[Federal Register Volume 88, Number 56 (Thursday, March 23, 2023)]
[Proposed Rules]
[Pages 17426-17429]
[FR Doc No: 2023-05668]

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DEPARTMENT OF TRANSPORTATION

Federal Aviation Administration

14 CFR Part 39

[Docket No. FAA-2023-0437; Project Identifier MCAI-2022-01358-E]
RIN 2120-AA64

Airworthiness Directives; Rolls-Royce Deutschland Ltd & Co KG
(Type Certificate Previously Held by Rolls-Royce plc) Turbofan Engines

AGENCY: Federal Aviation Administration (FAA), DOT.

ACTION: Notice of proposed rulemaking (NPRM).

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SUMMARY: The FAA proposes to supersede Airworthiness Directive (AD)
2021-26-13, which applies to all Rolls-Royce Deutschland Ltd & Co KG
(RRD) Trent 1000-A2, Trent 1000-AE2, Trent 1000-C2, Trent 1000-CE2,
Trent 1000-D2, Trent 1000-E2, Trent 1000-G2, Trent 1000-H2, Trent 1000-
J2, Trent 1000-K2, and Trent 1000-L2 model turbofan engines. AD 2021-
26-13 requires revision of the engine Time Limits Manual (TLM) life
limits of certain critical rotating parts and direct accumulation
counting (DAC) data files. Since the FAA issued AD 2021-26-13, RRD has
revised the TLM with more restrictive airworthiness limitations,
including updated life limits for certain critical parts and updated
DAC data files. This proposed AD would require revising the existing
approved maintenance or inspection program, as applicable, to
incorporate more restrictive airworthiness limitations, as specified in
a European Union Aviation Safety Agency (EASA) AD, which is proposed
for incorporation by reference (IBR). The FAA is proposing this AD to
address the unsafe condition on these products.

DATES: The FAA must receive comments on this NPRM by May 8, 2023.

ADDRESSES: You may send comments, using the procedures found in 14 CFR
11.43 and 11.45, by any of the following methods:
     Federal eRulemaking Portal: Go to regulations.gov. Follow
the instructions for submitting comments.
     Fax:<PHONE_NUMBER>.
     Mail: U.S. Department of Transportation, Docket
Operations, M-30, West Building Ground Floor, Room W12-140, 1200 New
Jersey Avenue SE, Washington, DC 20590.
     Hand Delivery: Deliver to Mail address above between 9
a.m. and 5 p.m., Monday through Friday, except Federal holidays.
    AD Docket: You may examine the AD docket at regulations.gov under
Docket No. FAA-2023-0437; or in person at Docket Operations between 9
a.m. and 5 p.m., Monday through Friday, except Federal holidays. The AD
docket contains this NPRM, the mandatory continuing airworthiness
information (MCAI), any comments received, and other information. The
street address for Docket Operations is listed above.
    Material Incorporated by Reference:
     For EASA service information identified in this NPRM,
contact EASA, Konrad-Adenauer-Ufer 3, 50668 Cologne, Germany; phone:
+49 221 8999 000; email: [email protected]; website: easa.europa.eu.
You may find this material on the EASA website at ad.easa.europa.eu.
     You may view this service information at the FAA,
Airworthiness Products Section, Operational Safety Branch, 1200
District Avenue, Burlington, MA 01803. For information on the
availability of this material at the FAA, call<PHONE_NUMBER>.

FOR FURTHER INFORMATION CONTACT: Sungmo Cho, Aviation Safety Engineer,
ECO Branch, FAA, 1200 District Avenue, Burlington, MA 01803; phone:
(781) 238-7241; email: [email protected].

SUPPLEMENTARY INFORMATION:

Comments Invited

    The FAA invites you to send any written relevant data, views, or
arguments about this proposal. Send your comments to an address listed
under ADDRESSES. Include ``Docket No. FAA-2023-0437; Project Identifier
MCAI-2022-01358-E'' at the beginning of your comments. The most helpful
comments reference a specific portion of the proposal, explain the
reason for any recommended change, and include supporting data. The FAA
will consider all comments received by the closing date and may amend
this proposal because of those comments.
    Except for Confidential Business Information (CBI) as described in
the following paragraph, and other information as described in 14 CFR
11.35, the FAA will post all comments received, without change, to
regulations.gov, including any personal information you provide. The
agency will also post a report summarizing each substantive verbal
contact received about this NPRM.

Confidential Business Information

    CBI is commercial or financial information that is both customarily
and actually treated as private by its owner. Under the Freedom of
Information Act (FOIA) (5 U.S.C. 552), CBI is exempt from public
disclosure. If your comments responsive to this NPRM contain commercial
or financial information that is customarily treated as private, that
you actually treat as private, and that is relevant or responsive to
this NPRM, it is important that you clearly designate the submitted
comments as CBI. Please mark each page of your submission containing
CBI as ``PROPIN.'' The FAA will treat such marked submissions as
confidential under the FOIA, and they will not be placed in the public
docket of this NPRM. Submissions containing CBI should be sent to
Sungmo Cho, Aviation Safety Engineer, ECO Branch, FAA, 1200 District
Avenue, Burlington, MA 01803. Any commentary that the FAA receives that
is not specifically designated as CBI will be placed in the public
docket for this rulemaking.

Background

    The FAA issued AD 2021-26-13, Amendment 39-21872 (86 FR 72840,
December 23, 2021) (AD 2021-26-13), for all RRD Trent 1000-A2, Trent
1000-AE2, Trent 1000-C2, Trent 1000-CE2, Trent 1000-D2, Trent 1000-E2,
Trent 1000-G2, Trent 1000-H2, Trent 1000-J2, Trent 1000-K2, and Trent
1000-L2 model turbofan engines. AD 2021-26-13 was prompted by an MCAI
originated by EASA, which is the Technical Agent for the Member States
of the European Union. EASA issued AD 2020-0241, dated November 5,
2020, to correct an unsafe condition identified as the manufacturer
revising the engine TLM life limits of certain critical rotating parts,
updating the direct accumulation counting data files, and updating
certain maintenance tasks.
    AD 2021-26-13 requires operators to update the airworthiness
limitations section (ALS) of their approved maintenance and inspection
program by incorporating the latest revision of the engine TLM life
limits of certain critical rotating parts and updating DAC data files
for each affected model turbofan engine. The FAA issued AD 2021-26-13
to prevent the failure of critical rotating parts.

Actions Since AD 2021-26-13 Was Issued

    Since the FAA issued AD 2021-26-13, EASA superseded EASA AD 2020-
0241 and issued EASA AD 2022-0210, dated October 17, 2022 (EASA AD
2022-0210) (referred to after this as the MCAI). The MCAI states that
the manufacturer published a revised TLM introducing new or more
restrictive tasks and limitations. These new or more restrictive tasks
and limitations include updating declared lives of certain critical
parts and updating DAC data files.
    You may examine the MCAI in the AD docket at regulations.gov under
Docket No. FAA-2023-0437.

Related Service Information Under 1 CFR Part 51

    The FAA reviewed EASA AD 2022-0210. EASA AD 2022-0210 specifies
instructions for accomplishing the actions specified in the applicable
TLM, including performing maintenance tasks, replacing life-limited
parts, and revising the existing approved maintenance or inspection
program, as applicable, by incorporating the limitations, tasks, and
associated thresholds and intervals described in the TLM. This material
is reasonably available because the interested parties have access to
it through their normal course of business or by the means identified
in ADDRESSES.

FAA's Determination

    These products have been approved by the aviation authority of
another country, and are approved for operation in the United States.
Pursuant to the FAA's bilateral agreement with the State of Design
Authority, it has notified the FAA of the unsafe condition described in
the MCAI described above. The FAA is issuing this NPRM after
determining that the unsafe condition described previously is likely to
exist or develop in other products of the same type design.

Proposed AD Requirements in This NPRM

    This proposed AD would retain none of the requirements of AD 2021-
26-13. This proposed AD would require revising the existing approved
maintenance or inspection program, as applicable, to incorporate more
restrictive airworthiness limitations, which are specified in EASA AD
2022-0210, and is also proposed for incorporation by reference. Any
differences with EASA AD 2022-0210 are identified as exceptions in the
regulatory text of this AD and discussed under ``Differences Between
this Proposed AD and the MCAI.''

