Status of the U.S. Endocrine Disruptor Screening Program (EDSP) Status of the U.S. Endocrine Disruptor Screening Program (EDSP) September

EPA’s Statutory Authority Federal Food, Drug, and Cosmetic Act (FFDCA) Federal Food, Drug, and Cosmetic Act (FFDCA) Requires EPA to: Requires EPA to: Develop a screening program using validated assays to identify chemicals that may have estrogenic effects in humans Develop a screening program using validated assays to identify chemicals that may have estrogenic effects in humans Test all pesticide chemicals (both active and inert ingredients) Test all pesticide chemicals (both active and inert ingredients) Authorizes EPA to obtain testing on: Authorizes EPA to obtain testing on: Other endocrine effects, as designated by the EPA Administrator (e.g., androgen and thyroid; endocrine effects in species other than humans) Other endocrine effects, as designated by the EPA Administrator (e.g., androgen and thyroid; endocrine effects in species other than humans) Other chemicals (non-pesticides) that: Other chemicals (non-pesticides) that: May have “an effect cumulative to that of a pesticide,” if a “substantial human population may be exposed” to the chemical May have “an effect cumulative to that of a pesticide,” if a “substantial human population may be exposed” to the chemical Safe Drinking Water Act (SDWA) Amendments Safe Drinking Water Act (SDWA) Amendments Allow EPA to require testing of chemical substances that may be found in sources of drinking water, if a substantial human population may be exposed to the substance Allow EPA to require testing of chemical substances that may be found in sources of drinking water, if a substantial human population may be exposed to the substance 2

EDSP Scope and Structure Established following recommendations of : The Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) of Estrogen, androgen and thyroid Estrogen, androgen and thyroid Human health, fish and wildlife Human health, fish and wildlife Pesticides, commercial chemicals, environmental contaminants Pesticides, commercial chemicals, environmental contaminants 3

EDSP Scope and Structure Two-Tiered Approach Two-Tiered Approach Tier 1 Tier 1 In vitro and in vivo screens In vitro and in vivo screens Detect potential to interact with endocrine system Detect potential to interact with endocrine system Tier 2 Tier 2 Tier 2 data called in only after review of Tier 1 data Tier 2 data called in only after review of Tier 1 data Multi-generation studies covering a broad range of taxa Multi-generation studies covering a broad range of taxa Provide data for hazard assessment Provide data for hazard assessment 4

Priority Setting Assay Validation Procedures EDSP Implementation  Assay Validation Development and validation of test assays Tier 1 screening & Tier 2 testing  Priority Setting Selecting chemicals to be screened  Procedures Developing procedures to require and administer EDSP data 5

Proposed EDSP Tier 1 Screening Battery In vitro Estrogen receptor (ER) binding – rat uterus Estrogen receptor α (hERα) transcriptional activation - Human cell line (HeLa-9903) [OECD Test Guideline 455] Androgen receptor (AR) binding – rat prostate Steroidogenesis – Human cell line (H295R) [US lead, validated in OECD program] Aromatase – Human recombinant In vivo Uterotrophic (rat) [OECD TG 440] Hershberger (rat) [OECD TG 441] Pubertal female (rat) Pubertal male (rat) Amphibian metamorphosis (frog) [OECD TG 231] Fish short-term reproduction [OECD TG 229] 6

Tier 2 Tests Mammalian two-generation rat (may be replaced by Extended F1-Generation) Avian reproduction (Japanese quail) [US lead, OECD validation program] Amphibian growth/reproduction (Xenopus) [US lead, OECD validation program] Fish life-cycle (medaka) [US lead, OECD validation program] Mysid life-cycle [US lead, OECD validation program]

SAP Battery Review Conclusions Chemicals testing positive in the battery of Tier 1 assays would be identified as potential estrogenic, androgenic and thyroid hormone active substances The ability to identify endocrine active substances is enhanced in the Tier 1 battery because the tests provide adequate replication and redundancy It was clear that the inclusion of apical assays of amphibian metamorphosis and fish short-term reproduction were important to detect endocrine active substances that may operate by mechanisms of action yet to be discovered The 15-day adult male assay proposed during some public comments would not be an appropriate substitute for the male and female pubertal assays because the pubertal assays provide for differences between the sexes and provide the only approach to testing for organizational- effects during development.

