Conclusion on the peer review of the pesticide risk assessment of the active substance fosetyl 1

Transcription

1 EFSA Scientific Report (2005) 54, 1-79 CONCLUSION ON PESTICIDE PEER REVIEW Conclusion on the peer review of the pesticide risk assessment of the active substance fosetyl 1 European Food Safety Authority 2 European Food Safety Authority (EFSA), Parma, Italy This scientific output, published on 12 June 2013, replaces the earlier version published on 18 January ABSTRACT The conclusions of the European Food Safety Authority (EFSA) following the peer review of the initial risk assessments carried out by the competent authority of the rapporteur Member State, France, for the pesticide active substance fosetyl are reported. The context of the peer review was that required by Commission Regulation (EC) No 1490/2002. The conclusions were reached on the basis of the evaluation of the representative use of fosetyl as a fungicide in citrus, cucumber and grapes. The reliable endpoints concluded as being appropriate for use in regulatory risk assessment, derived from the available studies and literature in the dossier peer reviewed, are presented. Missing information identified as being required by the regulatory framework is listed. Concerns are identified. European Food Safety Authority, 2013 KEY WORDS fosetyl-al, fosetyl, peer review, risk assessment, pesticide, fungicide 1 On request from the European Commission, Question No EFSA-Q , approved on 14 December Correspondence: pesticides.peerreview@efsa.europa.eu 3 The ADI for phosphonic acid has been amended to include a correction for the water content of the material tested in the 117-week rat study, and to account for the different molecular weights of the tested material and phosphonic acid. Corrections have been made to pages 3, 13, 14, 18, 46, and 53. Additions have also been made to the first page to include an abstract and keywords. Suggested citation: European Food Safety Authority, Conclusion on the peer review of the pesticide risk assessment of the active substance fosetyl. EFSA Scientific Report (2005) 54, doi: /j.efsa r Available online: European Food Safety Authority, 2006

2 SUMMARY Fosetyl is one of the 52 substances of the second stage of the review programme covered by Commission Regulation (EC) No 451/2000 4, 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 fosetyl-al in accordance with the provisions of Article 8(1) of the amended Regulation (EC) No 451/2000, which was received by the EFSA on 20 October Following a quality check on the DAR, the peer review was initiated on 26 March 2004 by dispatching the DAR for consultation of the Member States and the applicants Bayer CropScience (notification and submission made by Aventis CropScience prior to merger to form Bayer CropScience) and Industrias Afrasa S.A. (document J-II only). According to Commission Regulation (EC) No. 703/2001 there were 2 other notifiers, Calliope S.A. and Probelte S.A. who did not submit any data or reports. 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 30 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 a fungicide as proposed by the applicant which comprises foliar spraying in citrus, cucumber and/or grapes at application rates up to 7 kg (citrus), 4.5 kg (cucumber) and 2 kg (grapes) fosetyl per hectare. Fosetyl can be used only as a fungicide. Due to the fact that the aluminium salt, a variant of fosetyl, is used in the formulated product, it should be noted that the evaluated data belong to the variant fosetylaluminium (fosetyl-al), unless otherwise specified. The representative formulated products for the evaluation were "Aliette" ("EXP10369F") and "Verita/Elico" ("EXP10745D "), both water dispersible granules (WG). The latter contains fenamidone as a second active substance. Formulations containing fosetyl and fosetyl-aluminium, respectively, are registered in most of the EU Member States. Adequate methods are available to monitor all compounds given in the respective residue definition, i.e. sum of fosetyl, phosphonic acid and their salts in food of plant and animal origin; fosetyl and its salts in soil and water and fosetyl in air. However, a confirmatory method for water is needed. With the available method for the determination of residues in air it is not possible to distinguish between residues of fosetyl and of its salts as required in the proposed residue definition. The methodology used is GC with FP or FI detection. A multi-residue method like the Dutch MM1 or the German S19 is not applicable to due the nature of the residues. 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. 4 OJ No L 53, , p OJ No L 224, , p. 25 EFSA Scientific Report (2005) 54,