Differences Between This Proposed AD and the MCAI

    Where paragraph (3) of EASA AD 2022-0210 specifies revising the
approved Aircraft Maintenance Programme within 12 months after the
effective date of EASA AD 2022-0210, this proposed AD would require
revising the ALS of the existing approved maintenance or inspection
program, as applicable, within 90 days after the effective date of this
AD.

Explanation of Required Compliance Information

    In the FAA's ongoing efforts to improve the efficiency of the AD
process, the FAA developed a process to use some civil aviation
authority (CAA) ADs as the primary source of information for compliance
with requirements for corresponding FAA ADs. The FAA has since
coordinated with other manufacturers and CAAs to use this process. As a
result, the FAA proposes to incorporate by reference EASA AD 2022-0210
in the FAA final rule. This proposed AD would, therefore, require
compliance with EASA AD 2022-0210 in its entirety through that
incorporation, except for any differences identified as exceptions in
the regulatory text of this proposed AD. Using common terms that are
the same as the heading of a particular section in the EASA AD does not
mean that operators need comply only with that section. For example,
where the AD requirement refers to ``all required actions and
compliance times,'' compliance with this AD requirement is not limited
to the section titled

``Required Action(s) and Compliance Time(s)'' in EASA AD 2022-0210.
Service information required by the EASA AD for compliance will be
available at regulations.gov by searching for and locating Docket No.
FAA-2023-0437 after the FAA final rule is published.

Costs of Compliance

    The FAA estimates that this AD, if adopted as proposed, would
affect 32 engines installed on airplanes of U.S. registry.
    The FAA estimates the following costs to comply with this proposed
AD:

                                                 Estimated Costs
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                                                                                Cost per       Cost on U.S.
               Action                        Labor cost           Parts cost        product         operators
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Revise the continuous airworthiness   1 work-hours x $85 per               $0              $85           $2,720
 maintenance program.                  hour = $85.
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Authority for This Rulemaking

    Title 49 of the United States Code specifies the FAA's authority to
issue rules on aviation safety. Subtitle I, section 106, describes the
authority of the FAA Administrator. Subtitle VII: Aviation Programs,
describes in more detail the scope of the Agency's authority.
    The FAA is issuing this rulemaking under the authority described in
Subtitle VII, Part A, Subpart III, Section 44701: General requirements.
Under that section, Congress charges the FAA with promoting safe flight
of civil aircraft in air commerce by prescribing regulations for
practices, methods, and procedures the Administrator finds necessary
for safety in air commerce. This regulation is within the scope of that
authority because it addresses an unsafe condition that is likely to
exist or develop on products identified in this rulemaking action.

Regulatory Findings

    The FAA determined that this proposed AD would not have federalism
implications under Executive Order 13132. This proposed AD would not
have a substantial direct effect on the States, on the relationship
between the national Government and the States, or on the distribution
of power and responsibilities among the various levels of government.
    For the reasons discussed above, I certify this proposed
regulation:
    (1) Is not a ``significant regulatory action'' under Executive
Order 12866,
    (2) Would not affect intrastate aviation in Alaska, and
    (3) Would not have a significant economic impact, positive or
negative, on a substantial number of small entities under the criteria
of the Regulatory Flexibility Act.

List of Subjects in 14 CFR Part 39

    Air transportation, Aircraft, Aviation safety, Incorporation by
reference, Safety.

The Proposed Amendment

    Accordingly, under the authority delegated to me by the
Administrator, the FAA proposes to amend 14 CFR part 39 as follows:

PART 39--AIRWORTHINESS DIRECTIVES

0
1. The authority citation for part 39 continues to read as follows:

    Authority:  49 U.S.C. 106(g), 40113, 44701.

Sec.  39.13  [Amended]

0
2. The FAA amends Sec.  39.13 by:
0
a. Removing Airworthiness Directive 2021-26-13, Amendment 39-21872 (86
FR 72840, December 23, 2021);
0
b. Adding the following new AD:

Rolls-Royce Deutschland Ltd & Co KG: Docket No. FAA-2023-0437;
Project Identifier MCAI-2022-01358-E.

(a) Comments Due Date

    The FAA must receive comments on this airworthiness directive
(AD) by May 8, 2023.

(b) Affected ADs

    This AD replaces AD 2021-26-13, Amendment 39-21872 (86 FR 72840,
December 23, 2021).

(c) Applicability

    This AD applies to Rolls-Royce Deutschland Ltd & Co KG (Type
Certificate previously held by Rolls-Royce plc) Trent 1000-A2, Trent
1000-AE2, Trent 1000-C2, Trent 1000-CE2, Trent 1000-D2, Trent 1000-
E2, Trent 1000-G2, Trent 1000-H2, Trent 1000-J2, Trent 1000-K2, and
Trent 1000-L2 model turbofan engines, all serial numbers.

(d) Subject

    Joint Aircraft System Component (JASC) Code 7200, Engine
(Turbine/Turboprop).

(e) Unsafe Condition

    This AD was prompted by the manufacturer revising the engine
Time Limits Manual life limits of certain critical rotating parts,
updating the direct accumulation counting data files, and updating
certain maintenance tasks. The FAA is issuing this AD to prevent the
failure of critical rotating parts. The unsafe condition, if not
addressed, could result in failure of one or more engines, loss of
thrust control, and loss of the airplane.

(f) Compliance

    Comply with this AD within the compliance times specified,
unless already done.

(g) Required Actions

    Except as specified in paragraph (h) of this AD: Perform all
required actions within the compliance times specified in, and in
accordance with, European Union Aviation Safety Agency (EASA) AD
2022-0210, dated October 17, 2022 (EASA AD 2022-0210).

(h) Exceptions to EASA AD 2022-0210

    (1) Where EASA AD 2022-0210 defines the AMP as the approved
Aircraft Maintenance Programme on the basis of which the operator or
the owner ensures the continuing airworthiness of each operated
engine, this AD defines the AMP as the Aircraft Maintenance Program
on the basis of which the operator or the owner ensures the
continuing airworthiness of each operated airplane.
    (2) Where EASA AD 2022-0210 refers to its effective date, this
AD requires using the effective date of this AD.
    (3) This AD does not require compliance with paragraph (1) of
EASA AD 2022-0210.
    (4) This AD does not require compliance with paragraph (2) of
EASA AD 2022-0210.
    (5) Where paragraph (3) of EASA AD 2022-0210 specifies revising
the approved AMP within 12 months after the effective date of EASA
AD 2022-0210, this AD requires revising the existing approved
maintenance or inspection program, as applicable, and airworthiness
limitations section within 90 days after the effective date of this
AD.
    (6) This AD does not adopt the ``Remarks'' paragraph of EASA AD
2022-0210.

(i) Provisions for Alternative Actions and Intervals

    After performing the actions required by paragraph (g) of this
AD, no alternative actions and associated thresholds and intervals,
including life limits, are allowed unless they are approved as
specified in the provisions of the ``Ref. Publications'' section of
EASA AD 2022-0210.

(j) Alternative Methods of Compliance (AMOCs)

    The Manager, ECO Branch, FAA, has the authority to approve AMOCs
for this AD, if requested using the procedures found in 14

CFR 39.19. In accordance with 14 CFR 39.19, send your request to
your principal inspector or responsible Flight Standards Office, as
appropriate. If sending information directly to the manager of the
certification office, send it to the attention of the person
identified in paragraph (k) of this AD and email to: [email protected]. Before using any approved AMOC, notify your
appropriate principal inspector, or lacking a principal inspector,
the manager of the local flight standards district office/
certificate holding district office.

(k) Additional Information

    For more information about this AD, contact Sungmo Cho, Aviation
Safety Engineer, ECO Branch, FAA, 1200 District Avenue, Burlington,
MA 01803; phone:<PHONE_NUMBER>; email: [email protected].

