OCTOBER 2017 Reconsideration of Procymidone: Human health risk assessment report (including Toxicology and Work Health Safety) © Australian Pesticides and Veterinary Medicines Authority 2017 ISBN 978-1-925390-88-9 (electronic) Ownership of intellectual property rights in this publication Unless otherwise noted, copyright (and any other intellectual property rights, if any) in this publication is owned by the Australian Pesticides and Veterinary Medicines Authority (APVMA). Creative Commons licence With the exception of the Coat of Arms and other elements specifically identified, this publication is licensed under a Creative Commons Attribution 4.0 Australia Licence. This is a standard form agreement that allows you to copy, distribute, transmit and adapt this publication provided that you attribute the work. A summary of the licence terms is available from https://creativecommons.org/licenses/by/3.0/. 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CONTENTS iii CONTENTS EXECUTIVE SUMMARY 1 1 ADVICE AND RECOMMENDATIONS 2 Approval Status 3 Product Registration 3 Public Health Standards 3 Label Statements 4 First Aid Instructions 4 Safety Directions 4 Re-entry or Re-handling Statement 5 Warning Statements 5 2 REASONS FOR THE REVIEW 6 Hazard Characterisation 6 Chemistry—Active Constituent 6 Physical and chemical properties 7 Impurities of Toxicological Concern 7 International Toxicology Assessments 8 The Joint FAO/WHO Meeting on Pesticide Residues (JMPR) 8 United States Environmental Protection Agency (US EPA) 8 European Commission (EC) 9 Toxicology hazard profile 9 Summary toxicology report 11 Mode of action 11 Metabolism and Toxicokinetics 12 Metabolites of procymidone 15 Percutaneous absorption 15 Acute toxicity 16 Short-Term Repeat-Dose Toxicity 16 Subchronic Toxicity 17 Chronic Toxicity 17 Reproductive Toxicity 18 Developmental Toxicity 20 Carcinogenicity and Genotoxicity 27 Mechanistic Studies 28 Other studies 30 Human Toxicity 31 Formulated products 32 3 HEALTH STANDARDS 33 Public Health Considerations of Procymidone in Australia 33 Approval Status 33 iv RECONSIDERATION OF PROCYMIDONE: HUMAN HEALTH RISK ASSESSMENT REPORT (INCLUDING TOXICOLOGY AND WORK HEALTH SAFETY) Impurity Limits 33 Acceptable Daily Intake (ADI) 34 Acute Reference Dose (ARfD) 35 Poisons Scheduling 35 4 OCCUPATIONAL EXPOSURE, RISK ASSESSMENT & MANAGEMENT 36 Procymidone Products and Use Patterns 36 NOAEL for Occupational and Residential Risk Assessment 40 NOAEL for occupational exposure 40 NOAEL for post-application exposure 40 Dermal absorption factor 42 Inhalation absorption factor 44 Occupational Exposure Assessment 44 Exposure during use 45 Occupational Risk Assessment 56 Risk for Repeat Exposure 56 Seed treatment for onions, lupins and pre-plant garlic clove treatment 59 Risk from re-entry/re-handling exposure 61 Occupational Risk Management 64 Risk management measures for use of the product 65 Re-entry or Re-handling Statement 67 Warning statement 67 5 PUBLIC EXPOSURE, RISK ASSESSMENT AND RISK MANAGEMENT 68 Public Exposure 68 Accidental Exposure 68 Bystander Exposure 68 Dietary Exposure 68 Public Post-application Exposure 68 Turfgrass residues 68 ABBREVIATIONS 73 REFERENCES 79 Studies evaluated in the 2015 review 79 Studies evaluated in the 2007 review 79 Secondary citations 87 Other references 88 APPENDIX I: EVALUATED STUDIES 90 Metabolism and toxicokinetics 90 Acute toxicity studies 140 Active Constituent 140 Oral toxicity 140 CONTENTS v Inhalational Toxicity 141 Skin sensitisation 143 Metabolites/Degradants 144 Products 144 Short-term repeat-dose studies 144 Oral Administration 144 Dermal Administration 145 Subchronic toxicity studies 147 Materials and Methods 147 Results 147 Chronic toxicity studies 152 Observations 153 Clinical Chemistry 153 Haematology 154 Urinalysis 154 Testosterone Analysis 154 Gross Necropsy 154 Organ Weights 154 Materials and Methods 155 Results 156 Haematology, clinical chemistry and urinalysis 159 