3 The two sources of fosetyl-al cannot be regarded as equivalent from an analytical point of view (see point 1). However, the RMS concluded preliminary (in the evaluation table, rev. 1-0, ) that based on the available data they can be regarded as equivalent, due to the fact that the differences are not of toxicological and/or ecotoxicological concern (corresponds to the Tier II approach in Sanco/10597/2003 rev. 7). However, due to the fact that data on the manufacturing process (AFRASA source) are missing a final conclusion on the equivalence cannot be made. This assessment was neither peer reviewed nor discussed in expert meetings. For the moment it is not possible for the EFSA to confirm or disagree with the assessment of the RMS with respect to toxicological and ecotoxicological aspects, since the background of its decision is not transparent (lack of documentation). Fosetyl-Al is rapidly and totally absorbed and widely distributed. It is characterised by low toxicity after oral administration as well as after dermal administration and inhalatory exposure. Fosetyl-Al is neither a skin sensitiser nor a skin irritant, but is a severe eye irritant. Therefore, the classification with R41 (risk of serious damage to eyes) is proposed. Fosetyl-Al did not induce adverse effects after repeated exposures. The NOAEL of 500 mg/kg bw/day was considered to be an overall NOAEL for short-term toxicity, with histopathological changes in the kidney, impairment of calcium/phosphorous metabolism, calculi and hyperplasia in the urinary tract at higher doses. Fosetyl-Al did not show any genotoxic or carcinogenic potential and did not induce any signs of reproductive toxicity neurotoxic potential. Phosphonic acid is the major metabolite in plants and in in vivo experimental studies. Acute toxicity is low. It is not a skin irritant while it is a slight eye irritant. It does not show any genotoxic potential. An ADI for the metabolite phosphonic acid was set at 2.25 mg/kg bw per day. The ADI for fosetyl-al is 3 mg/kg bw/day and the AOEL is 5 mg/kg bw/day, SF 100. An ARfD for fosetyl-al was not set because of the low acute toxicity. Both with the UK POEM and the German model the estimated operator exposure to fosetyl-al does not exceed the AOEL under the reported condition of use. The exposure of re-entry workers and bystanders does not exceed the AOEL. The elementary chemical structure of fosetyl-al determines its metabolic fate in plants and animals. The initial step is the hydrolysis of the ethyl ester bond with phosphonic acid and ethanol as the major plant metabolites. Ethanol is further dissipated by volatilisation or degraded and incorporated in natural constituents of plant and animal tissues. Phosphonic acid has a lower ADI than fosetyl and is present as residue at higher concentrations. Therefore the residue definition for plant and animal products needs to take phosphonic acid into consideration and was proposed to be the sum of fosetyl, phosphonic acid, and their salts expressed as phosphonic acid. Supervised residue trials were submitted according to the representative uses supported by the applicant, allowing a robust risk assessment for the consumer to be made and MRLs to be proposed. Industrial transformation of citrus and grapes leads to a transfer of residues to juice and wine, containing amounts of residues which are very similar to that present in the raw materials. Livestock (essentially ruminants) may be exposed to residues of fosetyl and phosphonic acid through consumption of citrus pomace. However, the transfer of these residues to milk and other edible tissues is very low, resulting in concentrations below the limit of quantification of analytical methods. The risk assessment demonstrated that consumers, including the most vulnerable ones, are exposed to residues well below the ADI. The available data on the fate and behaviour of fosetyl-al in soil are considered sufficient to identify the only major breakdown products were ethanol, phosphonic acid [(HO) 2 HPO or more simply H 3 PO 3 ], phosphate, Aluminium, carbon dioxide (>70% of the applied carbon radioactivity in 4-16 EFSA Scientific Report (2005) 54,

4 days) and water unextracted radioactivity (20-24% of the applied carbon radioactivity). Fosetyl-Al and ethanol exhibited very low persistence in soil, phosphonic acid exhibited medium to high persistence in soil and has the potential to accumulate from use in successive years, but soil levels would be expected to plateau after ca. 6 seasons of use. It was considered that the intended uses of fosetyl-al do not add significant levels of phosphate and aluminium to soil compared to the amounts naturally present in, or in the case of phosphate routinely added to, agricultural soil. Fosetyl-Al and ethanol exhibit very high mobility in soil. Phosphonic acid exhibits low mobility in soil. Groundwater modelling using FOCUS models and scenarios indicates that for the intended uses applied for, the potential for groundwater contamination by fosetyl-al or its soil breakdown products is minimal. In surface water systems fosetyl-al degrades rapidly to form ethanol (which also degrades rapidly so is only transient) and phosphorous acid, which is then expected to partition to the sediment and subsequently transform to phosphate as experimental data confirm occurs in soil. The available aquatic exposure assessments only considered the spray drift route of entry to surface water. Assessments resulting from the runoff and drainage routes of entry should be completed by Member States for the soil degradation product phosphonic acid when considering individual product authorisations. The EPCO Expert s meeting requested the EFSA to only report the new risk assessment for birds and mammals according to the guidance document SANCO/4145/2000 because several concerns were raised about the risk assessment in the DAR which was based on the residue data by Hoerger and Kenaga (1973). The acute and short term risk to herbivorous and insectivorous birds in cucumber is low. The long term risk to herbivorous and insectivorous birds in cucumbers is high in the first tier risk assessment. It was considered by the EPCO Expert s meeting that herbivorous birds in cucumber will only be exposed during a short period as only the seedling stage and the fruits of cucumber will be eaten by birds as the hairy leaves are unpalatable. The EPCO Expert s meeting considered that the long term risk to herbivorous birds in cucumber might be considered addressed if after a short term exposure no long term effects are visible. The RMS considers in the addendum of July 2005 that it is unlikely that short term exposure to fosetyl-al will lead to long-term effects as the NOEL of birds is based on the highest tested concentration of 1500 mg/kg feed in the reproduction study. To refine the long term risk for insectivorous birds in cucumber, the EPCO Expert s meeting did not accept the proposed PT-value but accepted the PD-value of for yellow wagtail. The resulting refined TER value is above the Annex VI trigger value indicating a low long term risk to insectivorous birds in cucumber. The acute and short term risk to insectivorous birds in citrus is low. The EPCO Expert s meeting agreed to use the great tit as a focal species to refine the identified first tier long term risk to insectivorous birds in citrus. The resulting refined TER value of 6.9 is above the Annex VI trigger value indicating a low long term risk to insectivorous birds for the use of fosetyl-al in citrus. The acute and short term risk to insectivorous birds in grapes is low. The EPCO Expert s meeting requested the RMS to recalculate the refined long term risk to insectivorous birds for a blackbird consuming 100% small insects. The resulting refined TER value of 7.2 is above the Annex VI trigger value indicating a low long term risk to insectivorous birds for the use of fosetyl-al in grapes. The acute and long term risk to medium herbivorous mammals in cucumber can be regarded as low. A high acute and long term first tier risk to small herbivorous mammals was concluded for the representative use in citrus. The EPCO Expert s meeting questioned the use of wood mouse as a focal species to refine this risk. As a result the EPCO expert s meeting decided to set a data requirement for the notifier to submit a refined risk assessment for herbivorous mammals in citrus as the presence of voles can not be excluded in this crop. Further data to address this risk have been submitted by the notifier after the EPCO expert s meeting and were evaluated by the RMS in the addendum of 30 August 2005 but not peer reviewed due to the late submission date. A full risk assessment for herbivorous mammals in citrus can only be concluded after further consideration of this evaluated data. The acute risk to small herbivorous mammals in grapes can be considered as low. The long term risk to mammals in grapes is considered to be high in the first tier risk assessment. The EFSA considers it not appropriate to extrapolate residue data from lettuce to grass and hence a DT 50 value EFSA Scientific Report (2005) 54,

