Priority-setting for the Endocrine Disruptor Screening Program: Pesticide Active Ingredients Penelope A. Fenner-Crisp Office of Pesticide Programs U.S. Environmental Protection Agency

Food Quality Protection Act Mandates EPA MUST: –Screen pesticides (both actives and others) for estrogenic effects that may affect human health ( may include other effects) –Develop a screening and testing program by August 1998 –Implement the screening and testing program by August 1999 –Report to Congress by August 2000

Proposed Implementation Strategy Current Size of the Universe –~~ 950 pesticide active ingredients currently registered in U.S. –~~ 450 have uses on food/feed –(~~ 2500 “other” ingredients (inerts))

Proposed Implementation Strategy Proposed elements of the strategy –Issue exemptions –Sort and prioritize “other” (inert) ingredients using the EDPSDB –Revise 40 CFR 158 to include EDSP –Run Pilot program with active ingredient substances –Issue orders periodically for groups of substances

Proposed Implementation Strategy Exemptions- –Issue exemptions for those “biological substance(s) or other substance(s) …. anticipated not to produce any effect in humans similar to an effect produced by a naturally occurring estrogen” or other such endocrine effect…. –Would cover both active and other (inert) ingredients

EPA’s ENDOCRINE DISRUPTOR SCREENING PROGRAM Currently-registered “Other” Ingredients (Inerts) SORT Category 1: Hold All other Chemicals HTPS Category 2: Insufficient Data, Set Priorities for Tier 1 Screening Tier 2 Testing Hazard Assessment Category 4: Adequate Data Category 3: Need Tier 2 Test Data Total Universe of Chemicals Est 87,000 Commercial Chemicals < 10,000 lbs Production Polymers Exempted Chemicals

Proposed Implementation Strategy Currently-registered Other Ingredients –Formerly known as inerts –Will be sorted for priority along with other substances using the EDPSDB –Special attention will be given to overlap with chemicals also on TSCA inventory, especially those identified for the HPV and Children’s Chemical Evaluation programs

EPA’s ENDOCRINE DISRUPTOR SCREENING PROGRAM To-be-registered Pesticides-Actives and Others SORT Category 1: Hold All other Chemicals HTPS Category 2: Insufficient Data, Set Priorities for Tier 1 Screening Hazard Assessment Tier 1 Screening Tier 2 Testing Category 4: Adequate Data Category 3: Need Tier 2 Test Data Total Universe of Chemicals Est 87,000 Commercial Chemicals < 10,000 lbs Production Polymers Exempted Chemicals

Proposed Implementation Strategy: To-Be-Registered Active and Other Ingredients Amendment of 40 CFR 158 to include EDSP components Requirements may vary with class and use pattern, e.g., –Requirements may or may not apply at all –Requirements may be required prospectively or triggered

EPA’s ENDOCRINE DISRUPTOR SCREENING PROGRAM Already-registered Pesticide Actives SORT Category 1: Hold All other Chemicals HTPS Category 2: Insufficient Data, Set Priorities for Tier 1 Screening Tier 2 Testing Hazard Assessment Category 4: Adequate Data Category 3: Need Tier 2 Test Data Total Universe of Chemicals Est 87,000 Commercial Chemicals < 10,000 lbs Production Polymers Exempted Chemicals

Part 158 Toxicology Data Requirements- Human Health Acute oral toxicity Acute dermal Acute inhalation Primary eye irritation Primary dermal irritation Dermal sensitization 2 Subchronic feeding studies 2 Chronic feeding studies 2 Carcinogenicity studies 2 Prenatal developmental toxicity studies Two-generation reproduction study General metabolism study Mutagenicity studies Dermal penetration 21-day dermal toxicity study Subchronic inhalation or dermal study (2 Immunotoxicity studies) Acute or subchronic delayed neurotoxicity Acute neurotoxicity study Subchronic or chronic neurotoxicity Developmental neurotoxicity Scheduled controlled operant behavior Peripheral nerve function Sensory evoked potential