(l) Material Incorporated by Reference

    (1) The Director of the Federal Register approved the
incorporation by reference (IBR) of the service information listed
in this paragraph under 5 U.S.C. 552(a) and 1 CFR part 51.
    (2) You must use this service information as applicable to do
the actions required by this AD, unless this AD specifies otherwise.
    (i) European Union Aviation Safety Agency AD 2022-0210, dated
October 17, 2022.
    (ii) [Reserved]
    (3) For EASA AD 2022-0210, contact EASA, Konrad-Adenauer-Ufer 3,
50668 Cologne, Germany; phone: +49 221 8999 000; email:
[email protected]; website: easa.europa.eu. You may find this EASA
AD on the EASA website at ad.easa.europa.eu.
    (4) You may view this service information at the at the FAA,
Airworthiness Products Section, Operational Safety Branch, 1200
District Avenue, Burlington, MA 01803. For information on the
availability of this material at the FAA, call<PHONE_NUMBER>.
    (5) You may view this material that is incorporated by reference
at the National Archives and Records Administration (NARA). For
information on the availability of this material at NARA, email:
[email protected], or go to: www.archives.gov/federal-register/cfr/ibr-locations.html.

    Issued on March 14, 2023.
Christina Underwood,
Acting Director, Compliance & Airworthiness Division, Aircraft
Certification Service.
[FR Doc. 2023-05668 Filed 3-22-23; 8:45 am]
BILLING CODE 4910-13-P


[Federal Register Volume 86, Number 154 (Friday, August 13, 2021)]
[Notices]
[Pages 44731-44736]
[FR Doc No: 2021-17378]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2020-N-1245]

Drug Products Approved in Abbreviated New Drug Applications
Before the Enactment of the Hatch-Waxman Amendments; Establishment of a
Public Docket; Request for Comments

AGENCY: Food and Drug Administration, Health and Human Services (HHS).

ACTION: Notice; establishment of a public docket; request for comments.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing
the establishment of a public docket to solicit comments on several
issues related to FDA's post-approval regulation of certain drug
products approved in abbreviated applications before the Drug Price
Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman
Amendments) amended the Federal Food, Drug, and Cosmetic Act (FD&C Act)
to establish the current abbreviated new drug application (ANDA)
process. Because these pre-Hatch-Waxman abbreviated new drug
applications (referred to in this notice as ``PANDAs'') were submitted
and approved under the provisions of the FD&C Act that apply to 505(b)
new drug applications, they can serve as a reference listed drug (RLD)
for ANDAs and can also be a listed drug relied on by 505(b)(2)
applications. PANDAs have historically been overseen by FDA's Office of
Generic Drugs, and FDA is aware that there may be some confusion about
the applicability of certain statutory and regulatory provisions to
PANDAs. FDA is seeking input from holders of PANDAs and other
interested persons regarding whether there are regulatory or policy
rationales for treating PANDAs differently from other 505(b)
applications in certain respects.

DATES: Submit either electronic or written comments by December 13,
2021.

ADDRESSES: FDA is establishing a docket for public comments on this
document. The docket number is FDA-2020-N-1245. The docket will close
on December 13, 2021. Submit either electronic or written comments by
that date. Please note that late, untimely filed comments will not be
considered. Electronic comments must be submitted on or before December
13, 2021. The https://www.regulations.gov electronic filing system will
accept comments until 11:59 p.m. Eastern Time at the end of December
13, 2021. Comments received by mail/hand delivery/courier (for written/
paper submissions) will be considered timely if they are postmarked or
the delivery service acceptance receipt is on or before that date.
    You may submit comments as follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:

     Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No.
FDA-2020-N-1245 for ``Drug Products Approved in Abbreviated New Drug
Applications Before the Enactment of the Hatch-Waxman Amendments;
Establishment of a Public Docket; Request for Comments.'' Received
comments, those filed in a timely manner (see ADDRESSES), will be
placed in the docket and, except for those submitted as ``Confidential
Submissions,'' publicly viewable at https://www.regulations.gov or at
the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through
Friday,<PHONE_NUMBER>.
     Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852,<PHONE_NUMBER>.

FOR FURTHER INFORMATION CONTACT: Melissa Mannion, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 75, Room 1611, Silver Spring, MD 20993, 301-796-
2747<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION:

I. Background

A. Abbreviated New Drug Applications Before the Hatch-Waxman Amendments

    After the enactment of the FD&C Act (Pub. L. 75-717) in 1938, new
drug products were required to be approved on the basis of safety
before they could be marketed. Between 1938 and 1962, if a drug product
obtained approval, FDA considered drug products that were identical,
related, or similar to the approved product to be covered by that
approval; such identical, related, or similar products were marketed
without independent approval. An identical, related, or similar drug
includes another brand, potency, dosage form, salt, or ester of the
same drug moiety related in chemical structure or known pharmacological
properties (see 21 CFR 310.6(b)(1)). In 1962, the Kefauver-Harris Drug
Amendments (Pub. L. 87-781) amended the FD&C Act to require that new
drug products also be shown to be effective in order to obtain approval
of a new drug application (NDA). After the enactment of the Kefauver-
Harris Drug Amendments, FDA initiated the Drug Efficacy Study
Implementation (DESI) to evaluate the effectiveness of drug products
that had been approved between 1938 and 1962 solely on the basis of
safety. DESI also covered the identical, related, or similar products
that had entered the market without approval. If drug products were
determined to be effective for one or more indications,\1\
manufacturers that were already marketing under an NDA were required to
submit a supplement to update the application and revise the product
labeling as necessary. Manufacturers of drug products that were
identical, related, or similar were required to submit applications for
their drug products.
---------------------------------------------------------------------------

    \1\ If a drug product was found to be less than effective for
one or more labeled indications in FDA's initial DESI review, the
Agency provided an opportunity to submit additional data and
eventually an opportunity for a hearing on those indications found
to be less than effective. FDA considered the basis of any hearing
request and either granted or denied the hearing request and
published its final determination in the Federal Register. If FDA's
final determination classified a drug product as effective for an
indication, those marketing that drug product and drugs identical,
related or similar to it were required to obtain approved
applications for continued marketing for that indication. If FDA's
final determination classified the drug product as lacking
substantial evidence of effectiveness for an indication, the product
and those identical, related or similar to it could no longer be
legally marketed for that indication.
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    FDA introduced the concept of an ``abbreviated new drug
application'' in 1968 \2\ as a vehicle for approval of certain drugs
affected by the DESI review, and in 1970, FDA published a final rule
establishing a regulatory pathway for submission of abbreviated
applications for these drugs (see 35 FR 6574 (April 24, 1970); see also
34 FR 2673 (February 27, 1969)). This abbreviated approval mechanism
was created to offer manufacturers of certain drugs a streamlined and
more administratively efficient path to seek FDA approval as part of
the DESI review (47 FR 46622 at 46631 to 46632 (October 19, 1982)).
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    \2\ See the Washington briefing on FDA's drug efficacy review,
FDA Papers, at pp. 10-12 (March 1968) and Address of Commissioner
James L. Goddard, M.D., at the Alpha Omega Alpha Lecture at Yale New
Haven Medical Center on New Drug Research and Development (April 17,
1968).
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    When a drug product subject to the DESI review was determined to be
effective for one or more indications, FDA would issue a Federal
Register notice (DESI notice) for that drug product describing the DESI
review findings and stating whether abbreviated new drug applications
that met specified criteria could be submitted to FDA (see generally 35
FR 11273 (July 14, 1970); 35 FR 6574) for products that had not been
marketed under an NDA. Such a finding allowed manufacturers to submit
an abbreviated new drug application (i.e., a PANDA) in lieu of an NDA.
    For approval of PANDAs, FDA relied on the evidence of effectiveness
that had been provided, reviewed, and accepted during the DESI process.
FDA evaluated the safety of these drug products on the basis of
information included in NDAs submitted prior to 1962, as well as the
subsequent marketing experience with the drugs (see 54 FR 28872 at
28873 (July 10, 1989)). PANDAs were submitted under section 505(b) of
the FD&C Act and approved under section 505(c) of the FD&C Act.\3\
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    \3\ The content of section 505(b) of the FD&C Act regarding the
required contents of an application remained largely unchanged
following the enactment of the Hatch-Waxman Amendments, except for
changes related to new patent submission requirements and, for
applications submitted pursuant to section 505(b)(2) of the FD&C
Act, patent certification requirements.

