Conclusion regarding the peer review of the pesticide risk assessment of the active substance. cyprodinil. finalised: 14 December 2005

Transcription

1 Conclusion regarding the peer review of the pesticide risk assessment of the active substance cyprodinil finalised: 14 December 2005 SUMMARY Cyprodinil is one of the 52 substances of the second stage of the review programme covered by Commission Regulation (EC) No 451/2000 1, as amended by Commission Regulation (EC) No 1490/ This Regulation requires the European Food Safety Authority (EFSA) to organise a peer review of the initial evaluation, i.e. the draft assessment report (DAR), provided by the designated rapporteur Member State and to provide within one year a conclusion on the risk assessment to the EU-Commission. France being the designated rapporteur Member State submitted the DAR on cyprodinil in accordance with the provisions of Article 8(1) of the amended Regulation (EC) No 451/2000, which was received by the EFSA on 16 January Following a quality check on the DAR, the peer review was initiated on 4 March 2004 by dispatching the DAR for consultation of the Member States and the sole applicant Syngenta Ltd. Subsequently, the comments received on the DAR were examined by the rapporteur Member State and the need for additional data was agreed in an evaluation meeting in September Remaining issues as well as further data made available by the notifier upon request were evaluated in a series of scientific meetings with Member State experts in January March A final discussion of the outcome of the consultation of experts took place with representatives from the Member States on 28 September 2005 leading to the conclusions as laid down in this report. The conclusion was reached on the basis of the evaluation of the representative uses as fungicide as proposed by the applicant which comprises foliar spraying to control fungi from the classes Ascomycetes, Basidiomycetes and Deuteromycetes in winter wheat and apple at application rates of 750 g (wheat) and 225 g (apple) cyprodinil per hectare. Cyprodinil can be used only as fungicide. The representative formulated products for the evaluation were "UNIX 75 WG" and "CHORUS 50 WG", both water dispersible granules (WG), registered under different trade names in Europe. 1 OJ No L 53, , p OJ No L 224, , p of 78

2 Adequate methods are available to monitor all compounds given in the respective residue definition, except for food of animal origin. Residues in food of plant origin can be determined with a multimethod (The German S19 method has been validated). For the other matrices only single methods are available to determine residues of cyprodinil. Sufficient analytical methods as well as methods and data relating to physical, chemical and technical properties are available to ensure that quality control measurements of the plant protection product are possible. Cyprodinil is absorbed to a high degree (>80%) within 48 hours, based on rat excretion data. The acute oral and dermal toxicity is low as well as during inhalatory exposure. It is not a skin or an eye irritant but is a skin sensitizer (Magnusson and Kligman test). Classification for sensitization properties is needed and the proposed risk phrase is Xi; R43 May cause sensitization by skin contact. Reduced body weight some minor changes in haematological and blood parameters were observed at the top dose during repeated exposure. There is no genotoxic, carcinogenic or neurotoxic potential for cyprodinil and no adverse effects were seen on reproduction parameters. None of the metabolites ( 3 CGA , 4 CGA , 5 NOA , 6 CGA , and 7 CGA ) were of toxicological concern. The acceptable daily intake (ADI) and acceptable operator exposure level (AOEL) is 0.03 mg/kg bw/day with a safety factor of 100 used and no acute reference dos (ARfD) was allocated due to the low acute toxicity of cyprodinil. The dermal absorption values are 0.5% for the concentrate and 6% for the dilution and the estimated operator exposure is below the AOEL for both UNIX and CHORUS without PPE according to the German model. The metabolic fate of cyprodinil in plants has been fully elucidated for the representative uses supported by the applicant. Based on the persistence of the product and the absence of metabolite of concern, the residue definition for monitoring and risk assessment in plant commodities is limited to cyprodinil. Residue studies were conducted in apples and wheat, supporting the setting of MRLs at 0.05 and 0.02* mg/kg respectively (* indicates that the LMR is set at the limit of quantification of the method of analysis.). In succeeding crops, no residues are expected at measurable level under normal conditions of use of the product and normal cropping practices. In animals a major metabolite of cyprodinil (CGA ) was identified and should be included in the residue definition. Feeding studies were carried out without analysis of this metabolite, and it is therefore not possible to propose MRLs for animal commodities. However, despite this lacking information, a consumer risk assessment was carried out taking into account the residues in plant commodities only, indicating that the exposure of the consumer is far 3 CGA : 4-cyclopropyl-6-methyl-pyrimidin-2-yl-amine 4 CGA : 3-(4-cyclopropyl-6-methyl-pyrimidin-2-yl-amino)-phenol 5 NOA : (2-amino-6-cyclopropyl-pyrimidin-4-yl)-methanol 6 CGA : 4-cyclopropyl-6-methyl-pyrimidin-2-ol 7 CGA : (6-cyclopropyl-2-phenylamino-pyrimidin-4-yl)-methanol 2 of 78

