Document nmRVMGpB9kqoV57vv0ZN7413a

i AiLZ 2 6 _ loi I P rl U?o<?-7 Toxicology and Descriptive Biology APFO Key Elements Data Exists Key Findings T53 o-3"HO)f'nfV""'rJi,' S J -*2;' Acute Toxicity Low to moderate toxicity oral/dermal/inhalation Irritation potential defined Not a sensitizer Repeated Dose Toxicity x Oral/dermal/inhalation rodent/non-rodent Liver primary target organ ko xz~o'0 CO Developmental Toxicity x Potency defined Oral/inhalation rat/rabbit cn Fetus not more sensitive than maternal Not associated with structural anomalies iu-uu ytu Contain 1 f Toxicology and Descriptive Biology APFO Key Elements Reproductive Toxicity Data Exists - Genetic Toxicity x Hcotoxicity - Acute x Key Findings Reproductive organs not a target Functional reproduction not defined Point mutation - Ames negative Chromosomal effects - in vivo, in vitro - negative Not a genotoxic agent Not acutely toxic to fish - invertebrates (Daphnia) - algae X Toxicology and Descriptive Biology APFO M ulti-generation Reproduction Study in Rats The objective of this study is evaluate the effect of APFO on the gonadal function, conception, parturition, and the growth and development of offspring of male and female rats over 2 generations involving the production of at least one set of litters in each generation. Work Plan - Initiated 11/00; first litters bom and currently in lactational phase. Result - Dose levels 1, 3, 10, and 30 mg/kg. Body weight effects - Males - 3 to 30 mg/kg Females - No obvious effects b APFO Pharmacokinetic Studies ADME Mass Balance: Rats Protein Binding: Rat/Man PBK Modeling: Rat/Man (Initiated 2Q 2001; estimated completion all portions 4Q/2002) 4- AFFO Pharmacokinetic Studies Project Element: ADME/Mass Balance Objective: To determine APFO absorption, distribution, metabolism and elimination following single and repeated doses in rats. Product: GLP ADME/Mass Balance report Payoff: Ability to use a scientifically defensible basis for development and validation of PBPK model r APFO Pharmacokinetic Studies Project Element: Protein Binding Objective: To determine the extent and type of APFO binding in rats and humans. Product: Manuscript/report describing species and gender-specific binding to proteins. Payoff: Ability to qualitatively and quantitatively compare APFO binding in rats and humans. G APFO Pharmacokinetic Studies Project Element: PBK Modeling Objective: To develop rat and human PBK models for APFO. Product: Manuscript/report describing PBK model development and application to APFO kinetics in rats and humans. Payoff: Ability to quantitatively relate APFO exposure to APFO concentration in the body. To understand how APFO effects in rats translated to man. 7 APFO Environmental Fate and Effects Studies Focus on: Physical Properties Environmental Fate Environmental Effects Bioconcentration % f APFO Environmental Fate and Effects Studies Physical - Chemical Properties APFO Molecular Weight Boiling/Melting Point Vapor Pressure Water Solubility Log Kow (octanol - water partition) Adsorption/Desorption onto glassware x x In progress In progress To be determined problematic, 3 plus phases Measure 3 APFO Environmental Fate and Effects Studies Environmental Fate Biodegradation: Completed; not biodegradable, OECD methodology Adsorption/Desorption: Sediment/sludge to be determined j 10 APFO Environmental Fate and Effects Studies Environmental Effects Chronic Toxicity: 21 Day Daphnia - Complete 90 Day Early Life Stage Study (Rainbow Trout) - to be conducted 1 Aquatic Chronic Toxicity Studies APFO Objective: The purpose of these tests is to determine the chemical concentrations that are associated with long-term chronic effects (NOEC, LOEC) on survival, growth and reproduction of a fish (rainbow trout) and an aquatic invertebrate (Daphnia) - Completed. Includes acute limit test Dose response, analytical confirmation of test concentrations Results: Assesses effects on survival, growth (length, weight), and Daphnid reproduction i% S um m ary o f w ork plan TOXICOLOGY1 Multigeneration reproduction PHARMACOKINETICS Mass balance--Rats Protein binding--Rat/M an PBK Modeling--Rat/M an Environmental Physical Properties Vapor Pressure Water Solubility - Log Kow Adsorption to Surfaces (Glass) Sediment/ S ludge-- Adsorption/ D esorption Effects--Chronic Toxicity--Trout Bioconcentration-- initial Assessment 1 1/ 0 0 to 3 Q /0 2 2 Q /0 1 TO 2 Q / 0 2 2 Q /0 1 TO 4 Q / 0 2 2 Q /0 1 TO 4 Q / 0 2 1Q / 0 1 TO 4 Q / 0 1 COMPLETED BY 4 Q / 0 2 C ompleted by 4 Q /0 2 1Q /01 to 2 Q /0 1 ij