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    Because the history of FDA review of applications for antibiotic
drug products is more complex and historically many were subject to
section 507 of the FD&C Act (21 U.S.C. 357 (1994 ed.); repealed upon
the enactment of the Food and Drug Administration Modernization Act of
1997 (Pub. L. 105-115)), the scope of this notice is limited to drug
products approved in PANDAs under section 505 of the FD&C Act prior to
the Hatch-Waxman Amendments; this notice does not cover applications
for antibiotic drug products that were originally submitted under
section 507 of the FD&C Act.\4\
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    \4\ Prior to the enactment of the Food and Drug Administration
Modernization Act of 1997, applications for antibiotic drugs were
generally approved for safety and effectiveness under section 507 of
the FD&C Act rather than under section 505 of the FD&C Act. For
purposes of section 507, the term ``antibiotic drug'' was defined as
any drug intended for use by man containing any quantity of any
chemical substance which is produced by a microorganism and which
has the capacity to inhibit or destroy microorganisms in dilute
solution (including the chemically synthesized equivalent of any
such substance). See 21 U.S.C. 357 (1964 ed.; 1994 ed.). Although
there was a mechanism for approving abbreviated applications for
antibiotics under section 507 that pre-dated the Hatch-Waxman
Amendments, in this notice the term PANDAs refers only to those
applications submitted under section 505(b) of the FD&C Act, and not
to applications for antibiotic drug products submitted under section
507 of the FD&C Act. FDA intends to address these antibiotic
products separately.
---------------------------------------------------------------------------

    Because PANDAs could be for products that were ``similar or
related'' to, and not just ``duplicates'' \5\ of, drug products
approved in NDAs before October 10, 1962, and listed in DESI notices
(pre-1962 NDA drug products), FDA's ``Approved Drug Products With
Therapeutic Equivalence Evaluations'' (Orange Book) lists both unique
products approved in PANDAs (i.e., no NDA was ever approved for the
identical drug product), and products approved in PANDAs that may be
duplicates of pre-1962 NDA drug products. In the Orange Book, a product
approved in a PANDA typically is identified as an ``ANDA.'' (The
application type for a product is identified in the Orange Book by
either an ``N'' (for an NDA) or an ``A'' (for an ANDA) before the
application number.)
---------------------------------------------------------------------------

    \5\ In the context of PANDAs, the term `duplicate' applied to a
drug product that was the same as an already approved drug product
in dosage form, route of administration, kind and amount of active
ingredient, indication(s), and any other conditions of use. See 54
FR 28872 at 28872 (July 10, 1989).
---------------------------------------------------------------------------

    Although the regulations establishing the pathway for PANDAs were
similar in some respects to the ANDA pathway created by the Hatch-
Waxman Amendments and described in section 505(j) of the FD&C Act, the
requirements under the old regulatory pathway (which evolved over the
decade-plus in which it was operational before the Hatch-Waxman
Amendments) also differed in many respects from current ANDA
requirements. For example, although the conditions of use and labeling
for PANDA products had to be in accord with the relevant DESI notice
(which frequently covered a class of drugs that included multiple
products and multiple active ingredients) (see, e.g., 36 FR 11227 (June
10, 1971); 35 FR 18215 (November 28, 1970); and 35 FR 12356 (August 1,
1970)), PANDA products were not required to have the same labeling as a
particular pre-1962 NDA drug product listed in the DESI notice. In
addition, although PANDAs were required to include adequate data to
assure biological availability of the drug if the relevant DESI notice
for that drug specified that such data should be submitted for the
formulation intended for marketing, PANDAs generally did not have to
include data to demonstrate bioequivalence to a particular pre-1962 NDA
drug product (see, e.g., 21 CFR 130.4(f)(3) (1971 ed.) and 21 CFR
314.2(f)(3) (1984 ed.)). In addition, drug products with a different
formulation, active ingredient, route of administration, dosage form,
or strength than the pre-1962 NDA drug products listed in the DESI
notice could be submitted in PANDAs. Prior to the Hatch-Waxman
Amendments, there were also no requirements related to patent listing
or patent certification or exclusivity for PANDAs or other applications
approved under section 505(c) of the FD&C Act.

B. Hatch-Waxman Amendments

    In 1984, the Hatch-Waxman Amendments added section 505(b)(2) and
section 505(j) to the FD&C Act. These sections provide an abbreviated
approval pathway for submission of two types of applications: Section
505(b)(2) new drug applications (505(b)(2) applications) and section
505(j) abbreviated new drug applications (for purposes of this notice,
referred to hereinafter as ``505(j) ANDAs''). A 505(b)(2) application
is an NDA submitted under section 505(b)(1) and approved under section
505(c) of the FD&C Act that contains full reports of investigations of
safety and effectiveness, where at least some of the information
required for approval comes from studies not conducted by or for the
applicant and for which the applicant has not obtained a right of
reference or use (e.g., the Agency's finding of safety and/or
effectiveness for a listed drug). A 505(j) ANDA is an application that
requests FDA approval to market a duplicate of a listed drug.\6\
Regulations implementing the Hatch-Waxman Amendments define a listed
drug as a new drug product that has been approved under section 505(c)
of the FD&C Act for safety and effectiveness or under section 505(j) of
the FD&C Act, which has not been withdrawn or suspended under section
505(e)(1) through (5) or section 505(j)(6) of the FD&C Act, and which
has not been withdrawn from sale for what FDA has determined are
reasons of safety or effectiveness. Listed drug status is evidenced by
the drug product's identification in the current edition of FDA's
``Approved Drug Products With Therapeutic Equivalence Evaluations''
(the list) as an approved drug. A drug product is deemed to be a listed
drug on the date of approval for the NDA or ANDA for that drug product.
(See Sec.  314.3(b) (21 CFR 314.3(b)), as amended at 81 FR 69580 at
69638 (October 6, 2016); see also section 505(j)(2)(A), (j)(7) of the
FD&C Act).
---------------------------------------------------------------------------

    \6\ In the context of the Hatch-Waxman Amendments, the term
duplicate generally refers to a ``drug product that has the same
active ingredient(s), dosage form, strength, route of
administration, and conditions of use as a listed drug . . .'' 54 FR
28872 at 28877.
---------------------------------------------------------------------------

    FDA regulations require an applicant to refer in its 505(j) ANDA to
the specific listed drug on which the applicant relies in seeking
approval of the 505(j) ANDA (Sec.  314.94(a)(3) (21 CFR 314.94(a)(3));
see also section 505(j)(2) of the FD&C Act). The listed drug that a
generic applicant seeks to duplicate is commonly referred to as the
reference listed drug (RLD) (see definition in Sec.  314.3(b)). A
505(j) ANDA applicant must show, among other things, that the proposed
generic drug is bioequivalent to the RLD, and that it has the same
active ingredient(s), conditions of use, route of administration,
dosage form, strength, and (with limited exceptions) labeling as the
RLD (section 505(j)(2)(A), (j)(2)(C), and (j)(4) of the FD&C Act; see
also Sec.  314.94(a)). We note that certain differences between an RLD
and a proposed generic drug product may be permitted in an ANDA if
these differences are the subject of an approved suitability petition
(see section 505(j)(2)(C) of the FD&C Act and 21 CFR 314.93). An
applicant may submit a suitability petition to FDA requesting
permission to submit an ANDA for a generic drug product that differs
from an RLD in its route of administration, dosage form, or strength or
that has one different active ingredient in a fixed-combination drug
product (ibid.).
    Because a 505(j) ANDA applicant is relying on FDA's finding that
the RLD

