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APPENDIX I

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APPENDIX I

    EUROPEAN COMMISSION

    HEALTH & CONSUMER PROTECTION DIRECTORATE-GENERAL

     Directorate E Safety of the food chain Unit E.3 - Chemicals, contaminants, pesticides

     Thiamethoxam

     SANCO/10390/2002 - rev. 2

     19 June 2006

    EU RESTRICTED

COMMISSION WORKING DOCUMENT - DOES NOT NECESSARILY REPRESENT

    THE VIEWS OF THE COMMISSION SERVICES

    DRAFT

    Review report for the active substance thiamethoxam

    Finalised in the Standing Committee on the Food Chain and Animal Health at its meeting on

    14 July 2006 in view of the inclusion of thiamethoxam in Annex I of Directive 91/414/EEC.

    1. Procedure followed for the evaluation process

This review report has been established as a result of the evaluation of the new active substance

    thiamethoxam, made in the context of the work provided for in Articles 5 and 6 of Directive

    91/414/EEC concerning the placing of plant protection products on the market, with a view to

    the possible inclusion of this substance in Annex I to the Directive.

In accordance with the provisions of Article 6(2) of Directive 91/414/EEC, the Spanish

    authorities received on 17 March 1999 an application from Novartis Crop Protection AG (now Syngenta), hereafter referred to as the applicant, for the inclusion of the active substance

    thiamethoxam in Annex I to the Directive. The Spanish authorities indicated to the Commission on 20 July 1999 the results of a first examination of the completeness of the dossier, with regard

    to the data and information requirements provided for in Annex II and, for at least one plant

    protection product containing the active substance concerned, in Annex III to the Directive.

    Subsequently, and in accordance with the requirements of Article 6(2), a dossier on

    thiamethoxam was distributed to the Member States and the Commission.

The Commission referred the dossier to the Standing Committee on the Food Chain and

    Animal Health in the meeting of the working group ‘legislation’ thereof on 20 July 1999, during

    which the Member States confirmed the receipt of the dossier.

In accordance with the provisions of Article 6(3), which requires the confirmation at Community

    level that the dossier is to be considered as satisfying, in principle, the data and information

    requirements provided for in Annex II and, for at least one plant protection product containing

    the active substance concerned, in Annex III to the Directive and in accordance with the

    procedure laid down in Article 20 of the Directive, the Commission confirmed in its Decision

    2000/181/EC

    1 of 23 February 2000 that these requirements were satisfied.

     1 OJ L 57, 2.3.2000, p.35.

    - 2 -

    Within the framework of that decision and with a view to the further organisation of the works related to the detailed examination of the dossier provided for in Article 6(2) and (4) of Directive 91/414/EEC, it was agreed between the Member States and the Commission that Spain would, as rapporteur Member State, carry out the detailed examination of the dossier and report the conclusions of its examination accompanied by any recommendations on the inclusion or non-inclusion and any conditions relating thereto, to the Commission as soon as possible and at the latest within a period of one year.

Spain submitted to the Commission on 21 January 2002 the report of its detailed scientific

    examination, hereafter referred to as the draft assessment report, including, as required, a recommendation concerning the possible inclusion of thiamethoxam in Annex I to the Directive.

    On receipt of the draft assessment report, the Commission forwarded it for consultation to all the Member States as well as to Novartis Agro S. A. (now Syngenta) being the sole applicant on 30

    January 2002.

    The Commission organised further an intensive consultation of specialised scientific experts from a representative number of Member States, to review the draft assessment report and the comments received thereon (peer review), in particular on each of the following disciplines :

- identity and physical /chemical properties ;

    - fate and behaviour in the environment ;

    - ecotoxicology ;

    - mammalian toxicology ;

    - residues and analytical methods ;

    - regulatory questions.

    The meetings for this consultation were organised on behalf of the Commission by the Biologische Bundesanstalt für Land und Forstwirtschaft (BBA) in Braunschweig, Germany, from November 2002 to July 2003.

    The report of the peer review (i.e. full report) was circulated, for further consultation, to Member States and the sole applicant on 14 October 2003.

    The dossier, draft assessment report and the peer review report (i.e. full report) including in particular an outline resume of the remaining technical questions, were referred to the Standing Committee on the Food Chain and Animal Health, and specialised working groups of this Committee, for final examination, with participation of experts from all Member States. This final examination took place from January 2004 to July 2006, and was finalised in the meeting of the Standing Committee on 14 July 2006.