5 from lettuce to grass to refine this risk. Also for this use, the representativeness of the wood mouse as a focal species was discussed at the EPCO Expert s meeting. Furthermore the meeting considered that the parameters of the focal wood mouse used to refine the risk should be clarified. Therefore the EPCO Expert meeting decided to set a data requirement for the Notifier to submit a refined risk assessment for herbivorous mammals in northern European grapes as the presence of voles can not be excluded in this crop and to clarify the parameters of the focal wood mouse for the refinement of the risk to mammals in grapes in southern Europe. Further data to address these requirements have been submitted by the notifier after the EPCO expert s meeting and were evaluated by the RMS in the addendum of 30 August 2005 but not peer reviewed due to the late submission date. A full risk assessment for herbivorous mammals in grapes can only be concluded after further consideration of this evaluated data. The acute risk to birds and mammals from consumption of contaminated drinking water is considered to be low for all representative uses evaluated. The short and long term risk to birds from consumption of contaminated drinking water is considered to be high for all representative uses evaluated except for birds in cucumber for which the short term risk can be considered as low. The long term risk to mammals is considered to be high for all representative uses evaluated. Therefore EFSA proposes a data requirement for the notifier to refine this risk to birds and mammals. This assessment was not discussed at the EPCO Expert s meeting nor peer reviewed. The risk to aquatic organisms for the representative use in citrus is high. A bufferzone of 5 metres is needed to address the risk from fosetyl-al and a bufferzone of 10 metres is needed to address the risk from H 3 PO 3. The risk to aquatic organisms for the representative use in cucumber should be considered as low. The risk to aquatic organisms from exposure to the lead formulation EXP10745D for the representative use in grapevine is high and e.g. a buffer zone of 20 metres is necessary to address this risk. The risk to bees from fosetyl-al and the lead formulations is regarded to be low. The EPCO Expert s meeting considered that the available semi-field study with the formulation EXP10369F addresses the risk to bees from the metabolite H 3 PO 3. For the use in grapes the risk to A. rhopalosiphi and the in-field risk to T. pyri is considered to be high. The risk to P. cupreus and C. carnea can be regarded as low. No study is available for the risk to C. septempunctata. For the use in citrus the in-field risk to T. pyri is considered to be high. The risk to A. rhopalosiphi, P. cupreus, C. septempunctata and A. bilineata can be regarded as low. For the use in cucumber the in-field risk to T. pyri is considered to be high. The risk to A. rhopalosiphi, P. cupreus and A. bilineata can be regarded as low. The EFSA considers that based on the available data no conclusion can be drawn for the risk to C. septempunctata at the in-field application rates of kg as/ha for cucumber and that due to the effects seen at 15 kg as/ha a potential risk cannot be excluded at this stage. The RMS proposes in the addendum of July 2005 that no requirements are done at this late stage of the evaluation process and proposes to pay particular attention to the in-field risk to non-target arthropods at MS level. The EFSA agrees that particular attention to the risk to non-target arthropods at MS level is necessary and that risk mitigation measures should be envisaged. But the EFSA considers that first it should be proofed that in-field recovery is possible within one year and therefore the EFSA proposes a data requirement for the Notifier to proof the in-field recovery within a year as this cannot be concluded from the available studies. This risk assessment was extensively revised after the EPCO expert s meeting. The risk to earthworms, other soil non-target macro-organisms, soil micro-organisms, non-target plants and biological methods of sewage treatment is considered to be low. EFSA Scientific Report (2005) 54,

