FAO SPECIFICATIONS AND EVALUATIONS FOR AGRICULTURAL PESTICIDES

Transcription

1 FOR AGRICULTURAL PESTICIDES FLUAZINAM 3-chloro-N-(3-chloro-5-trifluoromethyl-2-pyridyl)- α,α,α-trifluoro-2,6-dinitro-p-toluidine

2 TABLE OF CONTENTS FLUAZINAM DISCLAIMER Page INTRODUCTION 1 PART ONE SPECIFICATIONS 2 FLUAZINAM INFORMATION 3 FLUAZINAM TECHNICAL MATERIAL (AUGUST 2017) 4 FLUAZINAM SUSPENSION CONCENTRATE (AUGUST 2017) 5 PART TWO EVALUATIONS OF FLUAZINAM FAO/WHO EVALUATION REPORT ON FLUAZINAM 9 SUPPORTING INFORMATION 11 ANNEX 1: HAZARD SUMMAR PROVIDED B PROPOSER 13 ANNEX 2: REFERENCES FAO/WHO EVALUATION REPORT ON FLUAZINAM 16 SUPPORTING INFORMATION 18 ANNEX 1: HAZARD SUMMAR PROVIDED B PROPOSER 22 ANNEX 2: REFERENCES 35 APPENDIX 1: ANALTICAL METHOD FOR DETERMINATION OF IMPURIT 5 IN TC AND SC 41

3 DISCLAIMER 1 FAO specifications are developed with the basic objective of promoting, as far as practicable, the manufacture, distribution and use of pesticides that meet basic quality requirements. Compliance with the specifications does not constitute an endorsement or warranty of the fitness of a particular pesticide for a particular purpose, including its suitability for the control of any given pest, or its suitability for use in a particular area. Owing to the complexity of the problems involved, the suitability of pesticides for a particular purpose and the content of the labelling instructions must be decided at the national or provincial level. Furthermore, pesticides which are manufactured to comply with these specifications are not exempted from any safety regulation or other legal or administrative provision applicable to their manufacture, sale, transportation, storage, handling, preparation and/or use. FAO disclaims any and all liability for any injury, death, loss, damage or other prejudice of any kind that may arise as a result of, or in connection with, the manufacture, sale, transportation, storage, handling, preparation and/or use of pesticides which are found, or are claimed, to have been manufactured to comply with these specifications. Additionally, FAO wishes to alert users to the fact that improper storage, handling, preparation and/or use of pesticides can result in either a lowering or complete loss of safety and/or efficacy. FAO is not responsible, and does not accept any liability, for the testing of pesticides for compliance with the specifications, nor for any methods recommended and/or used for testing compliance. As a result, FAO does not in any way warrant or represent that any pesticide claimed to comply with a FAO specification actually does so. 1 This disclaimer applies to all specifications published by FAO.

4 Page 1 of 45 INTRODUCTION FAO establishes and publishes specifications* for technical material and related formulations of agricultural pesticides, with the objective that these specifications may be used to provide an international point of reference against which products can be judged either for regulatory purposes or in commercial dealings. From 2002, the development of FAO specifications follows the New Procedure, described in the 1 st edition of the Manual on Development and Use of FAO and WHO Specifications for Pesticides (2002) - currently available as 3 rd revision of the 1 st edition (2016) -, which is available only on the internet through the FAO and WHO web sites. This New Procedure follows a formal and transparent evaluation process. It describes the minimum data package, the procedure and evaluation applied by FAO and the Experts of the FAO/WHO Joint Meeting on Pesticide Specifications (JMPS). [Note: prior to 2002, the Experts were of the FAO Panel of Experts on Pesticide Specifications, Registration Requirements, Application Standards and Prior Informed Consent, which now forms part of the JMPM, rather than the JMPS.] FAO Specifications now only apply to products for which the technical materials have been evaluated. Consequently from the year 2000 onwards the publication of FAO specifications under the New Procedure has changed. Every specification consists now of two parts namely the specifications and the evaluation report(s): Part One: The Specification of the technical material and the related formulations of the pesticide in accordance with chapters 4 to 9 of the Manual on development and use of FAO and WHO specifications for pesticides. Part Two: The Evaluation Report(s) of the pesticide, reflecting the evaluation of the data package carried out by FAO and the JMPS. The data are provided by the manufacturer(s) according to the requirements of chapter 3 of the FAO/WHO Manual on Pesticide Specifications and supported by other information sources. The Evaluation Report includes the name(s) of the manufacturer(s) whose technical material has been evaluated. Evaluation reports on specifications developed subsequently to the original set of specifications are added in a chronological order to this report. FAO specifications developed under the New Procedure do not necessarily apply to nominally similar products of other manufacturer(s), nor to those where the active ingredient is produced by other routes of manufacture. FAO has the possibility to extend the scope of the specifications to similar products but only when the JMPS has been satisfied that the additional products are equivalent to that which formed the basis of the reference specification. Specifications bear the date (month and year) of publication of the current version. Evaluations bear the date (year) of the meeting at which the recommendations were made by the JMPS. * NOTE: PUBLICATIONS ARE AVAILABLE ON THE INTERNET AT OR IN HARDCOP FROM THE PLANT PROTECTION INFORMATION OFFICER.

5 Page 2 of 45 PART ONE SPECIFICATIONS SPECIFICATIONS 2 FLUAZINAM INFORMATION 3 FLUAZINAM TECHNICAL MATERIAL (AUGUST 2017) 4 FLUAZINAM SUSPENSION CONCENTRATE (AUGUST 2017) 5

6 Page 3 of 45 FLUAZINAM INFORMATION Identity of the active ingredient ISO common name Fluazinam (ISO 1750 published) Chemical name(s) IUPAC 3-chloro-N-(3-chloro-5-trifluoromethyl-2-pyridyl)- trifluoro-2,6-dinitro-ptoluidine CA 3-chloro-N-[3-chloro-2,6-dinitro-4-trifluoromethyl) phenyl]-5-(trifluoromethyl)-2- pyridinamine Synonyms IKF-1216, B-1216, PP192 Structural formula Cl O 2 N Cl CF 3 N NH O 2 N CF 3 Molecular formula C13H4Cl2F6N4O4 Relative molecular mass CAS Registry number CIPAC number 521 Identity tests Retention time in reversed-phase HPLC, UV- and IR-spectra