3 below the ADI of cyprodinil. Based on the metabolism data, the expected residue levels in animal commodities are expected to be very low and not of a nature to significantly influence the outcome of the intake calculations based on plant commodities only. The available data demonstrate that in soil cyprodinil degrades to the major (>10% applied radioactivity (AR)) metabolites CGA and CGA The minor breakdown products 8 CGA , 9 CGA and CGA were also identified. Mineralization of the phenyl and pyrimidyl rings accounted for only 6-14%AR and %AR respectively after days incubation at C. The corresponding values for residues not extracted by acetonitrile including Soxhlet extraction were %AR and %AR. In most studies Cyprodinil exhibited moderate persistence in soil with the major metabolites CGA and CGA exhibiting very low persistence and moderate to high persistence respectively. In field studies this pattern of soil persistence was confirmed with there being evidence that the analysed extractable breakdown products (CGA , CGA and CGA ) declined in concentration after their maximum measured concentrations. However it was observed in the 1 laboratory experiment with a more acidic soil (ph 5.2) and in a very acidic (ph 4.9) soil in 1 German field experiment, that cyprodinil exhibited very high persistence. Cyprodinil could therefore be more persistent in very acid soils (around ph 5 and below), though the available database (2 acidic soil experiments) is too small to confirm this hypothesis. Member States which have significant areas of acidic soils in arable or horticultural production should request additional information to confirm if this is a real correlation and if it is confirmed, further information to address the consequences of higher persistence in acidic soils. In guideline batch soil adsorption studies cyprodinil and CGA exhibited low mobility. CGA exhibited medium to low mobility in soil, with adsorption of CGA appearing to be ph dependent (lowest adsorption at highest soil ph). In sediment water systems cyprodinil dissipated from water relatively rapidly, partitioning to sediment where it exhibited high persistence. It did degrade to the metabolite CGA which was a major sediment but minor water metabolite. This metabolite exhibited moderate persistence. The major sink in the mass balance was the formation of residues not extracted by acetonitrile:water Soxhlet extraction. Mineralization of the pyrimidyl ring to CO 2 was low < 5%AR after 260 days. This value for the phenyl ring was slightly higher at up to 11%AR. The available aquatic exposure assessment is appropriate for assessing the spray drift route of entry to surface water for the representative uses applied for, for annex 1 listing. The drainage and runoff routes of entry have not been assessed. These routes of entry should be taken into account by MS 8 CGA : 4-(4-cyclopropyl-6-methyl-pyrimidin-2-yl-amino)-phenol 9 CGA : 4-cyclopropyl-6-methyl-2-phenylamino-pyrimidin-5-ol 3 of 78

4 when these routes of entry to surface water are relevant and the pertinent risk assessment to aquatic organisms should be completed. The available FOCUS groundwater modelling indicates that the potential for groundwater contamination as a consequence of the representative uses applied for, for annex 1 listing for cyprodinil and its major soil metabolites CGA and CGA is minimal when soil ph is above 5. This assessment appropriately covered the observed lower soil adsorption of CGA at higher soil ph. As there is evidence cyprodinil might be more persistent in very acidic soils, MS that have significant areas of such soils associated with pertinent plant production and vulnerable groundwater leaching situations should require applicants to provide groundwater exposure assessments to cover this situation. A high long term risk was identified for insectivorous birds for the representative use in cereals (application to late growth stages). The EPCO experts meeting agreed that a risk assessment for early growth stages in cereals should be conducted since it is not fully justified that growth stage BBCH 32 of wheat can be regarded as a late growth stage. The RMS presented a risk assessment for early growth stages in addendum 2. The TER values for the long term risk to insectivorous birds, herbivorous birds and herbivorous mammals were 2.8, 4.8 and 1.7, respectively, indicating a high risk to birds and mammals from the intended use in wheat if the product is applied to early growth stages. A refined long-term risk assessment for insectivorous birds and a refined long-term risk assessment for herbivorous mammals was provided by the notifier and summarized in addendum 3. Addendum 2 and addendum 3 are not peer reviewed. The RMS considers the risk to herbivorous birds as low since the first tier TER value of 4.8 is close to the trigger of 5 and based on the NOEC from the highest tested dose in a reproduction study. However, it should be taken into account that the argumentation provided in addendum 2 is not peer reviewed. A high risk to birds and mammals from uptake of contaminated drinking water was shown in a first tier risk assessment for the representative use in cereals and a high long term risk to birds for the representative use in orchards. The risk to birds and mammals from uptake of contaminated earthworms and fish is considered to be low. The risk to birds and mammal of secondary poisoning and the risk from uptake of plant metabolites is considered to be low. Crustaceans (Cladocera) were the most sensitive group of aquatic organisms. The first tier risk assessment for the representative use in apples indicated a high acute and chronic risk to fish and daphnids. For the representative use in cereals a high acute and chronic risk was identified only for daphnia. Additional single species tests were used to reduce the acute TER trigger value from 100 to 10 in the higher tier risk assessment. The risk assessment based on the endpoints from single species tests resulted in TER values which meet the relevant acute and chronic Annex VI trigger values taking into account buffer zones of 40 m (orchards) and 10 m (cereals). Depending on the outcome of the PPR opinion on the use of the microcosm study, the results of the microcosm study could be taken into account at MS level for further risk refinement. 4 of 78

5 The risk to bees, other non-target arthropods, earthworms, soil non-target macro-organisms, soil nontarget micro-organisms, other non-target-organisms and biological methods of sewage treatment was assessed as low. Key words: cyprodinil, peer review, risk assessment, pesticide, fungicide 5 of 78