6 TABLE OF CONTENTS Abstract... 1 Summary... 2 Table of contents... 6 Background... 8 The active substance and the formulated product Conclusions of the evaluation Identity, physical/chemical/technical properties and methods of analysis Mammalian toxicity 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 products 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 earthworms Risk to other soil non-target macro-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 Overview of the risk assessment of compounds listed in residue definitions triggering assessment of effects data for the environmental compartments EFSA Scientific Report (2005) 54,

7 7.1. Soil Ground water Surface water and sediment Air List of studies to be generated, still ongoing or available but not peer reviewed Conclusions and Recommendations Particular conditions proposed to be taken into account to manage the risk(s) identified Critical areas of concern Appendices Abbreviations EFSA Scientific Report (2005) 54,

8 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. Fosetyl-Al 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 fosetyl-al, hereafter referred to as the draft assessment report, to the EFSA on 20 October 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 26 March 2004 to the Member States and the main applicant Bayer CropScience 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 expert 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 30 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 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 A. 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. 1-1 of 13 October 2004) the consultation report EFSA Scientific Report (2005) 54,

9 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 30 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. EFSA Scientific Report (2005) 54,

10 THE ACTIVE SUBSTANCE AND THE FORMULATED PRODUCT Fosetyl is the ISO common name for ethyl hydrogen phosphonate (IUPAC). Due to the fact that the aluminium salt, a variant of fosetyl, is used in the formulated product, it should be noted that the evaluated data belong to the variant fosetyl-aluminium (fosetyl-al), unless otherwise specified. Fosetyl and fosetyl-aluminium, respectively, belong to the class of organophosphorus fungicides such as pyrazophos and tolclofos-methyl. Fosetyl is taken up via leaves and roots and acts by inhibiting germination of spores or by blocking development of mycelium and sporulation. The representative formulated products for the evaluation were "Aliette" ("EXP10369F") and "Verita/Elico" ("EXP10745D"), both water dispersible granules (WG). The latter contains fenamidone as a second active substance. Formulations containing fosetyl and fosetyl-aluminium, respectively, are registered in most of the EU Member States. The evaluated representative uses as fungicide comprise foliar spraying to control diseases caused by Phytophthora, Pseudoperonos pora cubensis, Phomopsis viticola, Plasmopara viticola,pseudopeziza and Tracheiphila in citrus, cucumber and/or grapes at application rates up to 7 kg (citrus), 4.5 kg (cucumber) and 2 kg (grapes) fosetyl-al per hectare. Fosetyl can be used only as fungicide. CONCLUSIONS OF THE EVALUATION 1. Identity, physical/chemical/technical properties and methods of analysis The minimum purity of fosetyl-aluminium as manufactured should not be less than 960 g/kg as given in the FAO specification 384/TC/S/F (2000). According to the definition used within the EU, the technical material does not contain any relevant impurity. However, according to the FAO criteria two compounds are mentioned in the specification. The maximum content in the technical material should not be higher than 10 g/kg for inorganic phosphite and 10 g/kg for water (384/WG/S/F, 2000). From an analytical point of view the two sources cannot be regarded as equivalent. However, the RMS concluded preliminary (in the evaluation table, rev. 1-0, ) that based on the available data they can be regarded as equivalent, due to the fact that the differences are not of toxicological and/or ecotoxicological concern (corresponds to the Tier II approach in Sanco/10597/2003 rev. 7). However, due to the fact that data on the manufacturing process (AFRASA source) are missing a final conclusion on the equivalence cannot be made. This assessment was neither peer reviewed nor discussed in expert meetings. At the moment it is not possible for EFSA to confirm or disagree with the assessment of the RMS with respect to toxicological and ecotoxicological aspects, since the background of its decision is not transparent (lack of documentation). During the peer review process some data gaps have been identified. A shelf-life study for the "EXP10745D" formulation is required, due to the fact that analytical method which was used in the submitted one is not applicable for formulations containing fosetyl-al and another active substance. Beside this, the assessment of the data package revealed no particular area of concern in respect of the identity, physical, chemical and technical properties of fosetyl-al or the respective formulations. The main data regarding the identity of fosetyl-al and its physical and chemical properties are given in Appendix A. The content of fosetyl-al in the representative formulations are 800 g/kg (pure) for "EXP10369F" and 667 g/kg (pure) for "EXP10745D". The latter contains in addition 44.4 g/kg of fenamidone. The maximum content of water should be 15 g/kg and for inorganic phosphite it should be 1%, expressed as aluminium phosphite of fosetyl-al content in the formulation (FAO 384/WG/S/F, 2000). It should be noted that the content of inorganic phosphite for the "EXP10369F" formulation is outside of the FAO limits. EFSA Scientific Report (2005) 54,

