Document zd2rGxdNn583OBLQmY388Xzoz

: 5p AR 226 _ 10] MR U2 "Toxicology and Descriptive Biology Key Elements Acute Toxicity Data Exists x Repeated Dose Toxicity x Developmental Toxicity x Key Findings Ei - a2 Low to moderate toxicity: oral/dermal/inhalation Irritation potential defined Not a sensitizer Oral/dermal/inhalation rodent/non-rodent Liver primary target organ Potency defined Oral/inhalation rat/rabbit = = s 3% ~~ = Z- 58 8 Fetus not more sensitive than maternal Nanootmaaslsioecsiated with structural - "nntain NO CBI | Toxicology and Descriptive Biology Key Elements Reproductive Toxicity Genetic Toxicity Ecotoxicity - Acute Data Exists - x 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 2 Toxicology and Descriptive Biology i APFO Multi-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 born 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 3 APFO Pharmacokinetic Studies * ADME Mass Balance: Rats * Protein Binding: Rat/Man + PBK Modeling: Rat/Man (Initiated 2Q 2001; estimated completion all portions 4Q/2002) uw APFO 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 . s 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. 6 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 " 8 } 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 ' 9 APFO Environmental Fate and Effects Studies Environmental Fate Biodegradation: Completed; not biodegradable, OECD methodology Adsorption/Desorption: Sediment/sludge to be determined 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 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 ofa 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 12 SUMMARY OF WORK PLAN A -------------------- = ToxicoLoay: = MULTIGENERATION REPRODUCTION PHARMACOKINETICS == PMRAOSTSEIBNALBAINNCDEI--NRGA--TRSAT/MAN = PBK MODELING--RAT/MAN 11/00703Q/02 o 220Q//0011170024Q0//0022 | 2Q/01 1040/02 ENVPIHRYOSNIMCEANLTAPLROPERTIES == VWAaPrOeRr PSRoELSuSaUiLRTEy - Lock, = SEDIME=NTA/DSSOLRUPDTGIEO--NATDOSOSRUFRTFIACOENS/D(EGLSAOSRSP)TION "= EBFIFOECCOTNSCE--NCTHRRAOTNIIONC--TIoNIXTIICAMLYA--STSREOSUSTMENT 1Q/01 70 4/01 CCoommppLLeeTTeenDBBYY 4400//0022 12/01 7020/01 - 13