6 TABLE OF CONTENTS Summary... 1 Table of Contents... 6 Background... 7 The Active Substance and the Formulated Product... 8 Specific Conclusions of the Evaluation Identity, physical/chemical/technical properties and methods of analysis Mammalian toxicology Absorption, distribution, excretion and metabolism (Toxicokinetics) Acute toxicity Short term toxicity Genotoxicity Long term toxicity Reproductive toxicity Neurotoxicity Further studies Medical data Acceptable daily intake (ADI), Acceptable operator Exposure Level (AOEL) and Acute reference dose (ARfD) Dermal absorption Exposure to operators, workers and bystanders Residues Nature and magnitude of residues in plant Primary crops Succeeding and rotational crops Nature and magnitude of residues in livestock Consumer risk assessment Proposed MRLs Environmental fate and behaviour Fate and behaviour in soil Route of degradation in soil Persistence of the active substance and their metabolites, degradation or reaction products Mobility in soil of the active substance and their metabolites, degradation or reaction Fate and behaviour in water Surface water and sediment Potential for ground water contamination of the active substance their metabolites, degradation or reaction products Fate and behaviour in Air Ecotoxicology Risk to terrestrial vertebrates Risk to aquatic organisms Risk to bees Risk to other arthropod species Risk to earthwoms Risk to other soil non-target organisms Risk to soil non-target micro-organisms Risk to other non-target-organisms (flora and fauna) Risk to biological methods of sewage treatment Residue definitions List of studies to be generated, still ongoing or available but not peer reviewed Conclusions and Recommendations Critical areas of concern Appendix 1 List of endpoints for the active substance and the representative formulation Appendix 2 Abbreviations used in the list of endpoints of 78

7 BACKGROUND Commission Regulation (EC) No 451/2000 laying down the detailed rules for the implementation of the second and third stages of the work program referred to in Article 8(2) of Council Directive 91/414/EEC, as amended by Commission Regulation (EC) No 1490/2002, regulates for the European Food Safety Authority (EFSA) the procedure of evaluation of the draft assessment reports provided by the designated rapporteur Member State. Cyprodinil is one of the 52 substances of the second stage covered by the amended Regulation (EC) No 451/2000 designating France as rapporteur Member State. In accordance with the provisions of Article 8(1) of the amended Regulation (EC) No 451/2000, France submitted the report of its initial evaluation of the dossier on cyprodinil, hereafter referred to as the draft assessment report, to the EFSA on 16 January Following an administrative evaluation, the EFSA communicated to the rapporteur Member State some comments regarding the format and/or recommendations for editorial revisions and the rapporteur Member State submitted a revised version of the draft assessment report. In accordance with Article 8(5) of the amended Regulation (EC) No 451/2000 the revised version of the draft assessment report was distributed for consultation on 4 March 2004 to the Member States and the main applicant Syngenta Ltd. as identified by the rapporteur Member State. The comments received on the draft assessment report were evaluated and addressed by the rapporteur Member State. Based on this evaluation, representatives from Member States identified and agreed in an evaluation meeting on 27 September 2004 on data requirements to be addressed by the notifier as well as issues for further detailed discussion at expert level. A representative of the notifier was attending this meeting. Taking into account the information received from the notifier addressing the request for further data, a scientific discussion of the identified data requirements and/or issues took place in experts meetings organised on behalf of the EFSA by the EPCO-Team at the Federal Office for Consumer Protection and Food Safety (BVL) in Braunschweig in January March The reports of these meetings have been made available to the Member States electronically. A final discussion of the outcome of the consultation of experts took place with representatives from Member States on 28 September 2005 leading to the conclusions as laid down in this report. During the peer review of the draft assessment report and the consultation of technical experts no critical issues were identified for consultation of the Scientific Panel on Plant Health, Plant Protection Products and their Residues (PPR). In accordance with Article 8(7) of the amended Regulation (EC) No 451/2000, this conclusion summarises the results of the peer review on the active substance and the representative formulation 7 of 78

8 evaluated as finalised at the end of the examination period provided for by the same Article. A list of the relevant end points for the active substance as well as the formulation is provided in appendix 1. The documentation developed during the peer review was compiled as a peer review report comprising of the documents summarising and addressing the comments received on the initial evaluation provided in the rapporteur Member State s draft assessment report: the comments received the resulting reporting table (rev. 1-2 of 28 October 2004) the consultation report as well as the documents summarising the follow-up of the issues identified as finalised at the end of the commenting period: the reports of the scientific expert consultation the evaluation table (rev. 2-1 of 28 September 2005) Given the importance of the draft assessment report including its addendum (compiled version of September 2005 containing all individually submitted addenda) and the peer review report with respect to the examination of the active substance, both documents are considered respectively as background documents A and B to this conclusion. THE ACTIVE SUBSTANCE AND THE FORMULATED PRODUCT Cyprodinil is the ISO common name for 4-cyclopropyl-6-methyl-N-phenylpyrimidin-2-amine (IUPAC). Cyprodinil belong to the class of pyrimidine fungicides such as fenarimol and pyrimethanil. Cyprodinil is taken up via leaves and by inhibiting both the penetration and the mycelial growth of the fungi. The representative formulated products for the evaluation were "UNIX 75 WG" (winter wheat) and "CHORUS 50 WG" (apple), both water dispersible granules (WG), registered under different trade names in Europe. The evaluated representative uses as fungicide comprise foliar spraying to control to control fungi from the classes Ascomycetes, Basidiomycetes and Deuteromycetes in winter wheat and apple at application rates of 750 g (wheat) and 225 g (apple) cyprodinil per hectare. Cyprodinil can be used only as fungicide. 8 of 78