Organ weights, gross pathology and histopathology 160 Reproduction studies 161 Mortality, clinical signs, bodyweight, and food and procymidone consumption in F0 parents 162 Reproductive parameters in parental animals 163 Pup parameters 163 Materials and Methods 165 Results 165 Material and methods 167 Developmental studies 169 Materials and Methods 169 Results 169 Mortality, clinical signs, bodyweight, food consumption and necropsy changes in maternal animals 171 Uterine parameters 172 Naturally delivered pups 173 APPENDIX II: LIST OF CLINICAL CHEMISTRY, HAEMATOLOGY & URINALYSIS PARAMETERS 201 APPENDIX III: ORGANS FOR WEIGHT DETERMINATION AND HISTOPATHOLOGICAL EXAMINATION 202 APPENDIX IV: REPRODUCTIVE AND DEVELOPMENTAL INDICES 203 APPENDIX V: STANDARD FUNCTIONAL OBSERVATIONAL BATTERY (FOB) PARAMETERS 204 vi RECONSIDERATION OF PROCYMIDONE: HUMAN HEALTH RISK ASSESSMENT REPORT (INCLUDING TOXICOLOGY AND WORK HEALTH SAFETY) List of tables Table 1—List of registered procymidone products and approved active constituent holders (October 2017) 2 Table 2—Summary of physico-chemical properties 7 Table 3—Summary of acute toxicity of the procymidone products 32 Table 4—Studies and associated NOAEL/LOAELs relevant for the establishment of Health standards 34 Table 5—Registered procymidone products and use patterns (1 October 2017) 36 Table 6—Uses and application rates for 500 g/L SC procymidone products (October 2017) 38 Table 7—Summary of NOAELs relevant for WHS assessment 41 Table 8—In vitro dermal absorption of procymidone suspension concentrate (neat and diluted) in rat and human epidermis after 24 h exposure (Owen, 2002) 43 Table 9—In vivo dermal absorption of procymidone suspension concentrate (neat and diluted) in rat after 24 h exposure (Savides, 2002) 43 Table 10—Dermal absorption rate of procymidone (calculated in vivo human) 44 Table 11—Estimates of systemic exposure to procymidone in the 500 g/L products (mg/kg bw/d) 47 Table 12—Worker exposure to metalaxyl from the liquid flowable formulation 50 Table 13—Calculated daily systemic exposure to procymidone in seed treatment for onions, lupins and pre-plant garlic clove treatment 51 Table 14—Summary of scenarios used for re-entry assessment 52 Table 15—Post-application activities assessed for 500 g/L procymidone products 53 Table 16—Post-application exposure estimates after use of 500 g/L procymidone products 54 Table 17—MOE for workers using 500 g/L procymidone products 56 Table 18—MOE* for workers exposed to procymidone from using the products listed in table 5 in seed treatment for onions, lupins and pre-plant garlic clove treatment 59 Table 19—Recommended applications and PPE for procymidone products as of October 2017 60 Table 20—Post-application activity MOE for workers after use of the 500 g/L procymidone products 61 Table 21—Summary of days after treatment for post-application activities (500 g/L procymidone products) 63 Table 22—Precautionary/hazard statements and PPE indicated from acute hazard associated with the use of the 500 g/L procymidone products 64 Table 23—First Aid Instructions for all procymidone products 65 Table 24—Safety Directions for all procymidone products 65 Table 25—Systemic exposure estimates for procymidone for children playing on turf following application of the 500 g/L products 71 Table 26—MOE* estimates for procymidone for children playing on turf following application of the 500 g/L products 71 Table 27—Excretion of radioactivity in urine and faeces 91 Table 28—Levels of 14C-procymidone related radioactivity in blood or tissues 92 Table 29—Metabolites in blood, urine and faeces 93 Table 30—Excretion of radioactivity in urine and faeces 95 Table 31—Metabolites in urine and faeces 96 Table 32—Levels of 14C-radioactivity in blood, urine and faeces 99 Table 33—Toxicokinetic parameters of radioactivity in plasma (n=4) 101 Table 34—Cumulated excretions of radioactivity in urine and faeces (% of dose) 101 Table 35—Major metabolites