    The present review report contains the conclusions of this final examination; given the importance of the draft assessment report, the peer review report (i.e. full report) and the comments and clarifications submitted after the peer review as basic information for the final examination process, these documents are considered respectively as background documents A, B and C to this review report and are part of it.

    The review of thaimethoxam did not reveal any open questions or concerns, which would have required a consultation of the Scientific Committee on Plants or of the European Food Safety Authority which has taken over the role of that Committee.

    - 3 -

2. Purposes of this review report

    This review report, including the background documents and appendices thereto, have been developed and finalised in support of the Directive 2007/6/EC concerning the inclusion of

    thiamethoxam in Annex I to Directive 91/414/EEC, and to assist the Member States in decisions on individual plant protection products containing thiamethoxam they have to take in accordance with the provisions of that Directive, and in particular the provisions of article 4(1) and the uniform principles laid down in Annex VI.

    This review report provides also for the evaluation required under Section A.2.(b) of the above mentioned uniform principles, as well as under several specific sections of part B of these principles. In these sections it is provided that Member States, in evaluating applications and granting authorisations, shall take into account the information concerning the active substance in Annex II of the directive, submitted for the purpose of inclusion of the active substance in Annex I, as well as the result of the evaluation of those data.

    In parallel with the provisions of Article 7(6) of Regulation 3600/92 for existing active substances, the Commission and the Member States will keep available or make available this review report for consultation by any interested parties or will make it available to them on their specific request. Moreover the Commission will send a copy of this review report (not including the background documents) to the applicant.

    The information in this review report is, at least partly, based on information which is confidential and/or protected under the provisions of Directive 91/414/EEC. It is therefore recommended that this review report would not be accepted to support any registration outside the context of Directive 91/414/EEC, e.g. in third countries, for which the applicant has not demonstrated possession of regulatory access to the information on which this review report is based.

3. Overall conclusion in the context of Directive 91/414/EEC

    The overall conclusion from the evaluation is that it may be expected that plant protection products containing thiamethoxam will fulfil the safety requirements laid down in Article 5(1)(a) and (b) of Directive 91/414/EEC. This conclusion is however subject to compliance with the particular requirements in sections 4, 5, 6 and 7 of this report, as well as to the implementation of the provisions of Article 4(1) and the uniform principles laid down in Annex VI of Directive 91/414/EEC, for each thiamethoxam containing plant protection product for which Member States will grant or review the authorisation.

    Furthermore, these conclusions were reached within the framework of the uses which were proposed and supported by the sole data submitter and mentioned in the list of uses supported by available data (attached as Appendix IV to this Review Report).

    Extension of the use pattern beyond those described above will require an evaluation at Member State level in order to establish whether the proposed extensions of use can satisfy the requirements of Article 4(1) and of the uniform principles laid down in Annex VI of Directive 91/414/EEC.

    - 4 -

4. Specific conclusions which are highlighted in this evaluation

     4.1 Residues of thiamethoxam in foodstuffs

    The review has established that the residues arising from the proposed uses, consequent on application consistent with good plant protection practice, have no harmful effects on human or animal health. The Theoretical Maximum Daily Intake (TMDI) for a 60 kg adult is 5.36 % of the Acceptable Daily Intake (ADI), based on the FAO/WHO European Diet (August 1994). Estimates of acute dietary exposure of adults and toddlers in oranges, mandarins, grapefruit, pears, apples, peaches, tomatoes, peppers, cucumbers, courgettes, melons and potatoes do not exceed the Acute Reference Dose (ARfD).

     4.2 Exposure of operators, workers and bystanders

    The review has identified acceptable exposure scenarios for operators, workers and bystanders, which require, however, confirmation for each plant protection product in accordance with the relevant sections of the above mentioned uniform principles.

     4.3 Ecotoxicology

    The review has also concluded that under the proposed and supported conditions of use there are no unacceptable effects on the environment, as provided for in Article 4 (1) (b) (iv) and (v) of Directive 91/414/EEC, provided that certain conditions are taken into account as detailed in section 7 of this report.

5. Identity and Physical/chemical properties

    The main identity and the physical/chemical properties of thiamethoxam are given in Appendix I.

The active substance shall have a minimum purity of 980 g/kg technical product.

    The review has established that for the active substance notified by the applicant (Novartis Crop Protection AG, now Syngenta), none of the manufacturing impurities considered are, on the basis of information currently available, of toxicological or environmental concern.

6. Endpoints and related information

    In order to facilitate Member States, in granting or reviewing authorisations, to apply adequately the provisions of Article 4(1) of Directive 91/414/EEC and the uniform principles laid down in Annex VI of that Directive, the most important endpoints as identified during the evaluation process are listed in Appendix II.