7 Page 4 of 45 FLUAZINAM TECHNICAL MATERIAL FAO Specification 521 / TC (August 2017 * ) This specification, which is PART ONE of this publication, is based on an evaluation of data submitted by the manufacturers whose names are listed in the evaluation reports (521/2008 & 521/2017). It should be applicable to TC produced by these manufacturers but it is not an endorsement of those products, nor a guarantee that they comply with the specifications. The specification may not be appropriate for TC produced by other manufacturers. The evaluation reports (521/2008 & 521/2017), as PART TWO, form an integral part of this publication. 1. Description The material shall consist of fluazinam together with related manufacturing impurities, in the form of a yellow solid, having a weak aromatic hydrocarbon-like or strong musty odour, free from visible extraneous matter and added modifying agents. 2. Active Ingredient 2.1 Identity tests (521/TC/M/2, CIPAC Handbook O, p. 69, 2017) The active ingredient shall comply with an identity test and, where the identity remains in doubt with at least one additional test. 2.2 Fluazinam content (521/TC/M/3, CIPAC Handbook O, p. 69, 2017) The fluazinam content shall be declared (not less than 960 g/kg) and, when determined, the average measured content shall not be lower than the declared minimum content. 3. Relevant impurities (Note 1) chloro-N-(3-chloro-5-trifluoromethyl-2-pyridyl)- α,α,α-trifluoro-4,6-dinitro-otoluidine (Note 1) Maximum: 3 g/kg. Note 1 This impurity is named «Impurity 5» CAS-Nr A peer validated method is provided in Appendix 1. * Specifications may be revised and/or additional evaluations may be undertaken. Ensure the use of current versions by checking at:

8 Page 5 of 45 FLUAZINAM SUSPENSION CONCENTRATE FAO Specification 521 / SC (August 2017 * ) This specification, which is PART ONE of this publication, is based on an evaluation of data submitted by the manufacturer whose name is listed in the evaluation report (521/2008). It should be applicable to SC produced by this manufacturer but it is not an endorsement of those products, nor a guarantee that they comply with the specifications. The specification may not be appropriate for SC produced by other manufacturers. The evaluation report (521/2008), as PART TWO, forms an integral part of this publication. 1 Description The material shall consist of a suspension of fine particles of technical fluazinam, complying with the requirements of FAO specification 521/TC (August 2017), in the form of a light-yellow, homogeneous suspension, in an aqueous phase together with suitable formulants. After gentle agitation the material shall be homogeneous (Note 1) and suitable for further dilution in water. 2 Active ingredient 2.1 Identity tests (521/SC/M/2, CIPAC Handbook O, p. 72, 2017) The active ingredient shall comply with an identity test and, where the identity remains in doubt, shall comply with at least one additional test. 2.2 Fluazinam content (521/SC/M/3, CIPAC Handbook O, p. 72, 2017) The fluazinam content shall be declared (g/kg or g/l at 20 2ºC, Note 2) and, when determined, the average content measured shall not differ from that declared by more than the following tolerance: Declared content in g/kg or g/l at 20 Permitted tolerances 2 C Above 250 up to 500 g/l ± 5% of the declared content Note: in each range the upper limit is included 3 Relevant impurities 3.1 By-products of manufacture (Note 3) 5-chloro-N-(3-chloro-5-trifluoromethyl-2-pyridyl)- α,α,α-trifluoro-4,6-dinitro-o-toluidine Maximum: 0.3 % of the fluazinam content found under Physical properties 4.1 ph range (MT 75.3) ph range: 7 to 9 (undiluted) * Specifications may be revised and/or additional evaluations may be undertaken. Ensure the use of current versions by checking at:

9 Page 6 of Pourability (MT 148.1) Maximum residue: 5% 4.3 Spontaneity of dispersion (MT 160, CIPAC Handbook F, p. 391, 1995) (Note 5) A minimum of 90% of the fluazinam content found under 2.2 shall be in suspension after 5 min in CIPAC Standard Water D at 30 ± 2 C. 4.4 Suspensibility (MT 184, CIPAC Handbook K, p. 142, 2003) (Note 4) A minimum of 85 % of the fluazinam content found under 2.2 shall be in suspension after 30 min in CIPAC Standard Water D at 30 ± 2 C. 4.5 Wet sieve test (MT 185, CIPAC Handbook K, p. 149, 2003) (Note 5) Maximum: 0.1% of the formulation shall be retained on a 75 µm test sieve. 4.6 Persistent foam (MT 47.1, CIPAC Handbook O, p.177, 2017) (Note 6) Maximum: 25 ml after 1 min. 5 Storage stability 5.1 Stability at 0 C (MT 39.3) After storage at 0 ± 2 C for 7 days, the formulation shall continue to comply with the clauses for: - suspensibility (4.4) - wet sieve test (4.5) 5.2 Stability at elevated temperature (MT 46.3) After storage at 54 ± 2 C for 14 days, the determined average active ingredient content must not be lower than 95 % relative to the determined average content found before storage (Note 7) and the formulation shall continue to comply with the clauses for: - ph range (4.1) - pourability (4.2) - spontaneity of dispersion (4.3) - suspensibility (4.4) - wet sieve test (4.5) Note 1 Before sampling to verify the formulation quality, inspect the commercial container carefully. On standing, suspension concentrates usually develop a concentration gradient from the top to the bottom of the container. This may even result in the appearance of a clear liquid on the top and/or of sediment on the bottom. Therefore, before sampling, homogenize the formulation according to the instructions given by the manufacturer or, in the absence of such instructions, by gentle shaking of the commercial container (for example by inverting the closed container several times). Large containers must be opened and stirred adequately. After this procedure, the container should not contain a sticky layer of non-dispersed matter at the bottom. A suitable and simple method of checking for a non-dispersed sticky layer "cake" is by probing with a glass rod or similar device adapted to the size and shape of the container. All the physical and chemical tests must be carried out on a laboratory sample taken after the recommended homogenization procedure.