is safe and effective, FDA's general practice is to designate as RLDs
drug products that have been approved under section 505(c) for safety
and effectiveness. Similarly, FDA regulations require a 505(b)(2)
applicant to identify in its application each listed drug for which FDA
has made a finding of safety and effectiveness on which the applicant
relies in seeking approval of its proposed drug product (21 CFR
314.54(a)(1)(iii)).
    Listed drugs appear in the Orange Book, and beginning in 1992, the
Orange Book also began identifying which listed drugs were designated
as RLDs to aid 505(j) ANDA applicants. The listed drugs that were
designated as RLDs were labeled with a ``+'' sign in the paper version
of the Orange Book, and with the word ``Yes'' in the column titled RLD
in the electronic version of the Orange Book. Before 2017, the ``+''
sign and the word ``Yes'' in the column labeled RLD were used to denote
at times an RLD and at other times a reference standard, which is the
drug product selected by FDA that an applicant seeking approval of a
505(j) ANDA must use in conducting an in vivo bioequivalence study
required for approval of the ANDA (Sec.  314.3(b)).
    The reference standard selected by FDA is ordinarily the RLD.
However, at times the reference standard is a drug product other than
the RLD. For example, if the NDA RLD is no longer marketed, FDA
generally will select as the reference standard a previously approved
505(j) ANDA that refers to that RLD. Where the RLD was no longer
marketed and FDA selected a new reference standard, FDA's practice
prior to 2017 was to identify the reference standard with the ``+''
sign in the paper version of the Orange Book and ``Yes'' in the RLD
column of the electronic version of the Orange Book; FDA also would
move the previously identified RLD to the discontinued section of the
Orange Book without a ``+'' sign in the paper version or RLD
designation in the electronic version of the Orange Book.
    Because the ``+'' sign or RLD designation in some cases identified
drug products that were RLDs as well as reference standards, and in
other cases identified reference standards that were not also the RLD,
there may have been some confusion among 505(j) ANDA applicants about
which product to cite as the RLD when the reference standard and RLD
were not the same drug product. Inconsistent use of terminology, as
well as certain long-standing FDA practices, may have added to this
confusion.

C. FDA's Current Identification of RLDs and Reference Standards in the
Orange Book

    In 2017, FDA began to separately identify in the Orange Book which
listed drugs, including some in the ``Discontinued Drug Product List''
(discontinued section), are designated as RLDs, and which listed drugs
in the Active Section (i.e., in the sections entitled ``Prescription
Drug Product List'' and ``Over-the-Counter Drug Product List'') are
selected as reference standards. In the electronic version of the
Orange Book, there is one column that identifies RLDs and a separate
column that identifies reference standards. In the printed version of
the Orange Book, the RLDs and reference standards are identified by
distinct symbols.
    These changes to the Orange Book were intended to provide clarity
to 505(j) ANDA applicants as to which listed drugs are the RLDs (versus
the reference standards) for a drug product. For some drug products,
however, these changes revealed that no product is identified as being
approved under an NDA (in either the active or discontinued sections of
the Orange Book) that could serve as an RLD for a 505(j) ANDA. The lack
of an RLD is confusing because the Orange Book reflects that there are
approved ANDAs for the drug product, including ANDAs identified as
reference standards. One reason for this lack of an RLD is that some of
the products listed in the Orange Book and identified as being approved
in an ``ANDA'' are actually drugs that were approved for safety and
effectiveness under section 505(c) of the FD&C Act in PANDAs that
appeared to have been identified as RLDs before the 2017 update to the
Orange Book. As noted previously, products approved in PANDAs could be
unique products that differed from products approved under pre-1962
NDAs in various ways, including in their active ingredient, route of
administration, dosage form, or strength. In addition, even when
certain listed drugs approved in a PANDA appear to be pharmaceutical
equivalents (as defined in Sec.  314.3(b)) of products approved under
an NDA, these products can differ from the products approved under the
NDA in other respects, including in the approved conditions of use
reflected in the labeling or in their formulation, and may not have
been determined to be bioequivalent to the products approved under an
NDA. Further, even if the drug product approved in a PANDA was a
duplicate of a drug product that was at one time also approved and
marketed under an NDA, if the product approved under the NDA was no
longer marketed when the Orange Book was first published in October
1980, it was not listed in the Orange Book.

D. Designation of Additional Drugs as RLDs

    In light of the changes to the Orange Book in 2017, FDA examined
the types of products for which there were no RLDs designated and
determined that many were approved in PANDAs. After consideration of
the history of PANDAs, FDA determined that it was appropriate and
consistent with FDA's general practice regarding the designation of
RLDs to designate PANDA products as RLDs because these products were
approved for safety and effectiveness under section 505(c) of the FD&C
Act. In addition, as noted in section I.C, many of these products
appeared to have been identified as RLDs before the 2017 update to the
Orange Book. Designation of the PANDA products as RLDs provides clarity
both to prospective 505(j) ANDA applicants seeking to make generic
versions of these products, and to applicants of 505(b)(2) applications
that there is a finding of safety and effectiveness for these products
that may be relied upon for approval. In addition, it is aligned with
FDA's efforts to help advance competition and increase patient access
to more affordable medicines.
    FDA has begun adding RLD designations for PANDAs to the Orange Book
and will continue making these designations as expeditiously as
resources permit. If a prospective 505(j) ANDA applicant is seeking to
duplicate a product approved in a PANDA that has not yet been
designated as an RLD by FDA, the prospective applicant may submit
controlled correspondence to FDA identifying the drug it intends to
duplicate and asking FDA to designate that drug as an RLD (see FDA's
guidance for industry, ``Controlled Correspondence Related to Generic
Drug Development,'' announced in 85 FR 81928 (December 17, 2020)).\7\
---------------------------------------------------------------------------

    \7\ For the most recent version of a guidance, check the FDA
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.
---------------------------------------------------------------------------

    To aid stakeholders in identifying PANDAs, FDA has posted a list of
the products currently included in the Orange Book and identified as an
``ANDA'' in the Orange Book that were approved in a PANDA for safety
and effectiveness under section 505(c) prior to the enactment of the
Hatch-Waxman Amendments. This list includes only PANDAs described in
this notice, i.e.,

those abbreviated applications submitted under section 505(b) of the
FD&C Act and does not include applications for antibiotic drug products
approved under section 507 of the FD&C Act before the enactment of the
Food and Drug Administration Modernization Act of 1997 (FDAMA). This
list is available under ``Additional Resources'' on FDA's ``Approved
Drug Products with Therapeutic Equivalence Evaluations (Orange Book)''
web page (available at https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book). In addition, the Orange Book provides information about
the approval date of listed drugs,\8\ allowing interested persons to
refer to this information to determine which products identified as
being approved in an ANDA in the Orange Book were approved before the
enactment of the Hatch-Waxman Amendments.\9\
---------------------------------------------------------------------------

    \8\ For products approved prior to January 1, 1982, the
electronic version of the Orange Book indicates the product was
``Approved Prior to Jan. 1, 1982'' under Product Details in the
Approval Date field, and the printed version of the Orange Book has
a blank Approval Date field. For products approved on or after
January 1, 1982, the electronic and printed versions of the Orange
Book provide the specific date of approval in the Approval Date
field.
    \9\ The Hatch-Waxman Amendments were signed into law on
September 24, 1984. PANDAs that were submitted before September 24,
1984, were processed by FDA in accordance with the procedures that
existed before the passage of the Hatch-Waxman Amendments. See
November 16, 1984, letter to interested persons from Harry M. Meyer,
Jr., M.D., Director, FDA's Center for Drugs and Biologics. The list
of PANDAs posted on FDA's Orange Book web page (https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book) includes all the
abbreviated applications approved on or before September 24, 1984.
FDA is aware that certain applications submitted before this date
but approved after this date and identified as ANDAs in the Orange
Book were approved under section 505(c) of the FD&C Act; FDA will
update this list as appropriate to include such applications. If a
prospective 505(j) ANDA applicant is seeking to duplicate a product
approved after September 24, 1984, and the applicant believes the
application for the product was submitted before that date and
approved under section 505(c) of the FD&C Act, the prospective
applicant may submit controlled correspondence to FDA identifying
the drug they intend to duplicate and asking FDA to designate that
drug as an RLD. The controlled correspondence should include any
information known to the prospective applicant that supports the
belief that the identified drug was approved in a PANDA. When FDA
receives such designation requests, it will evaluate whether the
product was approved under section 505(c) of the FD&C Act in
determining whether to grant the request.
---------------------------------------------------------------------------