9 SPECIFIC CONCLUSIONS OF THE EVALUATION 1. Identity, physical/chemical/technical properties and methods of analysis The minimum purity of cyprodinil as manufactured should not be less than 980 g/kg. At the moment no FAO specification exists. The technical material contains no relevant impurities. It should be noted that the proposed specification (max values) for non-relevant impurities are above the values found in the technical material used for toxicological and ecotoxicological tests. Due to an outstanding amended specification or a confirmation that these differences are not of toxicological and ecotoxicological concern, the specification for the technical material with respect to the maximum content of the impurities should be regarded as provisional at the moment. Beside this, the assessment of the data package revealed no particular area of concern. The content of cyprodinil in the representative formulations "UNIX 75 WG" and "CHORUS 50 WG" is 750 g/kg (pure) and 500 g/kg (pure), respectively. Sufficient test methods and data relating to physical, chemical and technical properties are available. Also adequate analytical methods are available for the determination of cyprodinil in the technical material and in the representative formulation as well as for the determination of the respective impurities in the technical material. Therefore, enough data are available to ensure that quality control measurements of the plant protection product are possible. Adequate methods are available to monitor all compounds given in the respective residue definition, i.e. cyprodinil in food of plant origin; cyprodinil in soil, water and air. Residues in food of plant origin can be determined with a multi-method (The German S19 method has been validated). For the environmental compartments only single methods are available. The methodology used is HPLC with UV detection. The need for an analytical method for food of animal origin depends on the setting of respective MRLs (see 3.2). Due to the fact that at the moment it is not possible to propose MRLs, a final assessment is not possible. However, it should be noted that no analytical method for the determination of CGA is available. The acceptability of the provided method for the determination of cyprodinil cannot be concluded until MRLs have been proposed. The discussion in the experts meeting (EPCO 20, March 2005) on identity, physical and chemical properties and analytical methods was limited to the specification of the technical material and some clarification with respect to certain physical and chemical properties of cyprodinil as well as to analytical methods used for the technical material. 9 of 78

10 2. Mammalian toxicology Cyprodinil was discussed at EPCO experts meeting for mammalian toxicology (EPCO 14) in February ABSORPTION, DISTRIBUTION, EXCRETION AND METABOLISM (TOXICOKINETICS) Cyprodinil is absorbed to a high degree (>80%) within 48 hours, based on excretion data. The excretion is mainly via urine 52-63% and 33-45% is found in faeces. A large amount (39%) seems to be excreted via bile as demonstrated with bile cannulated rats. It is widely distributed but there was no evidence of accumulation, after 7 days the amount tissue residues was <1% of the dose. Cyprodinil is extensively metabolised (only 3-8% is excreted unchanged in the faeces), by sequential oxidation of the phenyl and /or pyrimidyl rings. About 18 metabolites were identified. The metabolism of Cyprodinil in goats and hens has a similar pattern as in the rat. 2.2 ACUTE TOXICITY The acute toxicity is low i.e. oral and dermal LD 50 > 2000 mg/kg bw as well as during inhalatory exposure i.e. LC 50 > 1.2 mg/l air. It is not a skin or an eye irritant but is a skin sensitizer (Magnusson and Kligman test). Classification for sensitization properties is needed and the proposed risk phrase is Xi; R43 May cause sensitization by skin contact. 2.3 SHORT TERM TOXICITY The short term effects of cyprodinil were studied in one 28-day range finding study in the rat and 90- day studies in the rat, mouse and dog as well as a 1-year dog study. A 28-day dermal study in the rat was also performed. Reduced body weight and some minor changes in haematological and blood parameters were observed at the top dose (1000 mg/kg bw/day). The relevant oral NOAEL is 3.2 mg/kg bw/day from the 90-day rat based on minor changes in blood biochemistry parameters and hypertrophy in the pituitary (males) at around 19 mg/kg bw/day which was confirmed at the experts meeting (initially the RMS proposed a NOAEL of 19 mg/kg bw/day). The relevant dermal NOAEL is 5 mg/kg bw/day. No studies were submitted on repeated inhalation. 2.4 GENOTOXICITY In the DAR the genotoxic properties of cyprodinil were studied in a battery consisting of four in vitro studies (of which two Ames tests) and one in vivo study. The purity was 99.5% in all tests. The overall conclusion is that there is no mutagenic or genotoxic potential for cyprodinil. 2.5 LONG TERM TOXICITY One 2-year study in the rat and one 18-month study in the mouse were submitted in the dossier. The liver was the main target and degenerative changes were observed at the doses 40 mg/kg bw/day Clear NOAELs were manifested and no carcinogenic effects were observed either in the rat or the 10 of 78