11 Sufficient test methods and data relating to physical, chemical and technical properties are available. Also adequate analytical methods are available for the determination of fosetyl-al in the technical material and in the representative formulations. 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. sum of fosetyl, phosphonic acid and their salts in food of plant and animal origin; fosetyl and its salts in soil and water. However, for water a confirmatory method is needed. An analytical method for the determination of phosphonic acid (and it salts) in water would be available, but it was not possible to obtain a lower LOQ than 2 µg/l in drinking water. In contrast to the decision of the expert meeting, RMS and EFSA are of the opinion that the method for water was sufficiently validated (n = 5 for each fortification level), but as mentioned above a confirmatory method is missing. It should be noted that in contrast to the decision at the expert meeting and the guidance document SANCO/825/00, an enforcement method for soil is needed, because the DT 90 is higher than 3 days. Nevertheless, it should be noted that the DT 90 of ca 4 5 days is just above the "trigger" value. However, the LOQ of the analytical method (0.1 mg/kg) is not in compliance with the requirements of Annex II (Normally, it should exceed 0.05 mg/kg). It should be also noted that the LOQ of the enforcement method for food of plant origin is not in compliance with the criteria of Annex VI and SANCO/825/00, where is stated that the LOQ should be 0.1 mg/kg in cases where the MRL is > 0.1 mg/kg. Moreover, in case the residue would be just the "sum of fosetyl, its salts and phosphonic acid expressed as fosetyl", the enforcement methods would not able to distinguish between residues of phosphonic acid and of its salts. With the available method for the determination of residues in air it is not possible to distinguish between residues of fosetyl and of its salts as required in the proposed residue definition. The methodology used is GC with FP or FI detection. A multi-residue method like the Dutch MM1 or the German S19 is not applicable to due the nature of the residues. The discussion in the expert meeting (EPCO 20, March 2005) on identity, physical and chemical properties and analytical methods was limited to issues on the specification of the technical material, certain properties of fosetyl-al and the formulations and to issues on the enforcement methods. 2. Mammalian toxicity Fosetyl-Al was discussed at EPCO experts meeting for mammalian toxicology (EPCO 18) in February Absorption, Distribution, Excretion and Metabolism (Toxicokinetics) The toxicological data package of fosetyl-al is based on the main notifier s source. Fosetyl-Al is rapidly and totally absorbed within 48 hours from administration, based on urinary and faecal excretion (also expired air). The large amount of radioactivity present as CO 2 shows the occurrence of an extensive metabolic transformation. The presence of 14 C-ethanol in urine confirmed and indicated the presence of naturally occurring components from the 14 C-ethyl moiety of the parent. EFSA Scientific Report (2005) 54,

12 After repeated doses absorption is extensive (>90% 24 hours post administration, and excretion is rapid, >70% in air and urine). The major urine component is fosetyl-al, accounting for % of the dose, and with other minor components, accounting for 0.07 to 1.11% of the administered dose. After single oral administration to rats of 3000 mg/kg bw of radiolabeled fosetyl-al, excretion was shown to be very rapid, mainly occurring within 24 hours after administration, through exhaled air (50% approximately) and urinary excretion was around 32-33%. Overall, mean values for faecal excretion were 1.85% in males and 3.30% in females within168 hours from administration. After repeated oral exposures, large amount of CO 2 were excreted indicating the removal of the labelled ethyl group and the subsequent metabolism via acetaldehyde and acetate giving rise to naturally occurring molecules. Also phosphate anion is a major component being eliminated in the urine. Fosetyl-Al widely distributes to all tissues, with the highest amounts in kidneys, liver, lungs, spleen, fat, adrenal glands, gonads, tissues with a high metabolic activity. Tissue levels were between 1.2 to 6% of the administered dose at 168 hours from administration after a single oral administration and between 6.9 and 9.5% at 72 hours from the administration Acute toxicity Fosetyl-Al is characterised by low toxicity after oral administration (LD 50 > 7080 mg/kg bw) as well as after dermal administration (LD 50 >2000 mg/kg bw) and inhalatory exposure (LC 50 >5.11 mg/l in rats). Fosetyl-Al is neither a skin sensitiser nor a skin irritant, but is a severe eye irritant. Therefore, the classification with R41 (risk of serious damage to eyes) is proposed Short term toxicity Short term toxicity of fosetyl-al has been assessed in rodents (6-week oral study in mice; two 90-day oral studies in rats and a 28-day dermal study in rats) and in dogs (90 days, oral). Fosetyl-Al did not induce adverse effects after oral administration, except for a marginal increase in the incidence and severity of extramedullary haematopoiesis in the spleen at the top dose (1922 and 2499 mg/kg bw/day in males and females, respectively) in an old study (1977) whose results were considered doubtful. Dermal application of fosetyl-al (1050 mg/kg bw/day) for 28 days in rats caused dermal irritation, no signs of systemic toxicity were recorded. The most recent oral 90-day rat study (Dange 1999) was acceptable and showed no effects up to 1270 mg/kg bw/day that would be the relevant short term NOAEL. The experts, however, considered that, for the overall short term NOAEL, also the mechanistic studies should have been taken into consideration. In these studies, increased calcium levels in urine were observed at ppm and above and treatment related changes in the urinary bladder, kidney and ureters were seen at ppm and above. The NOAEL of 500 mg/kg bw/day from the study by Osborne (1989, 13-week rats) was considered to be an overall NOAEL for short-term toxicity, with histopathological changes in the kidney, impairment of calcium/phosphorous metabolism, calculi and hyperplasia in the urinary tract at higher doses Genotoxicity Genotoxicity of fosetyl-al was assessed in a battery of in vivo and in vitro tests (purity of the test material ranged from 97 to 99.7%). All the studies gave negative results, clearly indicating the absence of any genotoxic potential for fosetyl-al. EFSA Scientific Report (2005) 54,