II. Additional Issues for Consideration and Request for Comments

    The Agency is seeking input from holders of PANDAs and other
interested stakeholders on several issues related to FDA's post-
approval regulation of drug products approved in PANDAs. As explained
in section I of this notice, PANDAs were submitted under section 505(b)
and approved under section 505(c) of the FD&C Act, which are the same
provisions under which NDAs are submitted and approved. However, PANDA
products have historically been overseen by FDA's Office of Generic
Drugs and are included in the definition of abbreviated new drug
application for user fee purposes under the Generic Drug User Fee
Amendments (GDUFA),\10\ which specify that this term includes an
abbreviated new drug application submitted pursuant to regulations in
effect prior to the implementation of the Drug Price Competition and
Patent Term Restoration Act of 1984 (see 21 U.S.C. 379j-41). PANDAs are
not included in the FD&C Act statutory definition of the term
abbreviated drug application, which is limited to applications
submitted under section 505(j) of the FD&C Act (see 21 U.S.C. 321(aa)).
---------------------------------------------------------------------------

    \10\ See Title III of the Food and Drug Administration Safety
and Innovation Act (Pub. L. 112-144) and Title III of the FDA
Reauthorization Act of 2017 (Pub. L. 115-52).
---------------------------------------------------------------------------

    FDA recognizes that PANDAs may have been treated similarly to
505(j) ANDAs in some respects over the decades after the enactment of
the Hatch-Waxman Amendments, and that there may be confusion among
holders of PANDAs about the applicability of certain statutory and
regulatory provisions to their products and in particular, whether
their products are subject to the requirements that apply to other
505(b) applications or to those that apply to 505(j) applications (to
the extent there are differences between the two), including with
respect to requirements regarding labeling updates, patent listing,
eligibility for exclusivity, and certain drug safety-related
requirements or procedures.
    For example, with respect to labeling updates, FDA is aware that
some PANDA holders have followed procedures applicable to 505(b)
applications when proposing labeling updates for their products (e.g.,
submitting labeling supplements and making labeling changes independent
of the pre-1962 NDA product or products that were listed in the DESI
notice). However, FDA is also aware that some PANDA holders have
followed procedures applicable to 505(j) ANDA holders when proposing
labeling updates for their products (e.g., submitting labeling
supplements to conform to labeling changes approved for a pre-1962 NDA
product listed in a relevant DESI notice).
    With respect to patent listing, to FDA's knowledge, PANDA holders
have neither sought to list patent information in the Orange Book for
their products after the enactment of the Hatch-Waxman Amendments, nor
have they submitted patent listing information when submitting
supplements to their approved applications during the years after the
enactment of the Hatch-Waxman Amendments. Similarly, PANDA holders have
generally not submitted supplements containing reports of new clinical
investigations or sought exclusivity under provisions applicable to
505(b) applications (see, e.g., section 505(c)(3)(E)(iv) and
505(j)(5)(F)(iv) of the FD&C Act) following enactment of the Hatch-
Waxman Amendments.
    FDA is also aware that there may be confusion among PANDA holders
about the applicability of certain safety-related requirements to their
applications. For example, section 505(o) of the FD&C Act, which
relates to postmarket studies and clinical trials and labeling, and
section 505-1 of the FD&C Act, which relates to risk evaluation and
mitigation strategies, reflect some differences in the safety-related
requirements or procedures that apply to 505(b) application holders
versus 505(j) ANDA holders, and PANDA holders may consider the
requirements that apply to 505(j) ANDA holders to also apply to their
applications.
    Although, as noted in section I of this notice, PANDAs are section
505(b) applications, FDA understands, as outlined above, that the
holders of some PANDAs may have been following various requirements
applicable to 505(j) ANDAs over the years after the enactment of the
Hatch-Waxman Amendments, and that for them to instead follow
requirements applicable to 505(b) applications could be a change in
practice. FDA also understands that PANDAs are a unique category of
505(b) applications and that there could be valid reasons to treat
PANDAs differently from other 505(b) applications in certain
circumstances, to the extent permitted by the applicable statutory
provisions.
    FDA is seeking input from PANDA holders and other interested
stakeholders on whether there are regulatory or policy reasons for
treating PANDAs differently from other 505(b) applications, consistent
with the statutory requirements for applications submitted under
section 505(b) and approved under section 505(c) of the FD&C Act. To
facilitate this input, FDA has developed the following list of
questions. These questions are not meant to be exhaustive, and FDA is
also

interested in any other pertinent information stakeholders would like
to share on this topic. In all cases, FDA encourages stakeholders to
provide the specific rationale and basis for their comments, including
any available supporting data and information.
Questions
    1. Given the legal requirements in place for applications submitted
under section 505(b) and approved under section 505(c) of the FD&C Act,
are there regulatory or policy rationales for treating PANDAs
differently from other 505(b) applications in certain respects, in
particular with respect to the following:
    1.1. Labeling requirements, including requirements related to
updating product labeling to reflect certain types of newly acquired
safety-related information by submitting a ``changes being effected''
(CBE-0) supplement to FDA?
    1.2. Patent listing requirements?
    1.3. Eligibility for exclusivity?
    1.4. Certain safety-related requirements, such as the postmarket
studies and clinical trials or safety-labeling change requirements in
section 505(o) of the FD&C Act or the risk evaluation and mitigation
strategies requirements in section 505-1 of the FD&C Act?
    In responding to the questions above, please provide a specific
rationale for treating these applications differently.
    2. To the extent that PANDA holders are expected to make changes to
their current practices, what factors should FDA consider in
determining a reasonable amount of time for PANDA holders to make such
changes to their practices?
    3. Are there additional steps FDA should take to highlight for
PANDA holders that their ``abbreviated new drug application'' is a
PANDA, i.e., that it is a 505(b) application?
    4. Are there additional steps FDA should take beyond posting the
list on the Orange Book website to aid other interested persons in
identifying PANDAs?
    5. Are modifications needed to the list of PANDAs posted on the
Orange Book website for accuracy? For example, are some PANDAs missing
from the list?
    6. Are there other issues FDA should consider in assessing the
regulatory framework for PANDAs under the FD&C Act? Please provide
specific examples and explain FDA's authority to address these issues.

    Dated: August 10, 2021.
Lauren K. Roth,
Acting Principal Associate Commissioner for Policy.
[FR Doc. 2021-17378 Filed 8-12-21; 8:45 am]
BILLING CODE 4164-01-P


EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: [Kable Bo Davis<PHONE_NUMBER>]

INSTRUCTIONS:  Please utilize this outline in preparing the pesticide petition.  In cases where the outline element does not apply, please insert "NA-Remove" and maintain the outline. Please do not change the margins, font, or format in your pesticide petition. Simply replace the instructions that appear in green, i.e., "[insert company name]," with the information specific to your action.

TEMPLATE:

[E. I. DuPont de Nemours and Company]

[Insert petition number]

	EPA has received a pesticide petition ([insert petition number]) from [E. I. DuPont de Nemours and Company], [Chestnut Run Plaza, 974 Centre Road, Wilmington, Delaware 19805] proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180.

(Options (pick one)

   	1. by establishing a tolerance for residues of

	[Triflumezopyrim, 2,4-dioxo-1-(5-pyrimidinylmethyl)-3-[3-(trifluoromethyl)phenyl]-2H-pyrido[1,2-a]pyrimidinium inner salt] in or on the raw agricultural commodity [rice, grain] at [0.2] parts per million (ppm).  EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of  FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

	1. Plant metabolism. [The metabolism of three radiolabelled forms of [[14]C]triflumezopyrim was investigated in rice plants under separate soil and foliar treatment regimes. Single applications [[14]C]triflumezopyrim were made at ca. 300 g a.s./ha to soil surrounding rice seedlings and two 35 g a.s./ha foliar applications were made to immature rice plants  growing under flooded conditions. Immature rice foliage and mature crop fractions (straw, chaff and grain) were extracted and extracts analyzed to determine the nature of triflumezopyrim derived residues, and define a metabolic pathway for triflumezopyrim in rice plants. Following soil application [[14]C]triflumezopyrim uptake into rice was low in immature foliage,  in straw and  in grain. Triflumezopyrim was the principal extractable residue in immature foliage , straw and grain  samples. Crop residues were higher following foliar applications as compared to soil applications. Triflumezopyrim was again the major extractable component in immature foliage , straw  and grain . Triflumezopyrim metabolism in rice resulted in numerous low level metabolites regardless of the treatment regimen (foliar or soil application).

