When Animal Testing Is DIM D ifficult , I mpossible, M eaningless

1. When Animal Testing IsDIMDifficult, Impossible,Meaningless Chad B. Sandusky, Ph.D. Physicians Committee for Responsible Medicine, Washington DC, USA

2. EPA’s High Production Volume(HPV) Program • High production volume chemicals (>1,000,000 pounds per year) • Assess existing hazard data • Assess and fill data “gaps” • No risk assessment (limited exposure considerations)

3. ENDPOINT GUIDELINE ANIMALS Acute toxicity to fish OECD 203 40-120 Acute lethality-oral OECD 425 3-10 Repeat dose-28 or 90 days OECD 407 OECD 408 40-65 Combined reproduction/ developmental screen OECD 421 675 Combined repeat dose/ reproduction/developmental screen OECD 422 675 Animal Tests Required TOTAL: 750 – 800 up to 2000 animals; hundreds of thousands of dollars

4. Examples of Current Animal Welfare Principles • Use in vitrogenotoxicity versus in vivo unless impossible • No repeat dose/reproductive testing neededfor closed system intermediates • Maximize use of existing data • Use weight-of-evidence to avoid “checklist toxicology” • Use SAR to form chemical categories and extrapolate between members

5. Extended HPV Program • Original program ended in 2005 • EHPV initiated in 2006 • PCRM has worked with ACC to develop expanded Animal Welfare Guidelines • Based on experience from review of hundreds of HPV test plans and in context of goals of a hazard screening program • Specific examples provided below

6. Specific Strategy Examples 1. Highly Reactive Materials Aluminum alkyls • Highly reactive to air and water • Supported by physical-chemical properties • No mammalian nor ecotoxicity feasible • Testing is Difficult

7. Specific Strategy Examples 2. Acidic/Corrosive/Irritating Materials Benzene and Hydroxybenzene sulfonic acid • Strong acids • Completely ionized in aqueous environment • Expected to cause localized corrosive effects in GI tract • EPA agreed that mammalian testing would not yield “Meaningful” results

8. Specific Strategy Examples 3. Rapid Hydrolysis Triisopropyl borate (TIPB) • Rapidly hydrolyzes to boric acidand isopropanol in aqueous environment • EPA agreed to accept bench hydrolysis study at stomach acid pH = 1.2 • Rapid hydrolysis to well studied products could be used to meet SIDS • No additional animal testing required

9. Summary of Strategies • Highly reactive materials • Acidic/Corrosive/Irritating materials • Rapid hydrolysis to well characterized materials • Others include • Data from analogs • Weight-of-evidence • Gases • 40 chemical-specific examples and counting, reducing numbers of animals by the thousands • Reduced dermal testing using data from in vitro percutaneous absorption studies (OECD 428)