13 2.5. Long term toxicity Peer review of the pesticide risk assessment of the active substance fosetyl Long term toxicity of fosetyl-al was tested in a 2-year oral study in dogs, in a 2-year oral rat study and in a 2-year oral study in mice. Mice did not show any treatment related effect, even at high doses (around 4000 mg/kg bw/day). Testes were the main target organ in dogs. Males treated at high doses displayed testicular degeneration. The NOAEL of the study was 288 mg/kg bw/day. In rats, effects in the urinary tract were recorded, such as calculi and hyperplasia of the urinary bladder epithelium in females at doses of ppm; at the same dose, males showed a higher incidence of transitional cell papilloma and carcinoma in the urinary bladder. The NOAEL from this study was 348 and 450 mg/kg bw/day for males and females, respectively. Two mechanistic studies were conducted in order to assess the mode of action of fosetyl-al during long term exposures. It was hypothesised that the renal tumours could result from a chronic irritation rather than a true carcinogenic effect of fosetyl-al. The ingestion of high doses of fosetyl-al is a possible cause of functional alterations of renal excretion, while the formation of calculi may induce a chronic irritation of the urinary bladder epithelium, leading therefore to the development of transitional cell papilloma and carcinoma of the urinary bladder. The relevant NOAEL for long-term effects was discussed by the experts and it was agreed to be about 300 mg/kg bw/day, based on the 2-year studies in rats and dogs. In conclusion, no carcinogenic potential for fosetyl-al is evident Reproductive toxicity In a multigeneration rat study, fosetyl-al did not induce any sign of reproductive toxicity. The NOAELs for maternal and reproductive toxicity are 1782 and 1997 mg/kg bw/day in males and females respectively (highest does tested). The overall results indicated that fosetyl-al dose not induce teratogenic effects in rats and rabbits, with an overall NOAEL of 300 mg/kg bw/day from the rabbit study Neurotoxicity Fosetyl-Al did not show any evidence of neurotoxic potential Further studies Mechanistic studies: see section 2.5 Studies on metabolites Phosphonic acid is the major metabolite of fosetyl-al in plants and in in vivo studies. Acute toxicity: phosphonic acid was found to be of low acute oral, dermal and inhalatory toxicity (oral LD mg/kg bw; dermal LD mg/kg bw, LC 50 >6.14 mg/l). It is not a skin irritant while it is a slight eye irritant. Phosphonic acid was also tested in some in vitro and in vivo genotoxicity assays, without showing any genotoxic potential. The NOAEL from a 90-day oral study in rats was 400 mg/kg bw/day, based on soft faeces, increased water intake and urinary sodium excretion at 2000 mg/kg bw/day. In a 117-week oral study in rats, phosphonic acid did not induce any major effect at very high doses, and it is unlikely to pose a carcinogenic hazard to humans. Further revision of this last result for phosphonic acid has been undertaken by EFSA after the peer-review. Considering that this 117-week rat study had been performed with the hydrated monosodium phosphonate, a correction has been made for the content of water (25.9% of the tested material) and for the molecular weight of EFSA Scientific Report (2005) 54,