11 mouse. The NOAELs are 2.7 mg/kg bw/day and 3.2 mg/kg bw/day in the rat males and females, respectively and around 200 mg/kg bw/day for the mouse. 2.6 REPRODUCTIVE TOXICITY One multigeneration study in the rat in order to determine the reproductive effects of cyprodinil is presented in the DAR. There were no direct effects on reproductive performance or fertility observed. The parental NOAEL was 5.2 mg/kg bw/day based on reduced body weight gain. The relevant NOAEL for reproduction was 218 mg/kg bw/day. No teratogenic or developmental effects of cyprodinil were observed, examined in one study in the rat and one in the rabbit. The NOAEL for maternal and foetal/developmental effects in the rat is 200 mg/kg bw/day in the rat based on reduced body weight in the dams and delay of ossification in the pups. In the rabbits, the maternal NOAEL is 150 mg/kg bw/day based on reduced body weight gain and food consumption and the developmental NOAEL is > 400 mg/kg bw/day. 2.7 NEUROTOXICITY No sign of neurotoxicicity was observed in the general studies. In an acute neurotoxicity study in the rat the LD 50 is above 2000 mg/kg bw and in a 90-day study the NOAEL is above 600 mg/kg bw/day. 2.8 FURTHER STUDIES Metabolism Several studies on the soil metabolites CGA and CGA were performed to conclude on the toxicological relevance. A minor amount of CGA (0.014%) was found in rat metabolism studies. For both metabolites the acute oral LD 50 was above 2000 mg/kg bw and no mutagenic potential was detected in an Ames test. Furthermore, metabolites were found in rotational crop and were also tested. They were NOA and CGA and they were both of low acute toxicity i.e. LD 50 > 2000 mg/kg bw and no mutagenic potential was detected in an Ames test. CGA was found in tomato fruits and was of low acute toxicity i.e. LD 50 > 2000 mg/kg bw: Furthermore, it had no mutagenic potential as tested in an Ames test. In conclusion, none of the metabolites seems to be of toxicological concern. Mechanistic study In order to study the incidence and severity of renal tubular basofilia in the F0 males of the twogeneration study in the rats, the proliferating activity was assessed by histopathological staining. No evidence for an induction of renal tubular proliferation was seen in the F0 males. The occurrence may reflect a progressive nephropathic lesion of 78

12 2.9 MEDICAL DATA Few adverse effects are related to slight but reversible eye irritation as skin sensitization ACCEPTABLE DAILY INTAKE (ADI), ACCEPTABLE OPERATOR EXPOSURE LEVEL (AOEL) and ACUTE REFERENCE DOSE (ARfD) ADI The ADI is based on the NOAEL of 3 mg/kg bw/day from the long term study in the rat with a safety factor of 100 used. The ADI is 0.03 mg/kg bw/day. AOEL Initially, the RMS proposed an AOEL of 0.19 mg/kg bw/day based on the NOAEL of 19 mg/kg bw/day from the 90-day study. However, the NOAEL of the study was discussed at the experts meeting. The experts agreed that there were adverse effects such as histological findings in the liver, and not only effects on the weight at that dose level. Consequently, the NOAEL should be 3.14 mg/kg bw/day instead. The experts agreed on an AOEL based on the NOAEL of 3.14 mg/kg bw/day from the 90-day study in the rat with a safety factor of 100 used. The AOEL is rounded to 0.03 mg/kg bw/day. ARfD Due to the low acute toxicity of cyprodinil no ARfD is allocated DERMAL ABSORPTION One in vivo study in the rat was performed and an in vitro comparative study on rat and human skin. The RMS initially proposed that based on the in vivo absorption data approximately 22% and 1.9% was absorbed after 24 hours for dilution and concentrate, respectively. Based on the results in the in vitro study the RMS proposed that the difference in permeability between human and rat skin was approximately 19 times for the formulation and 7.5 times for the concentrate Thus, the proposed dermal absorption values for the formulation were 1.14% and 0.7% for the dilution and concentrate, respectively. This issue discussed was in the experts meeting due to a comment from another MS regarding the dermal absorption values. It was concluded that the amount absorbed (including skin residues) after 48 hours should be used. The values were 5.4% for the concentrate and 27% for the dilution. Taking the in vitro data into consideration the experts agreed on correction factors of 10.9 for the concentrate and 4.5 for the dilution which resulted in dermal absorption values of 0.5% for the concentrate and 6% for the dilution of 78

13 2.12 EXPOSURE TO OPERATORS, WORKERS AND BYSTANDERS There are two representative plant protection products to be applied as foliar spray presented in the DAR, UNIX 75WG and Chorus 50WG containing 750 g cyprodinil/kg and 500 g cyprodinil/kg, respectively. Estimations of operator exposures are presented in the DAR and show exposures below the AOEL. However, re-calculations of the estimated operator exposure were needed due to the revised dermal absorption values (0.5% for the concentrate and 6% for the dilution) as well as AOEL (0.03 mg/kg bw/day), see 2.10 and A rough estimation was performed at the experts meeting and the expert agreed that the exposure would probably still be below the AOEL. Operator exposure New calculations of the operator exposure are presented in the addendum. 1) UNIX According to the intended uses submitted by the notifier the maximum applied dose is 0.75 kg cyprodinil/ha and the minimum volume 200 L. The only supported use is vehicle mounted boom sprayer. The estimated operator exposure is below the AOEL without PPE, according to the German model (work rate 20 ha/day). According to calculations with UK POEM, (work rate 50 ha/day), the AOEL is exceeded even with the use of PPE, see table beneath. Estimated exposure presented as % of AOEL (0.03 mg/kg bw/day), according to calculations with the German and UK POEM models. The default for body weight of operator is 70 kg in the German model and 60 kg in the UK-POEM model. Model No PPE With PPE* During M/L: With PPE* During M/L and A: German 94% 29% 13% UK POEM 1093% 1033% 597% * PPE (personal protective equipment): M/L: Mixing and loading, A: application. German model: gloves + coverall + boots, UK POEM: gloves 1) CHORUS According to the intended uses submitted by the notifier the maximum applied dose is kg cyprodinil/ha and the mixing volume 500 L. The only supported use is tractor drawn airblast sprayer. The estimated operator exposure is below the AOEL without PPE, according to the German model (work rate 8 ha/day). According to calculations with UK POEM (work rate 15 ha/day), the AOEL is exceeded even with the use of PPE, see table beneath of 78