Triflumezopyrim was extensively metabolised in livestock (goats and poultry) and in rice and succeeding crops. While minor differences in short-lived (transient) metabolic intermediates were observed, the overall metabolic pathway in plants and animals was consistent. The proposed metabolic pathway for triflumezopyrim in plants and livestock included (a) hydroxylation on the phenyl ring ortho to the trifluoromethyl group , (b) conjugation  to glucuronic acid and sulphate conjugates in goats (and rats), (c) oxidative defluorination  to form  hydroxy acids, (d) N-oxidation of the parent molecule , (e) oxidative or hydrolytic cleavage of parent , and (f) a series of oxidative hydrolysis, decarboxylation and rearrangement reactions of triflumezopyrim.]

	2. Analytical method. [The nature of residue of triflumezopyrim is adequately understood and an acceptable method is available for enforcement purposes.  The limit of quantitation at 0.01 mg/kg allows monitoring of triflumezopyrim residues at or above the proposed levels.]

	3. Magnitude of residues. [Field trials to meet country registration, and United States import tolerance, requirements were carried out in rice. The trials covered a wide range of locations, climates, and soil types and the data obtained reflect the commercial use of the triflumezopyrim-containing products in the major rice growing regions.  Analytes chosen for residue analysis were triflumezopyrim and one metabolite. Triflumezopyrim and the metabolite residues were measured in supervised magnitude of residue and processing trials.  The metabolite was included in the analysis of the field residue studies based on conservative assessments of the preliminary plant metabolism data. Further confirmatory analysis in the plant metabolism studies showed that the metabolite was an important plant metabolite. Further, the metabolite wasnot detected in any field trial samples. Therefore, the metabolite is considered not relevant for monitoring or dietary risk assessment.

On the basis of the data presented relating to metabolism of triflumezopyrim, it is evident that triflumezopyrim is the major residue in rice commodities following post-emergence application of triflumezopyrim and accordingly should be used for the purposes of defining the residue.

A rice processing study was also conducted at exaggerated rates to ensure quantifiable residues in the RAC.  Processing factors for brown rice, polished rice, bran and hulls were determined.

The field trials substantiated the results of the metabolism studies and support the proposed import tolerance for the United States.]

B. Toxicological Profile

	1. Acute toxicity.  [Triflumezopyrim has little to no significant acute toxicity via the oral, dermal, and inhalation routes of exposure. Triflumezopyrim is not a skin or eye irritant and does not cause skin sensitization. Based on these results, triflumezopyrim is classified for acute oral toxicity in Category III and is classified as Category IV for acute dermal and inhalation toxicity, for skin and eye irritation, and for skin sensitization according to the criteria of the U.S. EPA.

Study Type
Results
Category Determination
Acute Oral Toxicity in Rats
Male LD50 >5000 mg/kg
Female LD50 = 4930 mg/kg
Combined LD50 >4930 mg/kg

Category III
Acute Dermal Toxicity
LD50 >5000 mg/kg bw
Category IV
Acute Inhalation Toxicity
LC50>5.04 mg/L
Category IV
Primary Eye Irritation
Slight irritation clearing by 48 hours
Category IV
Primary Dermal Irritation
Not irritating
Category IV
Primary Dermal Irritation
Not sensitizing (Guinea Pig Maximization test)
Not a sensitizer
]

	2. Genotoxicty. [Triflumezopyrim was evaluated in a battery of in vitro and in vivo genotoxicity studies. The weight of evidence supports the conclusion that triflumezopyrim is not genotoxic.]

	3. Reproductive and developmental toxicity. [In the two-generation rat reproduction toxicity study, triflumezopyrim was administered in the diet to male and female rats at concentrations of 0, 100, 500, 1500, and 3000 ppm. The NOAEL for parental toxicity was 500 ppm based on reductions in body weight and nutritional parameters in P1 and F1 males and females at 1500 ppm and above. There were no test substance-related deaths or clinical observations, and no adverse effects on gross observations, organ weights, or microscopic alterations in P1 or F1 parental rats. The NOAEL for reproductive and fertility effects was 3000 ppm based on a lack of adverse, test substance-related effects in either the P1 or F1 generation at 3000 ppm, the highest dose tested. The data for mating, fertility, precoital interval length, gestation length, and implantation site counts were comparable across all groups for both generations. Additionally, there were no adverse, treatment-related effects noted on pup survival indices, estrous parameters, or sperm parameters at any concentration for either generation. The NOAEL for effects on pup growth and development was 1500 ppm based on a reduction in the body weight of F1 and F2 pups from birth and throughout lactation at 3000 ppm.

In the developmental toxicity study in rats, the NOAEL for maternal toxicity was 100 mg/kg bw/day based on reduced body weight and food consumption parameters at 200 mg/kg bw/day. No effects on survival, clinical observations, or gross pathology were observed at any dose. The NOAEL for fetal toxicity was 200 mg/kg bw/day based on a lack of adverse effects at the highest dose tested.

In the developmental toxicity study in rabbits, the NOAEL for maternal toxicity was 250 mg/kg bw/day based on reduced body weight and food consumption parameters, reduced defecation, and minimal hematology changes with associated increased spleen weights, at 500 mg/kg bw/day. No effects on survival or gross pathology were observed. The NOAEL for fetal toxicity was 500 mg/kg bw/day, the highest dose tested based on the absence of any adverse effects.]

	4. Subchronic toxicity. [The primary toxicological findings in short-term, repeated-dose oral toxicity studies in rodents included changes in body weight and nutritional parameters, increases in liver weight, and hepatocellular hypertrophy. The liver weight effects in rats and mice occurred in the absence of clinical or histopathological findings indicative of liver toxicity. Increases in cytochrome P450 liver enzyme content (total and specific isozymes), beta-oxidation activity, and mild reductions in bilirubin (rats) were noted in 28-day and/or 90-day studies in rats and mice, suggesting a non-adverse, adaptive, pharmacological response to increased metabolism due to exposure to triflumezopyrim. Hepatocellular hypertrophy accompanied the increases in liver weights in rats and mice (28 days and 90 days).  In rats, these liver effects were also associated with increased liver UDP-glucuronyltransferase activity (UDP-GT). However, the effects on UDP-GT were considered non-adverse as there were no correlative effects on thyroid hormones or thyroid pathology.

No evidence of a primary effect on the nervous system was observed in toxicity studies conducted with triflumezopyrim.  The NOAEL in an acute neurotoxicity study in rats was 100 mg/kg bw based on body weight gain reductions or body weight loss that occurred between the day of dosing and the day following dosing at dose levels of 500 and 1000 mg/kg. Accompany changes in neurobehavioral parameters and motor activity on the day of dosing occurred at the same dose levels.  There was no evidence of histopathology changes in nervous system tissues.  A subchronic neurotoxicity study was conducted during the course of the 90-day feeding study in rats.  The NOAEL for systemic toxicity was 1500 ppm (70 and 83 mg/kg bw/day for males and females respectively).  The NOAEL for neurotoxicity and neuropathology was 6000 ppm (274 and 316 mg/kg bw/day, respectively), the highest concentration tested, based on the lack of adverse, test substance-related effects on neurobehavioral and neuropathology parameters.

No adverse effects on immune system parameters were observed in a 28-day immunotoxicity study conducted in female rats.

Dogs were the most sensitive species to triflumezopyrim repeated-dose toxicity. The primary effects observed in feeding studies were reductions in body weight and nutritional parameters. At the highest dietary concentrations (10000 ppm for 28 days and 4000 ppm for 90 days), effects supported that these concentrations exceeded the maximum tolerated dose (MTD). No specific target organ was identified; most clinical and anatomic pathology effects were considered secondary to marked body weight and nutritional effects and associated non-specific stress. The NOAEL in dogs is 400 ppm, equivalent to 12.20 and 12.15 mg/kg bw/day in males and females, respectively, based on the results in the 90-day study.

Dermal application of triflumezopyrim to rats for 28 days did not result in any treatment-related findings up to and including a maximum dose of 1000 mg/kg bw/day.]

	5. Chronic toxicity. [The chronic toxicity and carcinogenic potential of triflumezopyrim was assessed in a 2-year feeding study in rats and an 18-month feeding study in mice.