14 monosodium phosphonate (104) versus phosphonic acid (82). Therefore the NOAEL expressed as phosphonic acid is mg/kg bw per day, resulting in an ADI of 2.25 mg/kg bw per day by applying an uncertainty factor of Medical data No reports of health effects have been recorded during more than 20 years of medical surveillance of workers involved in the manufacturing process of fosetyl-al technical Acceptable daily intake (ADI), Acceptable operator Exposure Level (AOEL) AND Acute reference dose (ARFD) ADI The NOAEL of 300 mg/kg bw/day based on the overall 2-year NOAEL values was selected as the relevant value to set the ADI, applying a safety factor of 100, resulting in an ADI of 3 mg/kg bw/day. AOEL The most relevant study for setting an AOEL is the mechanistic rat study (see point 2.3), resulting in an AOEL of 5 mg/kg bw/day (SF 100); as agreed by the experts. ARfD An ARfD for fosetyl-al was not set because of the low acute toxicity and the absence of severe acute effects Dermal absorption A GLP in vitro dermal penetration study has been presented in the DAR, showing that following exposure to the diluted formulation (1 g/l, WG 800 g/kg formulation, actual content 794 g/kg fosetyl- Al), the absorption was 11-fold higher through rat epidermis when compared to humans, resulting in a 0.28% absorption rate. Applying the same correction factor of 11 to the concentrated formulation (500 g/l), the absorption through human skin would be 0.02%. Some MS raised doubts about the reliability of the values proposed by the RMS, because the amount of radiolabel present in the skin was not considered as actually absorbed and because of the extrapolation of the 11-fold ratio rat vs human from the 1 g/l dilution to the 500 g/l. An extensive summary of the study is presented in the Addendum 2 and was discussed during the experts meeting. The experts agreed on a 1% dermal absorption value for both the diluted and the concentrated formulation (human in vitro study, 24 hour time point) as proposed by the RMS in the Addendum Exposure to operators, workers and bystanders The main applicant proposed two representative formulations for fosetyl-al: Aliette, a water dispersible granule preparation with content of pure fosetyl-al of 800 g/kg, to be used on citrus and cucumber. The second is a combi product. Verita/Elicio is a water dispersible granule containing fosetyl-al (667 g/kg) and fenamidone (44.4 g/kg) to be used in grapes. EFSA notes regarding the dermal absorption: despite the new dermal absorption value of 1% proposed by the RMS and agreed by the experts, in the addendum 2 the risk assessment was conducted with the values of 0.02% and 0.28% for the concentrate and the diluted formulation respectively; Furthermore, the AOEL considered in the Addendum is mg/kg bw/day, however the new AOEL of 5 mg/kg bw/day should be considered, as decided at the experts meeting. EFSA Scientific Report (2005) 54,

15 Operator exposure Two separate operator exposure/risk assessment were conducted for each product. 1) Aliette 80 WG: the assumptions considered are the following: Max application rate: 4.5 kg a.s. for cucumbers, 7 kg a.s. citrus; A rough estimate with the new dermal absorption value and the new AOEL was performed during the meeting and the expert agreed that the exposure would probably still be below the AOEL. An addendum has been prepared but it has not been peer reviewed. Both with the UK POEM and the German model the exposure to fosetyl-al contained in the PPP Aliette 80 WG does not exceed the AOEL under the reported condition of use (<5% of the AOEL). Estimated exposure presented as % of AOEL (5 mg/kg bw/day), according to calculations with the German and UK POEM model. 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 Aliette 80 WG German 2.6 % 0.7 % UK POEM 14 % 12 % 2) Verita (EXP 10745D) is a WG formulation containing 667 g/kg fosetyl-al and 44.4 g/kg fenamidone. It is intended to be applied to vineyard at doses up to 3 kg/ha. The assumptions considered are: Max application rate: 2 kg/ha fosetyl-al Work rate: 15 ha/day Application with tractor, low volume Based on these assumptions and considering the AOEL of mg/kg bw/day with no PPE worn, exposure is 1.4% of the AOEL with the German model and 10% with the UK POEM. These calculations were based on the dermal absorption value of the formulation Aliette consisting of solely fosetyl-al. As for fenamidone, it should be noted that the risk assessment presented in the addendum did not consider its role in determining the exposure. Nevertheless, based on the AOEL of fenamidone (0.3 mg/kg bw/day) and on dermal absorption values of 1.75% (concentrate), 4.3% (in-use dilutions), no exceedence of the AOEL should be expected only considering fenamidone under the reported conditions of use. Although fenamidone is included in Annex I; it should be noted that interactions between the two active ingredients have not been taken into consideration. Furthermore, a dermal absorption value for the formulation containing both active substances has not been agreed on. EFSA Scientific Report (2005) 54,