10 Page 7 of 45 Note 2 Note 3 Note 4 Note 5 Note 6 Note 7 Unless homogenization is carried out carefully, it is possible for the sample to become aerated. This can lead to errors in the determination of the mass per millilitre and in calculation of the active ingredient content (in g/l) if methods other than MT 3.3 are used. If the buyer requires both g/kg and g/l at 20 C, then in case of dispute the analytical results shall be calculated as g/kg. This impurity is named «Impurity 5» CAS-Nr A peer validated method is provided in Appendix 1. Chemical assay is the only fully reliable method to measure the mass of active ingredient still in suspension. However, simpler methods such as gravimetric and solvent extraction determination may be used on a routine basis provided that these methods have been shown to give equal results to those of the chemical assay method. In case of dispute, the chemical method shall be the referee method. This test detects coarse particles (e.g. caused by crystal growth) or agglomerates (crust formation) or extraneous materials which could cause blockage of spray nozzles or filters in the spray tank. The mass of sample to be used in the test should be specified at the application rate of use recommended by the supplier. Samples of the formulation taken before and after the storage stability test may be analyzed concurrently after the test in order to reduce the analytical error.

11 Page 8 of 45 PART TWO EVALUATION REPORTS FLUAZINAM Page 2017 FAO evaluation reports based on submission of information from Nutrichem (TC) 9 Supporting information 11 Annex 1: Hazard summary provided by the proposer 13 Annex 2: References FAO evaluation reports based on submission of information from Biosciences (TC, SC) 16 Supporting information 18 Annex 1: Hazard summary provided by the proposer 22 Annex 2: References 31 Appendix 1: Analytical method for determination of impurity 5 in TC and SC 41

12 Page 9 of 45 FLUAZINAM FAO/WHO EVALUATION REPORT 521/2017 Recommendations The Meeting recommended that (i) that the fluazinam TC proposed by Nutrichem Co., Ltd. should be accepted as equivalent to the fluazinam reference profile. (ii) to extend the existing TC specification to the technical material produced by Nutrichem Co., Ltd. Appraisal The Meeting considered data and supporting information submitted in April 2016 by Nutrichem Co., Ltd. (Nutrichem) for the determination of the equivalence for fluazinam TC (FAO specification 521/TC). The data submitted were in accordance with the requirements of the Manual on Development and Use of FAO and WHO specifications for Pesticides (2016, 3 rd revision of the First Edition) and supported the draft specifications. The reference specification and supporting data for fluazinam had been provided by Biosciences Europe SA and the FAO specifications had been published in Fluazinam has not been evaluated by the WHO IPCS or by the FAO/WHO JMPR. It was evaluated by US EPA in 2001, and in the European Union with inclusion into the positive list in Nutrichem did not propose specifications for fluazinam formulated products. The Meeting was provided with commercially confidential information on the manufacturing process and five batch analysis data on all impurities present at or above 1g/kg, as well as any relevant impurities below 1g/kg, and their manufacturing limits in the TC. Mass balances ranged from 98.99% to 99.25% in the 5-batch data. The maximum limits for the impurities were supported by the 5-batch data and they are statistically justified. The proposer declared the minimum purity of the fluazinam TC as 970 g/kg which is statistically justified and it is somewhat higher than the existing FAO specification (960 g/kg). The manufacturing process, impurity profile and five batch analyses were compared with the data submitted in the reference profile. Fluazinam TC manufactured by Nutrichem was found to differ slightly from the impurity profile of the reference: whereas impurity 5 was not detected above the limit of detection (see Appendix 1), it contains one additional impurity (a positional isomer of an impurity present in the reference specification). Therefore, a decision on equivalence based on Tier-1 data was not possible and additional toxicological studies were required. A mutagenicity study (Ames test) for fluazinam has been conducted as Tier-1 data. Fluazinam TC does not show mutagenicity in in vitro bacterial assays (OECD 471).

13 Page 10 of 45 On request by JMPS, Nutrichem provided a 28-days repeated dose GLP study according to OECD 407 in rats. The results of the study allow the conclusion that that the Nutrichem fluazinam TC has a no-observed-adverse-effect level (NOAEL) of 5 mg/kg. This value is very similar to the NOAEL found in the corresponding study with the reference TC. The Meeting therefore concluded that the Nutrichem fluazinam TC is not more hazardous than the reference TC produced by. The analytical method for the active ingredient (including identity tests) is CIPAC Method 4727 (521/TC/M/3) now published in Handbook O. The fluazinam content is determined by reversed phase LC, using UV detection at 240 nm and external standardisation. A fully validated method for analysis using reverse phase HPLC was also provided for the relevant impurity. Test methods for determination of physico-chemical properties of the technical active ingredient were OECD test methods. The Meeting concluded that fluazinam TC produced by Nutrichem was equivalent to the fluazinam reference TC based on Tier-2 evaluation and recommended extension of the existing TC FAO specification to the technical material produced by Nutrichem Co. Ltd.

14 Page 11 of 45 SUPPORTING INFORMATION FOR EVALUATION REPORT 521/2017

15 Page 12 of 45 Table 1. Chemical composition and properties of fluazinam technical materials (TC) Manufacturing process, maximum limits for impurities 1 g/kg, 5 batch analysis data Declared minimum fluazinam content Relevant impurities 1 g/kg and maximum limits for them Relevant impurities < 1 g/kg and maximum limits for them: Stabilisers or other additives and maximum limits for them: Confidential information supplied and held on file by FAO. Mass balances were % and percentages of unknowns were %. 970 g/kg None. none None. Parameter Value and conditions Purity % Method reference Study number Melting temperature range of the TC C 98.2 EPA Guideline NC Solubility in organic solvents g/l in methanol at 20 ± 0.5 C 15.18g/l in n-octanol at 20 ± 0.5 C 6.91g/l in n-hexane at 20 ± 0.5 C 98.2 EPA Guideline 830. NC FORMULATIONS AND CO-FORMULATED ACTIVE INGREDIENTS No specifications for formulated products have been proposed by Nutrichem. METHODS OF ANALSIS AND TESTING The analytical method for the active ingredient (including identity tests) is CIPAC Method 4727 (521/TC/M/3). The fluazinam content is determined by reversed phase LC, using UV detection at 240 nm and external standardisation, whereas the method for determination of impurities is a adequately validated reversed-phase HPLC method with UV-DAD detection. CONTAINERS AND PACKAGING No special requirements for containers and packaging have been identified. EXPRESSION OF THE CONTENT OF ACTIVE INGREDIENT The active ingredient is expressed as fluazinam.

16 Page 13 of 45 ANNEX 1 HAZARD SUMMAR PROVIDED B THE PROPOSER Note: Nutrichem provided written confirmation that the toxicological and ecotoxicological data included in the following summary were derived from fluazinam having impurity profiles similar to those referred to in Table 1, above.