14 Estimated exposure presented as % of AOEL (0.03 mg/kg bw/day), according to calculations with the German and UK POEM models. The default for body weight of operator is 70 kg in the German model and 60 kg in the UK-POEM model. Model No PPE With PPE* During M/L: With PPE* During M/L and A: German 61% 29% 11% UK POEM 240% 233% 180% * PPE (personal protective equipment): M/L: Mixing and loading, A: application. German model: gloves + coverall + boots, UK POEM: gloves Worker exposure The estimated (according to the German model) worker exposure is below the AOEL (23%). Bystander exposure The estimated bystander exposure is below the AOEL (5.4%). 3. Residues Cyprodinil was discussed at the EPCO experts meeting for residues (EPCO 19) in February NATURE AND MAGNITUDE OF RESIDUES IN PLANT PRIMARY CROPS The metabolism of cyprodinil has been investigated in potato, apple, peach, tomatoes and wheat. Two radiolabelled forms of cyprodinil, phenyl and pyrimidine labels, were used, allowing a full elucidation of its metabolism. Generally the metabolism is essentially similar in all crops. Cyprodinil is rather persistent and up to 60 days after application the parent compound remains the dominant residue, except in potato tubers where the metabolic pattern results from the translocation of degradation products through the plant or from the soil metabolism of the compound. The metabolism proceeds mainly by hydroxylation of the phenyl and pyrimidin rings followed by sugar conjugation. Cleavage of the amine bridge between the two ring systems represents a minor degradation route. Incorporation of ultimate degradation products in natural plant components has been demonstrated. In wheat straw and husk, formation of a thiolactic acid conjugate from the phenyl ring, further oxidated to a sulfoxide and subsequent sugar conjugation was also demonstrated. Based on these metabolism studies, the residue definition proposed for both monitoring and risk assessment is cyprodinil only. No metabolite was observed at such level justifying its inclusion in the residue definition. Although potatoes does not belong to the representative uses, it must be stated that this residue definition could represent a conflict with the metabolism study in potatoes and that any use on potatoes should be considered for metabolism, taking into account the application rate and the actual residue level to be expected in tubers. 45 supervised residue trials were performed on wheat (20) and apples (25) of 78

15 The number of relevant trials in apples is low for the proposed PHI of 60 days (7 trials for Northern Europe and 4 trials for Southern Europe). The applicant informed the RMS that another, more critical, GAP has been developed for a PHI of 7 days, for which a complete data base is available. However, this other GAP cannot be taken under consideration, as it was not supported as representative use. For the PHI of 60 days, the 7 data points for Northern Europe are sufficient for a reasonable MRL proposal and a reasonable execution of the risk assessment. The highest residue found in apples among these 7 trials is 0.03 mg/kg. For the south the data base is limited to 4 results and is therefore not sufficient for a robust assessment. In pomace, the highest residue found was 0.06 mg/kg. In wheat the data base is sufficient to cover the representative uses supported for Northern and Southern regions of EU. No residues were found in grains to exceed the LOQ (Limit Of Quantification, 0.02* mg/kg). In straw, the highest residue found was 0.27 mg/kg. Results of supervised residues trials are supported by storage stability studies indicating that residues are stable in crops for at least 24 months under deep freezer storage conditions. The effects of processing on the nature of residues were studied through a high-temperature hydrolysis study simulating pasteurization, baking, brewing, boiling and sterilization. No breakdown or reaction products were formed, indicating that no particular residue definition for processed commodities is needed. Due to the low amount of residues in apple and wheat according to the representative use, it was not needed to carry out transfer studies to determine the effect of processing on the residue levels SUCCEEDING AND ROTATIONAL CROPS Several rotational crops studies were submitted, under confined and field conditions. These studies demonstrated the possible occurrence of two plant metabolites in following crops (NOA ((2- amino-6-cyclopropyl-pyrimidin-4-yl)-methanol), and CGA (4-cyclopropyl-6-methylpyrimidin-2-ol)). These metabolites may be present at measurable in the tested succeeded crops for short plant back intervals. Considering the representative uses, apples being a perennial crop and crops following cereals not being expected to be planted before 120 days after application, no significant residues are expected under normal conditions of use of cyprodinil in following crops. The need for fixing a plant back interval for succeeding crops in case of crop failure should be examined at Member State level NATURE AND MAGNITUDE OF RESIDUES IN LIVESTOCK The metabolism of cyprodinil has been investigated in lactating goats and laying hens, using both label forms of the compound (phenyl and pyrimidine rings). It essentially results from hydroxylation of the phenyl ring followed by conjugation with sulphate or glucuronic acid. A minor pathway results from the cleavage of the amino bridge between the phenyl and the pyrimidine ring. Unchanged parent was only observed in eggs, as well as in cattle liver and fat. One major metabolite (CGA , 4- (4-cyclopropyl-6-methyl-pyrimidine-2-yl-amino)-phenol) was found in cattle tissues (muscle, liver and kidneys). The metabolism in livestock showed major similarities with the metabolism in rats of 78