    - 5 -

    7. Particular conditions to be taken into account on short term basis by Member

    States in relation to the granting of authorisations of plant protection products containing

    thiamethoxam

On the basis of the proposed and supported uses, the following particular issues have been

    identified as requiring particular and short term (within 12 months at the latest) attention from

    the Member States, in the framework of any authorisations to be granted, varied or withdrawn, as

    appropriate:

Member States

    - must pay particular attention to the potential for groundwater contamination,

    particularly of the active substance and its metabolites NOA 459602, SYN 501406

    and CGA 322704, when the active substance is applied in regions with vulnerable

    soil and/or climatic conditions;

    - must pay particular attention to the protection of aquatic organisms;

    - must pay particular attention to the long-term risk to small herbivorous animals if

    the substance is used for seed treatment.

Conditions of use shall include risk mitigation measures, where appropriate.

8. List of studies to be generated

No further studies were identified which were considered at this stage, and under the

    current inclusion conditions necessary in relation to the inclusion of thiamethoxam in

    Annex I.

9. Updating of this review report

The technical information in this report may require periodic updating to take account of

    technical and scientific developments as well as of the results of the examination of any

    information referred to the Commission in the framework of Articles 7, 10 or 11 of Directive

    91/414/EEC. Such adaptations will be examined and finalised in the Standing Committee on the

    Food Chain and Animal Health, in connection with any amendment of the inclusion conditions

    for thiamethoxam in Annex I of the Directive.

     - 1 -

    Thiamethoxam APPENDIX I

    Identity, physical and chemical properties

    17 March 2006

    APPENDIX I

    Identity, physical and chemical properties

    THIAMETHOXAM

Common name (ISO) Thiamethoxam

    Development Code (for new actives CGA 293343

    only)

    Chemical name (IUPAC) (E,Z)-3-(2-chloro-thiazol-5-ylmethyl)-5-methyl-

    [1,3,5]oxadiazinan-4-ylidene-N-nitroamine Chemical name (CA) 3-?(2-chloro-5-thiazolyl)methyl?tetrahydro-5-methyl-N-

    nitro-4H-1,3,5-oxadiazin-4 imine CIPAC No 637

    CAS No 153719-23-4

    EEC No 428-650-4

    FAO SPECIFICATION not available

    Minimum purity 980 g/kg

    Molecular formula CHClNOS 81053

    Molecular mass 291.7

    Structural formula

    O

    NNS

    ClNNON

    O

     - 2 -

    Thiamethoxam APPENDIX I

    Identity, physical and chemical properties

    17 March 2006 Melting point 139.1?C (= 412.3 K) (Purity: 99.7%) Boiling point Thermal decomposition starts at about 147?C (i.e.

    before the boiling point is reached) (Purity: 99.3%) Appearance Slightly cream fine crystalline powder (Purity: 99.7%) Relative density 1.57 • 10? kg / m? at 20?C corresponding to a relative

    density of 1.57.(Purity: 99.7%)

    Vapour pressure ln P [Pa] = - 15400.447 / T K + 32.81766 from fit of

    measurements between 90.5 and 121.0?C vapour

    pressure at 25?C : 6.6•10-9 Pa (extrapolated).

    (Purity: 99.7%)

    -10Henry's law constant 4.7 ? 10 Pa ? m? / mol.

    Solubility in water The solubility in pure water was determined to be : 4.1

    g / l at 25?C

    Thiamethoxam has no dissociation within the range pH

    2 to pH 12, that means the pH has no effect to the

    water solubility of the compound in the pH range 4 to

    10.

    (Purity: 99.7%)

    Solubility in organic solvents (Purity: 98.2%)

    acetone: 48 g / l

    ethyl acetate 7.0 g / l

    dichloromethane 110 g / l

    hexane < 1 mg / l

    toluene 680 mg / l

    methanol 13 g / l

    n-octanol 620 mg / l

Partition co-efficient (log P) P0.73 ? (0.0029) at 25?C owOW :

    log P: -0.13 ? (0.0017) at 25?C ow

    (Purity: 99.7%)

    -1 Hydrolytic stability (DT) pH k (s)DTdays) 5050 (

     Thia. Guan Thia. Guan

    5 n.d. n.d.

    -8-8 7 1.27 10 1.39 10640 572

    -7 -6 9 9.53 101.94 108.4 4.2

    (Purity: 98.3%)

    Dissociation constant Thiamethoxam does not have a dissociation constant

    within the range 2 to 12.