17 Page 14 of 45 Table 2. Toxicology profile of the technical material based on repeated administration Species Test Duration and conditions or guideline adopted Result Study ref. Rat, Wistar, females and males Repeated oral toxicity study OECD 407, GLP Dose-ranging study 1, 10, 100, 1000 mg/kg bw for 7 days; Main study, 0, 5, 10, 15 mg/kg bw per d for 28 d NOAEL > 15 mg/kg bw per d. Polyuria at 100 mg/kg bw and diarrhoea al decreased body weight gain at 1000 mg/kg bw Solanki 2017, confidential report Table 3. Mutagenicity profile of the technical material based on in vitro tests Species Test Purity % Note 2 Guideline, duration, doses and conditions Result Study number Salmonella typhimurium TA98, TA100, TA102, TA1535 and TA1537 Ames Test in vitro 98.1 OECD Guideline h 55 min 39.06, 78.13, , , , , and μg/plate Negative GL00491 The mutagenicity study (Ames test) for fluazinam has been conducted as Tier-1 data. Fluazinam does not show mutagenicity in in vitro bacterial assays (OECD 471). 2 Note: Purity is the content of pure active ingredient in the technical material, expressed as a percentage.

18 Page 15 of 45 ANNEX 2 REFERENCES Study number 16_ NC Author(s) year Study title. Study identification number. Report identification number. GLP [if GLP]. Company conducting the study. FAO/ WHO 2006 Manual on development and use of FAO and WHO specifications for pesticides. February 2006 Revision of First Edition. FAO Plant Production and Protection Paper. Revised. FAO 2014 FAO SPECIFICATIONS AND EVALUATIONS FOR AGRICULTURAL PESTICIDES day repeated dose study of fluazinam with 14-days recovery period,, Study Nr. 16_ , GLP Vapor pressure of Fluazinam TGAI. Study NC Report NC GLP Chemical and Physical Characterization of Fluazinam TGAI: Melting Point, Partition Coefficient and Solubility. Study NC Report NC GLP. NC (sorted by study number) GL Bacterial Reverse Mutation Test of Fluazinam TGAI Using Salmonella typhimurium Tester Strain (Ames Test) Report GL GLP.

19 Page 16 of 45 FLUAZINAM FAO/WHO EVALUATION REPORT 521/2008 Recommendations The Meeting recommended that (i) the new specification for fluazinam TC and SC formulations, proposed by Biosciences Europe SA (), and as amended, should be adopted by FAO. Appraisal The data for fluazinam were evaluated in support of new FAO specifications. Fluazinam is not under patent and has not been evaluated previously by the FAO/WHO JMPR and WHO/IPCS. It was evaluated by US EPA in 2001 and is currently under review by the European Commission. The draft specification and the supporting data were provided by Biosciences Europe SA in 2006, with further clarifications and data provided in The meeting considered the data on fluazinam, submitted by Biosciences Europe SA (), in support of proposed new FAO specifications for fluazinam TC and SC. Fluazinam is a yellow solid only slightly soluble in water. It undergoes hydrolysis which is not significantly affected by ph. It is susceptible to fairly rapid photolysis. It has no acid or basic properties. The meeting were provided with commercially confidential information on the manufacturing process and manufacturing specification for purity and impurities, supported by 5 batch analysis data. Mass balances were >990 g/kg and no unidentified impurities greater than 1 g/kg were reported. A statement was provided by the UK Pesticides Safety Directorate confirming that the confidential data on the manufacturing process and declaration of composition submitted to the FAO were the same as those submitted to the national regulatory authority. The data provided supported a minimum fluazinam content of 960 g/kg. The Meeting considered the relevance and limit for the impurity-5 [5-chloro-N-(3-chloro-5- trifluoromethyl-2-pyridyl)-α,α,α-trifluoro-4,6-dinitro-o-toluidine], CAS ) in fluazinam The company had proposed that the impurity-5 be considered relevant and that a limit for it be established at 3 g/kg. Toxicological studies were submitted documenting that impurity-5 causes reversible white matter vacuolation of unknown physiological significance in different parts of the central nervous system in rats, mice, and dogs, and is likely to be the cause of similar findings in animals treated with fluazinam TC. Based on the information provided by the proposer, the Canadian and European evaluations of the registration by of fluazinam, the Meeting noted that the long-term oral NOAEL of impurity 5 (with reference to white matter vacuolation) is 0.02 mg/kg, the overall NOAEL of fluazinam, 0.38 mg/kg, and the minimum content of the active ingredient is 960 g/kg.

20 Page 17 of 45 Based on the rules provided in the Manual (December second revision of the First Edition, Appendix J) it can be calculated that the RelHaz is 19.0, and the MTIHaz, The latter represents an increase of the toxicity of fluazinam at the maximal theoretical impurity 5 content in fluazinam by 79%. This being in excess of 10%, the impurity is relevant. The maximum limit for the impurity, Impmax, is 0.50% = 5 g/kg (JMPS, 2010). The limit for the concentration of impurity 5 in fluazinam, suggested by the proposer, is 3 g/kg, and thus acceptable to JMPS. It should be noted that the approach used here is normally limited by the Manual to cases, where the toxicity of the impurity is qualitatively similar to that of the active ingredient, what is not the case here. The justification for nevertheless using this approach is that rather than any specific toxicological end-point, the no effect level from long term study (life-time studies in rats and mice, and 1-year studies in dogs) is used for both the impurity and active ingredient. The Meeting is aware that the Canadian authority has established a limit of 1 g/kg, and the European Union, 2 g/kg, for impurity-5 in fluazinam. However, none of the authorities have in their publicly available documents provided the criteria for their established limit concentrations. Methods of analysis The collaborative validation of a reversed-phase HPLC method for determination of fluazinam and impurity-5 in TC and SC formulations was first presented at the CIPAC Meeting in El Salvador in Whereas the results presented fulfilled the requirements for a peer validation for the determination of impurity-5 in TC and SC formulation, the collaborative validation for fluazinam itself did not pass the hurdle for a minimum number of participating laboratories providing valid results (8 laboratories) and was again presented with a higher number of laboratories in 2010 in Slovenia. The method was then adopted as provisional CIPAC method and became a full method in The methods for impurities are based on reversed-phase HPLC and are adequately validated. Specification for SC The test methods proposed for physical properties of the SC were in accordance with the requirements of the Manual (FAO/WHO, 2006) with the following exception: i) The suspensibility and spontaneity of dispersion properties before and after storage (2 weeks at 54 C) were determined used CIPAC standard water C instead of standard water D as the tests were conducted before the use of CIPAC standard water D was required. The stability study conducted at 0 C used CIPAC standard water D. The proposer has therefore proposed limits for the clauses based on the data generated using CIPAC Standard water D.