Part 158 Toxicology Data Requirements- Ecological Effects Avian and Mammalian Species Avian oral LD50 Avian dietary LC50 Wild mammal toxicity Avian reproduction Simulated and actual field testing Aquatic Organisms Freshwater fish LC50 Acute LC50 freshwater invertebrates Acute LC50 estuarine and marine organisms Fish early life stage and aquatic invertebrate life cycle Fish life cycle Aquatic organism accumulation Simulated or actual field testing

Already-registered Pesticide Actives Category 3: Need Tier 2 Test Data Tier 2 Testing: 2-Generation Study Designs Category 4 Adequate Data Hazard Assessment Category 3/4 Have Adequate Data pre-EDSP, But Need Refinement of Toxicity Profile for EAT Potential Tailored testing: Screens Less Comprehensive tests Special Studies

PROPOSED SCREENING BATTERY (Tier 1) In vitro Screens –ER Binding / Reporter Gene Assay –AR Binding / Reporter Gene Assay –Steroidogenesis Assay with minced testis In vivo Screens –Rodent 3-day Uterotrophic Assay (sc) –Rodent 20-day Pubertal Female Assay with Thyroid –Rodent 5-7 day Hershberger Assay –Frog Metamorphosis Assay –Fish Gonadal Recrudescence Assay

SCREENING BATTERY EXAMPLE 1 In vitro Screens –ER Binding or Reporter Gene Assay* –AR Binding or Reporter Gene Assay* –Placental aromatase + –Steroidogenesis Assay with minced testis # In vivo Screens –Rodent 3-day Uterotrophic Assay (sc) –Rodent 20-day Pubertal Male Assay with Thyroid + –Rodent 20-day Pubertal Female Assay w/ Thyroid # –Rodent 5-7 day Hershberger Assay # –Frog Metamorphosis Assay –Fish Reproduction Screening Assay + Assays in yellow may replace assays in red #

SCREENING BATTERY EXAMPLE 2 In vitro Screens –ER Binding or Reporter Gene Assay* –AR Binding or Reporter Gene Assay* –Steroidogenesis Assay with minced testis # In vivo Screens –Rodent 3-day Uterotrophic Assay (sc) # –In-utero Assay + –Rodent 20-day Pubertal Female Assay w/ Thyroid # –Rodent 5-7 day Hershberger Assay # –Frog Metamorphosis Assay –Fish Reproduction Screening Assay + Assay in yellow may replace assays in red #

TIER 2 TESTING BATTERY Multi-generation studies of reproduction and development in: –Mammals –Birds –Fish –Invertebrates –Amphibians

TIER 2 TESTING BATTERY: LESS COMPREHENSIVE TESTS Alternative or Single-generation studies of reproduction and development in: –Mammals (Alternative test could be in utero assay described in Screening Battery Example #2) –Birds –Fish –Invertebrates –Amphibians

Proposed Implementation Strategy: Already-Registered Active Ingredients Original Proposal –Implement EDSP on timetable for FIFRA Reregistration and/or FQPA Tolerance Reassessment mandates

Proposed Implementation Strategy: Already-Registered Active Ingredients Current Proposal- –Phase 1- Pilot Program with “potentially high EAT hazard concern” substances –Later Phases Periodic issuance of FFDCA Section 408p orders for additional substances May make use of EDPSDB May integrate with timetable for Registration Renewal

Proposed Implementation Strategy: Already-Registered Active Ingredients Selection process for Phase 1 –Will identify chemicals of potential concern from both a human health and ecological effects perspective using existing published hazard/risk assessments (e.g., REDs), internal databases, Data Evaluation Records (i.e., study reviews), open literature and expert scientific judgment

Summary: Proposed Implementation Strategy Issue exemptions Sort and prioritize “other” (inert) ingredients using EDPSDB Revise 40 CFR 158 to include EDSP (for to-be-registered substances) Run Pilot program for (already- registered) active ingredient substances Issue orders periodically for groups of (already-registered) substances