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15176-Fipronil-Prf-Vol2-Toxicology.Pdf AUSTRALIAN PESTICIDES AND VETERINARY MEDICINES AUTHORITY AUSTRALIA CHEMICAL REVIEW PROGRAM REVIEW OF THE MAMMALIAN TOXICOLOGY AND METABOLISM/TOXICOKINETICS OF FIPRONIL prepared by Office of Chemical Safety & Environmental Health Office of Health Protection of the Department of Health and Ageing Canberra Finalised May 2007 Amended May 2009 Amended September 2009 TABLE OF CONTENTS TABLES ............................................................................................................................................................................ 5 ABBREVIATIONS ........................................................................................................................................................... 7 EXECUTIVE SUMMARY .............................................................................................................................................. 9 TOXICOLOGY HAZARD PROFILE OF FIPRONIL .............................................................................................. 10 SUMMARY TOXICOLOGY REPORT ...................................................................................................................... 12 INTRODUCTION ............................................................................................................................................................. 12 ABSORPTION, DISTRIBUTION, METABOLISM AND EXCRETION ..................................................................................... 12 ACUTE STUDIES ............................................................................................................................................................ 15 SHORT-TERM REPEAT-DOSE STUDIES .......................................................................................................................... 17 SUBCHRONIC STUDIES .................................................................................................................................................. 18 CHRONIC/CARCINOGENICITY STUDIES ......................................................................................................................... 18 REPRODUCTION STUDY ................................................................................................................................................ 20 DEVELOPMENTAL STUDIES ........................................................................................................................................... 20 GENOTOXICITY STUDIES............................................................................................................................................... 20 NEUROTOXICITY STUDIES ............................................................................................................................................ 21 METABOLITE STUDIES .................................................................................................................................................. 22 OTHER STUDIES ............................................................................................................................................................ 28 HAZARD ASSESSMENT.............................................................................................................................................. 30 TOXICOLOGICAL RESULTS FOR RISK ASSESSMENT ..................................................................................... 40 HUMAN EXPOSURE .................................................................................................................................................... 44 DIET ............................................................................................................................................................................. 44 WATER ......................................................................................................................................................................... 44 NON-DIETARY EXPOSURE CONSIDERATIONS ................................................................................................................. 44 CONSIDERATION OF PUBLIC HEALTH STANDARDS ...................................................................................... 45 APPROVAL STATUS ....................................................................................................................................................... 45 IMPURITY LIMITS .......................................................................................................................................................... 45 RESIDUE DEFINITION .................................................................................................................................................... 45 ACCEPTABLE DAILY INTAKE (ADI).............................................................................................................................. 46 ACUTE REFERENCE DOSE (ARFD) ............................................................................................................................... 46 DRINKING WATER QUALITY GUIDELINES .................................................................................................................... 46 RESOLUTIONS OF THE ADVISORY GROUP ON CHEMICAL SAFETY ................................................................................. 47 POISONS SCHEDULING .................................................................................................................................................. 47 FIRST-AID INSTRUCTIONS ............................................................................................................................................. 47 SAFETY DIRECTIONS..................................................................................................................................................... 47 RECOMMENDATIONS ............................................................................................................................................... 53 MAIN TOXICOLOGY REPORT ................................................................................................................................. 56 1 INTRODUCTION ................................................................................................................................................. 56 HISTORY OF PUBLIC HEALTH CONSIDERATIONS IN AUSTRALIA ..................................................................... 56 1.2 INTERNATIONAL TOXICOLOGY ASSESSMENTS ............................................................................................... 59 1.3 CHEMISTRY – TECHNICAL ACTIVE ................................................................................................................. 62 1.4 PRODUCTS ...................................................................................................................................................... 64 2 METABOLISM AND TOXICOKINETICS....................................................................................................... 64 2.1 MICE .............................................................................................................................................................. 64 2.2 RATS .............................................................................................................................................................. 65 2.3 COMPARATIVE STUDIES .................................................................................................................................. 70 2.4 DERMAL ABSORPTION (FORMULATIONS) ........................................................................................................ 75 3. ACUTE STUDIES ................................................................................................................................................. 80 3.1 ACTIVE CONSTITUENT.................................................................................................................................... 80 3.1.1 Median Lethal Dose Studies ..................................................................................................................... 80 3.1.2 Skin Irritation ............................................................................................................................................ 82 Not to be used for commercial or registration purposes without the consent of the owner of the cited information -2- 3.1.3 Eye Irritation ............................................................................................................................................. 82 3.1.4 Skin Sensitisation ...................................................................................................................................... 83 3.2 METABOLITES/DEGRADATION PRODUCTS...................................................................................................... 84 3.2.1 MB 46513 (desulfinyl fipronil) ................................................................................................................. 84 3.2.2 MB 45950 (fipronil sulfide) ...................................................................................................................... 85 3.2.3 MB 46136 (fipronil sulfone) ..................................................................................................................... 86 3.2.4 Other metabolites (oral toxicity) ..............................................................................................................
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