SAP Battery Review Recommendations Assays for ERß Assays for ERß Monitor only first estrus cycle Monitor only first estrus cycle Need validated ER antagonist assay Need validated ER antagonist assay Replace cytosolic assays with recombinant Replace cytosolic assays with recombinant Validate AR transactivation assay Validate AR transactivation assay Include perinatal developmental endpoints in Tier 1 if possible Include perinatal developmental endpoints in Tier 1 if possible Develop standardized procedures for hormone measurement Develop standardized procedures for hormone measurement Need to demonstrate a negative control in the pubertal assays Need to demonstrate a negative control in the pubertal assays Need new tests and endpoints for thyroid in Tier 1 Need new tests and endpoints for thyroid in Tier 1 New assay systems will be required for novel EAT mechanisms and other hormones New assay systems will be required for novel EAT mechanisms and other hormones

Priority Setting: First Chemicals to be Screened Issued the Final List of Chemicals for Initial Screening 15 April 2009 Issued the Final List of Chemicals for Initial Screening 15 April Pesticide actives 64 Pesticide actives 9 High ProductionVolume / pesticide inerts 9 High ProductionVolume / pesticide inerts Selection based on potential human exposure Selection based on potential human exposure Pesticide Active Ingredients: presence in food and water, residential use, and occupational contact Pesticide Active Ingredients: presence in food and water, residential use, and occupational contact HPV inerts in human and eco biomonitoring, water, air HPV inerts in human and eco biomonitoring, water, air Selected chemicals found in multiple exposure pathways. Selected chemicals found in multiple exposure pathways. Not a list of “known” or “likely” endocrine disruptors Not a list of “known” or “likely” endocrine disruptors 10

Policies & Procedures Orders EPA Intends to Issue Test Orders/DCIs EPA Intends to Issue Test Orders/DCIs Under FFDCA §408(p)(5) Under FFDCA §408(p)(5) Under FIFRA §3(c)(2)(B) Under FIFRA §3(c)(2)(B) Two Types of Orders (based on recipient) Two Types of Orders (based on recipient) Manufacturers and Importers Manufacturers and Importers Pesticide Registrants Pesticide Registrants 11

Test Orders Approximately 750 test orders will be issued for 67 chemicals. Approximately 750 test orders will be issued for 67 chemicals. Currently, EPA anticipates issuing test orders over several months period. Currently, EPA anticipates issuing test orders over several months period. Test Orders for chemicals will require all the assays in the Tier 1 battery. Test Orders for chemicals will require all the assays in the Tier 1 battery. Responses to Test Orders due 90 days from receipt Responses to Test Orders due 90 days from receipt Test data due 24 months from issuance of Test Order Test data due 24 months from issuance of Test Order 12

Possible Responses to Test Orders 1. I will generate new data. 2. I am citing existing data. 3. I am entering into an agreement to form a consortium to provide the data. 4. I am not subject to the Test Order. 5. I intend to voluntarily cancel the pesticide registration. 6. I intend to reformulate the product(s) to exclude this chemical from the formulation. 7. I am claiming a formulators’ exemption. 8. I have/am in the process of discontinuing the manufacture/import of this chemical. 9. I do not and will not sell my chemical for use as an inert ingredient to the pesticide market. 13

Next Steps Clearance of the Information Collection Request Clearance of the Information Collection Request Posting of final Test Method Protocols Posting of final Test Method Protocols Publication of final notice of Tier 1 Screening Battery Publication of final notice of Tier 1 Screening Battery Issuance of Test Orders Issuance of Test Orders Receipt of Responses Receipt of Responses Notification of Agency Decisions Notification of Agency Decisions 14

EDSP Timeline Proposed Chemical Selection Strategy Tier I Validation Tier II Development and Validation Development of Procedural Framework Initial List Final Tier I Screening Draft Initial List …