21 Page 18 of 45 SUPPORTING INFORMATION FOR EVALUATION REPORT 521/2008

22 Page 19 of 45 Uses Fluazinam is a contact fungicide with a multi-site mode of action. It uncouples oxidative phosphorylation at several metabolic pathways within the fungal cell. Fluazinam is a protectant fungicide and when applied to plants, remains primarily on the plant surface. It is used in agriculture on potatoes, vines, apples and onions in Europe against downy mildews such as Phytophtora Infestans. Identity of the active ingredient ISO common name Fluazinam (ISO accepted) Chemical name(s) IUPAC 3-chloro-N-(3-chloro-5-trifluoromethyl-2-pyridyl)- trifluoro-2, 6-dinitro-ptoluidine CA 3-chloro-N-[3-chloro-2, 6-dinitro-4-trifluoromethyl) phenyl]-5-(trifluoromethyl)-2- pyridinamine Synonyms IKF-1216, B-1216, PP192 Structural formula Cl O 2 N Cl CF 3 N NH O 2 N CF 3 Molecular formula C13H4Cl2F6N4O4 Relative molecular mass CAS Registry number CIPAC number 521 Identity tests HPLC: retention in reversed-phase HPLC, UV- and IR-spectra

23 Page 20 of 45 Table 1. Physico-chemical properties of pure fluazinam Parameter Value(s) and conditions Purity % Method reference Vapour pressure (7.5 ± 0.8) x 10-3 Pa at 20 C 99.8 % OECD 104, Melting point, boiling point and/or temperature of decomposition Solubility in water Melting point: 117 C Boiling point: not required as material is solid and does not have a low melting point Decomposition temperature: not required because the material is solid and does not have a low melting point ph x10-4 g/l ph x10-4 g/l ph x10-3 g/l 99.8 % EEC Base Set Methods (Annex V or dir. 79/831) versions Nov. 1989, Part A % OECD 105, Octanol/water partition coefficient log POW = 4.03 at 25 C 96.8% 40 CFR Pesticide Assessment Guidelines Subdivision D: Product Chemistry Guideline Hydrolysis characteristics Half-life = 5 days at 50 C at ph 4 for fluazinam; 4.5 and 2.7 days at ph 7 for the phenyl and pyridyl labels, respectively, and 3.5 and 3.9 days at ph 9 for the phenyl and pyridyl labels, respectively, both at 25 ºC. [ 14 C-phenyl] fluazinam (2.33 GBq mmol-1, 100% radiopurity) and [ 14 C- pyridyl] fluazinam (2.37 GBq mmol-1, 97.7% radiopurity) OECD 111 EPA OPPTS , Photolysis characteristics The half-life in sterile ph 5 buffer was 2.5 days for both labels. The major photolytic product was CO2 after 30 days). [ 14 C-phenyl] IKF (57.3 mci/ mmol, >99%), [ 14 C- pyridyl] IKF-1216 (66.2 mci/ mmol, >99%), IKF-1216, Lot No , 99.6% United States EPA Guideline EC Dissociation characteristics pka = % 40 CFR Pesticide Assessment Guidelines, Subdivision D: Product Chemistry Guideline 63-10

24 Page 21 of 45 Table 2. Chemical composition and properties of fluazinam technical materials (TC) Manufacturing process, maximum limits for impurities 1 g/kg, 5 batch analysis data Declared minimum fluazinam content Relevant impurities 1 g/kg and maximum limits for them Relevant impurities < 1 g/kg and maximum limits for them: Stabilisers or other additives and maximum limits for them: Melting or boiling temperature range of the TC and/or TK Confidential information supplied and held on file by FAO. Mass balances were % and no unknowns were identified. 960 g/kg Impurity-5: 5-chloro-N-(3-chloro-5-trifluoromethyl-2-pyridyl)- α,α,α-trifluoro-4,6-dinitro-o-toluidine Maximum 3 g/kg None None Data available on purified product (see Table 1). FORMULATIONS AND CO-FORMULATED ACTIVE INGREDIENTS The main formulation types available are suspension concentrates (SC). These formulations are registered and sold in many countries throughout the world in Europe, USA, Latin American Countries, Australia and some Asian countries. METHODS OF ANALSIS AND TESTING The fluazinam content is determined by reversed phase HPLC, using UV detection at 240 nm and external standardisation. The identity of the active ingredient is confirmed by comparison of retention times in HPLC and IR spectra. The analytical method for the active ingredient in TC and SC became a full CIPAC method (ISBN ), adopted at the 2011 CIPAC meeting in Beijing. The method is not yet published in a Handbook, but is available as a pre-published method. Test methods for determination of physical-chemical properties of the technical active ingredient were OECD, EPA or EC, respectively. CONTAINERS AND PACKAGING No special requirements for containers and packaging have been identified. EXPRESSION OF THE CONTENT OF ACTIVE INGREDIENT The active ingredient is expressed as fluazinam. Fluazinam has not been evaluated by the WHO IPCS or by the FAO/WHO JMPR. The WHO hazard classification of fluazinam is: There is no hazard classification for fluazinam

25 Page 22 of 45 ANNEX 1 HAZARD SUMMAR PROVIDED B THE PROPOSER Note: provided written confirmation that the toxicological and ecotoxicological data included in the following summary were derived from fluazinam having impurity profiles similar to those referred to in Table 1, above.

