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
amkaplan1@comcast.net
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
•
•
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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 71564 (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 17560 (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.