Endocrine Screening – Phase 1 TSCA 8(e) and FIFRA 6(a)(2) Requirements A. Michael Kaplan, Ph.D. December 13, 2010 A. Michael Kaplan & Associates, LLC

Chemicals Selected by EPA for Phase 1 Endocrine Screening Tier 1 EPA prioritized and selected 67 chemicals for the initial phase 58 – Active ingredient pesticides 9 – HPV substances reportedly used as inerts in pesticide formulations Caution: While the TSCA vs FIFRA jurisdictions may seem obvious, confirm that none of the active ingredient pesticides are listed on the TSCA inventory – if so, then there may be a dual reporting obligation.

Tier 1 Battery 5 in vitro Assays Androgen Receptor Binding (Rat Prostate) Aromatase (Human Recombinant) Estrogen Receptor Binding Estrogen Receptor Transcriptional Activation (Human Cell Line – Hela-9903) Steroidogenesis (Human Cell Line – H295R)

Tier 1 Battery 6 in vivo Assays Amphibian Metamorphosis (Frog) Fish Short-Term Reproduction Hershberger (Rat) Female Pubertal (Rat) Male Pubertal (Rat) Uterotrophic (Rat)

Timeframe for Reporting as specified in the Federal Food, Drug, and Cosmetic Act (FFDCA) Order While the testing orders were issued pursuant to the FFDCA, the results must be submitted to the Office of Pesticide Programs (OPP), U.S. Environmental Protection Agency (EPA) A Progress Report is due within 12 months from the Order’s issuance date While you may submit Study Reports as they are generated, you must submit the final Study Report and submission of the data to EPA within 24-months of the FFDCA Order issuance date EPA has developed standard data evaluation formats or templates that must be used for all study submissions (see test order for details) Failure to comply with any of the requirements in the Order may result in fines of $37,500 per day (TSCA) or suspension and possibly cancellation of registration (FIFRA)

TSCA Section 8(e) TSCA 8(e) requires that “any person who manufactures, (including imports), processes or distributes in commerce a chemical substance or mixture and who obtains information which reasonably supports the conclusion that such substance or mixture presents a substantial risk of injury to health or the environment shall immediately inform the Administrator (EPA) of such information unless such person has actual knowledge that the Administrator has been adequately informed of such information.”

TSCA Section 8(e) continued The reporting time period starts when any officer or employee of the Company who is capable of appreciating the significance of the information receives the data Reporting must be done within 30 calendar days Failure to report within this timeframe could result in fines of $37,500 per day

FIFRA Section 6(a)(2) FIFRA Section 6(a)(2) requires “If at any time after registration of a pesticide, the registrant has additional factual information regarding unreasonable adverse effects on the environment of the pesticide, he shall submit such information to the Administrator.” The reporting time period for submitting study results varies from 30 calendar days for serious adverse effects or completed studies, to 90 days or 1 year for incomplete studies depending on whether the studies are short-term (testing less than 90-days) or long-term studies (testing more than 90 days). Fines for failure to report appear to be variable.

Reporting Requirements under TSCA 8(e) and FIFRA 6(a)(2) On May 13, 1997, the Chemical Manufacturers Assoc., CMA (now the American Chemistry Council, ACC) pressed EPA for clarification of reporting requirements under TSCA 8(e) concerning the reportability of SAR, HTP screens and in vitro assays for endocrine effects. Guidance to-date has been limited to FR Vol. 63. No. 248, Monday, December 28, 1998 Notice page (ED Screening Program Statement of Policy – Notice)

Reporting Requirements under TSCA 8(e) and FIFRA 6(a)(2) continued “Based on the current state of the science, EPA considers the results of ED in vitro screening assays to be indicators of potential endocrine activity.” Further, “results from in vitro assays may suggest some mechanisms of endocrine activity.” “Thus the results of these in vitro assays are arguably within the scope of TSCA 8(e) and FIFRA 6(a)(2). At this time, however, EPA can not conclude that the results of these in vitro assays translate into an understanding of particular health or environmental hazards and risks in vivo.”

Reporting Requirements under TSCA 8(e) and FIFRA 6(a)(2) continued “Therefore, based on the current state of knowledge, EPA will not, at this time (1998), require submissions of TSCA 8(e) or FIFRA 6(a)(2) reports containing only the results of these in vitro assays.” “Registrants, manufacturers or importers are nevertheless, encouraged to submit the data voluntarily.” “If these test results are included with other information reportable under TSCA 8(e) or FIFRA 6(a)(2), then they must be reported.” ACC requested further clarification from EPA on the above highlighted issues in February 1999 and to the best of my knowledge, has not received any additional clarification.

Reporting Requirements under TSCA 8(e) and FIFRA 6(a)(2) continued EPA issued a FR Notice – Vol. 74 No. 71, Wednesday April 15, 2009 page (ED Screening Program – Policies and Procedures for Initial Screening). This FR Notice did not repeat the guidance from the previous 1998 FR Notice, nor clarify the questions raised. However, EPA in this second Notice did state that it does not require duplicative submission of EDSP results under TSCA 8(e) or FIFRA 6(a)(2). Any information submitted under TSCA or FIFRA does not need to be submitted again to satisfy the test order. Instead, manufacturers should cite to the previously submitted information.

Reporting under TSCA 8(e) and FIFRA 6(a)(2) -Summary- Based on guidance to date: – Positive in vitro assay results are not reportable under TSCA 8(e) and FIFRA 6(a)(2) timelines. – Positive in vivo assays (statistically or biologically significant findings suggestive of possible endocrine involvement; also see TSCA 8(e) guidance on the EPA web site) should be considered for reporting under the TSCA 8(e) and FIFRA 6(a)(2) timelines. – If submitting positive in vivo data and a Company/consortium has positive in vitro data, they should submit the information together. – While EPA has said they would use a weight-of-evidence to interpret the results from the full Tier 1 Battery, weight-of-evidence should not be used in deciding whether or not to report under TSCA 8(e) and FIFRA 6(a)(2).

Reporting under TSCA 8(e) and FIFRA 6(a)(2) -Summary continued- Under TSCA 8(e), one is required to notify EPA of the findings (most submissions are in the form of a letter); you are not required to send a copy of the final report. However, the EDSP Test Order requires a specific format and the complete final report. Under FIFRA 6(a)(2) companies are required to submit the final report. Decisions on how to report will be up to the Company or Consortium to decide.

Reporting under TSCA 8(e) and FIFRA 6(a)(2) -Summary continued- If a Company/Consortium chooses to submit individual study reports as they are generated to EPA according to the procedures articulated in the testing order, including the special format, and are submitted within the TSCA 8(e) 30 day timeframe, then the EPA Administrator is considered to have been adequately informed and a separate TSCA 8(e) filing would not be necessary. If a Company/Consortium decides to submit under TSCA 8(e) or FIFRA 6(a)(2) they should consider submitting according to the procedures articulated in the testing order, including the special format. Remember, duplicate submissions are not required.