26 Page 23 of 45 Table 3. Toxicology profile of fluazinam technical material, based on acute toxicity, irritation and sensitization. Species Test Duration and conditions or guideline adopted Result Rat Oral Batch no. 109; purity 95.3 % Single doses of 2500, 3200, 4000 and 5000 mg/kg bw fluazinam. 14-day observation period. Japanese MAFF acute oral toxicity study, in accordance with 59 Nohsan no (1985), GLP. Rat Dermal Batch no ; purity 98.5 % Single dose of 2000 mg/kg bw fluazinam. 14-day observation period Japanese MAFF acute oral toxicity study, in accordance with 59 Nohsan no (1985), GLP. Rat Inhalation Batch no. A629/1995; purity 97.3 % Concentrations of 1.0 mg/l, 1.1 mg/l and 4.0 mg/l. 4-hour nose-only exposure period. OECD Guideline 403 and U.S. EPA OPPTS Guideline , GLP. LD50: 4500 mg/kg bw (males) LD50: 4100 mg/kg bw (females) LD50 > 2000 mg/kg bw LC50 > 1.1 mg/l Rabbit Skin irritation Batch no. 1006; purity 97.9 % 4-hour exposure period, 13 day observation period. non-irritant U.S. EPA Pesticide Assessment Guidelines Subdivision F, Series 81-5, GLP. Rabbit (males and females) Eye irritation Batch no. 1006; purity 97.9 % 21-day observation period US EPA Pesticide Assessment Guidelines Subdivision F, 81-4 irritant Guinea Pig (males and females) Skin sensitisation Batch no ; purity 98.5 % Dermal responses to primary induction were assessed 24 and 48 hours after administration. sensitizer According to the GHS classification system, fluazinam is unclassified. Topical induction (for 48 hours under occlusive dressing at the injection test sites) was carried out on day 8. On day 22 the challenge phase was performed in the treated group and in the control group by applying 0.2 ml 70 % (w/v) solution of fluazinam in

27 Page 24 of 45 paraffin oil dermally under occlusive dressing for 24 hours on the right flank while the left flank received the vehicle only. U.S. EPA Pesticide Assessment Guidelines Subdivision F, No (Magnusson and Kligman) According to the GHS system, fluazinam would be unclassified. However this classification should be regarded with caution. On the basis of the original interpretation of the results, fluazinam was classified as a sensitizer. Cases of allergic contact dermatitis have been reported from workers from manufacturing site and users. Therefore fluazinam should be classified as sensitizing.

28 Page 25 of 45 Table 4. Toxicology profile of the technical material based on repeated administration (subacute to chronic) Species Test Duration and conditions or guideline adopted Mouse subchronic Batch 8203, purity 96.3 %; impurity 5: 0.008%) Repeated oral dosing, 4-Weeks. Dose levels: 0, 10, 50, 250 and 3000 ppm fluazinam, equivalent to 0, 1.6, 7.9, 39.5 and 455 mg/kg bw/d. No specific test guideline, GLP. Rat subchronic Batch 8203, purity 96.3 %; impurity 5: 0.008%) Repeated oral dosing, 4-Weeks. Dose levels: 0, 10, 50, 250 and 3000 ppm fluazinam, equivalent to 0, 1.26, 5.21, 26.1 and mg/kg bw/d. No specific test guideline, GLP. Dog subchronic Batch , purity 98.5 %; impurity 5: <0.005%) Repeated oral dosing, 4-Weeks. Dose levels: 1, 5, 25 and 150 mg/kg/d bw/d. No specific test guideline, GLP. Result Body weight gains of males receiving 3000 ppm and 250 ppm were significantly during the first 10 days of treatment. Statistically significant higher liver weights in males and females receiving 3000 ppm. Absolute and relative kidney weight of females of the 250 ppm and 3000 ppm dosing groups. Clinical chemistry findings for both sexes at dose levels of 3000 ppm. NOAEL: 50 ppm or 7.9 mg/kg bw/d. Lower body weight and reduced food intake at 3000 and 250 ppm. Higher relative liver weights in males and females receiving 3000 ppm. Histopathological changes in the liver at 3000 and 250 ppm. NOAEL: 50 ppm or 5.21 mg/kg bw/d for males and females. Reduced food intake and bodyweight in animals receiving 150 mg/kg bw/d. Increased liver weights in animals receiving 25 and 150 mg/kg bw/d). NOAEL: 5 mg/kg bw/d

29 Page 26 of 45 Species Test Duration and conditions or guideline adopted Rat Short-term Batch , purity 98.5 %; impurity 5: <0.005%) Repeated oral dosing, 90-Days. Dose levels: 0, 2, 10, 50 and 500 ppm fluazinam, equivalent to 0, 0.16, 0.82, 4.1 and 41 mg/kg bw/d U.S. EPA Guideline 82-1, GLP. Dog Short-term Batch , purity 98.5 %; impurity 5: <0.005%) Repeated oral dosing, 90-Days. Dose levels:1, 10 and 100 mg/kg/d bw/d. U.S. EPA Guideline 82-1, GLP. Rat Dermal Batch no ; purity 98.5 %; impurity 5: <0.005%). Repeated dermal dosing, 21-days. Dose levels: 10, 100 and 1000 mg/kg bw/d. U.S. EPA Guideline 82-2, GLP. Dog Long-term Batch , purity 95.3 %; impurity 5: 0.20%) Repeated oral dosing, 1-year. Dose levels: 1, 10 and 50 mg/kg bw/d No specific test guideline, GLP. Result Increased Liver weights in males at a concentration of 500 and 50 ppm. Microscopic liver findings at 500 ppm. NOAEL: 50 ppm or 4.1 mg/kg bw/d for males and females. Changes in absolute and relative liver weight and histopathological changes in this organ. NOAEL: 10 mg/kg bw/d. Microscopic liver findings at all dose groups. A mild toxic effect was also observed in the liver at 1000 mg/kg bw. Effects to the skin (acanthosis and dermatitis) observed at all dose groups compared to controls. NOAEL: <10 mg/kg/day Increase of liver weight and accompanying blood chemistry changes at 50 mg/kg bw/d. An increased incidence of liquefied contents of the gastrointestinal tract and mucosal lymphoid hyperplasia of the stomach at 50 mg/kg bw/d and partly in animals at 10 mg/kg bw/d. Vacuolation of white matter in the brain at 50 mg/kg bw/d. Females of the high dose group showed also vacuolation of white matter in the spinal cord. NOAEL: 1 mg/kg/day

