National Registration Authority for Agricultural and Veterinary Chemicals Section 4 EVALUATION OF THE MAMMALIAN TOXICOLOGY AND METABOLISM/TOXICOKINETICS ABBREVIATIONS.............................................................................................................................115 SUMMARY.........................................................................................................................................116 DISCUSSION......................................................................................................................................135 SUMMARY OF ACUTE TOXICOLOGY HAZARD.....................................................................147 MAIN TOXICOLOGY REPORT.....................................................................................................148 1. INTRODUCTION ......................................................................................................................148 1.1 Regulatory History of Health Considerations in Australia.............................................148 1.2 International Toxicology Assessments ..............................................................................152 1.3 Chemistry ............................................................................................................................154 1.4 End Use Products................................................................................................................154 2. METABOLISM AND TOXICOKINETICS ............................................................................155 2.1 Rat........................................................................................................................................155 2.2 Chicken ................................................................................................................................159 2.3 Goat......................................................................................................................................161 3. ACUTE TOXICITY ...................................................................................................................164 3.1 Technical-Grade Active Constituent.................................................................................164 3.1.1 Median Lethal Dose Studies.......................................................................................164 3.1.1.1 Oral, Dermal and Inhalational Studies .....................................................................166 3.1.1.2 Eye and Dermal Irritancy and Sensitisation Studies ...............................................168 3.2 Acute Toxicity of Parathion-Methyl End Use Products ..................................................169 3.2.1 Parathion-methyl 4 1b EC..........................................................................................169 3.2.1.1 Oral, Dermal and Inhalational studies......................................................................170 3.2.1.2 Eye and Dermal Irritancy & Sensitisation Studies ..................................................171 3.2.2 Parathion-methyl CS 240 g/L ....................................................................................172 3.2.2.1 Oral, Dermal and Inhalational Studies .....................................................................172 3.2.2.2 Eye and Dermal Irritancy & Sensitisation Studies ..................................................173 3.2.3 Parathion-methyl CS 450 g/L ....................................................................................174 3.2.3.1 Oral and Dermal Studies............................................................................................175 3.2.3.2 Eye and Dermal Irritancy & Sensitisation studies ...................................................176 3.2.4 Median Lethal Dermal Dose Study using "Flash 50\...............................................177 4. SHORT-TERM REPEAT-DOSE STUDIES............................................................................177 4.1 Dietary Administration to Mice for Four Weeks.............................................................177 4.2 Dermal Administration to Rats for One Month...............................................................178 4.3 Dermal Administration to Rabbits for Three Weeks.......................................................180 4.4 Dietary Administration to Dogs for Two Weeks..............................................................189 5. SUBCHRONIC TOXICITY ......................................................................................................190 5.1 Mouse...................................................................................................................................190 5.1.1 Dietary Administration for Three Months ...............................................................190 5.1.2 Dietary Administration for Two Months..................................................................191 5.2 Rat........................................................................................................................................195 5.2.1 Dietary Administration for Three Months ...............................................................195 5.3 Dog .......................................................................................................................................197 113 Not to be used for commerical or registration purposes without prior consent of the owners of cited information NRA Review of Parathion-methyl - Toxicology Assessment 5.3.1 Gavage Administration for Three Months ...............................................................197 5.3.2 Dietary Administration for Three Months ...............................................................197 6. CHRONIC TOXICITY..............................................................................................................201 6.1 Mouse...................................................................................................................................201 6.1.1 Dietary Administration for Two Years.....................................................................201 6.2 Rat........................................................................................................................................204 6.2.1 Dietary Administration for One Year.......................................................................204 6.2.2 Dietary Administration for Two Years.....................................................................211 6.3 Dog .......................................................................................................................................220 6.3.1 Dietary Administration for One Year.......................................................................220 7. REPRODUCTIVE TOXICITY .............................................................................................223 7.1 Rat........................................................................................................................................223 7.1.1 Two-Generation Dietary Study .................................................................................223 7.1.2 Three-Generation Dietary Study...............................................................................225 7.2 Mouse Sperm Morphology Assay......................................................................................227 8. DEVELOPMENTAL TOXICITY.............................................................................................228 8.1 Mouse...................................................................................................................................228 8.1.1 Intraperitoneal Teratology Study..............................................................................228 8.2 Rat........................................................................................................................................229 8.2.1 Intraperitoneal Teratology Study..............................................................................229 8.2.2 Intravenous Teratology Study ...................................................................................230 8.2.3 Gavage Teratology Studies ........................................................................................230 8.3 Rabbit ..................................................................................................................................234 8.3.1 Gavage Teratology Studies ........................................................................................234 9. GENOTOXICITY ......................................................................................................................236 9.1 Gene Mutation Assays........................................................................................................236 9.2 Chromosomal Effects..........................................................................................................238 9.3 Other Genotoxic Effects .....................................................................................................242 9.4 Published Genotoxicity Reviews........................................................................................244 10. SPECIAL STUDIES ...............................................................................................................245 10.1 Acute Neurotoxicity............................................................................................................245 10.1.1 Rat................................................................................................................................245