Innovative Alternatives to Animal Testing for Chemical Assessment

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)