16 Estimated exposure presented as % of AOEL (5 mg/kg bw/day), according to calculations with the German and UK POEM model. 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 Verita German 1.4% - UK POEM 10% - Worker exposure Aliette: the AOEL is not exceeded based on the new assumptions agreed during the experts meeting (1.2% and 0.19% of the AOEL for citrus and cucumbers, respectively). Verita: the AOEL is not exceeded based on the new assumptions agreed during the experts meeting (0.5% of the AOEL). Bystander exposure Aliette: the AOEL is not exceeded based on the new assumptions agreed during the experts meeting (0.05% of the AOEL). Verita: the AOEL is not exceeded based on the new assumptions agreed during the experts meeting (0.07% of the AOEL). 3. Residues Fosetyl-Al was discussed at the EPCO experts meeting for residues (EPCO 19) in February Nature and magnitude of residues in plant Primary crops Plant metabolism studies have been conducted in fruit (citrus, apples and pineapples) and fruiting vegetables (tomatoes), covering the scope of representative uses proposed by the applicant. A translocation study on grapes was also submitted. In addition the metabolism of 14 C fosetyl-al has been investigated in apple and vine leaves. Penetration and translocation through the plant of parent fosetyl-al is limited. The initial step of fosetyl-al metabolism proceeds through the hydrolytic cleavage of the ethyl ester bond with phosphonic acid and ethanol as the major plant metabolites. The metabolism of ethanol, when not lost by volatilisation, further consists in incorporation into natural products such as D- glucose, starch, lignin, cellulose or fatty acids. Due to the elementary nature of fosetyl-al, and given the similar results obtained on fruits and leafy parts of plant, it can be expected that the metabolic pattern should be similar in all crops. Phosphonic acid is considered to be toxicologically relevant and its level is generally higher than that of parent, therefore the residue definition should include both compounds and is proposed by the Expert meeting (EPCO 19) to be the sum of fosetyl, its salts and phosphonic acid expressed as fosetyl. However, as the method of analysis extracts not only phosphonic acid but also phosphonate salts, EFSA had been proposing a slightly different wording of the residue definition: sum of fosetyl, phosphonic acid and their salts expressed as fosetyl. Because of the slightly lower ADI set for fosetyl EFSA Scientific Report (2005) 54,

17 compared to phosphonic acid, the peer review had decided to express the total residue as fosetyl. However in the light of the recent correction of the ADI for phosphonic acid towards a lower value the total residues should be expressed as phosphonic acid. This residue definition is valid for monitoring and risk assessment purposes and is acceptable in terms of consumer safety. A sufficient amount of acceptable residue trials were carried out in accordance with the representative uses of fosetyl-al (8 trials on oranges, 7 trials on mandarins, 10 trials on grapes in Southern Europe, 8 trials on grapes in Northern Europe, 8 trials on cucumbers grown indoor and 3 trials on cucumbers grown outdoor in Northern Europe, this later small set of trials addressing a rather small market). Generally, residues of phosphonic acid were 1 order of magnitude higher than the residues of the parent compound. These residue trials can be considered as reliable on the basis of storage stability studies indicating that the sum of fosetyl, phosphonic acid and their salts is stable under storage conditions at < 20 C for at least 12 months. Actually, fosetyl is degraded under storage conditions in a way which varies from one plant matrix to the other, the phosphonic acid formed as a result of this degradation being stable. The information provided is sufficient to carry out a robust risk assessment for the consumer and to propose MRLs. One question was raised during the expert meeting (EPCO 19) whether treatment with fosetyl-al could increase the natural amount of aluminium in plants. Several trials were later submitted to the RMS on cucumbers, oranges and grapes where level of aluminium in untreated and treated samples could be compared. No significant difference was observed. However, these data have not been peer reviewed but are considered as acceptable and conclusive by EFSA. Studies are available on the effect of processing on the nature and the level of residues in processed commodities. Fosetyl-Al and phosphonic acid are hydrolytically stable under conditions representative of pasteurisation, baking, brewing, boiling and sterilisation. Processing studies for production of commodities of human consumption (wine, grape and citrus juice) are sufficient to conclude that the residue level (sum of fosetyl, phosphonic acid and their salts) in these products is quite similar to the residue level of the raw agricultural commodities (transfer factors of 0.9 for wine and grape juice and of 1.1 for citrus juice). After manual peeling, the level of residues in the pulp of oranges is in average 40% of the initial level in unpeeled fruits. 3 studies are also available to estimate the transfer of residues to citrus pomace which constitutes an important feed item. The results of these studies were rather dispersed, with calculated transfer factors of 0.1, 0.2 and 0.9. The expert meeting (EPCO 19) decided to adopt the transfer factor of 0.9 for wet citrus pomace as reference value representative of a worst case scenario in animal exposure assessments Succeeding and rotational crops Fosetyl-Al degrades in soil very rapidly to its metabolite, phosphonic acid. For that reason a study has been conducted to investigate the potential for phosphonic acid residues in succeeding crops. Cultivation of radishes, lettuce and barley 1 month after a soil treatment with phosphonic acid at 4.9 mg/kg soil, representing the concentration resulting from the application of 15 kg/ha of fosetyl-al (maximum dose applied during one growing season) results in levels of phosphonic acid higher than under natural conditions, but only slightly above the validated LOQ (Limit of Quantification) of 0.5 mg/kg for monitoring of products of plant origin. To manage this situation, the Rapporteur has proposed a pre-planting interval for rotational crops of 30 days, which provides an adequate protection of consumers, even if under particular, critical conditions, some residues above the LOQ could be observed Nature and magnitude of residues in livestock The metabolism of fosetyl-al was investigated in lactating goats. As in plants, fosetyl is first cleaved into ethanol and phosphonic acid. Ethanol is then degraded, excreted as CO 2 in expired air or reincorporated into natural products such as glucose, glycogene, EFSA Scientific Report (2005) 54,