30 Page 27 of 45 Species Test Duration and conditions or guideline adopted Result Rat Long-term/ Carcinogenicity Batch , purity 95.3 %; impurity 5: 0.20%) Dose levels: 0, 1, 10, 100 and 1000 ppm equivalent to 0, 0.04, 0.38, 3.82 and 40 mg/kg bw/d for males and 0, 0.05, 0.47, 4.87 and 53 mg/kg bw/d for females. No tumorigenic effects. Non-neoplastic effects in several organs at 100 and 1000 ppm dose levels. NOAEL 0.8 mg/kg per d for males and 0.47 mg/kg per d in females. No increased vacuolation in the white matter in the brain. Repeated oral dosing, 104 weeks Rat Long-term/ Carcinogenicity Batch , purity 95.3 %; impurity 5: 0.20%) Dose levels: 0, 25, 50 and 100 ppm equivalent to 0, 1.0, 1.9 and 3.9 mg/kg bw/d for males and 0, 1.2, 2.4 and 4.9 mg/kg bw/d for females. Repeated oral dosing, 104 weeks Japanese MAFF Test Guidelines (1985), U.S. EPA Guidelines and OECD Guideline No. 452, GLP Slightly increased liver, testes and epididymides weights and macroscopically in a higher incidence of small/flaccid testes observed at 100 ppm. Increased incidence of marked testicular atrophy in males of the 100 ppm group. No evidence of any tumorigenic potential in male or female rats. NOAEL: 50 ppm, equivalent to 1.9 mg/kg bw/d for males and 2.4 mg/kg bw/d for females. No vacuolation in the white matter of the brain Mouse Long-term/ Carcinogenicity Batch 1030/91; purity 97 %; impurity %.) Dose levels: 0, 1000, 3000 and 7000 ppm, equivalent to 0, 126, 377, and 964 mg/kg bw/d for males and 0, 162, 453, and 1185 mg/kg bw/d for females. Incidence of hepatocellular adenomas was elevated in the 3000 ppm group, but not in the 7000 ppm group in the males. Vacuolation in the brain and cervical spinal cord observed in all treated animal groups in males and females Repeated oral dosing, 104 weeks. No specific test guideline, GLP.

31 Page 28 of 45 Species Test Duration and conditions or guideline adopted Result Mouse Long-term/ Carcinogenicity Batch ; purity 95.3 %; impurity 5: 0.20%) Dose levels: 0, 1, 10, 100 and 1000 ppm, equivalent to 0, 0.12, 1.12, and 107 mg/kg bw/d for males and 0, 0.11, 1.16, and 117 mg/kg bw/d for females. Repeated oral dosing, 104 weeks. No specific test guideline, GLP. At 1000 ppm, increased liver weight, increased macroscopic liver lesions, microscopically, higher frequency of basophilic or eosinophilic hepatocytes and higher incidence of granulomatous hepatitis and aggregates of brown pigmented macrophages in high and mid-dose males and high dosed females. Increase of vacuolation of white matter in the brain in both sexes of the high dose groups. Increase in liver cell tumours was within historical control data. NOAEL: 10 ppm, equivalent to 1.12 mg/kg bw/d. Liver cell tumours were observed in the high dose group males, but the incidence remained within the historical control range. Rat Multigeneration / Reproduction Batch , purity 95.3 %; impurity 5: 0.20%) Dose levels: 0, 20, 100 or 500 ppm No specific test guideline, GLP. At 500 ppm: reduced body weight and body weight gain of F0 and F1 parental females during maturation and gestation and of F1 and F2 offspring during lactation. Reduced food intake was recorded for F0 females and F1 males and females during maturation. In the F1 generation, conception rate and fertility index were slightly reduced in the 500 ppm group. Gestation length was slightly increased in the high and intermediate dose groups. Numbers of implantation sites and mean litter sizes to day 4 post partum were slightly reduced for F1 animals of the high dose group and marginally lower in the intermediate group (100 ppm). Relative liver weights were significantly increased in both sexes of the highest dose group and also in females of the intermediate and low dose group of the F0 generation but there was no clear dose response observed. High dose males of the F1 generation showed also an increase of relative liver weight. Histopathologically, a statistically significant increase of periacinar hepatocytic fatty changes were detected in high dose males of F0 and F1 animals and also in F1 males of the 100 ppm group. NOAEL: for both systemic toxicity and reproductive parameters was considered to be 20 ppm, equivalent to approximately 1.5 mg/kg bw/d for males and 1.7 mg/kg bw/d for females.

32 Page 29 of 45 Species Test Duration and conditions or guideline adopted Rabbit Developmental Batch Lot , purity 98.5 % Dose levels: 0.3, 1 and 3 mg/kg bw /d Repeated oral dosing from day 6 to 19 of gestation No specific test guideline, GLP. Rabbit Developmental Batch Lot , purity 95.3 % Dose levels: 2, 4, 7 and 12 mg/kg bw fluazinam Repeated oral dosing from day 6 to 19 of gestation No specific test guideline, GLP. Rat Developmental Batch Lot , purity 98.5 % Dose levels: 10, 50 and 250 mg/kg bw fluazinam Repeated oral dosing from day 6 to 15 of gestation U.S. E.P.A. Guideline No Result NOAEL: 3 mg/kg bw/d for maternal toxicity 3 mg/kg bw/d for fetal toxicity. Slightly reduced maternal body weight gain from day 10 to day 20 of gestation. Reduced food intake in the 7and 12 mg/kg bw/d from day 13 to day 19. Macroscopic and microscopic lung and liver changes were observed at a dose level of 12 mg/kg bw/d. Slightly increased incidences of fetal abnormalities (placental abnormalities, some skeletal abnormalities including kinked tail tip, fused or incompletely ossified sternebrae and abnormalities of the head bones) were seen at the top dose. NOAEL: 4 mg/kg/day for maternal toxicity 7 mg/kg bw/day for fetal toxicity Reduced mean food consumption followed by a reduced rate of weight gain compared to controls at the dose rate of 250 mg/kg bw. Reduced fetal and placental weights in the 250 and 50 mg/kg bw/d group and indications of fetal immaturity. Increased incidence of gross morphological fetal abnormalities at the 250 mg/kg bw/d group. NOAEL for developmental effects: 10 mg/kg bw/d.