16 The proposed residue definition for monitoring and risk assessment is the sum of cyprodinil and CGA (free and conjugated) expressed as cyprodinil. It must be pointed out that for monitoring the residue definition could be restricted to one indicator compound only for each tissue. Cyprodinil is to be considered as fat soluble, due to its high partition coefficient and its obvious affinity for fat tissues. CGA does not exhibit this behaviour. The theoretical maximum dietary burden of livestock, taking into account the potential contribution of cereal grains and straw as well as apple pomace, was determined. Taking into account the outcome of the metabolism studies, residues are expected to be low in animal tissues, but, as far as CGA is concerned, potentially present at levels around the usual LOQ of monitoring methods of analysis in cattle liver and kidneys. A feeding study in lactating cows was submitted. The overdosing factor of the lower administered dose was about 20 fold in excess of the calculated potential dietary burden, and no residues of cyprodinil were found in edible organs and tissues. Unfortunately, the metabolite CGA was not determined in that study and it is therefore not possible to propose MRLs CONSUMER RISK ASSESSMENT A chronic dietary risk assessment has been carried out using the Theoretical Maximum Daily Intake (TMDI) calculation model of WHO using the WHO European typical diet for adult consumers as well as national diets of Germany for female child and of UK for high consumers in infants, toddlers, child and adult populations (97.5 th percentile of the distribution). Residues in apples and wheat were assumed to be at the level of the respective MRLs proposed on the basis of the supervised residue trials. Exposure resulting from the consumption of animal commodities could not be considered in the intake calculation due to the lack of a feeding study relevant for the proposed residue definition. However, the expected residue levels in animal commodities are expected to be very low and not of nature to significantly influence the outcome of intake calculations based on plant commodities only. The calculations made for these diets lead to TMDI values well below the ADI of cyprodinil. The highest calculated TMDI was 3 % for UK toddlers. No Acute Reference Dose has been proposed for cyprodinil. Therefore no acute risk assessment is needed PROPOSED MRLS The following MRLs are supported by the results of supervised residue trials for the representative uses: Apples: 0.05 mg/kg, based on the residue trials data for Northern Europe Wheat: 0.02* mg/kg, based on the residue trials data for both Northern and Southern Europe. (* indicates that the MRL is set at the limit of quantification of the method of analysis) MRLs for animal commodities according to the residue definition cannot be proposed due to the lack of a feeding study with analysis of the metabolite CGA of 78

17 4. Environmental fate and behaviour In January-February 2005 cyprodinil was discussed in the EPCO experts meeting on Environmental fate and behaviour (EPCO 16) FATE AND BEHAVIOUR IN SOIL ROUTE OF DEGRADATION IN SOIL Degradation of cyprodinil in soil was investigated in 9 different soils in the laboratory in the dark with incubations carried out at C and 30-75% field capacity or 40% maximum water holding capacity (MWHC) soil moisture content. Degradation was shown to involve hydroxylation of the phenyl or the pyrimidyl ring of cyprodinil to give the major (>10% applied radioactivity (AR)) metabolite CGA (meta-phenol derivative, max. 20 % applied radioactivity after 14 d) and minor (detected in traces) CGA (para-phenol derivative) and CGA (hydroxypyrimidyl derivative). Cleavage of the anilino-pyrimidyl bridge of cyprodinil and its hydroxy-phenyl derivatives gave the major metabolite CGA (amino-pyrimidine, max %AR after d) and then minor CGA (hydroxy-pyrimidine, < 5.1 %AR). A dimer of CGA and phenol were also detected in traces. The phenyl ring and the pyrimidyl ring were poorly mineralized: %AR after 91/92 d and %AR after 90/112 d, respectively. The corresponding figures for residues not extracted by acetonitrile including Soxhlet extraction were %AR and %AR. Further analysis of unextracted residue involving silylation, SEC and 13C-NMR spectroscopy suggest cleavage of cyprodinil molecules before covalent binding of cyprodinil residues to humic acids whereas sequestration in humin of either unchanged or slightly modified molecules of cyprodinil at high dose or cleavage products at normal dose could be a significant process. Studies on degradation of cyprodinil in soil under aerobic/anaerobic conditions (25 C) demonstrated that cyprodinil and its major metabolite CGA were stable under anaerobic conditions. No novel breakdown products were identified. In a laboratory soil photolysis experiment the degradation of cyprodinil was faster in light exposed samples than dark moist soil control samples. (Single first order DT d in the light (Florida Summer Sunlight Equivalent) d in the dark). No novel extractable breakdown products were identified in addition to those found in dark experiments. Residue not extracted by acetonitrile, acetonitrile:water and dimethyl formamide (max %AR for both the phenyl and pyrimidyl ring labels) was the main sink of the AR PERSISTENCE OF THE ACTIVE SUBSTANCE AND THEIR METABOLITES, DEGRADATION OR REACTION PRODUCTS The degradation rate of cyprodinil has been studied in 5 European and 1 US soil in the laboratory in the dark. For the European soils (OC %, ph ) at ca. 20 C and at 60-75% field capacity or 40%MWHC soil moisture, single first order DT 50 lab (calculated by linear regression, 17 of 78

