicology).
5.2 Maximum Residue Levels
No MRL for residues of metobromuron have been established in the annexes of Reg 396 / 2005 and therefore the default MRL of 0.01 mg/kg according to Art 18(1)(b) applies. Based on the individual results for 4-bromophenylurea an MRL of 0.01 mg/kg is proposed for potatoes. Notification of the MRL is not necessary.
5.3 Consumer risk assessment
Risk assessment for chronic exposure through diet
No acute or chronic risks were identified for the consumers using the EFSA PRIMO model rev 2.0. The highest TMDI, 10.5 % of ADI for metobromuron (FR Toddler), is calculated considering a default MRL of 0.01 mg/kg in all commodities and, for potato, the proposed MRL of 0.01 mg/kg multiplied by the conversion factor of 3.4 obtained from the List of Endpoints
Risk assessment for acute exposure through diet
The IESTI calculated using the HR of 4-bromoaniline amounts to 1.6 % of the ARfD for metobromuron (0.3 mg/kg bw).
EFSA’s peer review (EFSA Journal 2014;12(2):3541), in the mammalian toxicology area, a data gap is identified to address the relative toxicity of three plant metabolites included in the plant residue definitions. This data requirement will be dealt with by the RMS (France) for the approval of the substance, and confirmatory data is requested before 31 December 2016.
For the national authorisation of PROMAN additional data is submitted and evaluated. The three plant metabolites are not considered genotoxic. To address the toxicological relevance of the three plant metabolites there is referred to the TTC concept in line with the EFSA opinion (EFSA Journal 2012; 10(07):2799).
The TMDI in the national assessment accounts for 10.5 % of the ADI (0.008 mg/kg bw/d), which is 0.84 µg/kg bw/d. The IESTI is 1.6 % of the ARfD (0.3 mg/kg bw/d), which is 4.8 µg/kg bw/d. These exposure calculation remain below the corresponding acute and chronic threshold of toxicological concern levels of 1.5 and 5 µg/kg bw/d, respectively for the
intended use on potato only. It is therefore concluded that the relative toxicity of the three plant metabolites included in the plant residue definition for risk assessment is covered.
Conclusion
No risk for the consumer is expected. The product complies with the Uniform Principles.
Data requirements
No additional data required.
6 Environmental fate and behaviour
The List of Endpoints is taken from the EFSA Conclusion (EFSA Journal 2014;12(2):3541).
List of Endpoints Fate/behaviour (EFSA Conclusion, 2014) Route of degradation (aerobic) in soil (Annex IIA, point 7.1.1.1.1)
Mineralization after 100 days ‡ 10.8-19.7% (day 118, study end); 27.3% (day 168, study end)
Non-extractable residues after 100 days ‡ 55.8-74.1% (day 118, study end); 57.2% (day 168, study end)
Metabolites requiring further consideration
‡
- name and/or code, % of applied (range and maximum)
None
Route of degradation in soil - Supplemental studies (Annex IIA, point 7.1.1.1.2) Anaerobic degradation ‡
Mineralization after 100 days 4.0% (day 90 of anaerobic incubation, study end)
Non-extractable residues after 100 days 53.7% (day 90 of anaerobic incubation, study end)
Metabolites that may require further consideration for risk assessment – name and/or code, % of applied (range and maximum)
Desmethoxy-metobromuron (5.1% after 60 days, 14.9% after 90 days)
Soil photolysis ‡
Metabolites that may require further consideration for risk assessment – name and/or code, % of applied (range and maximum)
None
Rate of degradation in soil (Annex IIA, point 7.1.1.2, Annex IIIA, point 9.1.1) Laboratory studies ‡
Parent Aerobic conditions Soil type OC
% pH t. °C / % MWHC
DT50/DT90 (d)
DT50 (d)
20°C χ2 Method of
calculation
pF2/10kPa Silt,
Les Barges 1.7 7.7 25 / 75 % FC 25.7 / 85.3 33.8 5.88 SFO Silt loam,
Fislis 2.00 6.72 20 / pF2.0-2.5 24.6 / 81.3 24.6 3.91 SFO Clay,
Speyer 6S 1.44 7.30 20 / pF2.0-2.5 28.4 / 94.3 28.4 5.17 SFO Loamy
sand, Speyer 2.2
1.83 6.12 20 / pF2.0-2.5 49.7 / 165.1 49.7 3.25 SFO
Sandy loam, Longwoods
1-1.5 7.5 20 / pF2.0-2.5 40.3 / 133.8 40.3 2.2 SFO
Geometric mean - / - 34.3 - -
Desmethox y-
metobromur on
Aerobic conditions
Soil type OC
% pH t. °C / % MWHC
DT50/DT90 (d)
f. f.
kdp/kf
DT50 (d) 20°C pF2/10kPa
χ2
Method of
calculatio n
Sandy loam, Longwoods
1.53 7.33 20 / pF2.0- 2.5
49.9 / 165.6
- *
49.9 6.6 SFO
Clay,
Speyer 6S 1.79 7.13 20 / pF2.0- 2.5
72.5 / 240.9
-* 72.5 6.4 SFO
Silt loam,
Fislis 1.28 7.07 20 / pF2.0- 2.5
61.5 / 204.4
-* 61.5 6.1 SFO
Geometric mean (n=3) - / - - 60.6 - -
* desmethoxy-metobromuron as test item Field studies ‡
Parent Aerobic conditions Soil
type Location X1 pH Depth (cm)
DT50 (d) actual
DT90 (d) actual
χ2
DT50 (d) Norm.
Method of calculation Clay St. Aubin,
Switzerland 6.6 0-10 18.3 60.8 -* 8.8 SFO
Silt
loam Harthau,
Germany 6.3 0-60 4.1 55.1 10.7 5.4
DFOP for actual DT values, SFO for normalised
values
Loam La Chapelle de
Guinchay, N France
4.9 0-60 73.3 243.6 19.7 47.0 SFO
Sandy clay loam
Sevilla,
Spain 6.6 0-60 71.1 236.1 13.7 64.5 SFO
Clay Nimes,
S France 7.8 0-60 32.9 109.3 6.4 38.9 SFO
Geometric mean (n=5) - - - 22.4 -
* not reported, r2 = 0.9922
Met 1 Aerobic conditions – not studied Soil
type Location pH Depth (cm)
DT50 (d) actual
DT90 (d) actual
St. (r2) DT50 (d) Norm.
Method of circulation
- - - -
Geometric mean/median - - - - -
pH dependence ‡
(yes / no) (if yes type of dependence)
No Soil accumulation and plateau
concentration ‡
Not studied, not required
Laboratory studies ‡
Parent Anaerobic conditions Soil type pH
(CaCl2)
t. °C / % MWHC
DT50/DT90 (d)
DT50 (d) 20°C pF2/10kPa
St. (r2) Method of circulation Silt loam 6.43 20 / pF2.5 73.7 / 245.0 - 0.93348 SFO
Geometric mean/median - - - - -
Met 1 Anaerobic conditions – not studied Soil type pH t. °C / %
MWHC
DT50/DT9
0 (d)
f. f.
kdp/kf
DT50 (d) 20°C pF2/10kPa
St. (r2) Method of circulation
- - - -
Geometric
mean/median - - - - -
-
Soil adsorption/desorption (Annex IIA, point 7.1.2) Parent ‡