33 Page 30 of 45 Table 5. Mutagenicity profile of the technical material based on in vitro and in vivo tests Species Test Conditions Result Bacteria (E. coli & S. typhimurium) Reverse gene mutation, in vitro Batch no , purity 95.3% Testing Guidelines for Toxicological Studies, 59 NohSan No. 4200, GLP. Bacteria (E. coli & S. typhimurium) Reverse gene mutation, in vitro Batch no.109, purity 95.3% Japanese MAFF, NohSan No (1985), GLP. Mammalian cells (mouse lymphoma) Gene mutation, in vitro Batch A629/1995, Purity 98.4% OECD Guideline 476 (1997); Commission Directive 2000/32/EC (2000) Annex 4E B17 (L136, 65); U.S. EPA (1998) Health Effects Guidelines, OPPTS , EPA 712-C GLP Mammalian cells (hamster lymphocyte) Chromosomal aberration, in vitro Lot no. 109, Purity 95.3% Testing Guidelines for Toxicological Studies, 59 NohSan No. 4200, GLP. Negative Negative Negative Negative Bacteria (B. subtilis) in vitro DNA repair test (Rec-assay), in vitro Lot no. 109, Purity 95.3% Testing Guidelines for Toxicological Studies, 59 NohSan No. 4200, GLP. Negative Mouse Micronucleus, in vivo Batch No , purity of 95.6% Single oral dose at levels of 500, 1000 and 2000 mg/kg bw OECD Guideline 474 (1997), U.S. EPA Health Effects Guidelines (1991) and Japanese MAFF, 59 NohSan No (1985), GLP. Negative Fluazinam was tested for genotoxicity in a range of assays, both in vitro and in vivo. There was no evidence of genotoxicity in any of these assays.

34 Page 31 of 45 Table 6. Supplementary studies (mostly non-guideline) submitted in support of the relevance of impurity-5 and effect of vacuolation related to administration of fluazinam technical and impurity /1998 B-1216: 52-Week Toxicity Study in Oral Administration to Beagle Dogs. Report No. 86/055/512, Final report; 86/055/ /1998 Technical Fluazinam, Toxicity to Mice by Dietary Administration for Four Weeks. Report No. 49/ /1998 B-1216 Technical: Potential Carcinogenicity and Chronic Toxicity Study in Dietary Administration to Rats for 104 Weeks. Report No. 8/ /1996 B-1216: Potential Carcinogenicity Study in Dietary Administration to Mice for 104 Weeks. Report No. 9/ Comparative Study on Susceptibility to Neurotoxicity in Mice, Rats and Dogs. Report No Fluazinam Technical; Toxicological Effect on the Brain of Rats and Its Reversibility by Dietary Administration for 14 Days Followed by a 25-Day Recovery Period. Report No. AN Fluazinam Technical: Toxicological Effect on the Brain of Mice and Its Reversibility by Dietary Administration for Four or Twenty-Eight Days Followed by a 56-Day Recovery Period. Ltd., Report No. AN Impurity-5; An Impurity in Fluazinam Technical; Toxicological Effect on Brain and Optic Nerves of Mice Following a Single Oral Administration at Various Stages of Animal Age. Ltd, Report No. AN Impurity-5; An Impurity in Fluazinam Technical; Sensitivity Comparison on Brain of Mice and Rats Following 14-Day Oral Administration. Ltd., Report No. AN Impurity-5; An Impurity in Fluazinam Technical; Sensitivity Comparison on the Brain of Rats and Mice in 3- and 10-Week Olds Following 14-Day Oral Administration. Report No. AN An Acute Neurotoxicity Screening Study in Rats with Technical Fluazinam. Report No TX-003

35 Page 32 of 45 Table 7. Ecotoxicology profile of the technical material Species Test Duration and conditions Result Oncorhynchus mykiss Rainbow trout Daphnia magna Waterflea Chironomus riparius Midge Lemna gibba Duckweed Apis mellifera honey bee Acute Toxicity Batch no. 1030/91, purity 96.8 % w/w Mean measured concentrations were 10, 15, 28, 33 and 56 µg/l. Flow through, 96 hr U.S. EPA FIFRA Guideline 72-1, GLP. Acute Toxicity Batch no. 1030/91, purity 100% Mean measured concentrations were 34, 54, 94, 150 and 260 µg/l. Flow through, 48 hr OECD 202, GLP. Acute Toxicity Batch no. A629/1995, purity: 97.8 %. Mean measured concentrations were 0, 12, 33, 68, 120, 238 µg/l. Static, 48 hr No guideline followed, GLP. 7-Day Toxicity Batch no. A626/1995, purity: 98.4 %. acute oral and contact toxicity Mean measured concentrations were 0.859, 1.73, 4.58, 7.96, 17.5, 35.9 and 69.1 µg/l. Static renewal, 7-day ASTM 1991, EPA OPPTS , GLP. Batch no , purity 98.8 %. In the contact tests, the concentration range was 0, 20, 50, 100 and 200 µg ai/bee for the technical substance and 0, 1, 2 and 4 µg ai/bee for the formula- LC50 = 36 µg ai/l EC50 = 220 µg ai/l LC50 = 45 µg ai/l LC50 > 69.1 µg ai/l Acute LD50: >100 µg a.i./bee oral Acute LD50: >200 µg a.i./bee - contact

36 Page 33 of 45 Colinus virginianus Bobwhite quail tion. In the oral tests, the concentration range for both the technical and formulated material was 0, 10, 20, 50 and 100 µg ai/bee. 60 bees per tested dose, 48 hr observation UK MAFF Pesticides Safety Precautions Scheme, Document D3 (1979) acute toxicity Batch No , purity 95.3 % Oral intubation at dose levels of 0, 500, 1000 or 2000 mg/kg bw 14-day observation U.S. EPA FIFRA, No. 71-1, GLP One mortality occurred at 1000 mg/kg and six at 2000 mg/kg. Birds dosed at 2000 mg/kg exhibited toxic signs including subdued behaviour and ruffled feathers prior to death. Over days 0 to 7, bodyweight gain and female food consumption were slightly reduced at 2000 mg/kg. At post-mortem examination, the intestines of all birds that died during the study were observed to be red in colour. Anas platyrhynchos Mallard duck acute toxicity Batch No , purity 95.3 % Oral intubation at dose levels of 0, 484, 944, 2020, 3050 and 4190 mg/kg bw 14-day observation U.S. EPA FIFRA, No. 71-1, GLP LD50 = 1782 mg [TGAI]/kg bw No mortalities occurred at any dose level in the study. Female birds in the high-dose group (4190 mg/kg) were subdued on day 2. No other abnormalities were noted. LD50 > 4190 mg [TGAI]/kg bw