18 treating experiments with different radiolabels as replicates) were in the range d (mean 37 d, after normalising to 20 C and field capacity (-10kPa) as defined by FOCUS for use as modelling input this mean becomes 29 d). Because degradation virtually stopped after about 1 month, no degradation rate was derived from the acidic US soil (ph 5.2). Thus cyprodinil could be more persistent in very acidic soils. For 4 of the European soils, the single first order DT 50 of degradation of the major metabolite CGA was estimated using ModelMaker and the compartment model: cyprodinil flows to sink and CGA with CGA flowing to a sink. Data from the studies where parent was dosed was used as input for the model optimisation. (The kinetic analysis is described in detail in the addendum to the DAR dated March These DT50 were estimated to be d (mean 52 d, after normalising to 20 C and field capacity (-10kPa) as defined by FOCUS for use as modelling input this mean becomes 39 d). The associated ModelMaker calculated molar kinetic formation fractions from cyprodinil were %, (mean 22%). Based on first order decline from the maximum observed CGA samples in each experiment, apparent dissipation single first order DT 50 for CGA were estimated to be d (mean 115 d, after normalising to 20 C and field capacity (-10kPa) as defined by FOCUS, if required as modelling input this mean becomes 86 days). The major metabolite CGA was rapidly degraded in soil and single first order DT 50 were in the range d (mean 0.6 d) for 3 soils (OC %, ph ) at 20 C, 40% MWHC in dark laboratory experiments when this metabolite was applied as test substance. Bare soil field dissipation studies were carried out in France (1 reliable value), Germany (4 reliable values), Switzerland (3 reliable values), USA (4 reliable values) and Canada (1 reliable value). Residues of cyprodinil, CGA , CGA and the minor metabolite CGA were analysed for (limit of quantification, (LOQ) 0.01mg/kg, equivalent to ca. 2% of the theoretical dose on a mass basis in a 10cm soil layer). Single first order DT 50 field for cyprodinil were in the range d for the European trials (mean 31.6 d, n = 8, soil ph ) and d (mean 65.8 d, n = 5, soil ph ) for the American trials. Overall, single first order DT 50 field were in the range d (mean 44.7 d, median 42 d) and DT 90 field were in the range d (mean 148 d) for 13 sites (soil ph ). A higher persistence (single first order DT 50 field 245 d) was observed in a very acidic soil (ph 4.9) in Germany. Thus cyprodinil was not persistent in most of the soils investigated. This was confirmed by long term field accumulation studies carried out at two Swiss sites (ph ) where no accumulation has been observed after application to cereals, apples and grapes. As observed in the 1 laboratory experiment with a more acidic soil (ph 5.2), cyprodinil was also persistent in a German field experiment where the soil was very acidic. Cyprodinil could therefore be more persistent in very acid soils (around ph 5 and below), though the available database (2 acidic soil experiments) is small to be definite about this hypothesis. Member States which have significant 18 of 78

19 areas of acidic soils in arable or horticultural production should request additional information to confirm this apparent correlation and address the consequences of higher persistence in acidic soils. The metabolite CGA was frequently detected in soil in these field studies (maxima of about 12 % of initial measured cyprodinil residues on a mass basis, max. 0.27mg/kg in a bare soil study dosed at 0.75kg/ha). Because of low measured concentrations, no meaningful DT 50 field could be calculated but a decrease in concentration was observed and the long term field accumulation studies showed no accumulation. For cereals, CGA was < mg/kg days after the last application, for orchard, it was < mg/kg one year after each 6th application and for grapes it was mg/kg one year after each 2nd application. For all crops, CGA had no tendency to accumulate. Accordingly, CGA is considered as not persistent under field conditions. The metabolites CGA and CGA were either not detected or rarely detected at concentrations close to the LOQ (0.01mg/kg) MOBILITY IN SOIL OF THE ACTIVE SUBSTANCE AND THEIR METABOLITES, DEGRADATION OR REACTION PRODUCTS In batch adsorption studies cyprodinil was strongly adsorbed on soil with K f oc in the range mL/g (mean 1706mL/g) and 1/n in the range (mean 0.84) for 5 soils (OC %, ph ). The metabolite CGA was less adsorbed with K f oc in the range mL/g (mean 488mL/g) and 1/n in the range (mean 0.73) for 4 soils (OC , ph ) with adsorption exhibiting ph dependence with the lowest adsorption being measured in the soil with the highest ph. This apparent ph dependence of adsorption for CGA must be taken into account when carrying out leaching assessments. Mean values for this metabolite should not be used as input to leaching models. The metabolite CGA was strongly adsorbed on 1 soil (OC 0.46 %, ph 6.3) with a K f oc of 1810ml/g and 1/n : Higher adsorption was observed on 4 other soils but the numerical results from the experiments in these soils can not be relied on, because degradation occurred during the equilibrium time of the experiments. The results do however confirm the relatively high adsorption potential of CGA Column leaching studies (4 soils, OC %, ph , 200 mm within 2 days) showed low mobility of cyprodinil ( % AR in the 0-2 cm upper soil layer, < 0.03 %AR in leachates). Aged residue column leaching studies (2 soils, OC %, ph , incubation for d at 20 C) confirmed the low mobility of cyprodinil whereas limited movement was observed for the metabolites (CGA and minor unknowns). For 200 mm artificial rainfall within 2 days, radioactivity in leachates was in the range % of column AR, as carbonates ( % of column applied), polar degradation products ( % of column AR), CGA (0.004 % of column AR) and cyprodinil (not detected % of column AR). For 508 mm artificial rainfall within 40 days, radioactivity in leachates was in the range % of column AR, as carbonates ( % of column AR), polar degradation products ( % of column AR), CGA (0.17 % of column AR) and cyprodinil (not detected % of column AR) of 78