    Quantum yield of direct photo-? = 0.013 ? 0.002

    transformation in water at >290 (Purity: 99.3%) nm

    Flammability not considered highly flammable (Purity: 98.2%)

     - 3 - Thiamethoxam APPENDIX I

    Identity, physical and chemical properties

    17 March 2006

    Explosive properties not considered an explosive (Purity: 98.2%)

    UV/VIS absorption (max.) 255 nm the ? = 16800 l / mol ? cm in neutral solution.

    No absorption maximum between 290 nm and 750 nm

    was observed.

    (Purity: 99.7%) Photostability in water (DT) 2.3 to 3.1 days (25?C; sterile conditions in aqueous 50

    buffer solutions at pH 5; 10 mg/l, sunlight (Xenon arc

    light) at 12 hours light/dark cycles over a total period of

    30 days)

    (Purity: 97.3%)

    - 4 -

    Thiamethoxam APPENDIX II

    END POINTS AND RELATED INFORMATION

    1. Toxicology and metabolism

    17 March 2006

    APPENDIX II

    END POINTS AND RELATED INFORMATION

    THIAMETHOXAM

1 Toxicology and metabolism

    Absorption, distribution, excretion and metabolism in mammals Rate and extent of absorption: Rapid and complete in the rat within 24 hours, based

    on urinary and biliary excretion. In the mouse, about

    75%, based on urinary excretion (14 daily doses). Distribution: Widely distributed. Highest residues in the liver Potential for accumulation: No evidence of accumulation Rate and extent of excretion: In the rat, 95% in urine and 5% in faeces within 168

    hrs.

    Toxicologically significant compounds: Parent compound and metabolites. Metabolism in animals: Completely metabolised at low dose levels (0.5 mg/kg

    bw), poorly metabolised (20 30%) at high dose

    levels (100 mg/kg bw) in the rat.

Acute toxicity

    Rat LD oral: 1563 mg/kg bw (Xn- R22) 50

    Rat LD dermal: >2000 mg/kg bw 50

    Rat LC inhalation: > 3.72 mg/l, 4 hrs exposure, nose-only. 50

    Skin irritation: Non-irritant

    Eye irritation: Non-irritant

    Skin sensitization (test method used Non-sensitiser (Maximisation method) and result):

Short term toxicity

    Target / critical effect: Liver (hypertrophy, inflammation, necrosis), kidney

    (male rat: ?-2-?globulin nephropathy), testes (tubular

    atrophy in the dog)

    - 5 -

    Thiamethoxam APPENDIX II

    END POINTS AND RELATED INFORMATION

    1. Toxicology and metabolism

    17 March 2006

    NOAEL = 10 ppm (1.4 mg/kg bw/day) 90-day mice Lowest relevant oral NOAEL / NOEL:

    NOAEL = 150 ppm (4.05 mg/kg bw/day) 1-year dog.

    NOAEL = 250 ppm (8.2 mg/kg bw/day) 90-day dog Lowest relevant dermal NOAEL / NOAEL = 60 mg/kg bw/day, 28-day rats NOEL:

    Lowest relevant inhalation NOAEL / No data. None required.

    NOEL:

    No genotoxic potential Genotoxicity

Long term toxicity and carcinogenicity

    Target / critical effect: Liver (hypertrophy, inflammation, necrosis) in mice

    and kidney (male rat ?-2-?globulin nephropathy) Lowest relevant NOAEL: 20 ppm (2.6 mg/kg bw/day) 18-month study in mice. Carcinogenicity: Increased incidence of liver cell adenoma and

    adenocarcinoma in mice at 500 ppm (64 mg/kg

    bw/day) and above.

Reproductive toxicity

    Target / critical effect - Reproduction: Germ cell loss/disorganization Sertoli cell vacuolation Lowest relevant reproductive NOAEL / 1000 ppm (62 mg/kg bw/day), 2 generation

    NOEL: reproduction toxicity study in rats Target / critical effect - Developmental Reduced fetal weight, delayed ossification and

    toxicity: increased post-implantation loss (rabbit only) at

    maternal toxic doses.

    Lowest relevant developmental 50 mg/kgbw/day (rabbit developmental study) NOAEL / NOEL:

    - Acute neurotoxicity study in rats: reduced locomotor Delayed neurotoxicity activity. NOAEL = 100 mg/kg bw.

    - 90-day neurotoxicity study in rats: no indications of

    neurotoxicity. NOAEL = 1500 ppm (95 mg/kg bw/day).

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