In rats, the NOAEL for chronic toxicity was 500 ppm in males and females (equivalent to 15.9 and 17.3 mg/kg bw/day, respectively). The primary findings in the study included marked reductions in body weight at dietary concentrations of 2000 and 8000 ppm; and based on the magnitude of the body weight effects at 8000 ppm (both sexes) and 2000 ppm (females), the changes were considered to have greatly exceeded the MTD.

Triflumezopyrim was not oncogenic in male rats. In the high dose females, a small increase in squamous cell carcinoma of the uterus/cervix was observed and was statistically significant by the Cochran-Armitage trend test only. At the same dose level there were also statistically significant increases in changes typified by uterine dilatation, inflammation, and hyperplasia of the endometrial epithelium and an increase in squamous cell hyperplasia in the cervix.   However, the finding of uterine tumors is not considered relevant for humans as the tumors occurred at a dose level that caused marked reductions in body weight considered to have greatly exceeded the MTD. Therefore, the biological relevance of toxicological findings under these conditions of severe systemic toxicity is highly questionable. Further, mechanistic studies demonstrated that triflumezopyrim is not a direct estrogen agonist, but did show decreases in prolactin suggesting the underlying mode of action is specific to rodents.

In mice, there were no treatment-related effects on body weight or any other in-life parameter in males or females administered triflumezopyrim up to and including a maximum dietary concentration of 7000 ppm for 18 months.

Hepatocellular adenomas were increased in high dose male mice, which was statistically significant by Cochran-Armitage trend test only. Mechanistic work supported the conclusion that the tumors were secondary to activation of the constitutive androstane receptor (CAR), a pronounced increase in cytochrome P450 2B gene expression, heptocelluar hypertrophy, and an increase in cell proliferation confirming a phenobarbital-like mechanism for liver tumor induction in rodents that is not relevant for humans.]

	6. Animal metabolism. [The metabolism of triflumezopyrim in animals (hens and goats) is adequately understood. [[14]C]Triflumezopyrim was rapidly absorbed, extensively metabolized, and excreted in livestock animals. Hens were dosed orally once a day for 14 consecutive days with three radiolabelled forms of [[14]C]triflumezopyrim. The recovery of the administered dose was >=89% with the majority eliminated in excreta and  in cage washes. Minimal transfer of [[14]C]triflumezopyrim equivalent residues to eggs and tissues was observed. Whole eggs and edible tissues accounted for <0.1% of the dose. Total radioactive residues (TRR) in whole eggs plateaued within 4 days.. TRR in liver were ca. 0.30 mg/kg and <=0.01 mg/kg in muscle and abdominal fat. Triflumezopyrim was the principal extractable component in Day 9-13 composite eggs and liver . Muscle and fat contained low levels of triflumezopyrim.

Goats were dosed orally once a day for 7 consecutive days with three radiolabelled forms of [[14]C]triflumezopyrim. . The recovery of the administered dose was >=80% with the majority eliminated in the feces , urine , and cage washes. Milk accounted for 1.2-2.3% of the dose and edible tissues accounted for <=0.4% of the dose. TRRs plateaued within 2 days in milk for the three radiolabels. The majority of radioactive residues (88-99%) was characterized or identified in tissues and milk. Triflumezopyrim was the major component in all tissues.]

	7. Metabolite toxicology. [Metabolites found in plants, in domestic animals, or those that could potentially enter the human diet via drinking water were common to those produced in the rat metabolism study. Therefore, no toxicological studies were considered warranted for metabolites of triflumezopyrim.]

	8. Endocrine disruption. [Based on the standard battery of required mammalian toxicology studies and additional work to evaluate potential estrogenicity, there is no evidence to suggest that triflumezopyrim directly affects the estrogen, androgen, or thyroid pathways.]

C. Aggregate Exposure

	1. Dietary exposure. [An import tolerance is proposed in this petition for residues of triflumezopyrim on rice grain with hulls.  This is the first proposed tolerances in the U.S. for commodities treated with triflumezopyrim.  For the purpose of assessing the potential dietary exposure, an exposure assessment was conducted using the Dietary Exposure Evaluation Model-Food Commodity Intake Database (DEEM-FCID(TM), Version 4.02) based on the National Health and Nutrition Examination Survey (NHANES) 2-day food consumption data for 2005-2010, and residues at proposed tolerance levels.]

   	i. Food. [Acute Dietary Exposure:  A conservative acute dietary risk assessment has been calculated based on a residue value of 0.014 mg/kg for brown rice based on the proposed MRL (rice grain with hull, 0.2 mg/kg) and the processing factor (brown rice, 0.069) [0.014 mg/kg = (0.2 mg/kg x 0.069)]. The assumption of 100% crop treated was applied. Estimates of the US acute dietary exposure from food was determined with Dietary Exposure Evaluation Model-Food Commodity Intake Database (DEEM-FCID(TM), Version 4.02) based on the National Health and Nutrition Examination Survey (NHANES) 2-day food consumption data for 2005-2010. The acute dietary exposure of the US population was conservatively determined to be 0.000019 mg/kg bw/day at the 95th percentile of exposure, <1% of the proposed acute reference dose of 1 mg/kg bw/day. The calculated acute dietary exposure of all US subpopulations was <1% of the proposed acute reference dose indicating there are no short-term consumer intake concerns.

   Chronic Dietary Exposure:  A conservative chronic dietary risk assessment has been calculated based on a residue value of 0.014 mg/kg for brown rice based on the proposed MRL (grain with hull, 0.2 mg/kg) and the processing factor (brown rice, 0.069) [0.014 mg/kg = (0.2 mg/kg x 0.069)]. The assumption of 100% crop treated was applied. Estimates of the US chronic dietary exposure from food was determined with Dietary Exposure Evaluation Model-Food Commodity Intake Database (DEEM-FCID(TM), Version 4.02) based on the National Health and Nutrition Examination Survey (NHANES) 2-day food consumption data for 2005-2010. The chronic dietary exposure of the US population was determined to be 0.000004 mg/kg bw/day, <1% of the proposed chronic reference dose of 0.12 mg/kg bw/day. The calculated chronic dietary exposure of all US subpopulations was <1% of the proposed chronic reference dose indicating there are no long-term consumer intake concerns.]

   	ii. Drinking water. [Since this will be an import tolerance use only, no drinking water exposures are anticipated.]

	2. Non-dietary exposure. [Since this will be an import tolerance use only, non-dietary exposures are not anticipated]

D. Cumulative Effects

	[Triflumezopyrim is an insecticide belonging to the mesoionic class of chemistry. The mode of action classification for triflumezopyrim is a Group 4E insecticide.  This is a sub-group of Group 4  -  nicotinic acetylcholine receptor (nAChR) competitive modulators.  This new insecticide for the control of rice hoppers has been reviewed by the IRAC MoA WG and a classification to Group 4E agreed.]

E. Safety Determination

	1. U.S. population. [Using the conservative exposure assumptions described above and based on the completeness of the toxicity data, it can be concluded that total dietary exposure to triflumezopyrim from the proposed use will be <1% the acute population adjusted dose (aPAD) and <1% and the chronic population adjusted dose (cPAD) for the overall US population.  EPA generally has no concern for exposures below 100% of the PAD because the PAD represents the level at or below which daily exposures will not pose appreciable risk to human health.  Thus, it can be concluded that there is a reasonable certainty that no harm will result from aggregate exposure to residues from the proposed import tolerance discussed in this petition.]

	2. Infants and children. [Using the conservative exposure assumptions described above and based on the completeness of the toxicity data, it can be concluded that total dietary exposure to triflumezopyrim from the proposed use will be <1% the acute population adjusted dose (aPAD) and <1% and the chronic population adjusted dose (cPAD) for infants and children.  Thus, based on the completeness and reliability of the toxicity data, the lack of toxicological endpoints of special concern, the lack of any indication that children are more sensitive than adults to triflumezopyrim, and the conservative exposure assessment, there is no reasonable certainty that no harm will result to infants and children from the aggregate exposure of residues of triflumezopyrim, including all anticipated dietary exposure.]

F. International Tolerances

	[Triflumezopyrim is a new active substance and there are currently no established MRLs.   An MRL is proposed for rice where triflumezopyrim is to be applied, as well as for an import tolerance for the United States.  This MRL is calculated using OECD MRL Calculator based on relevant residue data.]