NATIONAL REGISTRATION SCHEME FOR AGRICULTURAL AND VETERINARY CHEMICALS AUSTRALIA CHEMICAL REVIEW PROGRAM REVIEW OF THE MAMMALIAN TOXICOLOGY AND METABOLISM/TOXICOKINETICS OF METHAMIDOPHOS prepared by the Office of Chemical Safety of the Department of Health and Ageing Canberra The APVMA Review of Methamidophos TABLE OF CONTENTS ABBREVIATIONS ............................................................................................................................................... 4 EXECUTIVE SUMMARY ................................................................................................................................... 6 TOXICOLOGY HAZARD PROFILE ............................................................................................................... 7 SUMMARY TOXICOLOGY REPORT ............................................................................................................. 8 INTRODUCTION ................................................................................................................................................... 8 METABOLISM AND TOXICOKINETICS................................................................................................................... 8 ACUTE STUDIES ................................................................................................................................................ 10 SHORT-TERM REPEAT-DOSE STUDIES .............................................................................................................. 10 SUBCHRONIC STUDIES ...................................................................................................................................... 11 CHRONIC STUDIES............................................................................................................................................. 12 REPRODUCTIVE STUDIES ................................................................................................................................... 12 DEVELOPMENTAL STUDIES ............................................................................................................................... 13 GENOTOXICITY STUDIES ................................................................................................................................... 14 NEUROTOXICITY STUDIES ................................................................................................................................. 16 HAZARD ASSESSMENT .................................................................................................................................. 31 DISCUSSION ...................................................................................................................................................... 31 REPRODUCTION AND DEVELOPMENT .................................................................................................................. 33 NEUROTOXICITY ................................................................................................................................................. 33 DOSE LEVELS RELEVANT FOR RISK ASSESSMENT ............................................................................. 35 HUMAN EXPOSURE ........................................................................................................................................ 35 CONSIDERATION OF PUBLIC HEALTH STANDARDS ........................................................................... 35 APPROVAL STATUS ........................................................................................................................................... 35 ACCEPTABLE DAILY INTAKE ............................................................................................................................ 35 NDPSC CONSIDERATIONS ................................................................................................................................ 36 FIRST-AID INSTRUCTIONS ................................................................................................................................. 36 SAFETY DIRECTIONS ......................................................................................................................................... 36 RECOMMENDATIONS .................................................................................................................................... 38 MAIN TOXICOLOGY REPORT ..................................................................................................................... 40 1. INTRODUCTION ..................................................................................................................................... 40 1.1 HISTORY OF PUBLIC HEALTH CONSIDERATIONS IN AUSTRALIA .............................................................. 40 1.2 INTERNATIONAL TOXICOLOGY ASSESSMENTS ......................................................................................... 42 1.3 CHEMISTRY - ACTIVE CONSTITUENT ....................................................................................................... 45 1.4 PRODUCTS ............................................................................................................................................... 47 2. METABOLISM AND TOXICOKINETICS ........................................................................................... 48 2.1 RATS ....................................................................................................................................................... 48 2.3 RABBITS .................................................................................................................................................. 72 2.4 GOATS ..................................................................................................................................................... 73 2.5 MONKEYS ................................................................................................................................................ 80 2.6 HUMANS .................................................................................................................................................. 85 2.7 PROPOSED METABOLIC PATHWAY OF METHAMIDOPHOS IN THE RAT ........................................................ 93 3. ACUTE STUDIES ..................................................................................................................................... 94 3.1 ACTIVE CONSTITUENT ............................................................................................................................. 94 3.1.1 Median Lethal Dose Studies ......................................................................................................... 94 3.1.2 Skin Irritation Studies.................................................................................................................... 98 3.1.3 Eye Irritation Studies ................................................................................................................... 103 Not to be used for commercial or registration purposes without the consent of the owner of the cited information - 2 - Australian Pesticides & Veterinary Medicines Authority 3.1.4 Skin Sensitisation Studies ........................................................................................................... 107 3.2 METABOLITES/DEGRADATION PRODUCTS ............................................................................................. 113 4. SHORT-TERM REPEAT-DOSE STUDIES ......................................................................................... 114 4.1. ORAL ADMINISTRATION ................................................................................................................... 114 4.1.1 Rats.............................................................................................................................................. 114 4.2 DERMAL APPLICATION .......................................................................................................................... 119 4.2.1 Rats.............................................................................................................................................. 119 4.2.2 Rabbits ........................................................................................................................................ 122 4.3. INHALATIONAL ADMINISTRATION .................................................................................................... 125 4.3.1 Rats.............................................................................................................................................. 125 5. SUBCHRONIC STUDIES ...................................................................................................................... 135 5.1. ORAL ADMINISTRATION ................................................................................................................... 135 5.1.1 Mice ............................................................................................................................................ 135 5.1.2 Rats.............................................................................................................................................. 137 5.1.3 Dogs ............................................................................................................................................ 142 5.2 INHALATIONAL ADMINISTRATION .........................................................................................................